Path - Profiles

Path Profiles
A brief review of the major disorders covered in the pathology course.
By Sean H. – Fall 2012
“Anyone who imagines they can work alone winds up surrounded by nothing but rivals, without
companions. The fact is, no one ascends alone” – Lance Armstrong
2
Foreword
I’d like to begin by saying that everything we are doing is now is building towards something
absolutely amazing, and we will all get there together as a group. It is easy to fall into a “me versus
everyone” mentality or to constantly compete with each other by bringing them down, but that only
serves to hurt the ultimate goal of caring for our future patients. Healthcare is not an individual activity;
we will rely on each other, face similar obstacles, and struggle to keep the same people alive and
healthy.
On that note, I’d like to share my endeavors with you, my colleagues, in an effort to better all of
us and to help make an already stressful term easier. I encourage you to do the same, to foster a
campus wide culture of support and drive in the name of becoming the best doctors that we all can be.
With that said, good luck, and enjoy.
- Sean
The material contained herein is not to be used in any clinical scenario and the accuracy is not
guaranteed by the author. Medicine is a complex and dynamic field that is constantly evolving, and the
material presented is meant to be a simplification of the mainstream for the purpose of general medical
education.
The St. George’s University’s Pathology Department holds the rights to all images unless otherwise
specified. The information contained herein is based the notes, Robbin’s Basic Pathology 8th Edition,
Medscape Reference, and various free websites.
This study guide is intended for SGU student’s who already have access to these images, notes,
textbooks, and websites. Any reproduction or distribution outside of this intent is at the liability of
person(s) doing as such.
Path Profiles – Fall 2012

3
Table of Contents
Path Profiles – Major Sections
Hematopoietic 004
Cardiovascular 046
Pulmonary 094
Gastrointestinal (Not Completed)
Urogenital 145
Renal 189
Endocrine 215
Bone 237
Neuropathology 261

Hematopoietic 4
Hematopoietic
Red Blood Cell Disorders
Hereditary Spherocytosis 05
G6PD Deficiency 07
Sickle Cell Anemia 09
Thalassemia Major 12
Iron Deficiency Anemia 15
Megaloblastic Anemia 17
Aplastic Anemia 20
White Blood Cell Disorders

Infectious Mononucleosis 21
Burkitt’s Lymphoma 23
Hodgkin’s Lymphoma 25
Acute Lymphoblastic Leukemia 27
Chronic Lymphocytic Leukemia 29
Hairy Cell Leukemia 31
Multiple Myeloma 33
Acute Myeloblastic Leukemia 35
Chronic Myeloid Leukemia 37
Primary Myelofibrosis 39
Vignettes 41
Answers & Explanations 43

Hematopoietic 5
Hereditary Spherocytosis
Hereditary Spherocytosis is a hereditary to elevated levels of
Highlights
disorder that causes a type of extravascular serum reticulocytes.
- Spherocytes
hemolytic anemia with sphere shaped Extensive hemolysis
- Hemolytic Anemia
erythrocytes. may elevate serum
- Splenomegaly
indirect bilirubin and - Erythroid hyperplasia
It is common in northern Europeans
presents with jaundice. - Osmotic fragility
with a prevalence of 1 per 5,000.
Etiology
Signs & Symptoms
• Autosomal Dominant (75%) - Ankyrin
• Autosomal Recessive (25%) - β-spectrin • Anemia
• Splenomegaly
Pathogenesis • Jaundice
• CBC:
Normal RBC membranes are stabilized o Reticulocytosis
by horizontal spectrin proteins and vertical o Low MCHC
ankyrin proteins that attach the spectrin to • Peripheral Blood Smear: Spherocytes
membrane proteins. • Bone Marrow: Erythroid hyperplasia
• Splenomegaly: 500-1000g (150-200g)
In Hereditary Spherocytosis, one of
• RBCs have increased osmotic fragility.
these components is non-functional, leading to
membrane instability and loss of biconcavity.
Portions of the membrane are lost, and the cell
becomes a sphere to maintain the best volume
to surface area ration.
These abnormal RBCs get filtered out in

the spleen, where they are phagocytized by
macrophages. This causes both the hemolytic
anemia due to less RBCs and congestion &
eventual damage to the spleen.
In response to the hemolytic anemia,

there will be erythroid hyperplasia. This leads
Peripheral Blood Smear: Mix of normal biconcave erythrocytes and spherocytes. The spherocytes have the
appearance of a solid circle with no central translucence. The arrows point to them.

Hematopoietic 6
extravascular hemolytic anemia that involves

Complications the spleen, but in Hereditary Spherocytosis it, is
much more pronounced.
• Hemolytic crisis
• Aplastic crisis: Infection of bone marrow Additional Info
by Parvovirus B19
Treatment
Differentials • Transfusions
• Splenectomy – increases risk of some
Any cause of anemia may produce infections, especially in children.
similar symptoms, such as fatigue, pallor, and
tachycardia.
The presence of jaundice may indicate a

hemolytic anemia, but is not very specific.
Also with hemolytic anemias you will

see erythroid hyperplasia and reticulocytosis as
the marrow tries to compensate.
Other hemolytic anemias include:

• G-6-PD Deficiency
• Sickle Cell Anemia
• Paroxysmal Nocturnal Hemoglobinuria
• Malaria
The most characteristic aspect of HS is

the presence of spherocytes and splenomegaly.
Spherocytes can also appear in warm
autoimmune hemolytic anemia (WAIHA).
Splenomegaly, which can occur with any

Hematopoietic 7
G6PD Deficiency
Glucose-6-Phosphate Dehyrdogenase significantly distorted
Highlights
Deficiency (G6PD) is a hereditary disorder in cell, including bite
- Oxidative Insult
which RBCs become vulnerable to oxidatative cells, can be removed
- Impaired response to
injury. The consequence of this is hemolytic and phagocytized in
free radicals.
anemia, both intra and extravascular. the spleen. - Hemolytic anemia
One variant, A-, affects African Overall, the - Asymptomatic
between attacks
Americans and varies such that it has normal destruction of the
activity but doesn’t survive as long as the RBCs will cause
wildtype. hemolytic anemia.
Etiology Signs & Symptoms

X-linked mutation of G6PD. There Asymptomatic until exposure to
many disease causing variations. environmental factors that increase oxidative
stress, such as infections or medications.
Pathogenesis After insult, anemic symptoms become
apparent after 2-3 days. The bone marrow will
The process begins with some sort of compensate and continuation of the medication
oxidative insult, such as a medication or may not cause continuation of symptoms.
infection. In infections, free radicals that are • Possible splenomegaly
intended to kill phagocytized microbes escape.
• Jaundice
Normally these oxidants are inactivated • Dark brown urine
by reduced glutathione (GSH). G6PD is part of
the reaction that reduces GSH. • Peripheral Blood Smear:
o Heinz Bodies
Without G6PD, oxidants are free to o “Bite Cells”
disrupt cell components such as the globin • Labs: Decreased Haptoglobin
chains in hemoglobin. The Hb precipitates and
forms inclusions called Heinz bodies. This may
lead to disruption of the cell membrane and
lysis.
Alternatively, the membrane can

Complications
become distorted, and splenic macrophages will
try to remove the Heinz bodies, giving the Avoid oxidative drugs.
characteristic bite cells appearance. Also, any

Hematopoietic 8
Deficiency is the history of oxidative insult

Differentials (medication or infection) with no symptoms
between attacks, the Heinz bodies, and the bite
Any cause of anemia may produce cell appearance. Heinz bodies are also in HbH
similar symptoms, such as fatigue, pallor, and Disease.
tachycardia.
With hemolytic anemias you will see Additional Info

erythroid hyperplasia and reticulocytosis as the
marrow tries to compensate.
Common factors that induce symptoms:
The presence of splenomegaly may • Antimalarials
indicate an extravascular hemolytic anemia, but • Sulfonamides
is not very specific. Jaundice is also non-specific • Aspirin
to hemolytic anemia. • Vitamin K derivatives
• Infections
Other hemolytic anemias include:
• Hereditary Spherocytosis Patients will need to avoid Fava beans in
• Sickle Cell Anemia their diet if they have the Mediterranean
• Paroxysmal Nocturnal Hemoglobinuria variety mutation.
• Malaria
Decreased serum haptoglobin is indicative

of an intravascular hemolysis.
The main distinguishing aspects of G6PD
Peripheral Blood Smear: (Left) Crystal blue stain shows blue inclusion bodies of aggregated hemoglobin,
called Heinz Bodies. (Right) RBCs with crescent shaped sections missing from the normal circular structure.
Gives the appearance that they were bit, hence the name “bite cells.”

Hematopoietic 9
Sickle Cell Anemia

Sickle Cell Anemia is a hereditary integrity is lost, the cells accumulate calcium
extravascular hemolytic anemia. and become irreversibly sickled.
8% of African Americans are heterozygote, There are factors that contribute to the
with 1 out of every 600 having the disease. It is formation of sickling. Dehydration of the RBC
thought that being heterozygous will give will promote polymerization of HbS. As will
protection from Plasmodium falciparum acidosis or infections. Increase of these factors
malaria. may lead to a sickling crisis.
Sickle cells can occlude small capillaries,

Etiology but only in specific capillaries where flow is
sluggish enough to allow sickling. These
Autosomal recessive mutation in β-globin chain capillary beds are usually located in the spleen
and bone marrow. Inflammation also slows
of hemoglobin, creating HbS.
blood flow, and may allow for occlusion within
Carriers are said to have sickle cell trait, and can the inflamed area. Sickled cells also are able to
develop symptoms in extreme situations such adhere to endothelium, sometimes termed as
as high altitude or severe hypoxia. “sticky.” These obstructions can cause ischemic
tissue damage. This tissue damage will cause
Another mutation of β-globin is HbC, which can
inflammation and pain.
be coupled with HbS to produce HbSC disease
and sickle cell symptoms. The other major cause for sickle
symptoms is the removal of sickle cells by
splenic macrophages. The constant removal of
Pathogenesis
HbS is a missense mutation where a
glutamic acid is replaced with valine.
Homozygotes have HbS, heterozygote carriers
have half of their HbA hemoglobin is HbS. HbS
is able to polymerize once deoxygenated. The
polymers distort the cell, elongating it to
produce a sickle crescent shape. This is
reversible with reoxygenation, but each event
damages the membrane. Once membrane
Peripheral Blood Smear: The most notable feature here is the sickle shaped red blood cells and target cells.
The target cells had a darkly staining spot in the middle of the normally clear center of the biconcavity.

Hematopoietic 10
RBCs causes an extravascular hemolytic anemia.

A RBC typically has a lifespan of 120 days, but in Signs & Symptoms
sickle cell anemia the lifespan has been reduced
to about 20 days.
• Anemia
There will be compensation by the bone • Painful Crisis in abdomen, chest, joints,
marrow to produce more RBCs. This leads to and CNS
hyperplasia and expansion of the bone marrow. • Aplastic Crisis: Parvovirus Infection
A side effect is frontal bossing, or protuberance • Vascular congestion, thrombosis, and
of the cheek bones and/or forehead similar to infarction of any tissue
that seen in thalassemia. • Splenomegaly in youth
• Splenic hypoplasia & fibrosis in
The spleen itself will undergo adulthood
splenomegaly during childhood due to
congestion. After some time of this congestion • CBC: Hematocrit 18-30% (35-45%)
and stasis, the spleen undergoes progressive • Peripheral Blood Smear: Sickle Cells
hypoxic tissue damage and subsequent fibrosis,
called autosplenectomy. This causes functional
asplenia and increases susceptibility to
capsulated bacteria, the most notable infection
is Salmonella osteomyelitis.

Hematopoietic 11
Complications Highlights
- HbS & β-globin mutation
- Sickle shaped cells
• Acute Chest Syndrome: Pulmonary - Sickle due to deoxygenation
infarctions - Spleen removes cells
• Stroke - Splenomegaly in youth
• Autosplenectomy – Functional Asplenia - Auto-splenomegaly in adults
o Salmonella osteomyelitis - Capsular Bacteria Infections
• Gallstones
- Salmonella Osteomyelitis
- Pain Crisis
• Hemosiderosis
- Affects African Americans
• Frontal bossing
Differentials
The most distinguishing feature of sickle
Additional Info
cell anemia is the sickled cells on a peripheral
blood smear. Neonates do not exhibit symptoms of
sickle cell, as they have predominantly HbF
All hemolytic anemias have the
instead of HbA. Once they transition to HbA
potential for splenomegaly, jaundice, and
after 6 months of life they will develop
anemic symptoms. Sickle cell initially has
symptoms.
splenomegaly, but usually results in auto-
splenomegaly and fibrosis. This can help Treatment:
differentiate sickle cell anemia. • Transfusions
• Hydroxyurea
Any indication of capsular bacteria
o Inhibits DNA synthesis
infections, especially Salmonella osteomyelitis,
o Increases HbF
points to sickle cell.
o Anti-inflammatory – prohibits
An aplastic crisis secondary to WBC formation
Parvovirus is likely to be either hereditary o Increases MCV
spherocytosis or sickle cell. o NO release
Vasodilation
The hemosiderosis with anemia is Inhibits platelet
usually seen in sickle cell and the thalassemias. aggregation
Also take note of the patient biodata, Most common cause of death:
with African American or black having high rates • Children: Infection
of this disease. • Adults: Acute Chest Syndrome

Hematopoietic 12
Thalassemia Major
Thalassemia Major is a β-Thalassemia There is an imbalance of α and β-chains.
and is a disorder of reduced hemoglobin Unpaired α-globin precipitates causing
production and extravascular hemolytic anemia. membrane damage. The damage is enough to
cause extravascular hemolysis of the RBCs.
There is a higher incidence in Erythroblasts in bone marrow are also
Mediterranean, Asian, and African populations. susceptible to this damage, leading to
intramedullary lysis and reduced RBC output
Etiology called ineffective erythropoiesis.
There is an increase in dietary iron

Autosomal recessive mutation in the β- absorption. Low hepcidin, which is a negative
globin chain of hemoglobin. inhibitor of iron absorption, will increases iron
absorption. Compounded with transfusions,
There are two types of β-globin there will be hemosiderosis.
mutation, β0 and β+. β0 has no production of β-
globin, whereas β+ has reduced β-globin The bone marrow compensates with
synthesis. Homozygous or compound extreme hyperplastic erythropoiesis, which may
heterozygous assortment will develop eventually cause skeletal deformities and
Thalassemia Major. Seen as β /β , β+/β+, or
0 0
frontal bossing.
β0/β+.
Only one mutation (β/β0/+) will lead to

β-thalassemia trait, which is usually
asymptomatic but may present with mild
symptoms.
Pathogenesis
The mutations will prohibit or reduce
the synthesis of β-globin. Without the β-globin
there will be less HbA formation. This lowers
the Mean Corpuscular Hemoglobin
Concentration (MCHC) and produces cells that
are hypochromatic and microcytic.
Peripheral Blood Smear: The smear contains RBCs are hypochromatic, microcytic, and display poikilocytosis.
Also visible are target cells and erythroid precursors, namely reticulocytes and normoblasts.

Hematopoietic 13
Signs & Symptoms Differentials
• Anemia All hemolytic anemias have the

• Hepatosplenomegaly potential for splenomegaly, jaundice, and
• Lymphadenopathy anemic symptoms.
• Jaundice
Characteristics of Thalassemia major
• Hemosiderosis
include the hemosiderosis, low MCHC, and
• Frontal bossing/skeletal deformities
skeletal deformities. Also, it is mostly found in
Mediterranean, Asian, and African populations.
• CBC:
o Low MCHC Hemosiderosis and skeletal deformities
o Increased Reticulocytes are also seen in sickle cell anemia.
• Peripheral Blood Smear:
The low MCHC will give the appearance
Hypochromatic & microcytic
of hypochromic and microcytic RBCs, which is
• Hb electrophoresis
also seen in Iron Deficiency Anemia.
Complications
α-Thalassemia is similar to the β
• Secondary Hemochromatosis version, but with mutations in α-globin chain,
• Cardiac Failure with 2 copies from each parent.
Genotype Disease Symptoms
--/-- Hydrops fetalis Stillborn
-α/-- HbH Disease Severe anemia
-α/-α α-thalassemia May have mild

trait anemia
αα/--
αα/-α Silent Carrier Asymptomatic
Differences in α and β include:

• α-thalassemia will not have iron
overload or the need for transmission.
• α does not have as severe anemia.
Skull XR: Radiograph of the skull shows hair like filamentous growth protruding from the bone. Sometimes
described as a “crew cut” appearance. This is a product of extreme hyperplastic erythropoiesis.

Hematopoietic 14
Additional Info
• β-globin is found on chromosome 16.

• α-globin is foud on chromosome 11.
Affected individuals do not show symptoms

in the first 6 months of life due to the use of
HbF instead of HbA during the neonatal period.
Treatment:
• Transfusions
• Chelator
• Bone Marrow Transplant

Hematopoietic 15
Iron Deficiency Anemia

Diminished production of red blood cells
due to deficiency of iron. Signs & Symptoms
Etiology • Usually asymptomatic

• Anemia
• Pica
Chronic blood loss
• Colon cancer Peripheral Blood Smear:
• Hemorrhoids • Microcytic
• Parasites – hookworms • Hypochromic
• Menorrhagia
CBC/Labs:
Diet lacking in iron • Low MCV
• Vegetarians • Low MCHC
• Impoverished area • Low Hb, Hematocrit
• Low serum iron
Malabsorption
• Low serum ferritin
• Sprue/Celiac disease
• Low transferrin saturation
• Duodenum resection
Increased requirements Complications

• Pregnancy
Plummer-Vinson Syndrome: Difficulty

swallowing and upper esophageal webs.
Pathogenesis
Lack of iron available for heme
synthesis leads to decreased red blood cell
production and subsequent anemia.
Iron is absorbed in the duodenum in a

tightly regulated manner. There is no
regulatory pathway for the excretion of iron.
Peripheral Blood Smear: Red blood cells are hypochromatic and microcytic due to the lack of hemoglobin
production.

Hematopoietic 16
Differentials Highlights
- Anemia
- Low iron, ferritin
Iron deficiency anemia will have the - Pica
cascade of low iron indicators: serum ferritin, - Hypochromatic
free iron, transferrin saturation, MCV, and - Microcytic
MCHC. - May be due to a more serious
condition.
Hypochromatic and microcytic RBCs
indicated either iron deficiency or thalassemia.
Sideroblastic anemia has low

hemoglobin production due to disruption of the
actual process, but will have normal levels of
iron.
Additional Info
Normal iron content is about 6g for
men and 2g for women.
Iron is mostly is found in hemoglobin

(80%), with the rest found bound to
hemosiderin and ferritin. Concentration of
serum ferritin is a good indicator of iron
concentration, however, the best is a bone
marrow test.
Treatment: Iron supplementation

Hematopoietic 17
Megaloblastic Anemia
Inefficient erythropoiesis due to a symptoms, such as a Highlights
deficiency in either folate or vitamin B12. sore tongue or - Inefficient erythropoiesis
cheilosis. - Folate or B12 Deficiency
Etiology B12 deficiency
- Impaired DNA synthesis
- Hypersegmented
is commonly caused
neutrophils
by pernicious anemia,
Folate Deficiency - Increased homocysteine
which is due to B12
• Poor diets
autoimmunity against - Pernicious Anemia
• Pregnancy
parietal cells and - Methylmalonic Acid
• Alcoholics
intrinsic factor. IF is - Neurological symptoms
• Phenytoin & Methotrexate
produced by parietal
• Malabsorption in upper 1/3 small
cells and is required
intestine
for B12 absorption. In the western world, B12
Vitamin B12 deficiency is considered due to pernicious
• Vegan diet anemia unless proven otherwise.
• Pernicious anemia – IF deficiency
B12 has other functions, most notably in
• Gastrectomy/Ileum odd chain fatty acid degradation. It is a cofactor
• Pancreatic Insufficiency for turning methylmalonic-CoA into succinyl-
• Enteritis, sprue, Whipple’s CoA. Failure of this process leads to increased
• Diphyllobothrium latum, fish tape worm methylmalonic acid levels and demyelination.
The demyelination then leads to neurological
Pathogenesis symptoms, which is used to help distinguish
between folate and B12 deficiency.
Both folate and Vitamin B12 is involved

in DNA synthesis. A deficiency will cause
impaired DNA synthesis and cell replication.
The result is ineffective erythropoieses,
macrocytosis, and nuclear cytoplasmic
asynchrony.
The tissues most affected are those that

replicate often, such as the bone marrow and
gastrointestinal tract. This means that in
addition to the anemia, there will be GI
Bone Marrow: Hypercellular with megaloblastic erythroid progenitors. There is visible nuclear-cytoplasmic
asynchrony, reticulated chromatin, and basophilic cytoplasm.

Hematopoietic 18
Low B12 may also cause a folate trap, Labs:

with its inability to remove the methyl group • MCV >110 fL (82-92 fL)
from THF-Me and increases homocysteine. • MCHC is normal
Giving folate will exacerbate symptoms. • High Homocysteine
• Elevated methylmalonic acid (B12 only)
Signs & Symptoms • Low B12 or folate
B12 – Shilling Test: radioactive B12, check urine

Anemic symptoms
Gastrointestinal Symptoms
• Sore tongue Complications
• Cheilosis
Neurological symptoms in B12 only Thrombosis due to increased homocysteine

• Numbness
• Tingling
• Burning in hands and feet
• Unsteady gait Differentials
• Loss of proprioception
Peripheral Blood Smear: Megaloblastic anemia is determined by

• Hypersegmented neutrophils peripheral blood smears with hypersegmented
• Macro-ovalocytes neutrophils & macrocytosis and bone marrow
with megaloblastic hypercellularity. The
Bone Marrow: addition of GI symptoms will support this
• Hypercellularity syndrome.
• Megaloblasts
Distinguishing between the two
Peripheral Blood Smear: (Left) Hypersegmented neutrophils with more than 5 segments.
(Right) Macro-ovalocytes, which are RBCs that are enlarged and oval, with a loss of biconcavity.

Hematopoietic 19
megaloblastic anemias is done by lab tests and

clinical presentation.
• Folate deficiency will have low folate

and normal methylmalonic acid.
• B12 deficiency will have elevated
methylmalonic acid and neurological
symptoms.
The etiology of B12 deficiency is

determined with the Schilling Test. With
radioactive B12, a dietary deficiency will have
normal urine levels. Low levels are then given
B12 and IF. A normal urine level will indicate
pernicious anemia, where still low is due to
malabsorption.
Additional Info
• Treatment of B12 deficiency will resolve

anemia, but not the neurological
symptoms.
• May indicate gastric cancer.

Hematopoietic 20
Aplastic Anemia
Aplastic anemia is the is the generalized
loss of bone marrow progenitors leading to Complications
reduced RBC and WBC production.
Acute Leukemia
Etiology
Differentials
• Myelotoxic drugs
o Chemo Pancytopenia
o Benzene
• Primary Myelofibrosis
o Chloramphenicol
• Myelophthisic Anemia
• Viral – HIV, Hep D, E, G
• Aleukemic Leukemia
• Fanconi Anemia
• Granulomatous Disease
• Idiopathic (65%)
Pathogenesis Additional Info

May respond favorably with removal of toxin.
Not well know. Studies implicate
autoreactive T-Cells, but it’s still not known why Idiopathic type has poor prognosis.
they become autoreactive.
Treatment: Androgens, marrow transplant
Signs & Symptoms
• Anemia
• Pancytopenia
• Immunosuppression - severe infections
• Thrombocytopenia - hemorrhages
Bone Marrow Biopsy:

• Hypocellular, >90% fat
• Only lymphocytes and plasma cells
Bone Marrow Aspirate: “Dry Tap”
Bone Marrow Biopsy: Marked hypocellularity, with the empty space composed of fats (>90%). Remaining
cells are predominately lymphocytes and plasma cells

Hematopoietic 21
Infectious Mononucleosis
Disease of B-cell lympocytes that is heterophil anti-
mostly found inn adolescents and young adults. sheep red cell Highlights
Commonly referred to as “mono” or “kissing antibody that is - EBV
disease.” used to test for - Infects B-Cells
mononucleosis - Downey Cells (T-Cells)
(monospot test).
- Monospot Test
Etiology
Cytotoxic T-cells will attempt to remove
these latent B-cells, and are characteristically
Epstein-Barr Virus (EBV)
atypical. These are called Downey Cells. These
Downey Cells are also responsible for the
Pathogenesis lymphadenopathy.
Infection with EBV via oral contact Signs & Symptoms

(saliva). EBV initially infects oropharyngeal
epithelial cells. It eventually spreads to
lymphoid tissue in the tonsils and adenoids • Fever
where it infects B-cells. • Sore Throat
• Generalized Lymphadenopathy
There are two outcomes in an infected • Leukocytosis
B-cell, lysis and latency. With lysis, virus is • Malaise, fatigue & lethargy
released and more cells are infected. With • Splenomegaly
latency, which is by far the more common
outcome, the B-cell undergoes polyclonal Peripheral Blood Smear: Downey Cells
activation and proliferation. These proliferative
Monospot Test: Positive
cells specific antibodies, one of which is a
Complications
Hepatic dysfunction & jaundice
EBV is known to contribute to the formation of

several B-cell lymphomas, notably Burkitt’s
lymphoma and some Hodgkin’s lymphomas.
Peripheral Blood Smear: Atypical enlarged CD8+ T-Cell, called a Downey Cell. The membrane is irregular and
there is significant increase in cytoplasm to nucleus ratio. The nucleus is oval, indented, or folded.

Hematopoietic 22
Differentials
Most of the clinical presentation is nonspecific.
The malaise and fatigue is very prominent but
not diagnostic.
Characteristics of infectious mononucleosis:

• Downey Cells
• Positive heterophil reaction (monospot
test)
• Rising titer for EBV antigens
Cytomegalovirus (CMV) has similar symptoms,

and is distinguished by serology.

Hematopoietic 23
Burkitt’s Lymphoma
Tumor of the lymphatic system that
tend to grow outside of a node. Aka Small Signs & Symptoms
Noncleaved Lymphoma.
Usually develops in children and young Painless mass

adults. Has two forms, African (endemic) and • African: jaw
Sporadic (non-endemic). • Sporadic: Bowel, retroperitoneum,
ovaries
Etiology Leukemic presentations are uncommon.
Translocations involving MYC on chromosome 8

• t(8,14) – c-myc,IgH
• t(2,8) / t(8,22)
EBV
Pathogenesis
C-myc is a transcription factor and
becomes constitutively express by the
translocation. This causes proliferative cell
growth.
In African Burkitt’s, there is extranodal

growth that is large & grossly visible and
located near the jaw.
In Sporadic Burkitt’s, the extranodal

tumor usually grows in the bowel,
retroperitoneum, and ovaries.
Tumor Histology: Packed B-cells with 2-5 prominent nucleoli with a high mitotic rate. There is also a high
rate of cell death, which attracts macrophages to phagocytize the debris. This creates the clear zones. The
combination of dark basophilic tumor cells with white spots gives the characteristic “Starry Sky” appearance.

Hematopoietic 24
- Painless extranodal tumor
growths
Burkitt’s and Hodgkin’s Lymphoma both arise - African’s: Jaw
from the lymphatic system and have no or little - Sporadic: Abdomen
involvement of the bone marrow directly. - t(8,14)
The differences include:

• HL has RS cells surrounded by normal
WBC; Burkitt’s is proliferation of
neoplastic cells.
• HL starts in a single node and spreads
consecutively; Burkitt’s is extranodal
and has noncontiguous spread.
• HL rarely occurs in the Weldeyer ring or
mesenteric nodes; Burkitt’s commonly
does.
Additional Info
Surface Markers:
• IgM
• κ/λ
• CD19
• CD20
• CD10

Hematopoietic 25
Hodgkin’s Lymphoma
Sparse neoplastic Reed-Sternberg cells
surrounded by proliferative normal WBCs. See Signs & Symptoms
table for subtypes.
• Lymph Node Tumor
Etiology • Fever
• Night sweats
• Weight loss
Not well understood. No translocation.
• Cutaneous anergy
EBV appears to have a role.
Tumor Biopsy: RS cells
Pathogenesis
Arises in a single node or chain of
nodes. It then spreads to anatomically
contiguous lymphoid tissue. Complications
Reed-Sternberg (RS) cells are derived
from a germinal center or post-germinal center Second cancers with treatment
B-cell. RS cells release factors that will • Myelodysplastic syndromes
accumulate lymphocytes, macrophages, and • AML
granulocytes. A RS cell stops expressing its • Lung Cancer
immunoglobulin.
Highlights
- Reed-Sternberg Cells
- B Cell origin
- Painless growth
- Single nodes
- Contiguous spread
Tumor Histology: Presence of a Reed-Sternberg cell, which is a large cell with 2 multi-lobated nucleus and
abundant cytoplasm. The RS cell has mirror symmetry to it which gives it an “owl eye” appearance.
Surrounding the RS cell is normal lymphocytes, macrophages, and granulocytes.

Hematopoietic 26
Differentials
Non-Hodgkin’s lymphoma, specifically Burkitt’s,
both arise from the lymphatic system and have
no or little involvement of the bone marrow
directly.
The differences include:

• HL has RS cells surrounded by normal
WBC; Burkitt’s is proliferation of
neoplastic cells.
• HL starts in a single node and spreads
consecutively; Burkitt’s is extranodal
and has noncontiguous spread.
• HL rarely occurs in the Waldeyer ring or
mesenteric nodes; Burkitt’s commonly
does.
Presence of RS cells is diagnostic of Hodgkin’s.
Subtype Markers EBV Comments
Nodular Sclerosis CD15, CD30 (-) Most common
Young adults
Non-gender specific
Mixed Cellularity CD15, CD30 (+) 70% >55 years old
Lymphocyte Rich CD15, CD30 (+) 40% Older adults
Male > Females

Hematopoietic 27
Acute Lymphoblastic Leukemia

Neoplasm of immature lymphocytes
that are unable to differentiate and accumulate. Signs & Symptoms
80% of childhood leukemias, with peak
incidence at 4 years old. Mostly of pre-B-cell • Abrupt stormy onset
origin (85%). Pre-T-cell origin (15%) is more • Anemia
common in adolescent males between 15 and • Bone Pain
20 years old. • Thrombocytopenia - hemorrhaging
• Lymphadenopathy
• Hepatosplenomegaly
Etiology • CNS Symptoms
Peripheral Blood Smear: No blasts

Block in differentiation, causation not known.
CBC:
Pre-T-cell ALL has the NOTCH1 mutation, and
allows for T-Cell development outside of the • WBC > 100,000/µL or <10,000/µL
thymus. • Platelet < 100,000/µL
• Neutropenia
Pathogenesis Bone Marrow Biopsy: >25% blast cellularity
PAS stain – glycogen granules

• Block in differentiation, accumulation of
lymphocytes, and crowding of the bone
marrow.
• Marrow expansion and infiltration
causes bone pain.
• Pre-B-Cell commonly infiltrations CNS
and testicles.
• Pre-T-Cell forms an anterior mediastinal
mass.
Peripheral Blood Smear: The smear shows large immature lymphocytes cells with course, clumped
chromatin and 1 or 2 nucleoli. There is very little cytoplasm.

Hematopoietic 28
Myeloperoxidase (+)
Additional Info
Karyotype:
• Hyperploidy (>50 chromosomes) and
cryptic (12,21) translocation of TEL1 & Immunophenotyping to determine
AML1. This has a good prognosis subtype and differentiate from AML.
• Philadelphia chromosome or MLL gene Tdt (Terminal deoxytransferase)
on 11q23. This has a poor prognosis.
Surface markers:
Immunohistochemistry: Tdt • Pre-B-Cell – CALLA/CD10, CD19, CD20
• Pre-T-Cell – CD2-8
Treatment:
• Chemotherapy
• Bone marrow transplant
Differentials • Prophylaxis chemo
ALL is very similar in presentation to AML. Both

are positive for myeloperoxidase.
• ALL will have glycogen granules, Tdt,
possibly Philadelphia Chromosomes,
and CNS symptoms.
• AML will have Auer rods and surface
markers CD15, CD33, CD34, & CD64.
Highlights
- Immature B & T-Cells
- T-Cells have NOTCH1 mutation
- Ph chromosome, poor prognosis
- Glycogen granules & Tdt
Peripheral Blood Smear – PAS Stain: Lymphoblasts show PAS staining glycogen granules in their cytoplasm.

Hematopoietic 29
Chronic Lymphocytic Leukemia

CLL is a neoplasm of post-follicular B-
Cells, where their function is suppressed. Signs & Symptoms
Small Lymphocytic Lymphoma is almost
exactly the same, just with less lymphocytosis in • Can be asymptomatic
the serum. • Anemia
• Immunosuppression / Bacterial
Most common adult leukemia (~60) Infections
with a median survival of 4-6 years. Also affects • Generalized Lymphadenopathy (50-
men more than women at 2:1. 60%)
• Hepatosplenomegaly (50-60%)
Etiology • Hypogammaglobulinemia (50%)
• Possible thrombocytopenia
• Possible autoimmune hemolytic anemia
Karyotype Abnormalities (50%)
• Trisomy 12
• Deletions of chromosomes 11 and 12.
CBC: > 4,000 lymphocytes/mm3, otherwise call
No translocations (only lymphoid neoplasm) Small Lymphocytic Lymphoma
Peripheral Blood Smear: Smudge Cells

Pathogenesis
Surface Marker: CD5
The B-cells undergo a loss of function

leading to hypogammaglobulinemia and
proliferation. This causes crowding of the bone
marrow and subsequent anemia and
immunosuppression.
Paradoxical autoantibodies are made to

RBCs and other self tissues, but are produced by
non-neoplastic B-Cells. This will cause
autoimmune hemolytic anemia.
Peripheral Blood Smear: Small and compact lymphocytes with little cytoplasm and are very fragile. The
fragility can be seen with the presence of a smudge cell, which is an artifact of slide prep where a
lymphocyte bursts open..

Hematopoietic 30
- Trisomy 12
- Deletions in Ch 11 and 12
Prolymphocytic transformation - No translocations
- Smudge Cells
Richter Syndrome aka Diffuse large B-cell - CD5
lymphoma - Richter Syndrome
• Fever
• Loss of weight and muscle mass
• Lymphadenopathy
Differentials
CLL presents similarly to the many of the
leukemias/lymphomas. There are two main
distinguishing features of CLL:
• No translocations
• CD5, only this and mantle cell
lymphoma
Additional Info
Poor prognosis: 11q 17p
Surface Markers: CD19, CD20, CD 23, CD5,

immunoglobulins

Hematopoietic 31
Hairy Cell Leukemia

Hairy Cell Leukemia is a rare chronic The infiltration of the bone marrow can
leukemia of B-cells. It is named due to the cause crowding leading to anemia,
characteristic hair-like cytoplasmic projections pancytopenia, occasionally leukocytosis, and
seen on the effected B-cells. immunosuppression. This allows for
opportunistic infections.
It typically affects older males, and has
a good prognosis with treatment. Unlike other leukemias, there is little to
no involvement of lymph nodes.
Etiology
Signs & Symptoms
Idiopathic. There is a correlation with farming.
• Splenomegaly - Sequestration
Pathogenesis • Pancytopenia
• Immunosuppression
• Thrombocytopenia
The Hairy Cells proliferate and infiltrate • Hepatomegaly
various organs; mostly the spleen, bone • Possible Leukocytosis
marrow, and liver.
• Peripheral Blood Smear: Hairy Cells
The infiltration of the spleen causes
congestion and damage, giving splenomegaly. • Flow cytometry
The same can happen in the liver, but this is not • Bone Marrow Aspirate: Difficult, “Dry
as common. Tap”
Peripheral Blood Smear: (Left) Positive Tartrate Resistant Acid Phosphatase (TRAP) stain of a blood smear.
The cytoplasm stains red to indicate Positive TRAP, including the fine hair-like cytoplasmic projections.
(Right) B-lymphocytes with densely staining nuclei and fine hairlike projections.

Hematopoietic 32
- Rare Chronic Leukemia
- Older men
Hairy Cell Leukemia is a rare form of - Hair-like cytoplasmic projections.
chronic leukemia. The distinguishing aspects to - Splenomegaly
look for are no lymphadenopathy, - Pancytopenia
splenomegaly, occurring in an older male, TRAP - No lymphopathy
stain positive, and the presence of surface - Surface markers CD11c and CD103
markers CD11c and CD103. These markers are - Dry Tap
not usually present on other B-cell tumors.
Another indicator of Hair Cell Leukemia is a “dry
tap” on attempted bone marrow aspirate.
Additional Info
Surface Markers
• CD19
• CD20
• CD11c
• CD103
• CD25
• Surface Immunoglobulin
Treatment
• Chemotherapy – Purine Analog
• Splenectomy
• Bone Marrow Transplant
• Interferon

Hematopoietic 33
Multiple Myeloma
Multiple myeloma is the most common marrow stoma in
plasma cell dyscrasia and is a malignant response to the Highlights
neoplasm. It is characterized by proliferation of myeloma. This - Osteolytic Lesions
monoclonal plasma cells, also referred to as proliferation has - Anemia
myeloma cells, and their excretion of antibodies two consequences: - Immunosuppression
- Renal Insufficiency
or parts of antibodies. These excretions are release of its
- γ spike on electrophoresis
terms M components or M proteins. immunoglobulin
- t(4,14)
product and the
The peak incidence is 50-60 years of age - Amyloidosis
crowding of the
with a median survival of 4-5 years. bone marrow.
The immunoglobulin product, or M

Etiology component, is comprised of a complete
antibody or a partial antibody and is usually IgG,
There appears to be a strong but sometimes is IgA. The partial could be just
association of multiple myeloma with the light chain, in which case it would be
chromosomal translocation mutations of IgH termed a Bence-Joyce protein. The M
(immunoglobulin heavy locus) on chromosome component can build up in tissues; most
14 and various oncogenes including D cyclin. notably the kidney’s DCTs & CDs which leads to
This creates a fusion protein with the heavy renal insufficiency termed myeloma nephrosis.
chain and another protein.
The crowding causes reduced
D cyclin is responsible for regulating the erythrocyte production, leading to anemia, and
cell cycle between G1 and S. reduced white blood cell other than the
The most common of these mutations

is t(4,14).
Pathogenesis
Proliferation of the myeloma cells is
due to a combination of the mutation, such as
loss of D cyclin, and IL-6. IL-6 is released by the
fibroblasts and macrophages in the bone
Bone Marrow Aspirate: Excessive proliferation of plasma cells in the bone marrow. Normal bone marrow
has 2-3% plasma cells. The nuclei are prominent and occasionally have multiple nuclei per cell. There may
also be cytoplasmic inclusion bodies composed of immuno globins.

Hematopoietic 34
myeloma cells, leading to immunosuppression

and the subsequent opportunistic infections. Complications
The most common of these are S. aureus, S.
pneumoniae, and E. coli. AL Amyloidosis
IL-6 will stimulate the RANK-ligand, • Deposition of light chains
which will cause differentiation and activation Hyperviscosity syndromes
of osteoclasts. This produces osteolytic lesions • Aggregation of M proteins
in the spine, ribs, skull, and other bones. The • Not very common, more common in
lesions are radio translucent on Xrays. Because Lymphoplasmacytic lymphoma
of this, the patient will have severe bone pain,
brittle bones, and hypercalcemia. Differentials
Lymphoplasmacytic Lymphoma
• B-Cell lymphoma with plasma cell
proliferation.
Signs & Symptoms • Mostly IgM, not IgG
• No osteolytic lesions
• Bone pain, brittle bones Localized Plasmacytoma
• Hypercalcemia, confusion, lethargy • Solitary osteolytic or soft tissue lesions
• Anemia • Elevated M proteins
• Renal insufficiency • High risk of developing Multiple
• Opportunistic infections Myeloma.
• XR: Osteolytic lesions

• Bone Marrow: >10% Plasma cells in
bone marrow
• Electrophoresis: Gamma band spike in
either serum or urine.
Skull XR: This skull has multiple radio translucent spots scattered throughout the top region. These are
sometimes referred to as “punched out lesions.” These lesions are due to the osteolytic activity of
osteoclasts stimulated by RANK-ligand, which is elevated due to high IL-6.

Hematopoietic 35
Acute Myeloblastic Leukemia

Malignant disorder of the bone marrow
where hematopoietic precursors are arrested in Signs & Symptoms
an early stage of development.
Affects older adults, with a median age • Abrupt onset

of 50. More common in men. Has a poor • Anemia
prognosis. • Thrombocytopenia
• Immunosuppression
Main subtype is M3. • Mild splenomegaly
• Mild Lymphadenopathy
Etiology
• Bone Marrow Biopsy: >20% myeloid
blast or promyelocyte cellularity
Mutations in transcription factors
• Myeloperoxidase (+)
related to myeloid differentiation.
• Auer rods
Example - t(15,17) retinoic acid
receptor α (RANA) on 17 and Promyelocytic Complications
Leukemia (PML) on 15, creating a fusion
product. M3 subtype. PML is a tumor
suppressor gene. Increased risk for DIC in M3 subtyp
Pathogenesis
• Blocking differentiation of
promyelocytes.
• Accumulation of blasts
• Crowding leads to anemia &
immunosuppression
Peripheral Blood Smear: Lymphocytes with a high nucleus to cytoplasm ratio, azurophilic granules, and
multilobed nuclei.

Hematopoietic 36
M1: AML without Maturation

Differentials • Myeloperoxidase (+)
• Few granules
AML is very similar in presentation to ALL. Both • Mostly myeloblasts
are positive for myeloperoxidase. • t(8;14)
• ALL will have glycogen granules, Tdt, M2: AML with Maturation
possibly Philadelphia Chromosomes, • >20% myeloblast in bone marrow
and CNS symptoms. • t(8,21)
• AML will have Auer rods and surface M3: Acute Promyelocytic Leukemia
markers CD15, CD33, CD34, & CD64. • Auer rods
Auer rods only present in neoplastic myeloblast • t(15,17)
Markers CD15, CD33, CD34, and CD64 are • DIC
M4: Acute Myelomonocytic Leukemia
specific to AML.
• Esterase (+)
Additional Info M5: Acute Monocytic Leukemia
• Immature monocytes
Only t(15,17) mutation responds well to high • Esterase (+)
dose retinoic acid (Vitamin A). • No Auer rods
M6: Acute erythroleukemia
Surface Markers: CD13, CD14, CD15, CD33, • Follows chemo
CD34, CD64, CD117 (cKIT), M7: Acute Megakaryocytic Leukemia
• Platelet-specific antigen
Other Subtypes
• Myelofibrosis
M0: Minimally Differentiated AML
• Lacks Auer rods
PBS: Positive myeloperoxidase stain as indicated by the prominently darkened cells.
BM Aspirate: Neoplastic promyelocytes with course azurophilic granules, bilobed nuclei, and auer rods.

Hematopoietic 37
Chronic Myeloid Leukemia

Hyperproliferation of myeloid progenitors
that can still terminally differentiate. Increase Signs & Symptoms
in one or more elements in peripheral blood.
Affects 25-60 year olds with peak incidence • Anemia

at 40-50 and a median survival 3 years. • Basophilia
o Extreme splenomegaly,
Etiology dragging sensation of abdomen
• Splenic Infarctions – LUQ Pain
• Mutated tyrosine kinase. • Mild lymphadenopathy
• 95% BCR-ABL fusion gene t(9,22) aka • Thrombocytosis
Philadelphia chromosome. ABL is on 9,
BCR is on 22. BCR is a tyrosine kinase.
• Remaining is due to rearrangements Leukocyte Count:
that are cytogenetically cryptic or • >100,000 cells/µL
obscure. • Neutrophils, metamyelocytes, and
myelocytes
Pathogenesis Bone Marrow: Hypercellular but otherwise
normal appearing.
BCR-ABL generates growth signals
Karyotype: Philadelphia Chromosome
similar to the growth-factor receptor. There is
proliferation of granulocytes (Neutrophils,
Basophils, & Eosinophils) and megakaryocytes
(platelets). These mature and immature
granulocytes spill into blood stream.
There is compensation for the anemia

via extramedullary hematopoiesis, causing
hepatosplenomegaly. This can cause occlusion
of vessels in the spleen and splenic infarcts.
Peripheral Blood Smear: Increased neutrophils and neutrophil precursor cells, metamyelocytes and
myelocytes. There will also be increased basophils and eosinophils.

Hematopoietic 38
- Granulocytes/Megakaryocytes
- Philadelphia Chromosome
Accelerated Phase (50%) with gradual BCR-ABL t(9,22)
failure of treatment, increased anemia, - Splenic infarcts
thrombocytopenia, and finally resemble ALL - Basophilia
with a blast crisis. - Thrombocytosis
- Accelerated Phase & Abrupt Blast
The other half will develop an abrupt Crisis
blast crisis. 70% of these similar to AML, 30% - Gleevec
ALL.
Differentials
Philadelphia Chromosome usually
indicates CML. However, Ph chromosome is
also found in ALL.
Basophilia is a strong indicator of CML,

although could also be seen in Polycythemia
Vera. Polycythemia Vera is a proliferation of
RBCs, granulocytes, and megakaryocytes. It will
have no anemia and will have congestion.
The thrombocytosis is a good indicator

for CML, as only it and primary myelofibrosis
have it. Primary myelofibrosis will have no
Philadelphia chromosome, and the bone
marrow is hypocellular & fibrotic.
Additional Info
Treatment:
• Bone marrow transplant
• Gleevec, Imantinib mesylate, ia a BCR-
ABL inhibitor

Hematopoietic 39
Primary Myelofibrosis
Myeloid metaplasia that results in
fibrosis of the bone marrow and a shift to Signs & Symptoms
extramedullary hematopoiesis.
Median survival is 4-5 years. • Pancytopenia

• Splenomegaly up to 4,000g.
• Subcapsular splenic infarcts
Etiology • Moderate hepatomegaly
• Anemia
Mutation in JAK2 kinase (50%), a signaling • Immunosuppression
protein. • Thrombotic and hemorrhagic episodes
Over 50% is idiopathic.
Peripheral Blood Smear:

Pathogenesis • Poikilocytes, teardrop cells (dacrocytes)
• Leukoerythrocytosis
Early in course the bone marrow is Bone Marrow Biopsy: Reticulin stain,
hypercellular with all three major cell lines. hypocellular and fibrotic
Late in the disease it is mostly megakaryocytes
that are prominent and dysplastic. Platelets are
deformed, leading to thrombus formation and
hemorrhagic episodes.
Normal fibroblasts cause fibrosis.

Activated by platelet derived growth factor
(PDGF) and transforming growth factor β (TGF-
β). Eventually the bone marrow becomes
hypocellular and fibrotic.
Extramedullary hematopoiesis, first

starts in the spleen. Then occurs in the liver,
giving hepatomegaly. Also occurs in the lymph
nodes, but not enough for lymphadenopathy.
Peripheral Blood Smear: The RBCs show poikilocytosis, with elongation and tear drop cells (dacrocytes).
The general picture will give us leukoerythrocytosis, which is seen with the nucleated erythroid precursor in
the center and the polychromatic erythrocytes with blue coloration in the bottom right.

Hematopoietic 40
Pancytopenia
Complications • Aplastic Anemia
• Myelophthisic Anemia
• Blast crisis – AML (5-15%) • Aleukemic Leukemia
• Hyperuricemia and gout. • Granulomatous Disease
Differentials
Highlights
- JAK2 Kinase
Similar in presentation to CML, but with - Fibrosis of bone marrow
no Philadelphia Chromosome and with - Megakaryocytosis
hypocellular and fibrotic bone marrow. - PDGF and TGF-β
- Splenomegaly & infarcts
Polycythemia Vera is the proliferation - Pancytopenia
of mature myeloid cells, especially RBCs. - Thrombi & hemorrhaging
Similar to primary myelofibrosis that both have
thrombus formation. PV will have increased
granulocytes & platelets but won’t have
anemia.
Bone Marrow Biopsy: (Left) Fibrotic bone marrow of what was once hypercellular. There is less than 50%
fat and large sections in the bottom right show fibrosis. Spotted throughout are prominent megakaryocytes
that are dysplastic. This is confirmed with a reticulin stain (Right) that shows Type III collagen, which is an
integral part of fibrosis.

Hematopoietic 41
Vignettes
1) Edward, a 57 year old man, presents with 3) Peter, a 23 year old man, comes to your
severe back pain, lethargy, and a persistent office with yellow sclera, tachycardia, pale skin,
cough. His serum and urine electrophoresis and difficulty concentrating. Just 3 days ago
show a gamma band spike and radiography of you had seen Peter for strep throat, which you
his back show multiple punched out lesions in prescribed sulfamethoxazole. On a blood smear
the vertebrae. Which of the following is most it is noted that there are Heinz bodies present
directly responsible for the lytic bone lesions in his RBCs. Which is the most likely mutation
seen on the xray? responsible for Peter’s condition?
a) RANK-ligand a) Ankyrin
b) Destruction of the bone marrow b) HbS
c) Deposition of light chains c) G6PD
d) Type II Hypersensitivity d) β-spectrin
e) Staphylococcus aureus infection e) PIGA
2) A young male, Sven, comes to your office 4) A 28 year old African American male named
because the whites of his eyes have turned Eric presents with severe chest and joint pains.
yellow. He hasn’t taken any medication for the He appears anemic and complains of feeling
past few months, but does say he’s been too tired. You run blood tests and discover a low
tired to go outside and play. On examination hematocrit. On a peripheral blood smear, you
you detect splenomegaly. You order some notice elongated RBCs that look crescent
blood tests and they come back with elevated shaped. The treatment for controlling this
reticulocytes and the erythrocytes appear to disease does which of the follow?
have lost their biconcavity and they are
osmotically fragile. Which of the following is a) Corticosteroids
b) Increases HbF production
the most likely diagnosis?
c) Splenectomy
a) Sickle Cell Anemia d) Iron supplementation
b) Thalassemia e) Bone Marrow Transplant
c) G6PD Deficiency
d) Paroxysmal Nocturnal Hemoglobinuria
e) Hereditary Spherocytosis

Hematopoietic 42
5) Jefferson comes to you with pain in his upper

left abdomen, a dragging sensation in the same
area, and a general feeling of tiredness. On a
peripheral blood smear you see tear drop cells
and the slide appears to have
leukoerythrocytosis. You also do a bone
marrow biopsy and discover that large sections
of his bone marrow have become fibrotic.
Which of the following diseases shares the
increased risk of clots?
a) Acute Lymphoblastic Leukemia (ALL)

b) Acute Myeloblastic Leukemia (AML)
c) Chronic Lymphoblastic Leukemia (CLL)
d) Chronic Myeloid Leukemia (CML)
e) Hairy Cell Leukemia
6) Anne is a 4 year old girl with a painless

growth in her abdomen. You take a biopsy of
the growth located in a mesenteric node. It
shows sheets of clonal B-cells with spots of
clear areas, somewhat like a “Starry Sky.” What
is the most likely chromosomal translocation?
a) t(15,17)
b) t(4,14)
c) t(8,14)
d) t(15,22)
e) t(9,22)

Hematopoietic 43
Answers & Explanations

1) (A) Edward, a 57 year old man, presents with e) Staphylococcus aureus infection
severe back pain, lethargy, and a persistent
cough. His serum and urine electrophoresis S. aureus is a common opportunistic
show a gamma band spike and radiography of infection in MM. However, this would cause
his back show multiple punched out lesions in osteomyelitis, which would not have the
the vertebrae. Which of the following is most characteristic “punched out lesions” but
directly responsible for the lytic bone lesions may have evidence of osteolysis.
seen on the xray?
The electrophoresis shows high levels of 2) (E) A young male, Sven, comes to your office
immunoglobulins and combined with the because the whites of his eyes have turned
osteolytic lesions and history you would suspect yellow. He hasn’t taken any medication for the
multiple myeloma. The question then asks what past few months, but does say he’s been too
is the mechanism for the osteolytic lesions. tired to go outside and play. On examination
you detect splenomegaly. You order some
blood tests and they come back with elevated
a) RANK-ligand (Correct) reticulocytes, the erythrocytes appear to have
lost their biconcavity and they are osmotically
RANK-ligand is responsible for activating the fragile. Which of the following is the most likely
osteoclasts which reabsorbs the bone. Itself
diagnosis?
is stimulated by IL-6.
The key points here is that he has icterus,
b) Destruction of the bone marrow fatigue, splenomegaly, spherical (loss of
In multiple myeloma, the bone marrow isn’t biconcavity), and are osmotically fragile. The
so much destroyed as it becomes impaired icterus and fatigue are nonspecific symptoms,
in its ability to produce RBC and WBC. but may indicate an anemia. However,
spherical and osmotically fragile RBCs are
c) Deposition of light chains characteristic of Hereditary Spherocytosis. In
addition to that, splenomegaly is most likely in
This deposition does occur in MM, but it
HS compared to the other hemolytic anemias.
occurs more in the distal convoluted tubules
and collecting ducts. If systemic, this would
be primary amyloidosis.
a) Sickle Cell Anemia
d) Type II Hypersensitivity
Sickle Cell will have sickle shaped cells,
Antibody mediated hypersensitivity is not a which tend to block capillaries and can
major component of MM. There is no cause pain. These cells are degraded by the
autoimmunity. spleen.

Hematopoietic 44
b) Thalassemia a) Ankyrin
The RBCs here may be hypochromatic or This is the autosomal dominant mutation in
microcytic, but they retain their biconcavity Hereditary Spherocytosis, which would
and are not osmotically fragile. present with spherocytes, osmotic fragility,
and splenomegaly.
c) G6PD Deficiency
b) HbS
This may have splenomegaly, but the cells
would retain their biconcavity. Also, he This is the mutation name for Sickle Cell
doesn’t have a history of medications in the Anemia, which would not have Heinz
past 2-3 days and doesn’t have any bodies.
symptoms of infection.
c) G6PD (Correct)
d) Paroxysmal Nocturnal Hemoglobinuria
See stem answer.
This disorder is characterized by sensitivity
to complement and tends to occur during d) β-spectrin
sleep due to acidosis. Usually presents with This is the autosomal recessive mutation in
pancytopenia, thrombosis, and hemolytic Hereditary Spherocytosis.
anemia. Only one of these is present.
e) PIGA
e) Hereditary Spherocytosis (Correct)
This is the X-linked mutation in Paroxysmal
Nocturnal Hemoglobinuria.
3) (C) Peter, a 23 year old man, comes to your
office with yellow sclera, tachycardia, pale skin,
and difficulty concentrating. Just 3 days ago 4) (B) A 28 year old African American male
you had seen Peter for strep throat, which you named Eric presents with severe chest and joint
prescribed sulfamethoxazole. On a blood smear pains. He appears anemic and complains of
it is noted that there are Heinz bodies present feeling tired. You run blood tests and discover a
in his RBCs. Which is the most likely mutation low hematocrit. On a peripheral blood smear,
responsible for Peter’s condition? you notice elongated RBCs that look crescent
shaped. The treatment for controlling this
disease does which of the follow?
Peter presents with some non-specific anemia The stem describes Sickle Cell Anemia, with the
symptoms. The important things to note is that indicators being an African, anemic symptoms,
he recently starting taking a sulfamethoxazole sickle cells in the blood smear, and hemolytic
(the oxidative insult) and has Heinz bodies. crisis (chest & joint pain). The low hematocrit
These are characteristic of G6PD Deficiency, supports this as a hemolytic anemia. The
which is a X-linked genetic disorder with G6PD treatment options for sickle cell include
mutated. transfusion and hydroxyurea.

Hematopoietic 45
a) Corticosteroids of his bone marrow have become fibrotic.

Which of the following diseases shares the
Would help with reduce the increased risk of clots?
inflammation during the hemolytic crisis
and help alleviate the chest pain, but it The stem describes Primary Myelofibrosis. He
is not a treatment for sickle cell in has splenomegaly (dragging sensation) and
general. splenic infarcts (pain in URQ of abdomen). His
peripheral blood shows tear drops and
b) Increases HbF production (Correct) leukoerythrocytosis. What is characteristic is
Hydroxyurea works through several the fibrosis of the bone marrow. The only
mechanisms. One is by increasing HbF prominent cell line remaining are
production. It also inhibits DNA megakaryocytes, which release large amounts
synthesis, prohibits WBC formation of platelets, leading to thrombus formation or
(anti-inflammatory), and releases NO. hemorrhaging. There are two similar diseases
that also cause thrombocytosis: Polycythemia
c) Splenectomy Vera and Chronic Myeloid Leukemia. The other
choices are all thrombocytopenic.
Splenectomy is a treatment for
Hereditary Spherocytosis and Hairy Cell a) Acute Lymphoblastic Leukemia (ALL)
Leukemia. Sickle Cell Anemia will b) Acute Myeloblastic Leukemia (AML)
actually undergo autosplenectomy, so c) Chronic Lymphoblastic Leukemia (CLL)
removal will have no effect. d) Chronic Myeloid Leukemia (CML)
(Correct)
d) Iron supplementation
e) Hairy Cell Leukemia
Iron supplementation is the treatment
6) (C) Anne is a 4 year old girl with a painless
for Iron Deficiency Anemia. In Sickle Cell
growth in her abdomen. You take a biopsy of
Anemia, this is detrimental as there can
the growth located in a mesenteric node. It
be hemosiderosis.
shows sheets of clonal B-cells with spots of
e) Bone Marrow Transplant clear areas, somewhat like a “Starry Sky.” What
is the most likely chromosomal translocation?
A bone marrow transplant would cure
Sickle cell anemia, but this is typically Anne’s growth is Sporadic Burkitt’s Lymphoma.
not feasible to find a good match and This can be determined by the location of the
isn’t normally done. tumor and the characteristic “Starry Sky.” The
most common translocation in Burkitt’s
5) (D) Jefferson comes to you with pain in his Lymphoma is t(8,14).
upper left abdomen, a dragging sensation in the
same area, and a general feeling of tiredness. a) t(15,17) – AML Type M3
On a peripheral blood smear you see tear drop b) t(4,14) – Multiple Myeloma
cells and the slide appears to have c) t(8,14) – Correct & AML Type M1
leukoerythrocytosis. You also do a bone d) t(15,22) – Nothing
marrow biopsy and discover that large sections e) t(9,22) – Ph Chromosome, CML & ALL

Cardiovascular 46
Cardiovascular
Vascular Disorders
Atherosclerosis 047
Mönckeberg’s Medial Calcific Sclerosis 049
Hypertensive Vascular Disease 050
Temporal Arteritis 052
Takayasu Arteritis 054
Polyarteritis Nodosa (PAN) 055
Buerger’s Disease 056
Wegener Granulomatosis 057
Abdominal Aortic Aneurysm 059
Syphilitic Aortitis 061
Aortic Dissection 063
Berry Aneurysm 065
Cardiac Disorders
Myocardial Infarction 067
Acute Rheumatic Myocarditis 071
Calcific Aortic Stenosis 073
Mitral Valve Prolapse 074
Infective Endocarditis 076
Viral Myocarditis 078
Dilated Cardiomyopathy 079
Hypertrophic Cardiomyopathy 080
Restrictive Cardiomyopathy 082
Tetralogy of Fallot 083
Ventricular Septal Defect 085
Atrial Septal Defect 086
Vignettes 087
Answers & Explanations Path Profiles –090

Fall 2012
Cardiovascular 47
Atherosclerosis
Intimal lesions protrude into the
vascular lumen, and is composed of core of
cholesterol & lipids covered by a firm fibrous
cap, called an atheromatous plaque. Usually
affects elastic arteries, such as the aorta &
carotid as well as large and medium sized
muscluar arteries, notably the coronary
arteries.
Etiology
Risk factors
• Age
• Male
• Family History
• Genetics
• Hyperlipidemia/Hypercholesteremia
• Hypertension
• Smoking
• Diabetes
Pathogenesis
Response to injury hypothesis
• Endothelial injury
o Chronic or repetitive
o Turbulent flow
• Endothelial dysfunction
• Macrophage activation
• Macrophages and SM phagocytize lipids
& cholesterols
• SMC proliferation
• Occlusion of lumen
Plaques start as fatty dots, then fatty streak,

and end as an atheroma.

Cardiovascular 48
destructive of the
Signs & Symptoms Highlights
vessel, and - Intimal chronic
present with pain inflammation
and ulceration. - Cholesterol
Asymptomatic until complications arise.
There is also a - Atheromatous plaque
strong association - Aorta & Coronary arteries
Complications with smoking. - Lots of risk factors
- Response to injury
Aneurysm
- Complications cause
symptoms
• Weakening of vessel wall
• Stasis & thrombi formation
• AAA
Rupture Additional Info

• Acute event
• Thromboembolism
• Hemorrhage Stable Plaque
• More likely with unstable plaque • Mostly ECM and SMC
Occlusion by thrombus or critical stenosis Unstable Plaque (Vulnerable)

• Ischemia • Mostly macrophages & foam cells
• Complete obstruction can give MI • Fibrous cap is prone to rupture
• Gangrene of lower extremities
Differentials
Mönckeberg’s Sclerosis is also due to
deposition in the vessel wall; however the
depositions are calcium and located in the
tunica media. There is no occlusion and is
asymptomatic.
Buerger’s Disease is also a type of

arteriosclerosis, with thickening and hardening
of the vessel walls. However, it usually occurs
in the lower or upper extremities. The
arteriosclerosis also occurs in segments, is very
Histology: There are three main components to an atherosclerotic plaque: the fibrous cap (F) is composed of
SMC and dense collagen; Shoulder area, which is where the cap meets the vessel wall; and a necrotic core of
cholesterol, foam cells (lipid laden macrophages and SMC), necrotic debris, and fibrin (C).

Cardiovascular 49
Mönckeberg’s Medial Calcific Sclerosis

Calcium deposition in the vessel walls plaque is composed of cholesterols and lipids.
and is usually an incidental finding.
Buerger’s Disease is also a type of
arteriosclerosis, with thickening and hardening
Etiology of the vessel walls. However, it usually occurs
in the lower or upper extremities. The
Deposition of calcium in tunica media of arteriosclerosis also occurs in segments, is very
destructive of the vessel, and present with pain
blood vessels.
and ulceration. There is also a strong
Typically occurs in people over 50. association with smoking.
Pathogenesis
Highlights
• Calcium is deposited in tunica media. - Asymptomatic
• Does no damage nor occludes the - Calcium deposits
lumen. - Incidental Finding
- Non-clinical
Signs & Symptoms
Asymptomatic
Complications
Calcium deposits may induce bone formation.
Differentials
Atherosclerosis will cause occlusion of
the lumen, as well as aneurysms, ruptures, and
other complications such as ischemia (MI). The
Histology: There are basophilic calcium deposits within the tunica media. They do not reach the lumen nor
cause luminal shrinking or occlusion.

Cardiovascular 50
Hypertensive Vascular Disease

Hypertension has several effects on the Hyperplastic Arteriolosclerosis
body, including vascular changes. There are • Acute or severe hemodynamic stress
two types of vascular responses: Hyaline and • Hyperplasia of smooth muscle cells
Hyperplastic Arteriolosclerosis. • Duplication of the basement membrane
• The vessel wall gets thicker and the
Etiology lumen shrinks.
Hemodynamic stress from hypertension.

Signs & Symptoms
Pathogenesis Asymptomatic
Hyaline Arteriolosclerosis
Complications
• Chronic hemodynamic stress
• Plasma components leak through the • Aortic Dissection
vessels walls. • Cerebrovascular hemorrhage
• Smooth muscle cells expand the • Cardiac Hypertrophy & Congestive
extracellular matrix. Heart Failure
• The vessel wall gets thicker and the • Benign Nephrosclerosis
lumen shrinks
Histology: (Left) Hyaline Arteriolosclerosis has homogenous pink staining in a thickened arteriole wall and a
loss of structural detail. Note the small lumen in the center. (Right) Hyperplastic Arteriolosclerosis has
concentric laminated layers of smooth muscle and duplicated basement membranes, looks like an “onion.”

Cardiovascular 51
- Hypertension
- Hemodynamic Stress
Hyaline Arteriolosclerosis is also - Luminal Shrinking
characteristic of microangiography in diabetes. - Hyaline Arteriolosclerosis
It is also a normal degenerative process, with - Choric
elderly people having some sclerosis. However, - Leaking plasm
in hypertensive it is more generalized and - ECM
severe. - Normal in elderly
- Hyperplastic Arteriolosclerosis
Hyperplastic Arteriolosclerosis is also - Acute
seen in Malignant Hypertension. It is a disease - Hyperplasia
of extreme abrupt hypertension (>120mmHg
diastolic pressure) with renal failure, retinal
hemorrhages, and papilledema. This would also
present with fibrinoid necrosis in the vessel
walls.

Cardiovascular 52
Temporal Arteritis
Granulomatous inflammation of the Depending on location:
vessels, commonly in the carotid artery or • Temporal Artery – Facial pain and
temporal artery. Also can involve the aorta, headache
ophthalmic, and vertebral artery. • Ophthalmic Artery – Diplopia or vision
loss
Also called Giant Cell Arteritis.
Labs: Elevated ESR
Common in people over 50 years old.
Slightly more common in women.
Complications
Etiology
Vision loss
Possible T-cell mediated immune response.
Pathogenesis
• Granulomatous inflammation in the

inner media with fragmentation of the
internal elastic lamina.
• Lymphocyte and macrophage
infiltration with giant cells.
• Healed by collagenous thickening of the
vessel wall (intimal thickening).
• Lesions are segmented, requiring long
segments of vessel to diagnose.
Signs & Symptoms

Non-specific symptoms: fever, fatigue, weight
loss.
Histology: Granulomatous inflammation in the inner media with infiltration of lymphocytes (CD4>CD8),
macrophages, and occasional giant cells. There is also fragmentation of the internal elastic lamina.

Cardiovascular 53
- Granulomatous vasculitis
- Aka Giant Cell Arteritis
Temporal Arteritis is similar to - Temporal & Ophthalmic Arteries
Takayasu Arteritis. They have similar - >50 years of age
morphology and pathogenesis as well as - Idiopathic
unknown etiologies. Takayasu will occur in - Infiltration with lymphocytes &
younger people, usually women under 40 and is macrophages.
associated with people from Japan. Temporal - Vessel wall thickening & occlusion
Arteritis will occur in people older than 50. - Segmented lesions, need large and
multiple biopsies.
What may be more important is the - May lead to blindness
location of vasculitis. Temporal will occur
mostly in the head, where Takayasu will occur
mostly around the aortic arch. A good
differentiator is that Takayasu will have
diminished pulse in the upper extremities.
PAN is a vasculitis of smaller vessels,

and usually affects the kidneys and GI tract.
This will give things like hypertension and
melena, which are distinguishing features.
Kawasaki Syndrome is a vasculitis of all

arteries and usually occurs in infants and young
children < 4 years. It will have edema of the
hands & feet, desquamation rash, and enlarged
cervical lymph nodes. It is endemic in Japan.
Additional Info
Treatment: Immediate corticosteroids

Cardiovascular 54
Takayasu Arteritis
Granulomatous vasculitis of medium women under 40 and is associated with people
and large arteriers, aka “Pulseless disease.” from Japan. Temporal Arteritis will occur in
people older than 50.
Affects people younger than 50 and is
more common in females. What may be more important is the
location of vasculitis. Temporal will occur
Global distribution, but associated with mostly in the head, where Takayasu will occur
Japanese people. mostly around the aortic arch. A good
differentiator is that Takayasu will have
Etiology diminished pulse in the upper extremities.
PAN is a vasculitis of smaller vessels,

Idiopathic, possibly immune mediated. and usually affects the kidneys and GI tract.
This will give things like hypertension and
melena, which are distinguishing features.
Pathogenesis
Buerger’s Disease will also have a lack
of pulse in the upper extremities. But in
• Unknown, possibly immune mediated.
addition to that, it may also have diminished
• There is transmural fibrous of the aorta,
pulse in the lower extremities. Buerger’s will
usually around the aortic arch and great
also have ulcerations on the fingers and toes,
vessels.
and is strongly associated with smoking.
• Can also affect pulmonary arteries.
Kawasaki Syndrome is a vasculitis of all
Signs & Symptoms arteries and usually occurs in infants and young
children < 4 years. It will have edema of the
hands & feet, desquamation rash, and enlarged
Depressed pulse in upper extremities cervical lymph nodes. It is endemic in Japan.
- Pulseless Disease of upper extremity
- Granulomatous vasculitis
Takayasu Arteritis is similar to Temporal - <50 years old
Arteritis. They have similar morphology and - Japanese descent
pathogenesis as well as unknown etiologies. - Aortic arch & great vessels
Takayasu will occur in younger people, usually
Histology: Same as Temporal Arteritis. Granulomatous inflammation in the inner media with infiltration of
lymphocytes (CD4>CD8), macrophages, and occasional giant cells. There is also fragmentation of the
internal elastic lamina.

Cardiovascular 55
Polyarteritis Nodosa (PAN)

Systemic vasculitis of small and medium • Melena
arteries, exluding arterioles and capillaries. • Peripheral neuritis
• Renal failure
Also spares the pulmonary arterities.
o No glomerulonephritis
Etiology HBsAg: Found in 30%
Unknown. Hep B has been implicated.

Complications
Pathogenesis • Aneurysms
• Ruptures
• Ischemia
• Transmural inflammation of arterial • Thrombosis
wall.
• Healing with fibrous thickening of vessel
wall.
Differentials
• Different stages occur simultaneously in
same vessel. Temporal and Takayasu Arteritis are
• Mostly affects renal artery, leading to diseases of the large arteries with similar
hypertension and renal failure. pathogenesis. They will typically affect the
• Can also occur in the heart, liver, and GI aorta and the head vasculature. PAN occurs
tract. more in the viscera to elicit renal and GI
• GI involvement leads to melena and symptoms. Look for bouts of hypertension,
abdominal pain. abdominal pain, and melena.
Signs & Symptoms
• Episodic
• Acute or Chronic
• Non-specific: Fever, malaise, weight
loss
• Hypertension
• Abdominal Pain
Histology: Transmural inflammation with neutrophils, eosinophils, and macrophages. There is also fibrinoid
necrosis, as seen by the bright pink staining surrounding the vessel lumen.

Cardiovascular 56
Buerger’s Disease
Segmental, thrombosing, acute and subsequent gangrene
chronic inflammation of medium and small • Diminished pulse in upper and/or lower
arteries. Commonly affects tibial and radial extremities
arteries. Aka thromboangiitis obliterans.
Differentials
Etiology
Buerger’s Disease is similar to the other
Risk Factors vasculitis diseases, but with the addition of
• Heavy Smoking ulcerations and the strong association with
• Genetics heavy smoking. Also is the only vasculitis that is
• Male more common in Ashkenazi Jews or Indians.
• Age <40 years
Takayasu Arteritis will also have
• Ashkenazi Jew, Japanese, or Indian
diminished pulses in the upper extremities, but
will not also have it in the lower extremities
Pathogenesis which may occur in Buerger’s. Both of these
also occur more often in people of Japanese
descent.
There is a strong association with heavy
smoking, as it occurs almost exclusively with The other disease common to Japanese
smoking and resolves in the early stages if the people is Kawasaki Syndrome. This disease will
patient quits smoking. have edema of the hands & feet, a rash,
enlarged lymph nodes, and occurs in infants
It is suspected that smoking has a direct
toxicity to endothelium or an idiosyncratic PAN, another vasculitis, is more likely to
immune response to the same chemicals. have GI and renal symptoms, unlike Buerger’s.
Signs & Symptoms
• Superficial phlebitis
• Cold sensitivity
• Reynaud’s Phenomenon
• Foot pain with exertion
• Pain at rest
• Ulceration of toes, feet, or fingers with
Histology: Segmental acute and chronic vasculitis with focal necrosis, neutrophils, and granuloma formation,
called a microabscess, in small and medium sized arteries. Possible thrombus formation.

Cardiovascular 57
Wegener Granulomatosis
Triad of:
• necrotizing granulomatas of the Signs & Symptoms
respiratory tract
• necrotizing or granulomatous vasculitis • Pneumonitis
of small or medium arteries
• Bilateral nodular and cavitary infiltrates
• renal necrotizing glomerulitis. • Sinusitis
Limited Wegender Granulomatosis has no • Ulceration of mucosal nasopharynx
renal involvement. • Renal disease
• c-ANCA
More common in men with an average age
of onset of 40 years
Differentials
Etiology
Wegener’s is more of a disease of the
upper respiratory tract with significant vasculitis
• Idiopathic associated with it. This will have the
nasopharynx ulcerations and location of the
Pathogenesis vasculitis to help differentiate it from the other
vasculitis diseases.
• Pathogenesis is uncertain. Churg-Strauss, also called allergic

• Some form of cell-mediated granulomatosis and angiitis, is a similar disease
hypersensitivity but the etiology is associated with allergies and
• c-ANCA is present in 95% of cases
• Vascular lesions undergo progressive
fibrosis and organization.
• Renal lesions start with focal necrosis
but later becomes diffuse necrosis with
parietal cell proliferation that forms
crescentic glomerulonephritis.
Histology: Necrotizing vasculitis of a small artery and granulomatous inflammation, as indicated by the
presence of giant cells. The surrounding tissue is composed of fibroblasts and leukocytes.

Cardiovascular 58
asthma with peripheral eosinophilia. There is

Highlights
also presence of p-ANCA in about half of these
- Necrotizing granuloma of RT
patients. The lesions themselves are similar to
- Necrotizing granuloma of arteries
PAN and microscopic polyangiitis, but located in
- Renal necrotizing glomerulitis
the lungs, heart, spleen, peripheral nerves, and
- Men around 40
skin. Also CS will not have renal involvement. - Cell mediated hypersensitivity
Goodpasture’s Syndrome has lung and
- c-ANCA
renal involvement, and is due to anti-
glomerular basement membrane antibodies.
The lungs will be more hemorrhagic and the
kidneys will have glomerulonephritis. Serum
anti-GBM is a good indicator of Goodpasture’s
Syndrome.
Gross: (Left) Nasal ulceration. (Right) Lung cavity formation.

Cardiovascular 59
Abdominal Aortic Aneurysm

Weaking of the aortic vessel wall and
subsequent dilation of the vessel with the risk Signs & Symptoms
of a rupture.
Pulsating mass in the abdomen
Etiology CT or US: Dilated aorta
Atherosclerosis
•
Complications
• Matrix Metalloproteinases (MMP)
• Infections
• Rupture and massive hemorrhaging
• Ischemia of downstream tissues
Types of Abdominal Aortic Aneurysm: • Thrombus formation and possible
• Inflammatory AAA embolism
o Peri-aortic fibrosis with • Compression of adjacent structures
infiltration by lymphocytes,
plasma cells, and macrophages.
o Unknown cause
• Mycotic AAA
o Lesions are infected by
circulating microorganisms
o Suppurative causes media
damage
Pathogenesis
• Tunica media is damaged by

atherosclerosis or infection.
• Tunica media is weakened and thins
• Dilation due to intravascular pressure
• Eventually will rupture
Gross: Dilation of the abdominal aorta, between the renal arteries and the common iliac artery bifurcation.

Cardiovascular 60
- Dilation of the abdominal aorta
- Between renal arteries and
Syphilitic Aortitis is similar to AAA, common iliac bifurcation
however the location is closer to the aortic root - Atherosclerosis, infections
and is associated with aortic valvular - Tunica media damage
regurgitation. It will also have a long history of - Risk of rupture
syphilis. - Downstream ischemia
Aortic Dissection also involves the

aortic wall and has a risk of rupturing. The
differences are more pathogenesis and location.
Type B is also in the abdomen, but the more
common Type A is near the aortic root. Aortic
dissection also has the characteristic chest pain,
starting anteriorly and radiating to the back.
Additional Info
Treatment is surgery if aneurysm is ≥5cm
• Unruptured have 5% mortality
• Ruptured have >50% mortality

Cardiovascular 61
Syphilitic Aortitis
Aneurysm of the ascending aorta due to
a chronic syphilitic infection. Signs & Symptoms
Etiology • Dyspnea
• Difficulty swallowing
• Persistent cough
Tertiary syphilis due to infection with
• Chest pain
Treponema pallidum.
• Syphilitic rashes, ulcerations, CNS
symptoms
Pathogenesis
Murmur: Aortic regurgitation
• Inflammation of the adventitia and

hyperplasia of vasa vasorum
• Lumen narrowing of vasa vasorum
• Ischemia of aortic tunica media
• Inflammation and scarring
• Aortic aneurysm formation in the
ascending aorta followed by the aortic
arch.
• Aortic valve ring dilation causing
valvular insufficiency (aortic
regurgitation)
• Extreme hypertrophy of left ventricle,
called cor bovinum (cow’s heart)
• Encroachment of mediastinal
structures, causing respiratory
difficulties, difficulty in swallowing, and
persistent cough due to compression of
the recurrent laryngeal nerve.
• Erosion of the ribs or vertebrae cause
pain
Gross: This is a heart with the aortic root massively dilated and cut open to expose the interior vessel wall.

Cardiovascular 62
- Tertiary syphilis
- Narrowing of vasa vasorum lumen
• Rupture of the aneurysm - Ischemia of tunica media
• Heart failure (most common cause of - Inflammation, scarring, and thinning
death) - Dilation of ascending aortic
- Compression of surrounding structures
- Aortic regurgitation
Differentials - Left sided CHF
- Cor bovinum (massive hypertrophy)
AAA is similar to syphilitic aortitis,
however in AAA the location is in the abdomen.
There will be no aortic regurgitation or any of
the compression or CHF symptoms.
Aortic Dissection Type A occurs in the

same location and both have risks of rupture.
They both have compression symptoms,
valvular dysfunction, and chest pain. The big
differentiation here is history, with AD having
hypertension, pregnant, or a genetic cause and
SA having prior syphilis infection.

Cardiovascular 63
Aortic Dissection
The presence of blood within the walls
of the aorta. Signs & Symptoms
60 years of age
Most common in men 40-60
• Sudden onset of excruciating pain that
starts in the anterior chest and radiates
Etiology to the back and downwards.
wnwards.
• Loss of arterial pulses
• Hypertension • Syncope
• Marfan’s Syndrome (earlier
rlier onset) • Compression
o Defect in fibrillin (elastic fiber) o Persistent cough
• Ehlers-Danlos Syndrome (earlier onset) o Difficulty swallowing
o Defect in Type I & III collagen • Aortic valve dysfunction
synthesis
• Arterial cannulation – catheterization or Complications
cardiopulmonary bypass
• Pregnancy
• Rupture and massive hemorrhaging
• Retrograde dissection into aortic valve
Pathogenesis causing valvular dysfunction.
• Cardiac Tamponade
• ood to enter the
Intimal tear allows blood • Aortic insufficiency
vessel wall. • MI
o Surface defect
• Blood separates the inner 2/3 of aorta
from the outer 1/3.
• Can rupture into the surrounding
cavities or back into the aorta, called a
“double barreled” aorta.
2 types of Aortic Dissections:

• A starts at the ascending
scending aorta
o Most common and dangerous
• B does not involve the ascending aorta
o Usually begins distal to the
subclavian artery
Histology:: Blood is found within the tunica media (red), creating a false lumen.

Cardiovascular 64
- Blood in the aortic wall
- Marfan’s & Ehlers-Danlos Syndromes
AAA is can be in a similar location to - Double Barreled Aorta
Type B Aortic Dissection, and both have - Risk of rupture
dilation. Aortic dissection is more likely to be - Chest pain that starts anterior and
Type A and in the ascending aorta. Both have radiates back
risk of rupture. The differences come into the - Type A is ascending aorta ± more
pathogenesis and history. AD will have a history - Type B is descending aorta only
with hypertension, pregnant, or a genetic
cause, where AAA is more hypercholesteremia
or other atherosclerotic risk factors or
infections.
Syphilitic Aortitis will be in the same

location as Type A AD, and will have many of
the same presenting symptoms. Distinguishing
between the two is mostly that SA will have a
history of syphilis.

Cardiovascular 65
Berry Aneurysm
Outpouching aneurysm located within Risk Factors
the circle of willis, usually at bifurcations. Also • Old Age
called Saccular aneurysms. • Smoking
• Hypertension
Common locations:
• Diabetes
• ACA/Anterior Communicating (40%)
• Africans
• Middle Cerebral Artery (34%)
• Posterior Communicating (20%)
• Basilar/PCA (4%) Pathogenesis
Etiology • Defect in vascular wall

• Increased hydrostatic pressure
• Directional dilation and pouch
Congenital defects in the vascular walls
formation
that develop over time.
• Rupture
Associated with: o Increased intracranial pressure
• Cystic medial necrosis o Straining bowel movement
• Marfan’s Syndrome o Sex
• Ehlers-Danlos Syndrome • Subarachnoid hemorrhaging
• Polycystic Renal Disease
• Coarctation of the Aorta
Gross: A berry aneurysm is a thin walled out pouching of the arterial wall. There is no muscular wall or
intimal elastic lamia in the aneurysm. The adventitia is continuous with the normal arterial adventitia.

Cardiovascular 66
Signs & Symptoms Highlights

- Out pouching of arterial wall
- Commonly at bifurcations in the
Aneurysm itself is asymptomatic Circle of Willis
- Most common at the ACA/Anterior
Subarachnoid hemorrhaging has: Communication bifurcation
• Extreme headache - Associated with Marfan’s and
• Loss of consciousness Ehlers-Danlos
- Risk of rupture and subarachnoid
hemorrhaging.
Complications
Rupture and subarachnoid hemorrhaging
Differentials
AAA and aortic dissections both also
have a risk of rupture, however they occur in
very different locations and their dilation
schemes are different. AAA has luminal
dilation, AD expands into the surrounding area,
and Berry aneurysms out pouch in a
unidirectional way. Also, berry aneurysms are
completely asymptomatic until rupture,
whereas AAA at least has the pulsating
abdomen.

Cardiovascular 67
Myocardial Infarction
Ischemic Heart Diease, commonly called Labs/Markers:
a heart attack. • Troponin I – “Gold Standard”
o Rises 2-4 hours post event
Etiology o Peaks at 48 hours
o Returns to normal in 7-10 days
• CK-MB
Coronary Artery Occlusions o Re-infarctions
• Acute coronary artery thrombosis o Rises 4-6 hours post event
• Atherosclerosis o Peaks at 24 hours
• Vasospasms o Returns to normal by 72 hours
• Emboli
• Vasculitis Complications
Pathogenesis Dressler’s Syndrome
• Secondary pericarditis
• Occlusion of a coronary artery • Fever, pleuritic pain, and pericardial
• Reversible damage for the first 20 effusion
minutes
Rupture of myocardium – Cardiac Tamponade
• Myocyte coagulative necrosis
• Starts as subendocardial necrosis (<50% Rupture of septum – left to right shunt
of myocardial thickness). This gives a
depressed ST-segment on ECG. Rupture of papillary muscle – valvular
• Progresses to transmural necrosis, insufficiency
which give the elevated ST-segment on
Aneurysm – mural thrombi
ECG.

Angina, just the radiating chest pain, is
• Crushing chest pain that radiates to the also due to ischemia, but not enough to cause
left arm or jaw myocardial destruction. Is often recurrent and
• Diaphoresis (excessive sweating) can be classified as stable or unstable
• Dyspnea (progressively worsening, high MI risk). The
cardiac markers will not be elevated.
Aortic Dissection can start as intense

chest pain, which may be mistaken for a MI.

Cardiovascular 68
However, it will radiate to the back, unlike an

MI. The cardiac markers will not be elevated.
Syphilitic Aortitis presents similarly

with the chest pain and dyspnea, although it
also can present with a persistent cough or
dysphagia. Also, the cardiac markers will not be
elevated.
There are many things can cause chest

pain, so don’t just jump to MI. In practice, you
will have to rule this out first, but here look for
other symptoms or given details that will be
invaluable in distinguishing between them.

Cardiovascular 69
< 20 Minutes
Gross: Normal
Micro: Reversible Damage
Normal Cardiac - Histology – Term 1 – Fall 2011
20 Minutes – 4 Hours
Gross: Normal
Micro: Irreversible Damage
Complications: Shock, arrhythmias
4 – 24 Hours
Gross: Dark Mottling
Micro: Coagulative Necrosis. Monocyte
hypereosinophilia. Contraction bands.
1 – 3 Days
Gross: Mottling with yellow pallor
Micro: Neutrophil infiltration. Loss of nucleus
Complications: Fibrinous pericarditis
(transmural only).
4 – 7 Days
Gross: Mottling with yellow pallor
Micro: Macrophage infiltration
Complications: Rupture of ventricular wall
and cardiac tamponade. Mitral insufficiency

Cardiovascular 70
7 – 10 Days
Gross: Yellow with red borders
Micro: Fibrovascular granulation tissue
Complications: Aneurysm or mural
thrombus
10 – 14 Days
Gross: Red-grey with depressed borders
Micro: Established granulation tissue with
blood vessels.
Complications: Aneurysm or mural
thrombus
2 – 8 Weeks
Gross: Grey-white scar
Micro: Increased collagen and loss of
cellularity
> 2 Months
Gross: Complete scar
Micro: Dense collagen scar

Cardiovascular 71
Rheumatic Myocarditis
A Type II hypersensitivity (antibody Alternatively, may have one of the previous and
mediated) reaction against the heart, skin, and two minor manifestations:
joints following a strep throat infection. • Fever
Commonly seen in children between 5 and 15. • Arthralgia
Composed of acute symptoms and years later • Elevated acute phase reactants
development of chronic symptoms.
Complications
Etiology
Pancarditis
Post-streptococcal Type II Hypersensitivity. • Myocarditis
o Fibrosis
Pathogenesis o Mitral insufficiency
• Pericarditis
o Fibrinous or serofibrinous
• Initial infection with Group A exudate
streptococcus • Endocarditis
• Antibody formation against M protein o Valve fibrinoid necrosis and
• Cross reaction with glycoprotein in ECM vegetations
of the heart, skin, and joints.
• Symptoms arise about 2-3 weeks after Chronic Rheumatic Heart Disease
the initial infection. • Scarring of myocardium
• Damage is healed via fibrosis • Valvular stenosis & regurgitation
• Years after acute RHD, chronic RHD o Most commonly the mitral
symptoms begin to appear. valve
o Most common cause of mitral
stenosis
• Shortening, thickening, and fusion of
Signs & Symptoms chordae tendineae
o “Fish mouth” stenosis
Jones Criteria: Serological evidence of a prior

streptococcal infection and two or more of:
Differentials
• Carditis
• Migratory polyarthritis of large joints Calcific Aortic Stenosis is a normal
• Subcutaneous nodules degenerative process which had calcium
• Erythema marginatum of skin deposits on the aortic valve. It may result in left
• Sydenham chorea sided congestive heart failure, which is when it

Cardiovascular 72
would start being symptomatic. It will only stay Viral Myocarditis is an infection of the
in the aortic valve, whereas RHD is mainly in th
the myocardium, which RHD can also als infect. It is
mitral valve. Also, RHD can do both stenosis usually asymptomatic but with serious
and regurgitation whereas calcific aortic complications such as CHF and dilated
stenosis is just stenosis. cardiomyopathy. To differentiate, viral
myocarditis will be associated with a viral
Libman-Sacks
Sacks Endocarditis is a infection, most likely Coxsackie A & B.
complication of SLE with vegetation formation
on the leaflets of any valve but usually affects
the mitrall valve. It can cause regurgitation or
sometimes stenosis. The main differentiator
here is the history, with LSE having SLE and RHD
having prior streptococcus infection.
Mitral Valve Prolapse will also present

with mitral regurgitation, but a distinguish
distinguishing
feature is a midsystolic click. Also, MVP is
associated with Marfan’s and Ehlers
Ehlers-Danlos
Syndromes.
Infective Endocarditis is infections of

the valves with vegetations, and may present
with murmurs. However, this has many other
distinguishing symptomss such as Janeway
lesions, Roth spots, Osler nodes, or splinter
hemorrhages. There is also a connection with
prosthetic heart valves, so any indication of
such is more likely to be IE.
Histology:: Acute RHD that contains an Aschoff body,, which is a central zone of degraded hypereosinophilic
ECM with lymphocytes and plumb macrophages called Anitschkow cells,, which has central nuclei with ribbon
chromatin.
Gross: Both are of chronic RHD. (Left) Shows fibrosis of mitral valve and fusion of the chordae tendineae.
(Right) Shows vegetations on mitral with thickening and fusion of the chordae tendineae.

Cardiovascular 73
Calcific Aortic Stenosis

Calcification and vegetation of the aortic valve.
Signs & Symptoms
Etiology
• Initially asymptomatic (latent period 10-
20 years)
Senile Calcific Aortic Stenosis
• Angina
• Normal aging process
• Syncope
• Manifests 70-80s
• Congestive Heart Failure Symptoms
Calcification of Congenitally Deformed Valve o Dyspnea, Fatigue, etc
• Bicuspid Aortic Valve
Auscultation: Systolic crescendo-decrescendo
• Manifests 40-50s
murmur in right 2nd intercostal space.
ECG: Arrhythmias
Pathogenesis
• Mechanical stress by repeated use,

Differentials
wear and tear. This causes calcification
and fibrosis. Rheumatic Heart Disease scarring can
• Valve orifice compromised up to 70- also cause aortic stenosis with vegetations.
80% by mechanical obstruction. However, RHD usually targets mitral valve and
• Increased left ventricular pressure. can also affect the aortic valve. It will often
• Left ventricular concentric hypertrophy cause both stenosis and regurgitation.
to maintain cardiac output.
Libman-Sacks Endocarditis may cause
• Angina (ischemia) with hypertrophy.
vegetation of the aortic valve, or any valve but
• Syncope with hypoperfusion
usually also the mitral valve. This is a
manifestation of Systemic Lupus
Erythematosus. (LSE in SLE)
Metastatic Calcification can also cause

calcium deposits on the aortic valve. However,
there will be markedly increase serum calcium
and generalized calcium deposition.
Gross Aortic Valve: Heaped nodular calcified growths located within the cusps of the aortic valve. The valve
itself appears to have a bicuspid deformity, due to the presence of only two cusps and a raphe in the larger
of the two.

Cardiovascular 74
Mitral Valve Prolapse

Mitral valve balloons back into the left
atrium during systole. Sometimes will also Signs & Symptoms
affect the tricuspid, and occassionaly also the
aortic and pulmonary valves. Also called
• Asymptomatic
primary myxomatous mitral degeneration.
• Palpitations
Relatively common, affecting 3-5% of • Fatigue
the US. More common in women at 7:1. • Dyspnea
• Atypical Chest Pain
Etiology Auscultation: Midsystolic click
• Idiopathic Complications
• Common in Marfan’s syndrome and
Ehlers-Danlos syndrome.
• Mitral regurgitation
• CHF
Pathogenesis o Rupture of chordae tendineae
• Infective Endocarditis
• Ventricular arrhythmias
• Underlying intrinsic defect
o Sudden death
• Thinning of the fibrosa of the valve
• Deposition of mucoid material in
spongiosa Differentials
• Loss of leaflet integrity
• Enlarged mitral valve cusps, ballooned
Rheumatic Heart Disease may also
• Chordae tendineae may rupture
cause mitral regurgitation. It will have a history
of streptococcus infection and will not have a
midsystolic click.
Infective Endocarditis is infections of

the valves with vegetations, and may present
with murmurs. However, this has many other
distinguishing signs such as Janeway lesions,
Roth spots, Osler nodes, or splinter
Gross: Mitral valve leaflets are weakened and floppy, which will ballon back into the left atrium during
systole. They are also enlarged, rubbery, and thick. The chordae tendineae are elongated, thin, and have
the potential to rupture.

Cardiovascular 75
hemorrhages. There is also a connection with

prosthetic heart valves, so any indication of
such is more likely to be IE. Also won’t have a
midsystolic click.
Histology: Movat’s Stain (Left) Normal mitral valve. (Right) Primary Myxomatous mitral degeneration, with
the blue being mucoid deposits and yellow is collagen. The deposition of mucoid is located within the
middle spongiosa layer.

Cardiovascular 76
Infective Endocarditis
Infection of cardiac valves and formaion
of vegetations. Pathogenesis
Acute or subacute
• Acute – normal heart Infection establishes itself in the
• Subacute – abnormal heart endocardium.
Due to the high flow of blood and

Etiology relatively low diffusion into the valves, there is
little to no immune response and antibiotics
have little effect.
Native Valve
• Streptococcus viridans (50-60%)
o Abnormal valve
• Staphylococcus aureus (10-20%) Signs & Symptoms
o Normal valve
• HACEK Group: Haemophilus,
Actinobacillus, Cardiobacterium, • Splinter hemorrhages
Eikenella, Kingella • Janeway lesion
• Roth spots
Prosthetic Valve • Osler nodes
• Staphylococcus epidermidis • Mycotic embolism
Intravenous Drug Abuse • Changing murmur
• Staphylococcus aureus • Clubbing of fingers
o Tricuspid valve Acute
Fungal or Rickettsial • Abrupt onset
• High Grade Fever, Chills, & Malaise
Risks • High virulence
• Pre-existing cardiac abnormality • Ring Abcess
o Mitral valve prolapse
o Chronic rheumatic valvulitis Subacute
o Calcific Aortic Stenosis • Low grade fever & flu-like symptoms
• Prosthetic heart valves • Weight loss
• IV drug abusers • Splenomegaly
• Transient bacteremia • Granulation tissue
o Dental procedures • Low virulence
o Urinary catheterization
o endoscopy

Cardiovascular 77
Complications
Rheumatic Heart Disease also causes
vegetations with an infection, but in RHD it is
• Glomerulonephritis post-streptococcal infection so the microbe
• Septicemia cannot be isolated. RHD may also present with
• Arrhythmia arthritis or subcutaneous lesions. IE would have
• Systemic embolization the CV peripheral signs.
Mitral Valve Prolapse is a condition

Differentials that has the ability to form murmurs,
specifically mitral regurgitation. However, this
Nonbacterial Thrombotic Endocarditis is usually asymptomatic with the presence of a
is the presence of sterile vegetations. This is midsystolic click. Keep in mind, MVP increases
usually asymptomatic. Increases the risk of IE the risk of IE.
Calcific Aortic Stenosis can also develop

vegetations on the aortic valve, but there are
composed of calcium and occur in many elderly
people. A bicuspid deformity is typically seen in
this, but it could also increase the risk of IE.
Distinguishing features include the ability to
culture a specific pathogen, fever, the CV
peripheral signs (Roth spots, etc), or the
presence of a prosthetic valve all indicate IE.
Gross: (Left) Mitral valve with large vegetations at the closure of the leaflets. (Right) Prosthetic valve with
vegetations surrounding it.

Cardiovascular 78
Viral Myocarditis
Viral infectoin of the myocardium, most
likely by Coxsackievirus A or B and is often self Complications
limiting with no squelae.
• Arrhythmia
Etiology • CHF
• Dilated cardiomyopathy
• Coxsackievirus A & B
• CMV Differentials
• HIV
• Influenza May mimic a Myocardial Infarction
with similar chest pain. Cardiac enzymes will be
Pathogenesis elevated in both, but very mildly. A viral titer
can help in differentiating the two.
Myocyte damage by three mechanisms: Giant Cell Myocarditis is an

• Direct viral damage autoimmune disorder, associated with SLE &
• CD8+ Cell mediated killing thyrotoxicosis, with the formation of
• Cross-reactive antibodies granulomatous inflammation in the
myocardium. It is rapidly fatal. The etiology
and severity are the main differences here.
Signs & Symptoms
Parasitic Myocarditis is infection with
trypanosomes/cysts and eosinophilic
• Asymptomatic
infiltration. Pathogens include Trypanosoma
• Fatigue
cruzi (Chagas) or Trichinella spiralis (Trichinosis).
• Dyspnea
Clues for differentiation are eosinophils on
• Palpitations biopsy, history of travel to South America
• Flu-like symptoms (Chagas), or have cysts in their muscles
• Chest pain (Trichinosis).
Labs: Elevated TnI and CK-MB
Histology: Viral myocarditis has infiltration with

lymphocytes and focal necrosis in the affected
areas.

Cardiovascular 79
Dilated Cardiomyopathy
Primary disease of myocardium with
dilation of all chambers with hypertrophy. Complications
Usually occurs between 20 and 50 years of age.
Most common cardiomyopathy.
• Congestive Heart Failure
• Mural Thrombus & Embolization
Etiology • Arrhythmias
• Idiopathic Differentials
• Alcohol cytotoxicity
• Genetic mutations
Hypertrophic Cardiomyopathy also has
o Dystrophin (X-chromosome) an enlarged heart; however the ventricles
o Mitochondrial genes themselves are not dilated. The etiologies are
• Coxsackie Virus A and B also different. The murmurs are slightly
• Thiamine Deficiency different, with HCM having a harsh systole
• Pregnancy Associated murmur and DCM having mitral regurgitation
(also during systole).
Pathogenesis Restrictive Cardiomyopathy also has an
enlarged heart, but without the hypertrophy
• Progressive hypertrophy of myocytes and is usually restricted to just dilation of the
• Interstitial fibrosis atriums. This isn’t always the case so it’s not a
• Contractile dysfunction great differentiator. Look to differences in the
• Congestive Heart Failure etiology.
Signs & Symptoms
• Shortness of breath
• Exertional dyspnea
• Slow progression
• Mitral regurgitation
• Ejection fraction < 25% (50-65%)
Gross: All chambers are dilated and there is

hypertrophy of the walls. The arrow shows a mural
thrombus.

Cardiovascular 80
Hypertrophic Cardiomyopathy
Primary disease of myocardium with
hypertropy of the heart without dilation. A Signs & Symptoms
common cause of sudden death in young
athletes.
• Angina
Etiology • Harsh systolic ejection murmur
• Near normal ejection fraction
• Idiopathic
• Autosomal dominant Complications
o Missense mutation in
sarcomeric proteins
• MI
o β-myosin heavy chain (most
• Arrhythmias – Sudden death
common)
• Infective Endocarditis
o Myosin binding protein C
• Syncope with exercise
o Cardiac troponin T
o Functional aortic stenosis due
to hypertrophy of the
Pathogenesis ventricular septum.
• Ineffective contraction Differentials

• Release of growth factors
• Compensatory asymmetric hypertrophy
Secondary Hypertrophy due to
with myocytes and fibrosis.
Hypertension will have concentric hypertrophy
o Hypertrophy of the left
in response to chronic elevated pressures.
ventricle and ventricular
There may be reduction in the ventricle cavity.
septum
The main differences are no ventricular septum
• Loss of compliance due to fibrosis
hypertrophy and the etiology. Therefore,
• Impaired ventricular filling and ejection
hypertensive hypertrophy will not have the
fraction
harsh ejection murmur.
• Increased demand of oxygen and
nutrients, therefore ischemia Dilated Cardiomyopathy also has an
• Reduced stroke volume enlarged heart; however the ventricles are both
hypertrophic and dilated. The etiologies are
also different. Some key differences are HC is
mostly due to β-myosin heavy chain mutations
whereas DCM is more alcohol induced or
secondary to viral myocarditis. The murmurs

Cardiovascular 81
are slightly different, with HCM having a harsh

systole murmur and DCM having mitral
regurgitation (also during systole).
Restrictive Cardiomyopathy doesn’t

have hypertrophy so much as atrial dilation, but
the etiology is somewhat similar with impaired
ventricular compliance and filling. The
presentations are similar, so look for the atrial
dilations on CXR but keep in mind that RC
doesn’t also have just atrial dilation.
Differences in etiology are key here.
Gross: Hypertrophy of the ventricular septum without ventricular dilation. The ventricular chamber looks
like a “banana.”

Cardiovascular 82
Restrictive Cardiomyopathy
Primary diseases of myocardium that • Biopsy
has an enlargd flabby heart with loss of • ECG
compliance and dilation in both atria, but can
be all 4 chambers.
Complications
Etiology
• CHF
• Arrhythmias – Sudden Death
• Endomyocardial fibrosis (most
common)
o Children/young adults
Differentials
o Africa
• Loeffler endomyocarditis Dilated Cardiomyopathy will also have
o Hypereosinophilia the dilated chambers, although more likely to
• Radiation fibrosis be all of them. Also is accompanied by
• Amyloidosis hypertrophy. A very low ejection fraction is a
• Hemochromatosis good hint for DC, where just dilated atrium is a
• Metastasis good indicator for RC. Look at the etiologies, as
they will have the most distinguishing features.
Pathogenesis Hypertrophic Cardiomyopathy has the

enlarged heart, with hypertrophy but not
dilation. They do have similar pathogenesis
• Loss of ventricular compliance
with impaired ventricular filling. A good
• Impaired ventricular filling
differentiator is the harsh systolic murmur in
• Systemic hypoxia
HC. Otherwise look to the etiologies.
Signs & Symptoms
• Chest pain
• Arrhythmias
Gross: Enlarged heart with dilation in the atriums, although enlargement of all four chambers is possible.
The myocardium is firm due to fibrosis.

Cardiovascular 83
Tetralogy of Fallot
Congenital heart deformitity with four
characterized components: Complications
• Pulmonary stenosis
• Ventral Septal Defect • Infective Endocarditis
• Overriding Aorta • Pulmonary regurgitation
• Right ventricular hypertrophy • Paradoxical emboli
• Sudden cardiac death
Etiology • Stroke thrombi (polycythemia)
• Di George Syndrome
JAG1, NOTCH2
•
Differentials
Pathogenesis VSD is a component of ToF, but is
commonly found by itself. This is more a
• Anterosuperior displacement of the disease of infants or young children, and tends
infundibular septum to resolve on its own. It is a left-to-right shunt
• Abnormal division of the pulmonary when by itself, so no cyanosis. It can lead to
trunk and the aortic root. cardiomegaly and right sided CHF. Eventually
• Right to left shunt – cyanosis can become cyanotic it develops into an
Eisenmenger’s Complex.
Persistent Truncus Arteriosus is where

the truncus arteriosus fails to divide into the
Signs & Symptoms pulmonary trunk and aorta. Presents with VSD
and cyanosis as both ventricles need to pump
• Cyanosis into the same vessel. It is also associated with
• Exertional Dyspnea Di George Syndrome. Difference is detected on
• Stunted growth echo or US.
• Polycythemia Tricuspid Atresia is the complete
• Squatting to increase venous return occlusion of the tricuspid valve. Needs both
XR: Boot shaped heart ASD and VSD to bypass. Patient will be cyanotic
with RV hypoplasia and an enlarged mitral
Pulse oximetry valve. Has a high mortality rate. Is
differentiated with CXR, US, or echo to detect
ECG
the RV hypoplasia.

Cardiovascular 84
Transposition of the Great

Vessels is where the pulmonary and
aortic vessels are switched. Usually
incompatible with life unless there is
also an ASD. Is also cyanotic.
Lucile Packard Children’s Hospital: Ipch.org
Gross: Heart with pulmonary stenosis, a ventricular septal defect, overriding aorta, and right ventricular
hypertrophy.

Cardiovascular 85
Ventricular Septal Defect

Congenital heart defect in the
ventricular septum allowing for blood to flow Complications
between them as a left-to-right shunt. Is non-
cyanotic and is the most common congenital Eisenmenger’s Complex
heart defect.
• Reversal of shunt, cyanosis
• Due to increased pulmonary
Etiology hypertension as right side pressure
exceeds the left side pressure.
• Trisomy 13, 18, 21 Increased risk for infective endocarditis.

• Tetrology of Fallot
Fetal Alcohol Syndrome
•
Differentials
Pathogenesis ASD is a defect in the atria in a left-to-
right manner. This is usually asymptomatic until
Failure of ventricular septum fusion of adulthood. Difficult to differentiate based on
the intraventricular muscular ridge (grows presentation alone, other than the age of onset
upward from the apex) with the thinner with ASD more in adults. The etiologies are also
membranous portion that grows downward different, which is useful in differentiating.
from the endocardial cushion. Atrial fibrillation is also an indicator for ASD.
Most will close spontaneously during Patent Ductus Arteriosus is the failure
childhood. of the ductus arteriosus to close, allowing blood
to flow from the aorta to the pulmonary
arteries. Usually asymptomatic unless shunt
Signs & Symptoms reverses causing cyanosis. Can be detected
with a “machinery-like” murmur.
• Pansystolic heart murmur
Tetralogy of Fallot includes a VSD, but
• Pulmonary hypertension
is cyanotic and also has parts including an
• CHF
overriding aorta and pulmonary stenosis.
CXR: Cardiomegaly
Gross: VSD is located in the membranous

interventricular septum. Can also be in the
muscular septum (10%)

Cardiovascular 86
Atrial Septal Defect

Congenital defect in the arital septum
allowing blood to flow between them as a left- Complications
to-right shunt. Most common heart defect
found in adults.
• Paradoxical emboli
Can be of Secundum (90%) or Primum (5%) • Infectious endocarditis
types.
Eisenmenger’s Complex
• Reversal of shunt, cyanosis
Etiology • Due to increased pulmonary
hypertension as right side pressure
exceeds the left side pressure.
• Idiopathic
• Ostium primum type associated with
down syndrome Differentials
Pathogenesis VSD is a left-to-right shunt in the
ventricular septum. Presents similarly, so look
to age of onset with VSD more in children. The
• Ostium primum: septum primum and
etiologies are also different, which is useful in
endocardial cushion fail to fuse.
differentiating. Atrial fibrillation on ECG is also a
• Ostium secundum: septum secundum
good indicator for ASD.
fail to cover ostium secundum
Patent Ductus Arteriosus is the failure
of the ductus arteriosus to close, allowing blood
Signs & Symptoms to flow from the aorta to the pulmonary
arteries. Usually asymptomatic unless shunt
• Asymptomatic until adulthood reverses causing cyanosis. Can be detected
• Left-to-right shunt with a “machinery-like” murmur.
Auscultation: Wide fixed split S2 heart sound

• Delays closure of pulmonary valve
ECG: Atrial fibrillation
Gross: Atrial septum, typed on location as

secundum or primum. Secundum is higher,
primum is lower.

Cardiovascular 87
Vignettes
1) Maryanne, a 72 year old female, comes into most likely pre-disposing factor for Jack’s
your office for a normal check-up. She has a condition?
long history of diabetes and moderate
hypertension. Which of the following would a) Smoking
not be likely seen if you were able to look at b) Hypertension
c) Intimal tear
histological slides of her arterioles?
d) Atherosclerosis
a) A narrow lumen e) Treponema pallidium infection
b) Loss of structural details
c) Thickened vessel walls
d) Fibrinoid necrosis 4) Andrea has mild chest pain and flu-like
e) Homogenous pink staining symptoms. Coxsackievirus B was detected.
What is the most likely complication?
2) Andrea, a 47 year old female, comes to your
office complaining of chest pain, episodes of a) Giant Cell Myocarditis
fainting, and has difficulty breathing if she b) Dilated cardiomyopathy
exerts herself. She has no history of a c) Restrictive Cardiomyopathy
Streptococcus infection. On auscultation of the d) Vasculitis
right 2nd intercostal space you hear a murmur e) MI
after the first heart sound that has a crescendo-
decrescendo pattern. You perform an
echocardiogram, which tells you that there is 5) Bill was at home watching TV with his wife
left ventricle hypertrophy. What is the most Ronnie, when he complained about a severe
likely underlying cause of Andrea’s symptoms? headache. He went to bed to “sleep it off” and
was found dead the following morning. Bill was
a) Rheumatic Heart Disease 72, smoked, and had a history of hypertension
b) Atherosclerosis of the coronary arteries and diabetes. There was no recent history of
c) Mitral valve stenosis head trauma. On autopsy it is found that he
d) Pulmonary embolism suffered hemorrhaging of the parenchyma.
e) Aortic valve bicuspid deformity Where did the hemorrhage most likely originate
3) Jack is an elderly man who presents with from?
chest pain, dyspnea, and difficulty eating. On a) Bifurcation of the Anterior
examination you note a murmur typical of Communicating and ACA
aortic regurgitation. You take a chest xray and b) Middle Meningeal Artery
find that his heart is massively enlarged, which c) Bifurcation of the Posterior
you call “cor bovinum,” and that the aortic root Communication and MCA
lumen is massively dilated. If you were able to d) Middle Cerebral Artery
biopsy the aorta you would find the lumen of e) Bridging Veins
the vasa vasorum to be narrowed. What is the

Cardiovascular 88
6) Mabel has recently had a prosthetic mitral 9) Martin comes into the ED with severe chest
valve to correct a severe mitral valve prolapse. pain that goes into his left arm and he is
She has developed a fever and flu-like profusely sweating over the past hour. Blood
symptoms. A cardiac endoscope shows tests show elevated troponin I and CK-MB.
vegetations around the prosthetic valve. What Martin is an obese man with a long time history
is the most likely etiologic agent? of hypertension and uncontrolled
hypercholesteremia. He is admitted and kept
a) Cardiobacterium
under observation. On the 11th day, he passed
b) Streptococcus viridans away suddenly due to a mural thrombus. What
c) Staphylococcus aureus will be the most prominent feature of Martin’s
d) Staphylococcus epidermidis
heart histology on autopsy?
e) Actinobacillus
a) Dense collagen scar
7) Kaya is a 24 year old Japanese woman with
b) Fibrovascular granulation tissue
headaches, fatigue, pain in her fingers and c) Contraction bands
while walking. You suspect a vasculitis so you d) Neutrophil infiltration
perform an angiogram and find narrowing and
e) Myocytes without a nucleus
fibrosis of the aortic arch at the base of the
great vessels. This fibrosis causes a
characteristic sign of Kaya’s disease. What
other disease shares this sign? 10) Drew is a 43 year old that comes in with
ulceration of his nasal mucosa. His sinuses are
a) Buerger’s Disease painful, and he has a cough. His CXR shows
b) Polyarteritis Nodosa cavitations in his lungs. He is positive for c-
c) Kawasaki Disease ANCA and his labs indicate renal insufficiency.
d) Temporal Arteritis You biopsy his kidneys. What are you likely to
e) Wegener Granulomatosis see on a histological slide of this biopsy?
a) Antibody complex deposition

b) Antibody mediated destruction
8) Andrew presents with sudden excruciating c) Crescentic glomerulonephritis
chest pain that moved to his back and fainted
d) Bence-Jones proteins
on the way to the ED. He has been coughing
e) Normal tissue
and hasn’t been eating. Andrew has a history of
Marfan Syndrome. You perform a CXR which
shows enlargement of the ascending aorta and
aortic arch. What else is Andrew likely to have
or is at risk of developing?
a) Myocardial Infarction
b) Temporal Arteritis
c) Mitral Valve Prolapse
d) Ulceration of the Ankles
e) Treponema pallidium infection

Cardiovascular 89
11) Renton has an abrupt onset of high grade

fever, malaise, and has splinter hemorrhages on
his fingernails as well as clubbing. He admits to
using heroine on a regular basis. A blood
culture is draw and Staphylococcus aureus is
isolated. You auscultate his heart and discover
a murmur. Where is the murmur best heard?
a) Left midclavicular 5th intercostal space

b) Left parasternal 5th intercostal space
c) Left parasternal 3rd intercostal space
d) Left parasternal 2nd intercostal space
e) Right parasternal 2nd intercostal space
12) Debra is a 32 year old woman whom

recently developed cyanosis. Her CXR shows
right sided hypertrophy and her ECG shows
some atrial fibrillation. On auscultation you
detect a split S2 heart sound. What is the most
likely pathogenesis for Debra’s condition?
a) Failure of septum primum to fuse to

endocardial cushion
b) Failure of septum secundum to cover
ostium secundum
c) Failure of ventricular septum to fuse
with intraventricular muscular ridge
d) Failure of the ductus arteriosus to close
e) Failure of the truncus arteriosus to
divide

Cardiovascular 90

1) (D) Maryanne, a 72 year old female, comes culprits include Calcific Aortic Stenosis and
into your office for a normal check-up. She has Rheumatic Heart Disease.
a long history of diabetes and moderate
hypertension. Which of the following would a) Rheumatic Heart Disease
not be likely seen if you were able to look at There is no history of a streptococcus
histological slides of her arterioles? infection, which is required for a diagnosis
of Rheumatic Fever and subsequently RHD.
Maryanne is asymptomatic, elderly, chronic
hypertensive, and diabetic. All of these are Also there is no involvement of the mitral
characteristic of Hyaline Arteriolosclerosis. valve.
Every answer except (d) is characteristic of this b) Atherosclerosis of the coronary arteries
disease process. Fibrinoid necrosis is a
characteristic of Malignant Hypertension which Would likely have a S4 gallop or mitral
presents with Hyperplastic Arteriolosclerosis regurgitation. Usually there is no aortic
and would have renal failure, retinal valve involvement. Otherwise is similar in
hemorrhaging, and/or papilledema. presentation.
a) A narrow lumen c) Mitral valve stenosis

b) Loss of structural details
The murmur is indicative of aortic stenosis,
c) Thickened vessel walls
not mitral valve, given both by the sound
d) Fibrinoid necrosis (Correct)
and location. In addition, mitral valve
e) Homogenous pink staining
stenosis would not cause LV hypertrophy.
2) (E) Andrea, a 47 year old female, comes to
d) Pulmonary embolism
your office complaining of chest pain, episodes
of fainting, and has difficulty breathing if she Would present with right sided hypertrophy,
exerts herself. She has no history of a not the left.
Streptococcus infection. On auscultation of the
right 2nd intercostal space you hear a murmur e) Aortic valve bicuspid deformity
after the first heart sound that has a crescendo- (Correct)
decrescendo pattern. You perform an
Note Andrea’s age, which would help
echocardiogram, which tells you that there is
differentiate a bicuspid deformity from
left ventricle hypertrophy. What is the most
Senile Calcific Stenosis.
likely underlying cause of Andrea’s symptoms?
Andrea has angina, syncope, and some signs of

congestive heart failure. She also has a systolic
murmur with a crescendo-decrescendo pattern,
which is typical of an aortic stenosis. Common

Cardiovascular 91
3) (E) Jack is an elderly man who presents with b) Dilated cardiomyopathy (Correct)
chest pain, dyspnea, and difficulty eating. On c) Restrictive Cardiomyopathy
examination you note a murmur typical of d) Vasculitis
aortic regurgitation. You take a chest xray and e) MI
find that his heart is massively enlarged, which
you call “cor bovinum,” and that the aortic root
lumen is massively dilated. If you were able to 5) (A) Bill was at home watching TV with his
biopsy the aorta you would find the lumen of wife Ronnie, when he complained about a
the vasa vasorum to be narrowed. What is the severe headache. He went to bed to “sleep it
most likely pre-disposing factor for Jack’s off” and was found dead the following morning.
condition? Bill was 72, smoked, and had a history of
hypertension and diabetes. There was no
Jack has an aortitis of the aortic root with its
recent history of head trauma. On autopsy it is
associated symptoms of compression and
valvular involvement. A key feature here is the found that he suffered hemorrhaging of the
vasa vasorum lumen being narrowed, which is parenchyma. Where did the hemorrhage most
indicative of Syphilitic Aortitis. likely originate from?
Bill had a ruptured berry (saccular) aneurysm, as

a) Smoking
noted by the severe headache, subarachnoid
Predisposing factor for many vascular hemorrhaging, and lack of head trauma.
disorders, but not really for SA.
a) Bifurcation of the Anterior
b) Hypertension Communicating and ACA (Correct)
Would be applicable for aortic dissections Most common location (40%)

and other conditions, but isn’t related to the
b) Middle Meningeal Artery
pathogenesis in Syphilitic Aortitis.
Common location for epidural hemorrhage
c) Intimal tear
with trauma
This would be for aortic dissections
c) Bifurcation of the Posterior
d) Atherosclerosis Communication and MCA
Would be applicable to aortic aneurysms Third most common location (20%)
e) Treponema pallidium infection d) Middle Cerebral Artery

(Correct)
Second most common location (34%)
4) (B) Andrea has mild chest pain and flu-like e) Bridging Veins
symptoms. Coxsackievirus B was detected. Common location for subdural hemorrhage
What is the most likely complication? with trauma
a) Giant Cell Myocarditis

Cardiovascular 92
6) (D) Mabel has recently had a prosthetic a) Buerger’s Disease (Correct)

mitral valve to correct a severe mitral valve b) Polyarteritis Nodosa
prolapse. She has developed a fever and flu-like c) Kawasaki Disease
symptoms. A cardiac endoscope shows d) Temporal Arteritis
vegetations around the prosthetic valve. What e) Wegener Granulomatosis
is the most likely etiologic agent?
8) (C) Andrew presents with sudden
a) Cardiobacterium excruciating chest pain that moved to his back
and fainted on the way to the ED. He has been
Uncommon native valve coughing and hasn’t been eating. Andrew has a
b) Streptococcus viridans history of Marfan Syndrome. You perform a
CXR which shows enlargement of the ascending
Most common abnormal valve aorta and aortic arch. What else is Andrew
likely to have or is at risk of developing?
c) Staphylococcus aureus
Andrew has an aortic dissection, but the main
Most common normal valve and IV drug
thing to note is that he has Marfan Syndrome.
users
None of these options is a complication of aortic
d) Staphylococcus epidermidis (Correct) dissection, but Mitral Valve Prolapse and Berry
Aneurysms are common in people with Marfan
Most common prosthetic valve Syndrome.
e) Actinobacillus a) Myocardial Infarction

b) Temporal Arteritis
Uncommon native valve
c) Mitral Valve Prolapse (Correct)
d) Ulceration of the Ankles
e) Treponema pallidium infection
7) (A) Kaya is a 24 year old Japanese woman
with headaches, fatigue, pain in her fingers and 9) (B) Martin comes into the ED with severe
while walking. You suspect a vasculitis so you chest pain that goes into his left arm and he is
perform an angiogram and find narrowing and profusely sweating over the past hour. Blood
fibrosis of the aortic arch at the base of the tests show elevated troponin I and CK-MB.
great vessels. This fibrosis causes a Martin is an obese man with a long time history
characteristic sign of Kaya’s disease. What of hypertension and uncontrolled
other disease shares this sign? hypercholesteremia. He is admitted and kept
under observation. On the 11th day, he passed
Kaya has Takayasu’s disease, with being a away suddenly due to a mural thrombus. What
young (<40) women of Japanese descent with will be the most prominent feature of Martin’s
generalized unspecific symptoms. The fibrosis heart histology on autopsy?
of the aortic arch is typical of Takayasu’s, which
leads to loss of pulse in the upper extremities. Martin had a MI, with a fairly typical
Of the diseases given, only Buerger’s disease is presentation and had elevated cardiac enzymes.
known to be pulseless in the UE & LE. The main focus of this question is the histology

Cardiovascular 93
timeline, specifically what would be present it is the tricuspid valve that is affected with IV
around day 10. drug abuse. The tricuspid is heard best at (B).
a) Dense collagen scar – >2 months a) Left midclavicular 5th intercostal space
b) Fibrovascular granulation tissue
(Correct) – 7-14 days Mitral valve (normally most affected in IE)
c) Contraction bands – Early first day b) Left parasternal 5th intercostal space
d) Neutrophil infiltration – 1-3 days
e) Myocytes without a nucleus – 1-3 days, Tricuspid valve
myocytes will be gone by 7-10 due to
c) Left parasternal 3rd intercostal space
macrophages
Erb’s Point (Cardiovascular)
10) (C) Drew is a 43 year old that comes in with
ulceration of his nasal mucosa. His sinuses are d) Left parasternal 2nd intercostal space
painful, and he has a cough. His CXR shows
cavitations in his lungs. He is positive for c- Pulmonary valve
ANCA and his labs indicate renal insufficiency.
e) Right parasternal 2nd intercostal space
You biopsy his kidneys. What are you likely to
see on a histological slide of this biopsy? Aortic valve
Drew has Wegener Granulomatosis with the 12) (B) Debra is a 32 year old woman whom
ulceration of the nasal mucosa and lung recently developed cyanosis. Her CXR shows
cavitations. A good indicator here is c-ANCA. right sided hypertrophy and her ECG shows
Wegener’s might have renal involvement, which some atrial fibrillation. On auscultation you
manifests as crescentic glomerulonephritis. detect a split S2 heart sound. What is the most
likely pathogenesis for Debra’s condition?
a) Antibody complex deposition
b) Antibody mediated destruction Debra has an ASD that has developed
c) Crescentic glomerulonephritis (Correct) symptoms due to the increased right side
d) Bence-Jones proteins pressure (Eisenmenger’s Complex). It is further
e) Normal tissue indicated by the atrial fibrillation and split S2
heart sound. Of the two types of ASD,
11) (B) Renton has an abrupt onset of high
secundum is by far the more common.
grade fever, malaise, and has splinter
hemorrhages on his fingernails as well as a) Failure of septum primum to fuse to
clubbing. He admits to using heroine on a endocardial cushion
regular basis. A blood culture is draw and b) Failure of septum secundum to cover
Staphylococcus aureus is isolated. You ostium secundum (Correct)
auscultate his heart and discover a murmur. c) Failure of ventricular septum to fuse
Where is the murmur best heard? with intraventricular muscular ridge
d) Failure of the ductus arteriosus to close
Renton is an IV drug abuser with infective
f) Failure of the truncus arteriosus to
endocarditis (Staphylococcus aureus). Typically
divide

Pulmonary 94
Pulmonary
General, COPD, ad Restrictive
Atelectasis 095
Acute Respiratory Distress Syndrome 096
Emphysema 098
Chronic Bronchitis 100
Bronchial Asthma 102
Bronchiectasis 105
Idiopathic Pulmonary Fibrosis 107
Sarcoidosis 110
Infections / Pneumonias
Pneumonia 112
Atypical Interstitial Pneumonia 115
Hemodynamic / Vascular / Process

Lung Abscess 117
Pulmonary Edema 118
Pulmonary Thromboembolism 119
Pulmonary Hypertension 121
Diffuse Pulmonary Hemorrhagic Syndromes 123
Neoplastic
Lung Adenocarcinoma 124
Adenocarcinoma in-situ 127
Squamous Cell Carcinoma of the Lung 129
Small Cell Carcinoma 131
Bronchial Carcinoid 133
Pulmonary Hamartoma 135
Metastasis to the Lungs 136
Vignettes 138
Answers & Explanations 141

Pulmonary 95
Atelectasis
Alveolar collapse and loss of lung volume. Compression Atelectasis
• Mechanical collapse
• Resorption ateletasis (aka Obstruction)
• Compression ateletasis Contraction Atelectasis
• Contraction atelectasis (aka • Fibrosis restricts expansion
Cicartrization)
The hypoxia and cyanosis is due to shunting
inadequately oxygenated blood back to the
Etiology heart creating a ventilation-perfusion
imbalance.
Resorption Atelectasis
• Bronchus obstruction by mucus or Signs & Symptoms
mucopurulent plug is most common
• Bronchial asthma
• Chest Pain
• Bronchiectasis
• Dyspnea
• Chronic bronchitis
• Tachycardia
• Foreign bodies
• Cyanosis
Compression Atelectasis • Fever – Low grade
• Mechanical pressure
PaO2: Low
• Fluid – Pleural Effusion
• Blood - Hemothorax Spirometry
• Air – Pneumothorax
Contraction Atelectasis
• Fibrosis
• Restrictive Lung Diseases
Pathogenesis
Resorption Atelectasis
• Obstruction prevents air from reaching
the distal airways.
Gross: The right lung is normal. The left lung is a deep red, shrunken, and the lobes are separated. This is
obstructive atelectasis in a baby whose left bronchi failed to form.

Pulmonary 96
Acute Respiratory Distress Syndrome

Diffuse uncontrolled inflammation of • Damage to epithelium and/or
the lung parenchyma in response to injury. endothelium
• Increased vascular permeability
Etiology • Alveolar flooding
• Edema & Hemorrhaging
Acute injury to lung epithelium.

Signs & Symptoms
Common Direct Injury
• Pneumonia
• Rapid Onset
• Aspiration from the stomach
• Dyspnea
Common Indirect • Hypoxemia
• Sepsis • Cyanosis
• Severe trauma w/ shock
Uncommon Direct/Indirect
CXR: Bilateral interstitial infiltrate
• Pulmonary contusions
• Fat embolism CT: Fibrin rich edema that has the appearance
• Near-drowning of diffuse ground glass
• Cardiopulmonary bypass
PaO2: < 50mmHg and does not response well to
• Acute pancreatitis
oxygen
• Drug overdose
• Transfusion Echo: Rule out left-sided CHF
• Uremia
Pathogenesis
• Acute Damage
• Up regulation of NF-κB
• Macrophages release IL-8, IL-1, & TNF
• Neutrophil recruitment and activation
• Release of oxidants, proteases, PAF,
and leukotrienes
Lung Biopsy: Diffuse lung damage with capillary congestion, alveolar epithelial necrosis, edema,
hemorrhage, and extensive neutrophil infiltration. Hyaline membranes form around the alveolar space.

Pulmonary 97
- Uncontrolled acute
inflammation
• Multisystem organ failure - Response to epithelial injury
• Interstitial fibrosis of the lungs - NF-κB
• Mortality rate is about 60% - Neutrophils cause damage
- Doesn’t respond well to O2
Differentials
Congestive Heart failure
• Dyspnea and pulmonary edema
• Would likely have paroxysmal nocturnal
dyspnea
• Abnormal echo
Bilateral Pneumonia
• Not as severe as ARDS
• Would have more normal PaO2
• May trigger ARDS
COPD/Restrictive
• Presents with dyspnea, hypoxia,
cyanosis, and a cough.
• These are much more chronic,
whereas ARDS is very abrupt.
• ARDS will have an inciting injury
CXR: Diffuse, with nearly complete opacity, bilateral consolidations with a ground glass appearance.
http://imaging.consult.com/

Pulmonary 98
Emphysema
A Chronic Obstructive Pulmonary • Epithelial injury and proteolysis of ECM
Disease (COPD) with abnormal permanent • Destruction of alveolar parenchyma
enlargement of airspace beyond terminal
bronchioles. The airspace walls are destroyed Panacinar Emphysema
and does not undergo fibrosis. • Less anti-protease activity
• Tends to affect lobes near the base
Centriacinar, Panacinar, Septal, or Irregular • Pi mutations:
o PiMM – normal
Etiology o PiMZ – asymptomatic, high risk
of emphysema with smoking
o PiZZ – Very high risk of
• Centriacinar: smoking panacinar emphysema
o Respiratory bronchiole
o Upper lung zones
• Panacinar: α-1 antitrypsin deficiency
Signs & Symptoms
o Alveolar duct
o Lower lung zones • “Pink Puffers”
• Mutations in TFGB o Pursed lips
• Matrix metalloproteinases (MMP) • Dyspnea
• Barrel Chest
Pathogenesis • Prolonged expiration
• Cough
o Little sputum
Uncertain pathogenesis, hypotheses • Weak & weight loss
include imbalance between protease and anti- o “Exercise” from breathing
protease activity or oxidant-antioxidant. • Sits in a forward hunched position
Ultimately ends with fibrosis and • Late phase: Hypoxia, hypercapnia,
parenchyma degradation. respiratory acidosis
Centriacinar Emphysema
• Too much protease activity Spirometry
• Tends to affect upper lobes near the • FEV1:FVC Ratio: Reduced
apices • FVC: Normal
• Inhalation of toxic agents • FEV1: Decreased
• Inflammation • TLC: Increased
• Elastase, cytokines, oxidative stress,
and failure of antioxidants & XR: Flat diaphragm
antiprotease

Pulmonary 99
Asthma is another COPD that is

Complications recurrent episodes
sodes of dyspnea, wheezing,
cough. There is usually a known trigger, such as
dust or animal dander, that can cause a type II
• Cor pulmonale
hypersensitivity attack. Other causes include
• Liver cirrhosis
viral infections or drugs such as aspirin. The
• Hypoxemia
sputum will have Charcot-Leyden
Leyden crystals
cry and
• Respiratory acidosis
Curschmann spirals.. Also, a skin test for the
• Coma
trigger in atopic asthma will have a wheal and
flare response. Another distinguishing facet is
Differentials
als that it will have eosinophils in a lung biopsy.
Bronchiectasis is a COPD with

Like all COPDs,, emphysema has the permanent dilation of the th bronchi or
characteristic spirometry, cough, and dyspnea bronchioles. It will present similar to the other
due to limited airflow. A big difference is that COPDs, but with purulent, fetid,
fetid and/or bloody
emphysema is the only one located in the sputum due to the infections present.
acinar, not the bronchi or bronchioles.
Clinically, distinguishing features are barrel The Restrictive Pulmonary Diseases will
chest, “Pink Puffer” with pursed lips, and the have a different spirometry result, with a near
patient may sit forward in a hunched position to normal FEV1:FVC ratio, but lower in both
help with breathing. individually. They may also present with
dyspnea. Check Idiopathic Pulmonary Fibrosis
Chronic Bronchitis is a COPD that has for a more comprehensive description of each.
hypersecretion of mucus. As with emphysema,
chronic bronchitis is associated with smoking. Neoplasms of the lungs can also cause
These people will have a productive mucoid dyspnea and a cough. There may also be
cough and may be cyanotic,, giving the ““Blue hemoptysis or paraneoplastic
raneoplastic syndromes. A
Bloaters.” mass on a CXR or a biopsy will help
differentiate. May also present with cachexia.
Gross:: The lungs will be enlarged with a spongy appearance due to large alveoli and may have bulla
formation.
Histology:: The alveoli are enlarged with a thin septa, large pores of Kohn, and “free floating” alveolar septa
and air spaces

Pulmonary 100
Chronic Bronchitis
A Chronic Obstructive Pulmonary
Disease (COPD) characterized by hypersecretion Signs & Symptoms
of mucus.
• “Blue Bloaters”
Etiology • Productive Cough >= 3 consecutive
months in >= 2 consecutive years
• Mucoid sputum
• Smoking
• Hypoxia
• Urban dwellers/pollution
• Hypercapnea
• Can occur in conjuncture with
o Increase PaCO2
emphysema
o Respiratory drive by low pO2
o Doesn’t respond appropriately
Pathogenesis to O2 therapy
• Cyanosis
• Inhaled irritants
• Upper respiratory: Hypertrophy of
mucus glands Spirometry
• Large Airways: Hypersecretion of • FEV1:FVC Ratio: Reduced
mucosa • FVC: Normal
• Small Airways: Hyperplasia of goblet • FEV1: Decreased
cells in surface epithelium • TLC: Increased
• Infiltrate of CD8 T Cells, macrophages,
PMNs
• Airflow obstruction in distal small
airways
• SMC hyperplasia peribronchiolar
fibrosis
Histology: Marked enlargement of the mucus secreting glands with some neutrophils in the bronchial
mucosa. The ratio of glands to overall bronchial wall thickens is called the Reid index, with normal being 0.4
and >0.5 in chronic bronchitis.

Pulmonary 101
The Restrictive Pulmonary Diseases will

Complications have a different spirometry result, with a near
normal FEV1:FVC ratio, but lower in both
individually. They may also present with
• Cor pulmonale
• Atypical metaplasia or dysplasia
for a more comprehensive description of each.
Differentials Neoplasms of the lungs can also cause

dyspnea and a cough. There may also be
hemoptysis or paraneoplastic syndromes. A
Like all COPDs, chronic bronchitis has mass on a CXR or a biopsy will help
the characteristic spirometry, cough, and differentiate. May also present with cachexia.
dyspnea due to limited airflow. Chronic
bronchitis has a more productive mucoid cough
and marked cyanosis, giving the term “Blue
Bloaters.”
Emphysema is a COPD that is located

within the acinar. As with chronic bronchitis,
emphysema is associated with smoking. These
people will have a barrel chest, purse their lips
giving the term “Pink Puffers,” and may be
hunched over to help exhale. There will be a
cough, but with little sputum.

recurrent episodes of dyspnea, wheezing,
viral infections, drugs such as aspirin, or
occupational inhalations. The sputum will have
Charcot-Leyden crystals and Curschmann
spirals. Also, a skin test for the trigger in atopic
asthma will have a wheal and flare response.
Another distinguishing facet is that it will have
eosinophils in a lung biopsy.

permanent dilation of the bronchi or
bronchioles. It also has a productive cough, but
with purulent, fetid, and/or bloody sputum due
to the infections present instead of mucoid.

Pulmonary 102
Bronchial Asthma
A Chronic Obstructive Pulmonary • Early Phase
Disease (COPD) with recurrent episodes of o Bronchoconstriction
wheezing, breathlessness, and a cough. Attacks o Increased mucus
tend to occur at night or in the mornings o Vasodilation
• Late Phase (4-24 hours)
Etiology o Activation of eosinophils,
PMNs, T-cells
o Endothelial cells are activated
Atopy and recruit TH2 cells and
• Type I Hypersensitivity eosinophils.
• Allergy to dust, pollen, animal dander,
Non-Atopic Asthma
etc
• No prior sensitization
Non-Atopic • Secondary to viral infections of URT
• Viral infections • Serum IgE is normal
• Virus induced mucosal damage lowers
Drugs Induced
threshold of subepithelial vagal
• Aspirin - Cox inhibitors
receptors
Occupational • Inflammation similar to atopic asthma
• Chemicals, fumes, organics, etc
Drug Induced Asthma
• Drug provokes asthma
Pathogenesis
Aspirin
• Inhibits COX, lipo-oxygenase route
Atopic Asthma • Bronchoconstriction by leukotrienes
• Type I IgE mediated sensitivity reaction.
• Triggers such as dust, pollen, animal
dander, etc
• TH2 cytokines
o IL-4 stimulates IgE production
o IL-5 activates eosinophils
o IL-13 stimulates mucus
production and IgE production
• Mast Cell degranulation
Histology: This is a biopsy of bronchi. Note the eosinophils in the top left, smooth muscle hyperplasia,
basement membrane thickening, enlargement of the submucosal glands, and hyperplasia of the goblet cells.

Pulmonary 103
Occupational Asthma
• Asthma provoked by fumes, organic Complications
dusts, chemicals, and gases.
• Attacks follow repeated exposure Status asthmaticus
• Lowers threshold of subepithelial vagal • Severe paroxysm
receptors. • Does not respond to therapy
• Persists for days to weeks
Signs & Symptoms • Can be fatal
Cor pulmonale
• Recurrent sudden attacks of dyspnea,
wheezing, rhonchi
• Thick sputum
Differentials
• Hyperinflation of lungs
• Attacks last a couple of hours Like all COPDs, asthma has the
• Hyperventilation characteristic spirometry, cough, and dyspnea
• Hypoxia, hypercapnia, respiratory due to limited airflow. Asthma is episodic and
acidosis recurrent, unlike the other COPDs. There is also
Charcot-Leyden crystals and Curschmann spirals

in sputum
Skin Test: Wheal and Flare (Atopic)
Spirometry
• FEV1:FVC Ratio: Reduced
• FVC: Normal
• FEV1: Decreased <30%
• TLC: Increased
Microscopy: Sputum samples that contain Charcot-Leyden crystals (Left) and Curschmann spirals (Right).
Charcot-Leyden crystals are aggregates of eosinophilic major basic proteins and crystalloids, shown here I a
trichrome stain. The Curschmann spirals are whorls of shed epithelium.

Pulmonary 104
a trigger in atopic asthma, usually an allergy Also, p-ANCA is present in about half of the
such as dust, pollen, or animal dander. The cases.
sputum will have Charcot-Leyden crystals and
Curschmann spirals. Also, a skin test for the Eosinophilic Granuloma is a pulmonary
disease with dyspnea, cough, interstitial nodule,
trigger in atopic asthma will have a wheal and
flare response. Another distinguishing facet is and fibrocystic disease. It will have both
obstructive and restrictive changes on
that it will have eosinophils in a lung biopsy.
spirometry. Occurs exclusively in smokers. The
Emphysema is a COPD that is located culprit is Langerhans cell, not eosinophil , with
within the acinar. These people will have a Birbeck granules.
barrel chest, purse their lips giving the term
“Pink Puffers,” and may be hunched over to The Restrictive Pulmonary Diseases will
help exhale. There will be a cough, but with have a different spirometry result, with a near
little sputum.
Chronic Bronchitis is a COPD that has dyspnea. Check Idiopathic Pulmonary Fibrosis
hypersecretion of mucus. These people will for a more comprehensive description of each.
have a productive mucoid cough and may be
Neoplasms of the lungs can also cause
cyanotic, giving the “Blue Bloaters.”
dyspnea and a cough. There may also be
Asthma is another COPD that is hemoptysis or paraneoplastic syndromes. A
recurrent episodes of dyspnea, wheezing, mass on a CXR or a biopsy will help
cough. There is usually a known trigger, such as differentiate. May also present with cachexia.
occupational inhalations.

permanent dilation of the bronchi or
bronchioles. It also has a productive cough, but
with purulent, fetid, and/or bloody sputum due
to the infections present.
Churg-Strauss Syndrome is a small

vessel necrotizing vasculitis that is also
associated with asthma, allergies, lung infiltrate,
eosinophilia. There is granuloma formation
with infiltration with eosinophils in lung, heart,
spleen, and skin vasculature. It can also affect
peripheral nerves. The lesions themselves
resemble PAN and microscopic polyangiitis.

Pulmonary 105
Bronchiectasis
A Chronic Obstructive Pulmonary
Disease (COPD) with permanent dialation of Signs & Symptoms
bronchi and bronchioles due to des
destruction of
supporting tissue.
• Productive Cough with copious purulent
and fetid sputum
Etiology • Possible hemoptysis
• Clubbing of Fingers
• Obstruction and chronic infection Spirometry

• Foreign body • FEV1:FVC Ratio:: Reduced
• Tumor • FVC: Normal
• Congenital • FEV1: Decreased
o Cystic Fibrosis • TLC: Increased
o Kartagener Syndrome
• Necrotizing/Suppurative Pneumonia CXR: Bronchial dilation
o Staphylococcus aureus
o Klebsiella pneumoniae
Pathogenesis
• Obstruction
o Possibly due to infection
• Secondary infection
• Damaged or weakened bronchial walls
• Bronchiectasis
Positive Feedback Loop

• Persisting Necrotizing infection
• Additional Obstruction and damage
• Fibrosis
• Traction & Ectasia
Gross:: System of bronchioles dividing into smaller ones, with all of the dilated. Active infections can have
exudate in the airways with ulcerations in the walls. Healing of these ulcers will give peribronchiolar fibrosis.

Pulmonary 106
The Restrictive Pulmonary Diseases will

Complications have a different spirometry result, with a near
• Hypoxemia
• Hypercapnia
for a more comprehensive description of each.
• Pulmonary Hypertension
Idiopathic Pulmonary Fibrosis will have
Differentials a cough and dyspnea with exertion, but it is a
restrictive pulmonary disease, so the spirometry
will be different. It may also have cyanosis,
Like all COPDs, bronchiectasis has the which isn’t typical in bronchiectasis. The gross
characteristic spirometry, cough, and dyspnea looks somewhat similar, with IPF having
due to limited airflow. Bronchiectasis has a honeycomb change. This will have cystic
more productive purulent and/or fetid cough cavitations that resemble dilated bronchioles
due to active infections in the bronchi or but you are unable to follow the airways.
bronchioles.
Neoplasms of the lungs can also cause
Emphysema is a COPD that is located dyspnea and a cough, although it won’t be
within the acinar. These people will have a purulent or fetid. There may also be
barrel chest, purse their lips giving the term hemoptysis or paraneoplastic syndromes. A
“Pink Puffers,” and may be hunched over to mass on a CXR or a biopsy will help
help exhale. There will be a cough, but with differentiate. May also present with cachexia.
little sputum.
Chronic Bronchitis is a COPD that has

hypersecretion of mucus. These people will
have a productive mucoid cough and may be
cyanotic, giving the “Blue Bloaters.”

recurrent episodes of dyspnea, wheezing,
occupational inhalations. The sputum will have
Charcot-Leyden crystals and Curschmann
spirals. Also, a skin test for the trigger in atopic
asthma will have a wheal and flare response.
Another distinguishing facet is that it will have
eosinophils in a lung biopsy.

Pulmonary 107
Idiopathic Pulmonary Fibrosis

Restrictive Pulmonary disease involving
idiopathic fibrosis of the lung interstitium. The Signs & Symptoms
histological pattern is termed Usual Interstitial
Peumonia (radiologists and pathologists call IPF
• Progressive
this).
• Dyspnea on exertion
Mean survival is <= 3 years and affects • Non-productive cough
men more than women.
Biopsy is the gold standard investigation
Etiology Auscultation: Inspiratory crackle
Spirometry
Unknown • FEV1:FVC Ratio: Same
• FEV1: Decreased
Risks • FVC: Decreased
• Male • TLC: Decreased
• Smoking
• Age >60 years
Pathogenesis
Repeated cycles of epithelial activation
and injuries due to unknown agent.
Releases TGF-β1
• Activates fibroblasts and myofibroblasts
• Inhibits Caveolin, which normally
inhibits deposition of collagen and ECM.
• Also reduces telomerase, which
eventually leads to epithelial
activation/injury.
Usually occurs in the interstitium of the

lower lobes.
Histology: There is patchy interstitial fibrosis that over time becomes more collagenous and less cellular.
There will be some inflammation with lymphocytes, plasma cells, and neutrophils. Has temporal
heterogeneity.

Pulmonary 108
Some Collagen Vascular Diseases will

Complications present with interstitial fibrosis and UIP in
addition to their other symptoms. These
diseases include, but not limited to, SLE,
• Hypoxia/Cyanosis
rheumatoid arthritis, and systemic sclerosis.
• Cor pulmonale
Acute Interstitial Pneumonia, aka
Differentials Hamman Rich Syndrome, is an aggressive
restrictive pulmonary disease that may occur as
an acute phase of IPF. The presentation is
All the restrictive pulmonary diseases similar to that of ARDS like the hyaline.
with have similar spirometry results and
symptoms of dyspnea and varying degrees of Lymphoid Interstitial Pneumonia is a
hypoxia due to V-Q mismatch. IPF is the restrictive pulmonary disease with expansion of
prototype restrictive pulmonary disease due to the interstitium due to accumulation of
diffuse interstitial fibrosis. The main property lymphoid cells. It is also idiopathic and is
here is that it is idiopathic with UIP and the associated with connective tissues diseases,
other restrictive pulmonary diseases need to be autoimmunity, or HIV. May become lymphoma.
ruled out first.
Nonspecific Interstitial Pneumonia is

also idiopathic restrictive pulmonary disease,
but much less severe. Instead of UIP it will have
cellular and fibrosing histologic patterns
without honeycomb change or fibroblast foci.
Cellular patterns has chronic interstitial
inflammation, and fibrosing has interstitial
fibrosis without temporal heterogeneity, unlike
UIP. Also affects younger people.
Cryptogenic Organizing Pneumonia,

aka Bronchiolitis Obliterans Organizing
Pneumonia (BOOP), is also idiopathic restrictive
pulmonary disease with polypoid plugs of loose
connective tissue in the alveolar ducts, alveoli,
and bronchioles. The normal architecture is
preserved. This can resolve spontaneously or
with steroids.
Gross: Patchy fibrosis with preference for the lower lobes and a distribution in the subpleural regions along
the interlobar septum. There may be destruction of alveolar structure and subsequent formation of cystic
spaces lined by hyperplastic type II pneumocytes giving a gross honeycomb appearance.

Pulmonary 109
Respiratory Bronchiolitis (aka • Complicated by TB or PMF

Interstitial Lung Disease) is a restrictive • Increased risk of lung cancer
pulmonary disease in smokers. The
macrophages accumulate in the lumen of Asbestosis
respiratory bronchioles with eventual • Accumulation of asbestos
peribronchiolar fibrosis. • Mostly lower lobes
• Cellular and fibrotic reactions
Desquamative Interstitial Pneumonia is • Dyspnea with productive cough
a rare restrictive pulmonary disease in smokers, • Complicated by PMF
similar to respiratory bronchiolitis but in the • High risk of bronchogenic carcinoma,
alveoli instead of respiratory bronchioles will followed by mesothelioma
little interstitial fibrosis.
Berylliosis
Hypersensitivity Pneumonia (aka • Accumulation of Beryllium
Extrinsic Allergic Alveolitis) is a restrictive
• Exclusively in occupations such as
pulmonary disease with type III & IV
aerospace, nuclear power, and
hypersensitivity to inhaled organic agents.
electronic industries.
There is the formation of non-necrotizing
• Dyspnea, chest pain, & cough.
granulomata with giant cells in the alveoli,
• Forms non-caseating granulomas
leading to damage and fibrosis.
• CT may show a ground glass
Pneumoconiosis is a class of disease of appearance
environmentally induced (minerals, chemicals,
etc) that cause non-neoplastic disease. A brief Additional Info
description of each of the major ones follows:
Coal Worker’s Pneumoconiosis Treatment: Only lung transplant.

• Aka anthracosis
• Accumulation of carbon
• Asymptomatic
• Complicated by TB or progressive
massive fibrosis (PMF)
• Also seen in smokers and urban
dwellers
Silicosis
• Accumulation of silica
• Common in glass workers
• Silicotic nodules
• Mostly upper lobes
• Polarized microscopy show crystals
• Calcification in lymph nodes, giving
eggshell calcification in imaging

Pulmonary 110
Sarcoidosis
Multi-organ disease with non- unbalanced CD4+/CD8+ ratio
necrotizing granuloma formation and interstitial • Expansion of T-cell subsets
fibrosis. The interstitial fibrosis of the lungs will • TH1 response, accumulation of
lead to restrictive pulmonary disease. macrophages
• Macrophages release TNF
Etiology • Macrophages in granulomas convert
Vitamin D to active form, leading to
metastatic calcification
Unknown • Elevated ACE (unknown mechanism)
leads to hypertension
Risks
• <40 years old Common sites of manifestation:
• Danish, Swedish, African Americans • Spleen
• Non-smokers • Liver
• HLA-A1 & HLA-B8 • Lymph nodes
• Bone Marrow
Pathogenesis • Parotids (Mikulicz syndrome)
• Eyes (Sicca Syndrome)
• Legs (Erythema Nodosum)
• CD4+ T-cell response to unspecified • Nose/Checks/Lips (Lupus Pernio-Violet)
antigen
• Accumulation of CD4+ T-cells,
Gross: Here the lungs have non-caseating granulomas located near the hilum and involve the hilar and
paratracheal lymph nodes.
Histology: Non-caseating granuloma with non-necrotic tissue at the center surrounded by epitheloid cells,
foreign body type giant cells, and fibrosis. Eventually will replaced with hyaline fibrous scarring.

Pulmonary 111
Also, Primary TB will be centrally located with

Signs & Symptoms the Ghon’s complex extending to the hilar
lymph nodes. Secondary TB is located closer to
the apex and causes cavitations. Miliary TB will
• Gammaglobulinemia
have diffuse small granulomas in the lungs as
• Rheumatoid Arthritis
well as disseminated throughout the rest of the
• ACE Increase
body.
• Interstitial Fibrosis
• Non-Caseating Granuloma Histoplasmosis is a fungal infection that
can produce granuloma formation similar to
Episodic hypersensitivity reactions
Miliary TB in immunosuppressed people. Found
• Biopsy in soils enriched with bat & bird droppings.
• TNF in bronchoalveolar fluid
Berylliosis can also cause non-caseating
• Increased CD4+/CD8+ granulomas. It is very occupation specific due
• Diagnosis by exclusion to exposure to beryllium, with jobs in
aerospace, nuclear power, or electronic
Complications industries. Presents with dyspnea, cough,
and/or chest pain. Limited to only the lungs.
• Pulmonary fibrosis
• Cor pulmonale
• Peripheral Lymphadenopathy
• Cutaneous lesions
• Eye involvement
Differentials
Sarcoidosis has a restrictive lung
disease component, so it will have similar
spirometry results with the dyspnea and cough.
However, it is a multi-system disease, and will
present with many other extrapulmonary
symptoms.
Tuberculosis can also have granuloma

formation, but it will be caseating granulomas.
Histology: Two features that can be seen in sarcoidosis are: Schaumann bodies (Top) that are laminated
concretions of calcium & proteins and Stellate inclusions, aka asteroid bodies, (Bottom) which are visible in
the giant cells in the granuloma.

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Pneumonia
Pneumonia is a broad category that
covers inflammation of the lungs that is usually Pathogenesis
associated with fever and infiltrates in the air
space. Pneumonia is typically due to an Lobar Pneumonia
infection by bacteria, viruses, or fungi.
• Originates in the alveoli
There are two type of pneumonia • Spreads via pores of Kohn
pathogenesis:
Has four stages:
• Lobar Pneuomonia
• Congestion: Heavy, red, and boggy.
o Originates in the alveoli
Due to vascular congestion
• Bronchopneumonia (lobular).
• Red Hepatization: Lung has a liver like
o Originates in the bronchi
consistency. Alveolar space is packed
However, both present about the same, with PMNs, RBC, and fibrin
and a more useful categorization is community • Grey Hepatization: Dry, grey, and firm
acquired and nosomical (hospital acquired). with fibrinosupperative exudate in the
alveoli
• Resolution
Etiology
Bronchopneumonia
• Originates in the bronchi
Community Acquired
• Spreads through bronchi
• Streptococcus pneumonia
• Acute inflammatory response
o most common
• Increased vascular permeability
• Hemophilus influenzae
• Exudate enters adjacent alveoli
o COPD, children, cystic fibrosis
• May spread enough to become
• Moraxella catarrhalis
confluent, looks just like lobar
o COPD (2nd most common)
pneumonia
o Elderly
• Klebsiella pneumoniae
o alcoholics, malnourished, most Signs & Symptoms
common gram (-)
• Pseudomonas aeruginosa
• Fever
o Cystic fibrosis, chemo, burns
• Productive cough with rusty purulent
• Staphylococcus aureus
sputum
o secondary to viral infection, IV
• Chest pain
drug abuse
• Pleural rub with pleuritis

Pulmonary 113
CXR: Legionnaire’s Disease commonly

• Lobar – Entire lobe filled with exudate affects people with predisposing conditions
• Bronchopneumonia – patchy or entire such as cardiac, renal, immunologic, or
lobe(s) filled with exudate. Tends to be hematologic diseases. Organ transplant
bilateral. recipients are a high risk group. It will have
pneumonia symptoms, as well as neurological
Culture: to determine offending organism and GI symptoms. Can also present without the
pneumonia, and is then called Pontiac Fever.
Complications Look for antigens in the urine or fluorescent
antibody test with sputum.
• Tissue destruction of abscesses COPD will also have a productive cough

• Empyema and dyspnea, but is associated with smoking
• Fibrosis and won’t have a fever nor CXR with exudates.
• Sepsis: meningitis, arthritis, or infective
ARDS is a rapid onset uncontrolled
endocarditis
acute immune response that presents with
cough, dyspnea, fever, and cyanosis/hypoxia.
Differentials The CXR will both show diffuse exudates, but
ARDS will have exudates in the entire lungs
bilaterally. There will also be an evident trigger
Atypical Pneumonia is commonly called
for ARDS, which can include pneumonia.
a “walking pneumonia” due to being more mild.
The infection is confined to the alveolar septa
with little to no exudate in the alveolar air
space. It will have cough but with little sputum.
CXR: (Left) Bronchopneumonia showing patchy focal consolidations. (Right) The entire upper right lobe is
filled with exudate.
Images found at imaging.consult.com

Pulmonary 114
Additional Info
Klebsiella pneumoniae is a particularly
nasty pneumonia, with the patient coughing up
pieces of lung tissue, commonly referred to as
necrotizing pneumonia.
Gross Lungs: (Left) Bronchopneumonia showing multiple patchy consolidations that are slightly elevated
with a grey-red to yellow color. The surrounding tissue is hyperemic and edematous. (Right) Lobar
pneumonia showing the entire lower two lobes consolidated.

Pulmonary 115
Atypical Interstitial Pneumonia

Infection and inflammation in the
alveolar speta. Differs from typical pneumonia Signs & Symptoms
as there is no exudate in the aveoli. Commonly
referred to as “walking pneumonia” due to
• Low grade fever
relative mild symptoms.
• Headache, malaise
• Cough with minimal sputum
Etiology
• Mycoplasma pneumoniae CXR: Distinct interstitial markings

o most common
WBC: Moderate elevation
• Chlamydia pneumoniae
o 2nd most in young adults
• Respiratory Syncytial Virus (RSV) Complications
o Infants
• Cytomegalovirus (CMV) • Secondary Bacterial Infection
o Post transplant • Severe in immunocompromised,
• Influenza Virus infants, elderly, malnourished, and
o Immunocompromised alcoholics.
• Coxiella burnetii
o Farmers & veterinarians
o Q-fever Differentials
• Adenovirus, rhinovirus, rubeola,
varicella can also cause interstitial Typical Pneumonia will be more severe
pneumonia and will have a productive cough with rusty
colored sputum. The exudate will be in the
alveolar air space instead of being localized to
the septa.
Pathogenesis
COPD will also have a productive cough
and dyspnea, as well as a strong association to
• Pathogen attaches to respiratory smoking. It won’t have the mild fever or a CXR
epithelium with infiltrates.
• Necrosis
• Inflammation limited to septa ARDS is a rapid onset uncontrolled
• Some exudate may escape into alveoli acute immune response that presents with
• Risk of secondary bacterial infections cough, dyspnea, fever, and cyanosis/hypoxia.
The CXR will both show diffuse exudates, but

Pulmonary 116
ARDS will have exudate in the entire lungs

bilaterally. There will also be an evident trigger
for ARDS. On biopsy, both with have hyaline
formation at the septa, although it only forms in
atypical pneumonia in severe cases.
Histology: Lung parenchyma showing lymphocyte infiltration into the alveolar septa. The alveolar sacs
themselves are empty with little to no exudate. Severe cases, such as this one, can develop hyaline
membranes at the edge of the alveolar sacs.

Pulmonary 117
Lung Abscess
Secondary effect to other pathology
that is a region of lung parenchyma with Pathogenesis
liquefactive necrosis and is composed of pus,
debris, and cells.
• Damage to lung parenchyma
Occurs most often in the right lung. • Necrosis and inflammatory response
This is due to the more vertical right bronchus
where aspiration follows gravity. Signs & Symptoms
Etiology • Cough with copious foul smelling
purulent sputum
• Aspiration • Fever
o Especially alcoholic & coma • Chest Pain
• Bacterial • Weight Loss
o S. aureus • Clubbing
o K. pneumoniae
CXR: Lesion will be visible
o Pneumococcus
o Fusobacterium
o Peptococcus Complications
o Bacteroides
• Septic embolism
• Cicatrization
• Trauma
• Sepsis – Brain Abscess, Meningitis
• Idiopathic – Primary Cryptogenic Lung
• Hemorrhage
Abscess.
• Often follows oropharyngeal surgical
procedures or dental sepsis
Gross: Abscess cavity may be filled with suppurative debris or cavitation.

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Pulmonary Edema
Secondary effect to other pathology where
the alveolar space is filled with transudate. Complications
Etiology Cor pulmonale
• Left Heart Failure

• Primary Disorder of Parenchyma
o COPD
o Restrictive
o Cystic Fibrosis
• Disease of Vasculature
o Pulmonary Thromboembolism
o Wegener’s Granulomatosis
• Disorders affecting chest movements
• Pulmonary arterial constriction
Pathogenesis
• Increase Hydrostatic Pressure
Signs & Symptoms
• Edema
• Dyspnea
• Orthopnea / Paroxysmal Nocturnal
• Fatigue
• Cyanosis
• Frothy sputum (pink with blood)
Auscultation: Crackles
Gross: (Top) Lung with frothy transudate.

Histology: (Bottom) The alveolar air space is filled with pink transudate and the capillaries are congested and
engorged.

Pulmonary 119
Pulmonary Thromboembolism
Embolism that gets lodged in the Minor
pulmonary vasculature. • Small vessel obstruction
• Asymptomatic
Etiology
Signs & Symptoms
Deep Vein Thrombosis
• Asymptomatic (60-80%)
Risk Factors
• Dyspnea
• Virchow’s Triad
• Acute Cor Pulmonale
• Prolonged Bedrest, immobilization of
• Shock
legs
• Hypoxia
• Surgery
• Severe trauma
• CHF
• Oral Contraceptive • Pulmonary Angiography
• Trousseau’s Syndrome • CXR
• a-vO2 difference increased
Pathogenesis D-Dimers:
• Positive not specific to PE, detects
presence of thrombi
• Embolism from a thrombus elsewhere
• Negative can exclude PE
o Commonly a DVT
o Can be mural via paradoxical
emboli (left-to-right shunt) Complications
• Occlusion of pulmonary vasculature
• Ischemia and Infarction
Sudden Death
Massive
• 60% obstruction of vasculature Differentials
• Sudden death
• No infarct
Air Embolism can also become trapped
Major in the lung vasculature causing ischemia and
• Medium vessel obstruction infarcts. They tend to also lodge in the
• Infarction only in 10% due to collateral ventricles and brain. The patient will have neck
circulation via bronchial arteries wounds, thoracocentesis, hemodialysis, or
• Dyspnea, pain. some other way of getting air into the venous
system.

Pulmonary 120
Fat Embolism can also become lodged

in the lung vasculature, as platelets adhere to
the globules. This can present with DIC and Fat
Embolism syndrome, which has pulmonary
insufficiency, neurologic symptoms, anemia,
and thrombocytopenia. There will be a history
of broken bones, or damage to subcutaneous
tissue such as burns.
Amniotic Fluid Embolism can also

obstruct the lung vasculature. This occurs
shortly after birth, where some of the fetal
tissues make it into the mother’s bloodstream.
This will have DIC, pulmonary edema, and is
usually fatal.
Gross: This is a saddle embolism, located in the bifurcation of the pulmonary arteries. This is a massive
embolism and will cause occlusion of the arterial supply to both lungs. The patient most likely died
suddenly.

Pulmonary 121
Pulmonary Hypertension
A disease process of increased pressure Primary Sporadic
of the pulmonary vascular system, usually due • Genetic polymorphism increase
to COPD or restrictive diseases of the lungs. expression of 5-HTT (Serotonin)
Can be primary or idiopathic. transporter gene.
• Increased SM proliferation with
Etiology serotonin
Secondary
• COPD/Restrictive • Endothelial dysfunction
• Congenital Left-to-right shunts • Decreased PGI2 and NO, with increased
• Idiopathic endothelin
• BMPR2 mutations (Autosomal • Pulmonary vasoconstriction
dominant)
• Sporadic
Seen in young females (20-40 years)
Pathogenesis
Primary Familial Type
• TGF-β mediates endothelial and SM
dysfunction.
• BMPR2 binds TFG-β and inhibits
proliferation.
• Mutation of BMPR2 leads to a loss of
function and subsequent endothelial
and SM proliferation.
• Not everyone with BMPR2 mutation
will develop disease.
Histology: This is a small artery or arteriole with duplication of both the internal and external elastic
membranes, thick vessel walls, and a narrowed lumen.

Pulmonary 122
Signs & Symptoms
• Dyspnea
• Fatigue
• Chest Pain
ECG/Echo: Right sided heart hypertrophy
Complications
• Respiratory Distress
• Cyanosis
• Thrombosis
• Atheromas in pulmonary arteries
• Cor pulmonale - right sided heart failure
Histology: This is plexogenic pulmonary arteriopathy, where a tuft of capillary formation fills the lumen of
dilated small arteries. This is a development seen in chronic primary pulmonary hypertension.

Pulmonary 123
Diffuse Pulmonary Hemorrhagic Syndrome

Disease process of other autoimmune
pathological disorders. Non diffuse pulmonary Signs & Symptoms
hemorrhaging is due to other causes, such as
necrotizing pneumonia or congestion.
tion.
• Hemoptysis
• Anemia
Etiology • Diffuse Pulmonary Infiltrates
• Goodpasture
• Idiopathic Pulmonary Hemosiderosis
• Wegener’s Granulomatosis
Pathogenesis
Immune mediated damage of the pulmonary
vasculature.
Goodpasture
• Type II Hypersensitivity against α3 chain
of collagen IV.
• Also presents with glomerulonephritis
Idiopathic Pulmonary Hemosiderosis

• Unknown, but resembles Goodpasture
histology and without the renal
involvement
Wegener Granulomatosis
• Possibly cell-mediated
• Complete description can be foun
found in
the Cardiovascular section.
Histology:: Focal necrosis of the alveolar walls with intra

intra-alveolar
alveolar hemorrhages. There is also fibrous
thickening of the alveolar septa and hypertrophy of the septa llining
ining cells. Hemosiderin is seen in the days
following an acute presentation.

Pulmonary 124
Lung Adenocarcinoma
Primary tumor of glandular origin that • Mutations in EGFR, which typically
typically arises in the peripheral lungs and is a occur in women of far east descent, has
slow growing non-small cell lung cancer. Most a very poor prognosis and don’t
common lung cancer, especially in women, non- respond well to EGFR inhibitor
smokers, and in people under 45. therapies.
• Mutations in KRAS have a similar
Etiology problem, but it occurs downstream in
the signaling pathway.
Uncertain, but with these associations:

• Thyroid transcription factor 1 (TTF-1)
Signs & Symptoms
positive
• KRAS mutation • “Silent Killer”
• EGFR mutations • Cough
o Indicates a worst prognosis • Hemoptysis
• Obstruction of the bronchi
Not associated with smoking.
• Wheezing
• Chest pain
Pathogenesis • Clubbing
• Cachexia
• Accumulation of mutations that lead to CXR: Coin lesion
loss of cell cycle control. CT: Non-calcified nodule
• Atypical adenomatous hyperplasia is
the precursor to adenocarcinoma.
• Proliferation of neoplasm.
• Due to the glandular origins, it will
produce mucin, which is responsible for
any neoplastic syndromes or sputum.
• Metastasis. Around this time symptoms
begin to appear, giving the moniker
“Silent Killer” as at this point metastasis
has already occurred and treatment is
much more difficult.
Gross: Peripherally located mass that is grey-white and would be firm to the touch. It arises in association
with peripheral lung scars, sometimes referred to as “scar carcinoma.” The relationship is not well
understood, but it is thought that the scar follows the adenocarcinoma.

Pulmonary 125
mucin. An important difference is that it

Complications commonly forms many small diffuse nodules
throughout the lung instead of just one large
nodule, although it could do so.
• Superior Vena Cava Syndrome
• Pancoast Tumor Squamous Cell Carcinoma is another
• Horner’s Syndrome primary tumor, but located centrally near the
• Endocrine – paraneoplastic hilar lymph nodes. It originates from
• Recurrent Laryngeal– cough, epithelium cells and doesn’t produce mucin.
hoarseness This commonly affects older men, and is
• Effusions – pleural or pericardial associated with smoking. A common
paraneoplastic syndrome with SqCC is
Possible paraneoplastic (10%)
hypercalcemia due to release of PTH-like
• Trousseau’s Syndrome
peptide. On biopsy, look for keratin pearls,
• DIC which is characteristic of squamous cell
carcinomas.
Differentials Small Cell Cancer is an aggressive
cancer of neuroendocrine cells that is
Lung Adenocarcinoma in-situ is a characteristic of having paraneoplastic
similar neoplasm but instead of invasion it syndromes, notably Cushing’s Syndrome. It also
spreads on top of the existing structures. Both has a strong association with smoking. Serum
are located in the periphery, not strongly markers such as Synaptophysin, Chromogranin,
associated with smoking, and may have KRAS & CD56, PTH-like, gastrin, ACTH, and ADH may
EGFR mutations. In-situ may also produce help with differentiation, but many of these are
Histology: (Left) Biopsy that shows proliferation of glandular epithelial cells. Sputum microscopy (Right)
shows vacuolated cells full of mucinous secretions.

Pulmonary 126
dependent on which paraneoplastic syndromes

are present. Also, will not have mucin.
Bronchial Carcinoid is a neoplasm of

Kulchitsky neuroendocrine cells that fills
bronchi and peribronchial space. It tends not to
metastasize and presents with recurrent
pulmonary infections and a cough with or
without hemoptysis, although tends to be
asymptomatic. Rarely, these cells release
serotonin causing intermittent carcinoid
syndrome.
Hamartoma is a benign growth of

disorganized normal tissue that is asymptomatic
and is usually an incidental finding. Any
description of benign or normal tissue biopsies
implies a hamartoma.
Metastasis to Lungs from cancers

outside the lungs is very common, and present
with multiple masses instead of a single primary
tumor. Histochemistry will help to determine
the site of origin. The most common origin is
breast cancer.
Additional Info
Tends to metastasize to:
• Lymph Nodes
• Adrenal (50%)
• Liver (30-50%)
• Brain (20%)
• Bone (15-20%)
• Kidney (15%)

Pulmonary 127
Lung Adenocarcinoma in-situ

Primary tumor of glandular origin that
typically arises in the periphery of the lungs and Signs & Symptoms
grows over existing structures with no invasion.
Aka bronchioalveolar carcinoma and is a type of
• Initially asymptomatic, “Silent Killer”
non-small cell cancer. May form single nodule
• Chronic cough
but more commonly will form multiple diffuse
• Hoarseness
nodules.
• Chest pain
• Segmental atelectasis
Etiology
• Carcinogens
• Genetics
• Smoking is not implicated
• Adenocarcinomas are the most
common cancer in non-smoking women
<45 years old
Pathogenesis
• Accumulation of mutations in
bronchioalveolar stem cells that lead to
loss of control of the cell cycle.
• Proliferation of neoplasm.
• Grows along existing structures, termed
lepidic growth.
• May or may not produce mucin.
• Metastasis. Around this time symptoms
begin to appear, giving the moniker
“Silent Killer” as at this point metastasis
has already occurred and treatment is
much more difficult.
Histology: Adenocarcinoma growth over the existing architecture, seen here as columnar-like cells on the
outside of the alveolar septa. May have outward growths that look like a “butterfly on a fence.”

Pulmonary 128
syndromes, notably Cushing’s Syndrome. It also

Complications has a strong association with smoking. Serum
markers such as Synaptophysin, Chromogranin,
CD56, PTH-like, gastrin, ACTH, and ADH may
• Superior Vena Cava Syndrome
help with differentiation, but many of these are
• Pancoast Tumor
• Horner’s Syndrome
are present. Also, will not have mucin.
• Endocrine – paraneoplastic
• Recurrent Laryngeal– cough, Bronchial Carcinoid is a neoplasm of
hoarseness Kulchitsky neuroendocrine cells that fills
• Effusions – pleural or pericardial bronchi and peribronchial space. It tends not to
Possible paraneoplastic (10%)
• Trousseau’s Syndrome
• DIC asymptomatic. Rarely, these cells release
Differentials syndrome.

Lung Adenocarcinoma is a similar disorganized normal tissue that is asymptomatic
neoplasm but with invasion into the lung and is usually an incidental finding. Any
parenchyma. Both are located in the periphery, description of benign or normal tissue biopsies
not strongly associated with smoking, produce implies a hamartoma.
mucin, and may have KRAS & EGFR mutations.
However, adenocarcinoma will have a single
tumor in the lungs, whereas in-situ is more
likely to have multiple diffuse nodules.
Squamous Cell Carcinoma is another the site of origin. The most common origin is
primary tumor, but located centrally near the breast cancer.
hilar lymph nodes. It originates from
epithelium cells and doesn’t produce mucin.
This commonly affects older men, and is
associated with smoking. A common Additional Info
which is characteristic of squamous cell • Lymph Nodes
carcinomas. • Adrenal (50%)
• Liver (30-50%)
Small Cell Cancer is an aggressive • Brain (20%)
cancer of neuroendocrine cells that is • Bone (15-20%)
characteristic of having paraneoplastic • Kidney (15%)

Pulmonary 129
Squamous Cell Carcinoma of the Lung

A primary tumor of epithelial cell origin • Dyspnea
that typically arises centrally and is a non-small • Chest Pain
cell cancer. • Pulmonary osteoarthropathy
o Severe form of clubbing
clubbi
Etiology • Cachexia
Biopsy or Cytology
• p53 mutations
CXR
• Procarcinogen in cigarettes
• Radon (found naturally in soil)
Complications
Risks
• Male
• Old Age • Superior
uperior Vena Cava Syndrome
• Smoking (99%) • Pancoast Tumor
• Horner’s Syndrome
• Cytochrome P450 polymorphism
o PTH-like
like peptide -
Pathogenesis Hypercalcemia
• Recurrent Laryngeal– cough,
• Accumulation of mutations hoarseness
• Loss of control of cell cycle • Effusions – pleural or pericardial
pericardi
• Metaplasia to squamous cells • Paraneoplastic
• Proliferation of neoplastic cells
• Arise centrally, near the major bronchi
• Spread to hilar lymph nodes
• Then to Liver, Adrenals, Brain, Bone
and/or Kidneys
Signs
igns & Symptoms
• Cough
• Hemoptysis
Histology:: Biopsy of lung parenchyma near the bronchi. Presents with keratin pearls, which are the large
eosinophilic spheres. The basophilic grouping of squamous cells surrounding them are the neoplasm.

Pulmonary 130

Differentials tumor. Histochemistry will help to determine
Lung Adenocarcinoma and Lung breast cancer.
Adenocarcinoma in-situ are similar neoplasms.
Both are located in the periphery,, not strongly Additional Info
associated with smoking, produce mucin, and
may have KRAS & EGFR mutations. Also the they
tend to affect young non-smoking
smoking women
women.
• Lymph Nodes
Small Cell Cancer is an aggressive • Adrenal (50%)
cancer of neuroendocrine cells that is • Liver (30-50%)
characteristic of having paraneoplastic • Brain (20%)
syndromes, notably Cushing’s Syndrome
Syndrome. It also • Bone (15-20%)
has a strong association with smoking. Serum • Kidney (15%)
markers such as Synaptophysin, Chromogranin
Chromogranin,
CD56, PTH-like,
like, gastrin, ACTH, and ADH may
are present.

Kulchitsky neuroendocrine cells ls that fills
serotonin causing intermittent ent carcinoid
syndrome.


outsidee the lungs is very common, and present
Cytology:: Atypical epithelium with loss of nuclear polarity, pleomorphism, and hyperchromasia. The long
“tail” is termed “Keratin tadpole” and indicates malignancy with a poor prognosis. The stain used is
p63/cytokeratin 5/6 or 903 stain.

Pulmonary 131
Small Cell Carcinoma

A primary tumor of neuroendocine
progenitor cell origin that can arise either Signs & Symptoms
centrally or in the periphery. Strong association
with paraneoplastic syndromes, most likely of
• Cough
the lung carcinomas.
• Dyspnea
• Hemoptysis
Etiology • Chest Pain
• Cachexia
• p53 and RB1 frequently mutated Neuroendocrine Markers: Synaptophysin,

• BCL2 over expressed Chromogranin, CD56, PTH-like
o Anti-apoptotic
• BAX under expressed Paraneoplastic syndrome
o Pro-apoptotic o ACTH – Cushing Syndrome
• Strong relationship with smoking o ADH – SIADH
o Gastrin releasing peptide
o Calcitonin
Pathogenesis
• Arise in major bronchi or periphery

• Very malignant
• Arise fro neuroendocrine progenitor
cells of bronchial epithelium
• Commonly associated with ectopic
hormone production.
• Typically metastasized before diagnosis
Microscopy: Cytology (Left) and biopsy (Right) show small epithelium cells with scant cytoplasm, finely
granular chromatin, a high mitotic count, nuclear molding, and extensive necrosis.

Pulmonary 132

Complications syndrome.

Can but uncommon: disorganized normal tissue that is asymptomatic
• Superior Vena Cava Syndrome and is usually an incidental finding. Any
• Pancoast Tumor description of benign or normal tissue biopsies
• Horner’s Syndrome implies a hamartoma.
• Recurrent Laryngeal– cough, Metastasis to Lungs from cancers
hoarseness outside the lungs is very common, and present
• Effusions – pleural or pericardial with multiple masses instead of a single primary
• Paraneoplastic tumor. Histochemistry will help to determine
breast cancer.
Differentials
Cushing Syndrome is a cascade of
symptoms, including moon facies,
Lung Adenocarcinoma and Lung supraclavicular fat pads, buffalo hump, purple
Adenocarcinoma in-situ are similar neoplasms. striae, hirsutism, etc, and is due to chronic
Both are located in the periphery, not strongly elevated glucocorticoids. This can be from long
associated with smoking, produce mucin, and term use of corticosteroids or an endogenous
may have KRAS & EGFR mutations. Also they pathology. In small cell lung carcinoma, this is
tend to affect young non-smoking women. due to the release of ACTH by the neoplasm
Squamous Cell Carcinoma is another cells. It can also be Cushing Disease, which is
primary tumor and is located centrally near the due to a pituitary tumor that releases ACTH.
hilar lymph nodes. It originates from Other tumors include oat cell carcinoma,
epithelium cells and doesn’t produce mucin. carcinoid, or primary adrenal adenocarcinoma
This commonly affects older men, and is in the zona fasciculata.
associated with smoking. A common
which is characteristic of squamous cell
carcinomas.

Kulchitsky neuroendocrine cells that fills

Pulmonary 133
Bronchial Carcinoid
A primary tumor that originates from
Kulchitsky neuroendocrine cells and grows into Signs & Symptoms
the bronchial lumen. It tends to form centrally.
Good prognosis and is easily removed surgically.
• May be asymptomatic
• Cough
Etiology • Hemoptysis
• Recurrent infections
• Idiopathic
• Smoking or environmental factors are Complications
not associated.
Carcinoid Syndrome
Pathogenesis • Episodic
• Diarrhea
• Flushing
• Kulchitsky cell proliferation
• Cyanosis
o Neuroendocrine cell storing
• Due to serotonin release
serotonin
• Growth of mass into bronchial lumen or
peribronchial tissue Differentials
• Obstruction of airways
• If the neoplasm releases serotonin, may
Lung Adenocarcinoma and Lung
cause carcinoid syndrome, although this
Adenocarcinoma in-situ are similar neoplasms.
is rare.
Both are located in the periphery, not strongly
Typical (Low Grade) associated with smoking, produce mucin, and
• Well differentiated may have KRAS & EGFR mutations. Also they
• Low mitotic rate tend to affect young non-smoking women.
• No necrosis Squamous Cell Carcinoma is another
• Can spread to hilar lymph nodes primary tumor and is located centrally near the
• Metastasis is rare hilar lymph nodes. It originates from
epithelium cells and doesn’t produce mucin.
Atypical (Intermediate Grade)
This commonly affects older men, and is
• Less differentiated
associated with smoking. A common
• Higher mitotic rate
• Focal necrosis
• More likely to metastasize
• May have p53 mutation (20-40%)

Pulmonary 134
which is characteristic of squamous cell

carcinomas.
Small Cell Cancer is an aggressive

cancer of neuroendocrine cells that is
characteristic of having paraneoplastic
syndromes, notably Cushing’s Syndrome. It also
has a strong association with smoking. Serum
markers such as Synaptophysin, Chromogranin,
CD56, PTH-like, gastrin, ACTH, and ADH may
are present.


breast cancer.
Histology: Proliferation of neoplasm cells within the alveolar space and are small, round, uniform, and with
moderate cytoplasm.

Pulmonary 135
Pulmonary Hamartoma
Common slow growing benign
neoplasm of the lungs which is compromised of Complications
disorganized normal lung tissue. Can be
chondromatous (most common) or If due to granulomatous disease, possible
leiomyomatous (can be a mixture of both).
development into malignancy
If due to histoplasmosis or tuberculosis, has

Etiology calcification.
May be due to an inflammatory response to

a prior granulomatous infection, such as:
Differentials
• Tuberculosis
• Coccidiomycosis Any lung neoplasm will show a mass in
• Histoplasmosis the lungs. The hamartoma is asymptomatic and
• Mycobacteria is usually an incidental finding. The other lung
cancers start as asymptomatic, but will
Risks: eventually develop lesions. Look for key words
• Male with biopsy such as “normal lung tissue” or
• 40-50s “prior granulomatous infections.”
Pathogenesis
• Prior granulomatous infection

• Tissue becomes disorganized
• Grows at the same rate as the surround
tissue
Signs & Symptoms

Asymptomatic
Incidental finding on CXR as a coin lesion
Gross: A growth that is white, well demarcated,

solitary, and found in the periphery. This is
composed of disorganized normal lung tissue.

Pulmonary 136
Metastasis to the Lungs

Metastasis to the lungs from cancer’s
originating outside of the lungs. Pathogenesis
The lungs are one the most common
site of metastasis deposition, the other being Metastasis via hematogenous,
the liver. lymphatic, or cavity spread.
Metastatic deposits are also the most Sites of metastasis deposits include:
common type of lung cancer. • Parenchyma
• Pleura and pleural space
• Lymphatics
Etiology
Signs & Symptoms
Mostly from breast cancer.
Also from: • Dyspnea

• Colon Cancer • Hypoxia
• Renal Cell Carcinoma • Chest Pain
• Ovarian Caner • Hemoptysis
• Melanoma • Cachexia
• Sarcoma
Biopsy
CXR: Diffuse radio opaque lesions
CXR: Bilateral radio opaque nodules spread throughout the lungs.

Gross: Multiple white nodular lesions spread throughout the lungs bilaterally.

Pulmonary 137
- Metastasis from outside
- Breast Cancer
Primary tumor of the lungs will have a - Lungs are most common site
single primary tumor, not multiple lesions. for metastatic deposition
Histology or immunochemistry will show the
tumor origin.
• Vimentin indicates sarcoma

• Cytokeratin indicates carcinoma
• Desmin indicates rhabdomyosarcoma
Adenocarcinoma in-situ is an exception to

the single tumor rule, which can present with
multiple diffuse tumors.
The causes of hemoptysis are cancer, TB,

pneumonia, and bronchitis.
TB CXR will have a single lesion or multiple

cavities in the apex as well as a fever.
Pneumonia will have fever and culture growth
from the sputum. Bronchitis won’t have
parenchymal lesion on CXR.

Pulmonary 138
Vignettes
1) Tammy, a 36 year old Asian woman, comes 3) Janet comes to you with a fever and a
into the emergency room with difficulty productive cough that has rusty colored
breathing and chest pain. She appears to be sputum. Taking her history, you know that she
breathing rapidly and with difficulty. You doesn’t drink alcohol, smoke, have any chronic
auscultate her lungs and can barely hear breath diseases, or have any recent infections. You
sounds in the left lower lobe. You order a CXR perform a chest x-ray and see that her right
which shows a radio-opaque section over her lower and middle lobe are completely opaque.
lower left lobs and a coin lesion on the What is the most likely causative agent for
periphery of the left lung. What is currently Janet’s disease?
happening in Tammy’s lungs?
a) Klebsiella pneumoniae
a) Cicatrization atelectasis b) Staphylococcus aureus
b) Resorption atelectasis c) Haemophilus influenzae
c) Contraction atelectasis d) Pseudomonas aeruginosa
d) Compression atelectasis e) Streptococcus pneumoniae
e) ARDS
2) Jack is an obese alcoholic who has difficulty 4) Hannah comes to the ER because she has
breathing. On observation you note that his lips difficulty breathing and is coughing up specks of
and nail beds have a slight blue tinge. First you blood. You order a chest x-ray which shows
perform an echo which shows a normal heart. multiple radio opaque lesions bilaterally. Her
Then you order a chest x-ray, which shows family history has multiple family members with
bilateral interstitial infiltrate. You measure his a specific cancer. Which of the following
PaO2 and find that it is 43 mmHg. He is mutations does Hannah most likely have?
immediately placed on oxygen therapy, and his
PaO2 is re-evaluated at 48 mmHg. Which of the a) WT-1
following is most responsible for the up b) Rb
regulation of the pro-inflammatory cytokines? c) BRCA2
d) hMLH1
a) IL-8 e) APC
b) NF-κB
c) PAF
d) TGF-β
e) IL-10

Pulmonary 139
5) Betty present with difficulty breathing. As she 7) Clinton, a 46 year old smoker, has been
breaths, she purses her lips together and having difficulty breathing on exertion that has
hunches forward. She also has a chronic cough been progressively getting worse. On
with little to no sputum. With her history you auscultation you hear inspiratory crackles. His
discover that she takes aspirin to alleviate her CXR shows diffuse fibrosis, and a biopsy of the
chest pain and has been smoking for most of lung shows that all the fibrosis started at about
her life. On physical examination, you note that the same time. What is the most likely
she has a barrel chest, pedal edema, and restrictive pulmonary disease?
icterus. What is the most likely etiology of
Betty’s disease? a) Idiopathic Pulmonary Fibrosis
b) Acute Interstitial Pneumonia
a) α-1 antitrypsin deficiency c) Lymphoid Interstitial Pneumonia
b) Smoking d) Nonspecific Interstitial Pneumonia
c) Pulmonary Infection e) Pneumoconiosis
d) Type II Hypersensitivity
e) Aspirin
6) Eva, a 43 year old woman, is a long time 8) Fernando has difficulty breathing and a
smoker who comes in with a cough, purple lines persistent cough that is yellow and smells fetid.
on her abdomen, a new mustache, and what You note that his fingers are clubbed and his
looks like a buffalo hump on her back. On CXR, history has several recent pulmonary infections.
you see a coin lesion that is central. You run a His CXR shows bronchial dilations and fibrosis.
panel of serum markers and she is positive for Knowing Fernando’s diagnosis, which of the
synaptophysin and chromogranin. Eva’s major following congenital disorders is able to
complication that she presented with is due to contribute to the development of this disease?
what pathogenesis? a) Kartagener Syndrome
a) Hypervolemia b) Marfan Syndrome
b) Elevated glucocorticoids c) Turner Syndrome
c) Hypocalcemia d) α-1 antitrypsin deficiency
d) Increased gastric acid secretion e) EGFR Mutations
e) Hypercalcemia

Pulmonary 140
9) Erik, a smoker, comes into your office with a 11) Annabelle’s parents say that she has
cough, difficulty breathing, chest pain, and dark recurring episodes of difficulty breathing,
yellow urine. You do a CXR which shows a coughing, and wheezing whenever she is near a
lesion in the periphery of the lungs. Biopsy of cat. The attacks last a few hours and are very
the lesion shows sheets of small epithelium distressing for everyone. She had an attack just
cells with little cytoplasm, finely granular prior to coming to your office, and the parents
chromatin, nuclear molding, necrosis, and a give you a bit of her sputum. What would you
high mitotic count. Blood tests show expect to see in microscopy of the sputum?
synaptophysin and elevated ADH. What other
lung neoplasm has a neuroendocrine origin? a) Red Blood Cells
b) Lymphocytes
a) Adenocarcinoma c) Gram (+) Bacteria
b) Squamous Cell Carcinoma d) Charcot-Leyden Crystals
c) Bronchial Carcinoid e) Normal Sputum
d) Hamartoma
e) Bronchioalveolar carcinoma
10) Naomi, a 39 year old Japanese woman, 12) Darren goes to you, his GP, because of some
present with a persistent cough with sputum. difficulty breathing, mild chest pain, muscle
You perform a CXR which shows a coin lesion in twitches, and memory loss. He is a social
the upper periphery of her right lung. Biopsy of drinker and has been smoking for decades.
the lesion shows proliferation of gland Serum analysis shows hypercalcemia and PTH-
epithelium. What mutation that if Naomi had, like peptides. You take a CXR and find a
would have the worst prognosis? centrally located coin lesion near the hilum.
What characteristic feature would most likely
a) EGFR be seen on his biopsy?
b) P53
c) RB a) Normal Alveolar Structure covered by
d) WT neoplasm
b) Keratin Pearls
e) BCL2
c) Proliferative glandular epithelium
d) Vacuolated cells with mucin
e) Neoplastic cells in the bronchial lumen

Pulmonary 141

1) (D) Tammy, a 36 year old Asian woman, a) IL-8
comes into the emergency room with difficulty b) NF-κB (Correct)
breathing and chest pain. She appears to be c) PAF
breathing rapidly and with difficulty. You d) TGF-β
auscultate her lungs and can barely hear breath e) IL-10
sounds in the left lower lobe. You order a CXR
which shows a radio-opaque section over her
lower left lobs and a coin lesion on the 3) (E) Janet comes to you with a fever and a
periphery of the left lung. What is currently productive cough that has rusty colored
happening in Tammy’s lungs? sputum. Taking her history, you know that she
Tammy has adenocarcinoma complicated by doesn’t drink alcohol, smoke, have any chronic
pleural effusion. The effusion then occupies the diseases, or have any recent infections. You
space usually occupied by the lungs, causing perform a chest x-ray and see that her right
lower and middle lobe are completely opaque.
mechanical compression.
What is the most likely causative agent for
a) Cicatrization atelectasis Janet’s disease?
b) Resorption atelectasis
c) Contraction atelectasis Janet has pneumonia. The most common agent
d) Compression atelectasis (Correct) is S. pneumoniae. The others are also ruled out
e) ARDS by her history.
a) Klebsiella pneumoniae - Alcoholics

b) Staphylococcus aureus – Recent Viral
2) (B) Jack is an obese alcoholic who has Infection
difficulty breathing. On observation you note c) Haemophilus influenzae - COPD
that his lips and nail beds have a slight blue d) Pseudomonas aeruginosa – Cystic
tinge. First you perform an echo which shows a Fibrosis
normal heart. Then you order a chest x-ray, e) Streptococcus pneumoniae (Correct)
which shows bilateral interstitial infiltrate. You
measure his PaO2 and find that it is 43 mmHg.
He is immediately placed on oxygen therapy,
and his PaO2 is re-evaluated at 48 mmHg.
Which of the following is most responsible for
the up regulation of the pro-inflammatory
cytokines?
Jack has developed ARDS, which is in part

caused by the up regulation of NF-κB, which in
turn up regulates pro-inflammatory cytokines.

Pulmonary 142
4) (C) Hannah comes to the ER because she has 6) (B) Eva, a 43 year old woman, is a long time
difficulty breathing and is coughing up specks of smoker who comes in with a cough, purple lines
blood. You order a chest x-ray which shows on her abdomen, a new mustache, and what
multiple radio opaque lesions bilaterally. Her looks like a buffalo hump on her back. On CXR,
family history has multiple family members with you see a coin lesion that is central. You run a
a specific cancer. Which of the following panel of serum markers and she is positive for
mutations does Hannah most likely have? synaptophysin and chromogranin. Eva’s major
complication that she presented with is due to
Hannah has metastasis to her lungs, meaning
what pathogenesis?
she has cancer elsewhere. The most common
cancer to do this is breast cancer, which is Eva has small cell lung carcinoma with the
related to BRCA mutations. paraneoplastic syndrome of Cushing Syndrome.
Cushing Syndrome is due to elevated
a) WT-1 – Wilms Tumor
glucocorticoids, which are elevated due to the
b) Rb – Retinoblastoma and subsequent
increased ACTH released by the tumor.
osteosarcoma
c) BRCA2 – Breast Cancer & Ovarian a) Hypervolemia – ADH
(Correct) b) Elevated glucocorticoids (Correct)
d) hMLH1 – HNPCC Colon Cancer c) Hypocalcemia - Calcitonin
e) APC – FAP Colon Cancer d) Increased gastric acid secretion - gastrin
e) Hypercalcemia – PTH-like peptide
5) (A) Betty present with difficulty breathing. As

she breaths, she purses her lips together and 7) (D) Clinton, a 46 year old smoker, has been
hunches forward. She also has a chronic cough having difficulty breathing on exertion that has
with little to no sputum. With her history you been progressively getting worse. On
discover that she takes aspirin to alleviate her auscultation you hear inspiratory crackles. His
chest pain and has been smoking for most of CXR shows diffuse fibrosis, and a biopsy of the
her life. On physical examination, you note that lung shows that all the fibrosis started at about
she has a barrel chest, pedal edema, and the same time. What is the most likely
icterus. What is the most likely etiology of restrictive pulmonary disease?
Betty’s disease?
The main differentiator here from IPF is the lack
Betty has a typical emphysema presentation of temporal heterogeneity, because the biopsy
with the addition of liver involvement. The liver has all the fibrosis at about the same age.
involvement indicates α-1 antitrypsin deficiency
a) Idiopathic Pulmonary Fibrosis
over smoking.
b) Acute Interstitial Pneumonia
a) α-1 antitrypsin deficiency (Correct) c) Lymphoid Interstitial Pneumonia
b) Smoking d) Nonspecific Interstitial Pneumonia
c) Pulmonary Infection (Correct)
d) Type II Hypersensitivity e) Pneumoconiosis
e) Aspirin

Pulmonary 143
8) (A) Fernando has difficulty breathing and a c) Bronchial Carcinoid (Correct)

persistent cough that is yellow and smells fetid. d) Hamartoma
You note that his fingers are clubbed and his e) Bronchioalveolar carcinoma
history has several recent pulmonary infections.
His CXR shows bronchial dilations and fibrosis.
Knowing Fernando’s diagnosis, which of the 10) (A) Naomi, a 39 year old Japanese woman,
following congenital disorders is able to present with a persistent cough with sputum.
contribute to the development of this disease? You perform a CXR which shows a coin lesion in
Fernando has bronchiectasis due to the fetid the upper periphery of her right lung. Biopsy of
sputum, dilated bronchi, and pulmonary the lesion shows proliferation of gland
infections. The question then asks what epithelium. What mutation that if Naomi had,
congenital disorders are associated with would have the worst prognosis?
bronchiectasis, which is Cystic Fibrosis and Naomi has adenocarcinoma. A mutation in
Kartagener Syndrome. EGFR will make EGFR inhibitor therapy
a) Kartagener Syndrome (Correct) ineffective and has a worse prognosis. KRAS
b) Marfan Syndrome mutations have a similar problem, only KRAS is
c) Turner Syndrome downstream in the signaling pathway. The
d) α-1 antitrypsin deficiency other mutations are possible mutations in the
e) EGFR Mutations formation of cancer, but does not directly effect
the prognosis.
a) EGFR (Correct)
9) (C) Erik, a smoker, comes into your office b) P53
with a cough, difficulty breathing, chest pain, c) RB
and dark yellow urine. You do a CXR which d) WT
shows a lesion in the periphery of the lungs. e) BCL2
Biopsy of the lesion shows sheets of small
epithelium cells with little cytoplasm, finely
granular chromatin, nuclear molding, necrosis,
and a high mitotic count. Blood tests show
synaptophysin and elevated ADH. What other
lung neoplasm has a neuroendocrine origin?
Erik has small cell lung carcinoma, which

originates from neuroendocrine cells. The other
lung carcinoma that originates from
neuroendocrine cells is bronchial carcinoid,
which comes from Kulchitsky neuroendocrine
cells.
a) Adenocarcinoma
b) Squamous Cell Carcinoma

Pulmonary 144
11) (D) Annabelle’s parents say that she has

recurring episodes of difficulty breathing,
coughing, and wheezing whenever she is near a
cat. The attacks last a few hours and are very
distressing for everyone. She had an attack just
prior to coming to your office, and the parents
give you a bit of her sputum. What would you
expect to see in microscopy of the sputum?
Annabelle has asthma, which has Charcot-

Leyden Crystals and Curshmann Spirals in the
sputum.
a) Red Blood Cells

b) Lymphocytes
c) Gram (+) Bacteria
d) Charcot-Leyden Crystals (Correct)
e) Normal Sputum
12) (B) Darren goes to you, his GP, because of

some difficulty breathing, mild chest pain,
muscle twitches, and memory loss. He is a
social drinker and has been smoking for
decades. Serum analysis shows hypercalcemia
and PTH-like peptides. You take a CXR and find
a centrally located coin lesion near the hilum.
What characteristic feature would most likely
be seen on his biopsy?
Darren has squamous cell carcinoma, which

characteristically has keratin pearls.
a) Normal Alveolar Structure covered by

neoplasm
b) Keratin Pearls (Correct)
c) Proliferative glandular epithelium
d) Vacuolated cells with mucin
e) Neoplastic cells in the bronchial lumen

Reproductive & Urogenital 145
Reproductive & Urogenital
Ovaries Male Genital Tract

Simple Cyst 146 Urothelial Carcinoma 172
Polycystic Ovarian Disease 147 Nodular Hyperplasia of Prostate 174
Serous Cystic Neoplasms 149 Prostate Adenocarcinoma 175
Mucinous Cystic Neoplasms 152 Cryptorchism 176
Brenner Tumor 155 Seminoma Testis 177
Dermoid Cyst 156 Carcinoma of the Penis 178
Struma Ovarii 158 Breasts

Fibroadenoma 179
Dysgerminoma 159
Phyllodes Tumor 181
Ovarian Choriocarcinoma 160
Intraductal Papilloma s 182
Granulosa Cell Tumor 161
Paget’s Disease of the Breast 183
Fibro-Thecoma Tumor 162
Breast Carcinoma 184
Krukenberg Tumor 163
Sexually Transmitted Infections
Female Genital Tract
Condyloma Acuminatum 187
Endometrial Carcinoma 164
Genital Herpes 188
Uterine Fibroid - Leiomyoma 166
Cervical Carcinoma 167
Ectopic Pregnancy 169
Hydatidiform Mole 170
Gestational Choriocarcinoma 171

Simple Cyst
Simple non-neoplastic cyst due to an
unruptured follicular cyst or a sealed off corpus Differentials
luteum.
Simple Cysts are simple, they’re just a
Etiology cyst. They can be secondary, as in PCOD.
Chocolate cysts are cysts filled with

• Unruptured follicular cyst hemorrhagic tissue and is a complication of
• Ruptured and sealed off – corpus luteal endometriosis in the ovaries. It leads to fibrosis
and adhesions, which present with pain. May
cause infertility.
Pathogenesis
Endometrioid tumors may be cystic
with papillae, or otherwise resemble
• Prolonged estrogen state
endometrial carcinoma. May occur along side
o Obesity
with endometrial carcinoma, but is not a
o Cirrhosis
metastasis.
• Follicular cyst fails to rupture
o Anovulation Serous cystic neoplasms can resemble
• Alternatively can rupture and form into a simple cyst, since they have a serous cyst, but
a sealed off hemorrhagic corpus luteal they may be multiloculated or have papillae on
cyst the cyst wall.
• Tends to occur often and form multiple
cysts
Signs & Symptoms
• Asymptomatic if <2cm
• Painful
• Endometrial hyperplasia
Complications
Acute abdominal pain:
• Torsion Gross: A simple cyst filled with serous fluid and lined
• Rupture by a grey glistening membrane. Usually <2 cm in
diameter, but can be as large as 5 cm.

Polycystic Ovarian Disease

Persistent anovulation and
accumulation of simple cysts within the ovary. Signs & Symptoms
Aka Stein Leventhal Syndrome.
• Persistent anovulation
Etiology • Oligomenorrhea or Secondary
amenorrhea
• Excess estrogens
• Unknown
o Obesity
• Thought to be poor regulation of
o Endometrial hyperplasia
enzymes in androgen biosynthesis.
• Excess androgens
• Affects 3-6% of women in reproductive
o Hirsutism
age
o Virilization
o Excess estrogens
Pathogenesis Transvaginal US: Cysts are visible
Labs:
• Excess androgen secretion by ovary
• Androgens converted to estrogen by • High LH
adipose • Low FSH
• Estrogen inhibits FSH release • LH:FSH ratio >3
• Estrogen stimulates GnRH release • Hyperinsulinemia
• GnRH releases LH • High estrogen
• LH stimulates thecal cells to release • High androgens
androgens
Complications
• Infertility
• Masculinization/Hirsutism
• Obesity
• Endometrial Hyperplasia
Gross: The ovaries (seen here cut and split open) are enlarged with a thick capsule and hypertrophic stroma.
There will be multiple unruptured follicles and no corpus luteum.

Differentials
PCOD is fairly characteristic, and is the
main cause of persistent anovulation. The
enlarged encapsulated ovaries filled with simple
cysts are key characteristics. The LH:FSH ratio
will be large (>3) and will have symptoms
related to excess estrogen and androgens.
Serous cystic neoplasms will have a

serous cyst as well, but usually just one with no
thick ovarian capsule and will have psammoma
bodies on biopsy.
Anovulation:
• Pituitary lesions
• Hyperprolactinemia
• PCOD

Serous Cystic Neoplasms

Surface epithelial tumors that are of the Risk Factors
serous type. The three variants are similar is • Age
etiology and presentation, so they are grouped o Benign: 30-40 years old
together here. o Malignant: >50 years old
• Nulliparity
• Serous Cystadenoma
• Family history
o Benign
• BRCA1, BRCA2, HER2/NEU
• Borderline Serous Cystadenoma
• Use of oral contraceptives reduce risk
o in situ
• Serous Cystadenocarcinoma
o Most common malignancy in Pathogenesis
ovaries
o 2/3 are bilateral
• Accumulation of cancerous mutations
• Differentiation into serous type
Etiology o Fallopian tube like
o Columnar cells with cilia
• Production of serous material
Unknown
• Cyst formation
Gross: A large cystic mass which may be singular or multiloculated. Cystadenoma (Left) tends to have a
smooth glistening serosa. In contrast, the cystadenocarcinoma (Right) has nodular irregularities and more
papillary projections. Borderline (Middle) will also have the nodular irregularities.

Borderline:
• Often see mutations in BRAF and KRAS Complications
Cystadenocarcinoma:
Poor prognosis with nulliparity and a
• Often have mutations in p53 and BRCA1
family history.
Signs & Symptoms

Malignant Metastasis:
• Early is asymptomatic • Periaortic lymph nodes
• Enlarged mass
o Abdominal enlargement
o Sense of fullness
o Pelvic or back pain, can be
exacerbated by movements
o Increased urination frequency
Additional Info
Labs:
• 25% bilateral
• CA 125 – serum treatment marker
• 30-40cm
Microscopy: Cystadenoma (Left) will have a single layer of columnar ciliated cells lining the cysts, with
some dome-shaped secretory cells. There may be psammoma bodies or small papillae. Borderline (Middle)
is similar but has more disorder, with nuclear atypia, mitotic figures, and stratified epithelium. There is no
stromal invasion. Cystadenocarcinoma (Right) will have stromal invasion. There will be more psammoma
bodies and papillae/polyps, which is used to help determine malignancy.

The other ovarian tumors include:

Differentials
Germ Cell Tumors:
• Dermoid Cyst (Mature Teratoma)
Serous cystic neoplasms are relatively
• Struma ovarii
common ovarian tumors, with
• Carcinoid
cystadenocarcinoma being the most common
• Dysgerminoma
malignant ovarian tumor. If there is mention of
• Endodermal Sinus Tumor (Yolk Sac)
psammoma bodies or papillae, think serous,
• Choriocarcinoma
although mucinous can have them as well.
Sex Cord Tumors:
Serous also tends to be bilateral,
• Granulosa Cell
especially the malignant variety. The only other
• Fibroma
tumor that is mostly bilateral is Krukenberg,
• Theca Cell
which is metastasis from elsewhere with signet
ring cells. • Sertoli Leydig
• Mixtures of the above
Mucinous cystic neoplasms are rarer
than serous, but tend to have a better
prognosis. Look for the contents of the cyst and
the lack of psammoma bodies, papillae, and
cilia. Pseudomyxoma peritonei is a specific
complication to mucinous cancers of the ovaries
and appendix.
Another surface tumor is the

Endometrioid tumor. It produces solid and
cystic masses with papillae and a velvety
surface. The cysts are lined with endometrial
like cells but does not form normal
endometrium (not endometriosis). It can occur
alongside with endometrial carcinoma, but not
always and is not a metastasis.
Brenner Tumor is an interesting tumor

that grows transitional like epithelium in the
ovaries, similar to what is found in the urinary
lining. It is usually benign but can be malignant.
All surface epithelium tumors tend to

present the same clinically and have the CA 125
serum marker. The differences come down to
morphology.

Mucinous Cystic Neoplasms

Surface epithelial tumors that are of the
mucinous type. The three variants are similar is Signs & Symptoms
etiology and presentation, so they are grouped
together here.
• Early is asymptomatic
• Mucinous Cystadenoma • Enlarged mass
o Benign o Abdominal enlargement
• Borderline Mucinous Cystadenoma o Sense of fullness
o in situ o Pelvic or back pain, can be
• Mucinous Cystadenocarcinoma exacerbated by movements
o Malignant o Increased urination frequency
• Malignant:
o Progressive weakness
Etiology o Cachexia
US: Mass is visible

Unknown
Labs:
Risk Factors
• CA 125 – treatment marker
• Age
o Benign: 30-40 years old
o Malignant: >50 years old Complications
• Nulliparity
• Family history Borderline & Malignant
• BRCA1, BRCA2, HER2/NEU
• Use of oral contraceptives reduce risk Pseudomyxoma peritonei
• Peritoneal cavity filled with mucoid
material
Pathogenesis • Also a complication of mucocele of
appendix due to carcinoma
• Accumulation of cancerous mutations
Metastasis to:
• Over-expression of KRAS
• Liver
• Differentiation into mucinous type
• Lung
o endocervix like
• GIT
o Columnar cells without cilia
• Other ovary (50%)
• Production of mucinous material
• Cyst formation Better prognosis than serous

Gross: Multiloculated cysts filled with a gelatinous material that is rich in glycoproteins. Cystadenoma (Left)
will have a smooth and glistening serosa. Cystadenocarcinoma (Right) will have solid nodules.
Microscopy: Cysts are lined by tall columnar cells without cilia and apical mucus vacuoles. Cystadenoma
(Left) will have a single layer of cells, whereas Cystadenocarcinoma (Right) will have multiple layers along
with atypia and stromal invasion.


Differentials
Germ Cell Tumors:
• Dermoid Cyst (Mature Teratoma)
Mucinous cystic neoplasms are rarer
• Struma ovarii
than serous, but tend to have a better
• Carcinoid
prognosis. Look for the contents of the cyst and
• Dysgerminoma
the lack of psammoma bodies and papillae.
• Endodermal Sinus Tumor (Yolk Sac)
Pseudomyxoma peritonei is a specific
• Choriocarcinoma
complication to mucinous cancers of the ovaries
and appendix. Sex Cord Tumors:
• Granulosa Cell
Serous cystic neoplasms are relatively
• Fibroma
common ovarian tumors, with
• Theca Cell
cystadenocarcinoma being the most common
malignant ovarian tumor. If there is mention of • Sertoli Leydig
psammoma bodies or papillae, think serous, • Mixtures of the above
although mucinous can have them as well.
Serous will also have cilia.
Another surface tumor is the

Endometrioid tumor. It produces solid and
cystic masses with papillae and a velvety
surface. The cysts are lined with endometrial
like cells but does not form normal
endometrium (not endometriosis). It can occur
alongside with endometrial carcinoma, but not
always and is not a metastasis.
Brenner Tumor is an interesting tumor

that grows transitional like epithelium in the
ovaries, similar to what is found in the urinary
lining. It is usually benign but can be malignant.
All surface epithelium tumors tend to

present the same clinically and have the CA 125
serum marker. The differences come down to
morphology.

Brenner Tumor
Benign unilateral tumor of the ovaries
that is characteristic of having transitional Differentials
epithelium.
Brenner tumor is a surface epithelium
Etiology tumor that has a characteristic feature of
transitional epithelium. Also, mention of
“coffee bean” nuclei points to Brenner.
May come from urogenital remnants.
Otherwise if acts just like the other surface
epithelium tumors:
Pathogenesis • Serous cystic
• Mucinous cystic
Develop from surface epithelium or urogenital • Endometrioid
epithelium within germinal ridge
Thought to arise from Walthard cell rests
Signs & Symptoms

Clinically silent
If large enough may have:

• Abdominal pain
• Swelling
• Dysuria
• Increased frequency of urination
Labs:
• CA 125 – treatment marker
Complications
Occasionally malignant.
Microscopy: Abundance of stroma with nests of transitional-like epithelium, which is normally only found in
the urinary tract. These nests can be cystic and lined by columnar mucus secreting cells. The nest cell’s
nuclei have the appearance of “coffee beans.”

Dermoid Cyst
Germ cell tumor formed from multiple • Limbic encephalitis
germ layers that mostly form in the ovaries and • Infertility
testes. Most common germ cell tumor (95%). • 1% develop into malignant squamous
cell carcinoma
Aka benign mature cystic teratoma.
Etiology Differentials
Dermoid Cysts are pretty characteristic
• Teratoma arising from totipotent germ
with the ectopic growth of things like hair or
cells from 2-3 germ layers.
teeth.
Pathogenesis Immature Teratomas are much less

differentiated and malignant. Presence of
neuroepithelium suggests malignancy. These
• Mutation in totipotent stem cell(s) tend to occur in younger patients as well as in
• Proliferation of at least 2 germ layers men.
o Ectoderm
o Mesoderm Single layer teratomas include struma
o Endoderm ovarii and/or carcinoid tumors. Struma ovarii is
thyroid tissue with complete follicles in the
ovaries. This can lead to hyperthyroidism.
Signs & Symptoms Carcinoid tumors secrete serotonin and can
lead to carcinoid syndrome.
• Unilateral mass up to 10cm and may
contain hair, teeth, bone, cartilage,
thyroid, etc.
o Tend to form on the right side
• Asymptomatic
Complications
• Torsion
o Lower abdominal pain
o N/V
Gross: A 5 cm well-circumscribed mass with its contents

including hair and other normal ectopic tissues.

The other germ cell tumors are

endodermal sinus tumor (yolk sac), Additional Info
dysgerminoma, and choriocarcinoma.
Endodermal Sinus Tumors tend to • May be mixed with choriocarcinoma,

occur in children and young women. It is a endodermal sinus tumor, embryonal
malignant tumor with cystic space and papillary carcinoma
projections. There will also be Schiller-Duval
Bodies, which resemble glomeruli with layers of
epithelium around blood vessels. Serum
analysis will show high α-feto protein and α-1-
antitrypsin. Occurs in both ovaries and testes.
Dysgerminoma is a malignant tumor

that can occur with gonadal dysgenesis, such as
Turner’s syndrome. There will be elevated LDH
and maybe hCG as well.
Choriocarcinoma of the ovaries is a

non-gestational choriocarcinoma that is very
fatal and resistant to treatment. It rarely occurs
alone and incredibly rare in the ovaries, more
common (still rare) in the testes.
Surface Epithelium:
• Serous cystic
• Mucinous cystic
• Endometrioid
• Brenner
Sex Cord Tumors:

• Granulosa Cell
• Fibroma
• Theca Cell
• Sertoli Leydig
• Mixtures of the above
Microscopy: A random collection of various ectopic tissues. Here we see sebaceous units connected to cysts
and hair follicles. The dermoid cyst itself is lined by squamous epithelium.

Struma Ovarii
Mature thyroid tissue in the ovary. o Irritability
Occurs in people aged 40-60 years. o Short term memory loss
o Delusions
o Hallucinations
Etiology o Seizures
• Malignancy
Specialized or monodermal teratoma o >6cm = 75% chance
Pathogenesis Differentials
• Mutation of totipotent stem cell Struma ovarii has the characteristic of
• Differentiates along the line of a single ectopic thyroid in the ovaries. May have
abnormal tissue symptoms of hyperthyroidism without any
• May cause hyperthyroidism thyroid pathology.
Monodermal teratomas
Signs & Symptoms • Struma ovarii
• Carcinoid tumor
• Struma carcinoid (both)
• Asymptomatic in early stages
• Abdominal pain See Dermoid Cyst for a complete differential of
• Palpable mass germ cell tumors.
• Ascites
Biopsy: Thyroid follicles in ovary
Complications
• Hyperthyroidism
• Sterility
• Paraneoplastic syndromes
o Inflammatory limbic
encephalitis
Microscopy: Presence of thyroid follicles in the ovary. The follicles are filled with colloid and may act like
normal thyroid tissue without strong regulation from the pituitary (TSH).

Dysgerminoma
Unilateral malignant germ cell tumor.
Differentials
Etiology
Dysgerminoma will have the elevated
LDH and possible increased hCG. If there is
Risk Factors mention of Turner’s syndrome or
• 75% occur 10-20s pseudohermaphroditism, think dysgerminoma.
• Gonadal dysgenesis
o Turner’s Syndrome Male counterpart is seminoma testis.
o Pseudohermaphroditism
See Dermoid Cyst for a complete differential of
germ cell tumors.
Pathogenesis
Additional Info
• Germ cell tumor
• Some occur in gonadal dysgenesis, such
Good prognosis, chemo and radio sensitive
as Turner’s syndrome
• Can produce hCG (20% have)
Signs & Symptoms
• Asymptomatic in early stages

• Abdominal pain
• Palpable mass
• Vaginal bleeding
• Symptoms of pregnancy
o hCG
Labs:
• Elevated LDH
• Elevated hCG (not all cases)
Microscopy: Large cells with clear cytoplasm, well defined membranes, a central regular nucleus, and very
little stroma. There is lymphocytic infiltration with the occasional granuloma.

Ovarian Choriocarcinoma
Extremely rare non-gestational
choriocarcinoma. More common in testes. This Differentials
cancer almost always exists in combination with
other germ cell tumors. Ovarian Choriocarcinoma will not
present by itself, but alongside other germ cell
Etiology tumors. Tends to be asymptomatic until
metastasis. Biopsy of an ovarian tumor with a
high level of disorganization with anaplasia and
Not-specified syncytia points toward choriocarcinoma.
Gestational Choriocarcinoma tends to

Pathogenesis follow some form of pregnancy, normal or
pathological (usually a hydatidiform mole). It
Not-specified will present with abdominal pain and/or
irregular vaginal bleeding. This has a much
better prognosis.
Signs & Symptoms
See Dermoid Cyst for a complete differential of
germ cell tumors.
• Very fatal
• Asymptomatic
• Symptoms of metastasis Additional Info
Labs:
• Increased CGT & hCG • Resistant to treatment
o very poor prognosis
Complications
Metastasis
• Heme spread
• Lungs
• Liver
• Bone
Microscopy: Disorganized growth of cells with prominent nucleoli. Also seen is high mitotic activity,
necrosis, anaplasia, pleomorphism, giant cells, and syncytia.

Granulosa Cell Tumor

Sex chord tumor of granulosa cells.
Differentials
Etiology
There are three main types of sex chord
tumors that tend to mix and match.
• Occurs mostly in post-menopausal
Granulosa Cell Tumors tend to secrete
inhibin, which lowers FSH. They will also cause
Pathogenesis excess estrogen production.
Fibroma and Thecal Cell Tumors are

• Derived from granulosa cells in the
more benign, with increases in fibrosis or thecal
ovarian stroma
cells. These two are also common associated
• Secrete inhibin, used as a marker
with Basal Cell Nevus Syndrome or Meigs’
o Low FSH
Syndrome.
Signs & Symptoms Another type of sex chord tumor is

Sertoli-Leydig Cell Tumor (Androblastoma).
This is a benign tumor that occurs in the 2nd and
• Excess estrogen 3rd decade of life and leads to defeminization
o Precocious puberty and masculinization of the patient.
o Endometrial hyperplasia
o Cystic disease of the breast
o Endometrial carcinoma
Complications
• Excess androgens
o Masculinization
• Potential for malignancy
Microscopy: Densely packed sheet of cells that are cuboidal or polygonal. The spots of acidophilic material
are called Call-Exner bodies.

Fibro-Thecoma Tumor
Benign sex chord tumor of fibroblasts
and thecal cells. Individually would be call Differentials
fibroma or thecoma, respectively.
There are three main types of sex chord
Etiology tumors that tend to mix and match.
Granulosa Cell Tumors tend to secrete

May be part of basal cell nevus syndrome inhibin, which lowers FSH. They will also cause
• Defects in skin, nervous system, eyes, excess estrogen production.
endocrine, and bones
Fibroma and Thecal Cell Tumors are
• AD with PTCH mutation
more benign, with increases in fibrosis or thecal
cells. These two are also common associated
Pathogenesis with Basal Cell Nevus Syndrome or Meigs’
Syndrome.
• Not-specified Another type of sex chord tumor is

Sertoli-Leydig Cell Tumor (Androblastoma).
Signs & Symptoms This is a benign tumor that occurs in the 2nd and
3rd decade of life and leads to defeminization
and masculinization of the patient.
• Pelvic Mass
• Possible pain
Complications
Meigs’ Syndrome
• Tumor
• Ascites
• Hydrothorax on right side
Microscopy: Well differentiated fibroblasts with

scant collagenous connective tissue. Focal areas of
thecal differentiation may be present, which will
have large polygonal cells with lipid droplets.

Krukenberg Tumor
Metastasis to the ovaries.
Differentials
Etiology
Krukenberg Tumors tend to be bilateral
and are the only ovarian tumor discussed with
Metastasis from: signet rings. There may be mention of a
• GI Cancers primary tumor elsewhere, typically from the GI
o Diffuse gastric carcinoma tract or breast.
o Colon
o Appendix Primary Ovarian Tumors tend to be
o Gallbladder unilateral, but not always. Serous
o Biliary Tract Cystadenocarcinoma is usually bilateral. The
o Pancreas presentation may be similar for most ovarian
• Breast tumors. Look to specific characteristics of each
• Bladder individual tumor.
Pathogenesis
• Primary tumor forms elsewhere

• Spreads to ovaries
o Method of spread
undetermined
Signs & Symptoms
• Abdominal & Pelvic Pain

• Bloating
• Ascites
• Pain during sex
Biopsy: Mucin filled signet rings
Immunohistochemistry: Determine origin Microscopy: Mucin filled signet ring cells.

Krukenberg tumors tend to affect both
ovaries.

Endometrial Carcinoma
Cancer of the endometrium, seen as an
asymmetric exophytic mass. It is the most Signs & Symptoms
frequent cancer of female genital tract.
• Leukorrhea
Etiology • Irregular vaginal bleeding
• Enlarged uterus (end stage)
• Estrogen excess Investigations:

• Endometrial atrophy • Hysteroscopy
• Transvaginal US
Risk Factors:
• Biopsy
• Aged 55-65
• Increased estrogen sensitivity
o Obesity Complications
o Hypertension
o Nulliparous
Metastasis
o Estrogen replacement therapy
• Direct
o Myometrium
Pathogenesis o Cervix
o Vagina
o Rectum
Microsatellite Instability
• DNA mismatch repair gene mutation
• MLH1, MSH2
Cowden’s syndrome
• PTEN mutation
• Multiple hamartoma syndrome
• Increased risk of breast, thyroid, and
endometrium carcinomas
Gross: Presence of an asymmetric exophytic

mass with infiltrative growth into the
myometrium.

• Lymphatic
o Iliac & paraortic lymph nodes Additional Info
• Hematogenous
o Lung Prognosis best with early detection.
o Liver
Differentials
Endometrial carcinoma is the first thing you
think of with post-menopausal bleeding.
• Endometrial hyperplasia
o No myoinvasion
o Endometrial Polyp
• Leiomyoma
o Benign myometrium tumor
o May also have pain (torsion) or
menorrhagia, but usually no
bleeding outside of
menstruation.
• Mixed Mullerian Tumor
o Arise from residual Mullerian
mesodermal cells
o Large mass with hemorrhage &
necrosis
o Poor prognosis
Uterine Bleeding:
• Abortion
• DUB
• Endometriosis
• Chronic Endometritis
• Endometrial
hyperplasia/polyp/carcinoma
Microcopy: Presence of multiple glandular structures that originated in the mucosa. Also note the
myometrium invasion.

Leiomyoma
Benign growth of smooth muscle in the • Compression
uterus. Aka Uterine Fibroid o Increased frequency of
urination
Etiology • Spontaneous abortion
• Uterine inertia during birth
Idiopathic
Risk Factors Ultrasound

• African descent
• Estrogen therapy Complications
• Oral contraceptives
• Reproductive age
Very rarely become leiomyosarcoma
• Slow growing monoclonal neoplasm of
Leiomyosarcoma is the malignant form.
smooth muscle.
Primarily found in an older age group (post
• Stimulated by genetic factors or
menopause).
estrogens
• Rapid growth during pregnancy Adenomyosis, or endometrial tissue in
• Shrink post-menopause myometrium.
Signs & Symptoms
• Asymptomatic
• Menorrhagia
o Iron deficiency anemia
• Can undergo torsion with pain
• Infertility
• Dystocia
o Difficult child birth
Gross: Solid white growths with sharp edged delineation and whorled cut surfaces that can be intramural,
submucosal, or subserosal.

Cervical Carcinoma
Squamous Cell Carcinoma of the cervix. • May invade stroma, becoming a
There is a strong correlation with HPV carcinoma
infections. Peak incidence 30 years for CIN and • Otherwise may regress
45 for invasive carcinoma.
Signs & Symptoms

Etiology
• Asymptomatic
Risk Factors: • Dyspareunia
• Early age of first intercourse • Vaginal bleeding
• Multiple sex partners • Leukorrhea
• Infection with HPV 16, 18, 31, 33, 45,
and some others Investigations:
• Multiple pregnancies • Pap smear
• Smoking • Schiller test
• Rare in nuns, Jews, Muslims • Colposcopic biopsy
• Peak age is 45 years
Complications
Pathogenesis
Metastasis
• HPV infection • Direct – Bladder, Rectum, Pelvic Wall
• Low risk HPV leads to condyloma • Distant - Lymph node, Liver, Lung, Bone
• High risk HPV has integration of viral
DNA into host chromosomes
• Viral E6 inhibits p53 and E7 inhibits RB
• Progression of CIN I, II, III
• CIN III aka Carcinoma in situ
Microscopy: Cervical Intraepithelial Neoplasia (CIN) progresses from CIN I (Left) to CIN III (Right), although it
will not always continue the progression and may regress. CIN I is limited to the lower 1/3 of the epithelium.
CIN II (Middle) to the lower 2/3. CIN III is complete or near complete thickness.

Differentials
Rarely may develop as endocervical
adenocarcinoma or endocervical
adenosquamous carcinoma instead of
squamous cell carcinoma.
Cervicitis is inflammation of the cervix,

which may produce a vaginal discharge. Can be
due to infection or post-partum.
High risk HPV has also been noted in a

similar process in the vulval wall, giving VIN and
subsequent vulvar carcinoma.
Pap Smear: Normal (Top) shows large cells Microscopy: Invasive islands of squamous cells
with a large cytoplasm to nucleus ratio. A located within the stroma. There are keratin
smear of CIN II (Bottom) shows cells with large pearls, signifying squamous cell origin.
nuclei and varying cell size.

Ectopic Pregnancy
Pregnancy with the embryo being
embedded outside of the uterus. Commonly in Complications
the fallopian tube. Can also occur in the ovaries
or enter the peritoneal cavity and implant Rupture of fallopian tubes – hemorrhage
there.
• Can mimic appendicitis
• Impeded movement of fertilized egg.
Finding fetal tissue outside of the uterus is a
• Obstruction, inflammation of the good indication of an ectopic pregnancy. Look
fallopian tube. for a description of a normal pregnancy but an
o Fibrosis empty uterus.
o PID w/ tubal adhesions
• Abdominal Pain
o PID
Pathogenesis o Endometriosis
o Gestational Carcinoma
• Egg is fertilized o Many others
• Egg’s path is impeded or slowed • Amenorrhea
• Egg implants outside of the uterus o Hydatiform Mole
• Irregular Vaginal Bleeding
o Hydatiform Mole
Signs & Symptoms o Gestational Carcinoma
o Cervical Carcinoma
Triad of:
• Abdominal pain
• Amenorrhea
• Vaginal Bleeding
Labs: Rise in normal pregnancy hormones
US: Mass of fetal tissue
Gross: Implantation and development of a fetus in the fallopian tube.

Hydatidiform Mole
Abnormal pregnency in which a non-
viable fertilized egg implants into the uterus. Complications
Etiology Invasive mole

• Deep invasion of villi into myometrium
• Necrosis & hemorrhaging
Abnormal paternal contribution to fertilization.
• Embolisms
Risk Factors:
Gestational Choriocarcinoma
• In Asia
• Not the only etiology
• Younger than 20 and older than 40
• Prior hydatidiform moles
Differentials
Pathogenesis
An apparent pregnancy without fetal heart
sounds, or the appearance of a “cluster of
Complete mole: 2 sperm or 1 diploid sperm
grapes” is indicative of a hydatidiform mole.
fertilize empty egg.
• Abdominal Pain
Partial mole: Normal egg fertilized by 2 sperm
o Ectopic Pregnancy
giving a triploid karyotype.
o Endometriosis
Signs & Symptoms o Many others
• Irregular Vaginal Bleeding
o Ectopic Pregnancy
• Vaginal bleeding
• Amenorrhea
• Vomiting
• Uterine enlargement
Positive pregnancy test
US: “cluster of grapes” and/or absent fetus or

fetal heart sounds
Labs: elevated β-hCG

Gross: The uterus is filled with translucent
edematous villi that have an appearance of
“clusters of grapes.”

Gestational Choriocarcinoma
Trophoblastic tumor that grows after
some event related to pregnancy. Differentials
Etiology Usually there is a history of normal or

abnormal pregnancy (hydatiform mole). Similar
to a mole or ectopic pregnancy, but with no
Follows:
uterine enlargement or amenorrhea.
• Mole (50%)
• Abortion (25%) • Abdominal Pain
• Normal Pregnancy (23%) o Ectopic Pregnancy
• Ectopic Pregnancy (2%) o Hydatiform Mole
Will have villi
o Endometriosis
Pathogenesis o Gestational Carcinoma
o Many others
• Not known • Irregular Vaginal Bleeding
o Ectopic Pregnancy
o Hydatiform Mole
Signs & Symptoms o Gestational Carcinoma
• Irregular vaginal bleeding
• Abdominal pain Additional Info
• No uterine enlargement
Labs: Elevated β-hCG • Chemo effective due to presence of

paternal antigen.
Complications • Good prognosis.
Metastasis (Early via hematogenous):

• Lung
• Brain
• Liver
• Vagina
Microscopy: Tumor consisting of epithelial cells,

specifically cytotrophoblast and syncytiotrophoblast,
with necrosis. There is no chorionic villi present.

Urothelial Carcinoma
Malignant neoplasm of the bladder and
renal urine collection system. Aka Transitional Signs & Symptoms
Cell Carcinoma
Can be papillary (90%) or flat (10%) as • Painless hematuria

well as invasive or non-invasive. • Dull pain
• Urgency and frequency in urination
• Flank Pain
Etiology • Cachexia
Risk Factors: Complications

• Male (3:1)
• Peak Incidence at 50-80 years
• Infection • Metastasis: LN, liver, lung, bone
o Schistosomiasis • Hydronephrosis
• Phenacetin
Prognosis:
o Analgesic
• 57% 5 year survival rate
• Smoking
• Aniline Dye
o Used in rubber industry
• Cyclophosphamide
o Immunosuppressive drug
Pathogenesis
Occurs in:
• Renal Calyces
• Renal pelvis
• Ureters
• Bladder
Gross: This is a high-grade multinodular invasive neoplasm. It has grown into the bladder lumen and spread
over a wide area.

Differentials
Squamous Cell Carcinoma can also
arise in the bladder, but requires squamous
metaplasia. More common in schistosomiasis.
Adenocarcinoma is possible, but not

discussed in lecture.
Renal Cell Carcinoma presents

relatively similar, with hematuria, but with the
absence of dysuria and polyuria.
Microscopy: (Left) This is a low grade papillary carcinoma with increased cell layers, low cytological atypia,
and low mitotic activity. (Right) This is a high grade papillary carcinoma and cytologic atypia.

Nodular Hyperplasia of the Prostate

A type of Benign Prostatic Hyperplasia
with nodular growths in the prostate. Complications
Etiology • Hydronephrosis
• Bladder Stones
• Increased risk of bladder and kidney
• A process of aging.
infections.
• Common in men over 50
Prostatic Carcinoma presents similarly,
• Impaired cell death of unknown origin but with the possible addition of metastatic
o Androgens thought to play a manifestations. On DRE, it will be firm. On
role. biopsy, the glands will have only one layer of
• Accumulation of senescent cells epithelium.
Prostatitis is similar to BPH but is due to

Signs & Symptoms an infection, so will be tender on DRE and
presents with fever, leukocytosis, etc.
• Nocturia
• Increased urinary frequency
• Difficulty starting and stopping
urination
• Overflow dribbling
• Dysuria
Digital Rectal Exam: Enlarged & Nodular
Labs: Elevated PSA
Gross: Nodular surface and a narrow opening for

the urethra.
Microscopy: The nodules are fibromuscular or
fibroepithelial with glandular predominance. The
glandular proliferation occurs with dilated glands
with 2 layers of epithelium with no nuclear changes.

Prostate Adenocarcinoma
Cancer of the prostate. Second most Labs: Elevated PSA
common visceral cancer in men. The peak
Biopsy
incidence is at 65-75 years of age.
Etiology Complications
Early Metastasis
Unknown
• Common to bone
Possible Genes: • Brain via Batson’s venous plexus
• GSTP1
• ETS transcription factors
• BRCA2
Differentials
Higher incidence in African Americans Benign Prostatic Hyperplasia is the non-
malignant enlargement of the prostate, usually
Pathogenesis from the periurethral or transitional zones. On
DRE, it will be softer but enlarged. On biopsy, it
will still have 2 layers of epithelium in the
• Mostly unknown glands. The presentation itself will be similar,
• Increased androgens but without any metastatic manifestations.
• Early invasion & metastasis but slow
Signs & Symptoms
• Asymptomatic
• Dysuria
• Possible Compression Symptoms
o Increased Urinary frequency
o Nocturia
• Hematuria
Digital Rectal Exam: Hard
Microscopy: Small infiltrating glands with small lumens, prominent nuclei, atypia, and only a single layer of
epithelial cells (prostate normally has 2)

Cryptorchidism
The testes fail to descend into the
scrotal sac during development, leaving them in Signs & Symptoms
the inguinal canal or abdomen.
• Testis is not in the scrotal sac.
Etiology • May be palpable in the inguinal canal.
Poorly understood Complications

Could have:
• Anatomical anomalies • Sterility
• Hormonal dysfunction o If uncorrected by 2 years
• Mechanical • Germ Cell Tumor
o If uncorrected by 5 years
Likely to be an intrinsic defect of the testis due • Inguinal Hernia
to the fact that if one fully descends, it will have • Testicular Cancer
the same histology.
Pathogenesis
Normal Descent:
• Transabdominal Phase
o Dependent on mullerian
inhibiting substance
• Inguinoscrotal Phase
o Dependent on androgen
o Mediated by Calcitonin-Gene-
Related-Peptide
Defect usually occurs in inguinoscrotal phase
Unilateral, usually on the right side
Microscopy: No spermatogenesis is found within the seminiferous tubules and there is hyalinization &
thickening of the basement membrane of the spermatic tubules. There is an increase of the stroma with
fibrosis.

Seminoma Testis
Germ cell tumor of the testes. Similar
to a dysgerminoma found in women. More Differentials
common in white men with a peak incidence of
30-50 years of age. Testicular tumors are divided into
seminoma and non-seminoma classes. They all
Etiology tend to present the same, so differences are
made by age or histologically.
• Isochromosome 12p Age distribution:

• Expression of OCT3/4 and NANOG • Infants & Children – Teratomas, Yolk
• 25% have c-KIT mutations Sac
• 15 to 30 – Mixed germ cell
• 30 to 50 – Seminoma
Pathogenesis • >60 - Lymphoma
• Proliferation of seminiferous Histology/Differentiation:

differentiated cells. • Seminiferous – Seminoma
• Minimally – Embryonal
• Somatic – Teratoma
Signs & Symptoms • Trophoblastic – Choriocarcinoma
o Serum β-hCG
• Unilateral testicular mass • Yolk Sac – Yolk sac
• Dull ache in groin or abdomen o Serum AFP
• Testicular pain
Do Not Take a Biopsy - Risk of spread
Complications
Metastasis to lymph nodes
Overall a good prognosis wit radiotherapy or

surgery
Microscopy: Sheets of cells that have the appearance of a fried egg, being a large round cell with clear
cytoplasm and a large prominent central nucleus. The cells are divided into poorly demarcated lobules via
fibrous septa. There are also patches of lymphocytic infiltration.

Carcinoma of the Penis

Squamous cell carcinoma of the penis. o Does not progress to squamous
cell
Etiology
Signs & Symptoms
Risk Factors:
• HPV 16 & 18 • May be asymptomatic
• Uncircumcised • Painful
o Jews and Muslims tend to be • Purulent Lesions
circumcised
• 40-70 years of age Advanced Stage:
• Smegma • Hemorrhage
• Smoking • Fistula
• Urethral blockage
• Autoamputation
Pathogenesis
Complications
Penile carcinoma in situ:
• Bowen Disease
o Solitary lesion Metastasis via lymphatics
o On the shaft Prognosis:
o Seen as a plaque
• No metastasis - 66% 5 year survival
o 10% progress to squamous cell
• Metastasis – 27% 5 years survival
carcinoma
• Erythroplasia of Queyrat
o Solitary or multiple lesions
o On the glans
o Red patches with shiny plaques
o Progresses to squamous cell
carcinoma
• Bowenoid papulosis
o Multiple lesions
o On the shaft
o Papular
Gross: Patchy red lesion with shiny plaques on the glans penis, indicating Erythroplasia of Queyrat. This has
or is likely to progress to squamous cell carcinoma of the penis.

Fibroadenoma
Benign tumor of the breast. Most common
benign neoplasm in the breast. Signs & Symptoms
Etiology • Singular mobile & firm lump between 1-

10 cm
• Otherwise asymptomatic
• Estrogen
• Women 20-30s Mammogram
• Well circumscribed mass
Pathogenesis • Popcorn calcification
Biopsy/Fine Needle Aspiration

• Enlarges in later part of menstrual cycle
or pregnancy
• Regresses after menopause
Microscopy: Loose edematous myxoid fibroblastic stroma with glandular & duct-like epithelial lined spaces.
May be pericanalicular (Left), oval ducts surrounded by stroma, or intracanalicular (Right), elongated,
compressed, distorted ducts.

o More cellular stroma

Complications o Also mobile mass
• Carcinoma
• Low risk of carcinoma o Firm
o Immobile
o Peau d’ orange
o Paget’s Disease
Differentials
Fibroadenomas are benign and mobile,
so it will not involve the lymph nodes nor give
any symptoms of metastasis. This also occurs in
younger women, in contrast to the other
neoplasms which tend to occur in older women.
Other breast nodules include:

• Galactocele
o obstructed duct, may become
infected
• Fibrocystic Change
o Benign
o Non-proliferative
Blue domed cysts
Serous of turbid
Bilateral
o Proliferative
Hyperplasia
• Sclerosing Adenosis
o Benign
o Dense fibrous stoma
o Calcification
o Double layer of myoepithelial
cells
o Low risk of carcinoma
• Phylloides tumor
o Clue word: “leaf-like”
o Older age (40-50s)
Gross: Firm mass with a tan-white color with specks of a softer yellow-pink color representing glandular
areas.

Phyllodes Tumor
Large benign tumor. Aka cystosarcoma which is also a benign tumor that is firm and
phyllodes (antiquated) mobile. The big difference is age (phyllodes
tumor being in older women, fibroadenoma in
younger). A key word would also be “leaf-like.”
Etiology
Other breast nodules include:
• Older women, 40-50 (post menopause) • Galactocele
o Non-proliferative
Pathogenesis o Proliferative
• Sclerosing Adenosis
• Pre-ductal stroma • Carcinoma
• Frequency of chromosomal changes
increased with the grade of the tumor.
• High grade lesions tend to have EFGR
amplification
• Fast growing
Signs & Symptoms

Firm, mobile, and palpable mass
Complications
15% chance of malignancy
• Spread is hematogenous
• NOT lymphatics
Differentials
The most similar differential is fibroadenoma,
Microscopy: Highly cellular stroma of spindle cells with minimal stromal mitosis, sometimes referred to as
“leaf-like.” The stromal tissue is lined by epithelial cells.

Intraductal Papilloma
Papillae formation in the ductal lumen.
Differentials
Etiology
The main feature of this disease is the
nipple discharge and on histology will have the
• Common cause of serous or bloody papillae in the duct itself.
discharge in women over 50.
Nipple discharge disorders:
• Intraductal papilloma
Pathogenesis • Duct ectasia
• Comedo carcinoma
• Proliferative neoplasm without atypia • Proliferative FCC
• In large ducts will form a solitary papilla • Paget’s Disease/Carcinomas
in the lactiferous sinuses and will have
bloody discharge
• In small ducts will form multiple
papillae and be deeper.
Signs & Symptoms
• Serous or bloody discharge from nipple
Mammogram:
• Usually doesn’t show anything
• May show a mass or duct ectasia
Biopsy
Complications
If multiple there is a risk of papillary carcinoma
Metastasis (15%)
• Increased stroma mitosis
• Increased cellularity Microscopy: Delicate branching papillae in the ductal lumen
• Spreads via hematogenous with a fibrovascular core (Top), a double layer of myoepithelial
& epithelial cells (Bottom), and no mitosis or atypia.

Paget’s Disease of the Breast

Paget’s Disease of the Breast is a relatively Biopsy:
rare disease of the nipple which is highly • Paget cell
indicative of intraductal carcinoma. • PAS Positive
More details on the carcinoma are given in Mammogram: underlying intraductal carcinoma
the next profile.
Complications
Etiology
Depends on underlying intraductal carcinoma
• Unknown
Women over 50 years
•
Differentials
Pathogenesis Paget’s Disease has several distinguishing
characteristics, including the unilateral crusting
• Intraductal carcinoma in large ducts exudate, eczema, and other changes to the
• Spreads to skin, areola, and nipple nipple. Paget cells on biopsy confirms.
• Ductal Carcinoma in situ (DCIS)
Nipple discharge disorders:
• HER2/NEU increases chance of invasive
• Intraductal papilloma
carcinoma
• Duct ectasia
• Comedo carcinoma
Signs & Symptoms • Proliferative FCC
• Paget’s Disease/Carcinomas
• Unilateral crusting exudate
• Eczema
• Hyperemia
• Edema
• Fissuring
• Ulcer
• Oozing
• May have palpable mass
Microscopy: This slide depicts Paget’s cells, which are large cells with pale, vacuolated cytoplasm and large
nuclei. These cells will be localized to the epidermis with the highest concentration being in the basal layers.

Breast Carcinoma
This profile will cover the broad o Estrogen/progesterone effect
spectrum of breast carcinomas, mostly because • Environment
they behave similarily and have many of the
same properties. The major differences come
in with histological morphology.
Signs & Symptoms
In general, it can be non-infiltrating (in
• Can be asymptomatic – incidental
situ) or infiltrating as well as ductal (90%) or
finding
lobular (10%).
• Indurated immobile mass
o Upper outer quadrant (50%)
Etiology o Central (20%)
o Other quadrants (each 10%)
• Peau d’orange due to lymphedema
Risk Factors
• Geographic
o US more than Japan/Taiwan
• Genetic
o p53
o BRCA
• FCC w/ atypical epithelial hyperplasia
• Nulliparous
• First child after 30 years of age
• Early menarche, late menopause
• Obesity
o High fat diet – more estrogens
• Estrogen therapy
Pathogenesis
• Mostly unknown
• Hormonal influences
o Increased exposure to estrogen
o Ovarian tumors
Microscopy: Lobular carcinoma in situ (LCIS) with uniform monomorphic cells that have round nuclei. They
are arranged in loosely cohesive clusters with no lumen in the acini.

Mammogram: • Aneuploidy – poor prognosis

• Visible if calcified • Oncogene amplification
o LCIS tend not to show o Myc
• Only useful if older than 40 o Neu
o Younger breast is too dense o Rb
• Angiogenesis
Biopsy
o High cathepsin D
o High metastatic potential
• Good prognosis factors
o <2 cm
o No axillary LN
Complications o DCIS/LCIS
o ER+
Metastasis
• Lungs
Differentials
• Bone
• Liver Breast Carcinomas tend to be hard
• Adrenals nodules that are not moveable. They can
• Ovaries (Krukenberg) infiltrate the lymph nodes, which would give
the characteristic Peau d’ orange. Other
Metastasizing Behaviors: indicators include Paget’s disease or evidence of
• Non-metastasizing metastasis.
o DCIS
o LCIS Other breast nodules include:
• Uncommon Metastasis • Galactocele
o Colloid o obstructed duct, may become
o Medullary infected
o Infiltrating papillary
• Metastasizing
o All others
Prognostic Factors
• Staging (TNM)
• ER/PR Status
o ER-/PR+ has bad prognosis
• HER2/NEU – poor prognosis
o 20% responds to Herceptin
Microscopy: Invasive ductal carcinoma of NOS (Not Otherwise Specified) with a range of well developed
tubules to sheets of anaplastic cells. The tumor margins are irregular but well circumscribed with
lymphovascular invasion.

o Benign Additional Info
o Non-proliferative
Blue domed cysts Can occur in men with gynecomastia or with
Serous of turbid BRCA 2 mutations.
Bilateral
o Proliferative ER/PR Testing
Hyperplasia • Estrogen/Progesterone Receptors
• Sclerosing Adenosis • Indicates best treatment options
o Benign • ER+/PR+ - 70% respond to Tamoxifen
o Dense fibrous stoma • ER-/PR+ - 50% respond to Tamoxifen
o Calcification • ER+/PR- - 40% respond to Tamoxifen
o Double layer of myoepithelial • ER-/PR- - <10% respond, use chemo
cells
o Low risk of carcinoma
• Fibroadenoma
o Benign
o Mobile mass
• Phylloides tumor
o Clue word: “leaf-like”
o Mobile mass
Microscopy: Invasive lobular carcinoma with uniform monomorphic cells that have round nuclei that
invades with individual cells into the surrounding stroma. These invasive cells tend to align into strands or
chains, referred to as “Indian file.” Sometimes surrounds cancerous or normal acini, giving it a “bull’s eye”
pattern.

Condyloma Acuminatum
Genital warts that are transmitted sexually.
Differentials
Etiology
Condyloma Latum is a similar disorder
with white plaque-like papules on the genitals,
• HPV 6, 11, 40, 54 (Low risk HPV) however it is associated with secondary syphilis.
Cervical Carcinoma can be caused by

Pathogenesis the high-risk HPV (16,18), which forms flat
condylomas. These usually go undetected
• HPV infection clinically but can be picked up in screening such
• Uncontrolled proliferation as Pap smears.
o E6 inhibits p53
The other sexually transmitted diseases
o E7 inhibits Rb
may be able to form surface lesions:
o Activates Cyclin-E
• Chancroid will have a painful soft ulcer
and may also have an inguinal bubo.
• Syphilis will have a painless hard crust
Signs & Symptoms over an ulcer. Possibly followed by
secondary symptoms or tertiary
symptoms.
• Bumps/warts on genitals or perianal
• Genital Herpes will have vesicle
formation and is a latent recurring
infection due to HHV-2/1
Biopsy to confirm.
Complications
• Low risk for carcinoma
Histology: Perinuclear cytoplasmic vacuolization and

nuclear angular pleomorphism & koilocytosis. This is
characteristic of any HPV infection. There is marked
acanthosis, or epidermal hyperplasia, which gives the
gross protrusion of the wart.

Genital Herpes
Recurrent latent infection of vesicles
around the genitals or anus and is transmitted Complications
via sexual contact.
• Congenital Herpes – in neonates
Etiology • Visceral Infection (Disseminated
Herpes)
o Skin lesions
Herpes Simplex Virus: HHV-2 or HHV-1
o DIC
o Arthritis
Pathogenesis o Meningitis
o Encephalitis
• Contact with infected tissue (blister)

• Virus enters through a break in the Differentials
mucosa or skin
• Infection of epithelial cells The other sexually transmitted diseases
• Formation of blisters may be able to form surface lesions:
• Latency: neural ganglia
• Evasion: Inhibits TAP Transporter • Chancroid will have a painful soft ulcer
and may also have an inguinal bubo.
• Syphilis will have a painless hard crust
Signs & Symptoms over an ulcer. Possibly followed by
secondary symptoms or tertiary
• Painful lesions in the genitalia region symptoms.
• Condyloma acuminatum is wart
Primary infection also has: formation due to HPV 6,11 and is
• Dysuria relatively painless.
• Urethral discharge
• Lymphadenopathy
• Non-specific symptoms (malaise, etc)
Tzanck Smear: Cowdry Type A bodies & syncytia
Histology: Intraepithelial vesicle with necrotic

debris, neutrophils, and infected cells. These
infected cells have Cowdry Type A bodies, seen
as light purple (acidophilic) homogenous
intranuclear structures with a clear halo. Also
commonly seen is syncytia.

Renal 189
Renal
General Kidney Disorders
Acute Pyelonephritis 190
Benign Nephrosclerosis 192
Malignant Nephrosclerosis 193
Adult Polycystic Kidney Disease 194
Juvenile Polycystic Kidney Disease 196
Renal Cell Carcinoma 197
Hydronephrosis 199
Horseshoe Kidney 200
Glomerular
Minimal Change Disease 201
FSGS – Focal Segmental Glomerulosclerosis 202
Membranous Glomerulopathy 203
IgA Nephropathy 205
PSGN – Post-Streptococcal Glomerulonephritis 207
MPGN – Membranoproliferative Glomerulonephritis 209
RPGN – Rapidly Progressive Glomerulonephritis 211
Alport Syndrome 213

Renal 190
Acute Polynephritis
Bacterial infection of the kidneys.
Signs & Symptoms
Etiology
• Sudden onset
• Fever
Infectious Agents:
• Dysuria
• Escherichia coli
• Flank pain
• Proteus
• Nausea & Vomiting
• Klebsiella
• Costovertebral angle tenderness
• Enterobacter
Labs:
Risk Factors:
• Elevated BUN
• Catheter
• Elevated creatinine
• Female
• Elevated WBC
• Age
• Diabetes mellitus – vesicoureteral reflux Urinalysis:
• Immunosuppression • Pyuria
• Pre-existing renal lesion • Bacteruria
• WBC casts
Pathogenesis
• Ascending infection from the lower

urogenital tract.
• Possible hematogenous spread, but
much less common.
• Factors that promote ascending
infection include obstruction and stasis
of urine, vesicoureteral reflux, or
intrarenal reflux.
Gross: Kidney has yellow raised abscesses on the

surface.

Renal 191
hematuria and have a superimposed UTI.

Complications Overall, it presents very similarly. US may help
to distinguish, as does the nature and severity
Papillary necrosis of the flank pain. The serum renal panel may
not be as elevated, but not diagnostic.
• Seen in diabetics & UT obstruction
• Usually bilateral Drug Induced Nephritis is a
• One or more pyramids may be involved tubulointerstitial commonly caused by
antibiotics, NSAIDs, sulfonamides, allopurinol,
Pyonephrosis
and others. Presents with fever, rash,
• Occurs with total obstruction high in
eosinophilia, or be completely asymptomatic.
the UT
Urinalysis will show sterile pyuria, eosinophils,
• Pus fills the renal pelvis, calyces, and
WBC casts, and mild proteinuria. Serum tests
ureter
will show increased eosinophils, high
Perinephric Abscess BUN/creatinine, high K+, low HCO3.
• Abcess formation at the periphery of
the kidney under the capsule.
Differentials
Acute Polynephritis will have some of
the non-specific kidney symptoms, such as flank
pain and elevated BUN/creatinine. More
distinguishing features include pyuria,
bacteruria, & WBC casts in the urine, elevated
WBC, and other signs of infection.
Chronic Pyelonephritis covers recurrent

or persistent infections with renal scarring
leading to decline in renal functioning and
ESRD. It also tends to occur with anatomical
abnormalities
Nephrolithiasis (Kidney Stones) will also

have the sudden onset flank pain that will
radiate to the groin. It may also present with
Microscopy: Inflammation of the tubules with intratubular aggregates of neutrophils and tubular necrosis.
These aggregates for the WBC casts seen on urinalysis. There is also patchy interstitial suppurative
inflammation.

Renal 192
Benign Nephrosclerosis
The consequence of chronic high blood
pressure on the kidneys. Complications
Etiology • Low risk of Renal Failure
• Hypertension Differentials
• Diabetes mellitus
• More frequent in African Americans Malignant Nephrosclerosis differs in
• More frequent in the elderly that it is due to malignant hypertension (>120
diastolic). It will present with much more
Pathogenesis severe symptoms such as retinal hemorrhages
or encephalopathy. The morphologies are also
different.
• Long standing hypertension
• Medial and intimal thickening of the
large and small arteries
• Luminal narrowing
• Decreased pressure to arterioles and
capillaries
• Ischemic injury to glomerulus, tubules,
and interstitium.
• Collapse of GBM
• Collagen deposition in Bowman space
• Periglomerular fibrosis
• Sclerosis of the glomeruli
Signs & Symptoms
• Normal/Low Normal GFR

• Mild proteinuria
Gross: Slightly smaller sized kidney with a fine granular surface.
Microscopy: Hyaline arteriolosclerosis and glomerular sclerosis.

Renal 193
Malignant Nephrosclerosis
The consequence of malignant
hypertension on the kidneys Complications
Etiology • Renal Failure
• Malignant or accelerated hypertension Differentials

o May be due to underlying
chronic renal disease Benign Nephrosclerosis differs in that it
is due to chronic hypertension and has a much
Pathogenesis milder presentation. Won’t have fibrinoid
necrosis, instead will have hyaline
arteriolosclerosis.
• Endothelial injury
• Increased permeability of small vessels
• Focal death of endothelium
o Fibrinoid necrosis of arterioles
and small arteries
o Thrombus formation
• Swelling of the intima
• Damage to kidneys
o Release of renin
o Increased blood pressure
o Positive feedback loop
Signs & Symptoms
• Papilledema
• Retinal hemorrhages
• Encephalopathy
• Proteinuria
• Hematuria
Gross: Small pinpoint petechial hemorrhage, “flea-bitten.”

Microscopy: Swelling of the vascular intima, intravascular
thrombosis, and fibrinoid necrosis. There will also be hyperplastic
arteriolosclerosis

Renal 194
Adult Polycystic Kidney Disease

Autosomal dominant disease of the • Defects in cilia
kidneys in which they eventually are filled with • Defects in cell-cell and cell-matrix
cysts and lose their ability to function. interactions
Sometimes referred to as AD PKD. • Altered epithelial growth and
differentiation
Etiology o Abnormal ECM
o Cell proliferation
o Fluid secretion
• Mutation of PKD1 or PKD2 • Cyst formation in any level of the
nephron
Pathogenesis • Begins in adolescence
• Increase in size and number throughout
lifetime
• Defect in PDK1/2
o Encodes polycystin 1 or 2
o PDK2 is milder
nd
• 2 somatic hit required
o Cysts don’t develop in all
tubules
Gross: Bilateral multiple cyst formation with clear or turbid fluid which may also contain blood. Each cyst
ranges from tiny to 4 cm. The kidney size itself is increased.

Renal 195
• Clinically silent until about 4th decade of Juvenile Polycystic Kidney Disease has a
life similar gross morphology. The key difference is
o <50% are diagnosed within time of onset, with Juvenile PKD present at the
lifetime time of birth and Adult PKD pres ents late in life.
• Hypertension Other important differences are:
• Hematuria
• Autosomal dominant in adult, recessive
• Flank pain
in juvenile
• Nephrolithiasis
• PKD1/2 in adult, PKHD1 in juvenile
US: Visible cysts • The complications (there are many in
adult)
Biopsy:
• Arteriolar sclerosis
• Interstitial fibrosis
Complications
• End Stage Renal Disease

o No FSGS
• Hepatic Cysts
• Berry Aneurysms
• Urinary Infections
• Pancreatic Cysts
• Cardiac Valve Disease (MVP, AR)
• Colonic diverticular disease
• Abdominal wall and inguinal hernia
Death usually due to hypertension

complications or uremia.

Renal 196
Juvenile Polycystic Kidney Disease

Autosomal recessive disease of the
kidneys in which they rapidly develop cysts in a Complications
fetus and are usually present at birth.
Sometimes referred to as AR PKD.
• Survivors develop liver cirrhosis
• Mutation of PKHD1
Adult Polycystic Kidney Disease has a
o Encodes fibrocystin similar gross morphology. The key difference is
time of onset, with Juvenile PKD present at the
Pathogenesis time of birth and Adult PKD presents late in life.
Other important differences are:
• Defect in PPKHD1 • Autosomal dominant in adult, recessive

• Defects in cilia in juvenile
• Defects in cell-cell and cell-matrix • PKD1/2 in adult, PKHD1 in juvenile
interactions • The complications (there are many in
• Altered epithelial growth and adult)
differentiation
o Abnormal ECM
o Cell proliferation
o Fluid secretion
• Cyst formation in the collecting ducts
Signs & Symptoms
• Manifests at birth
• Hepatic Failure
• Renal Failure
Gross: Bilateral multiple cyst formation with

givingclear or turbid
a sponge like fluid which may
appearance. Thealso contain
kidneys areblood. Each
enlarged as cyst
well.
ranges from tiny to 4 cm. The kidney size itself is increased.

Renal 197
Renal Cell Carcinoma

Cancer of the kidneys.
Signs & Symptoms
Can be of three types:
• Clear Cell Carcinoma (70-80%)
• Papillary Renal Cell Carcinoma (10-15%) • Hematuria
o No RBC casts
• Chromophobe Renal Carcinoma (5%)
• Palpable mass
• Dull flank pain
Etiology
Ultrasound/CT/Biopsy
Mostly sporadic
Clear Cell Carcinoma:

• Autosomal Dominant RCCa
• Deletion of both VHL genes
o Neoplasms throughout body,
often bilateral
• Hereditary papillary RCCa
o Multiple masses
o Bilateral
o Younger age
Risk Factors:
• Old Age (6th decade)
• Men (2:1)
• Obesity
• Smoking
• Cadmium (Batteries)
• Dialysis
Pathogenesis
Arises from renal tubular epithelium
Gross: A singular yellow mass with a well defined border in the superior pole of the kidney and some
hemorrhaging. Tumors may infiltrate the renal vein in a snake-like pattern, and may make it into the IVC or
even the right ventricle. The renal vein will be dilated and thrombosed.

Renal 198
Complications Differentials
Paraneoplastic Syndromes: Renal Cell Carcinoma tends to be a
• Polycythemia singular mass that can snake into the venous
o erythropoietin system. The clinical presentation isn’t very
• Hypercalcemia characteristic, with hematuria, dull flank pain,
o PTH and maybe a palpable mass. This diagnosis
• Hypertension relies on imaging and biopsies to confirm.
o renin
Wilms Tumor is a renal tumor found in
• Cushing syndrome
children and is due to a mutation in WT-1.
o ACTH
Biopsy will show a blastema and have anaplasia.
• Feminization
• Masculinization Urothelial Carcinoma is a bladder
cancer that presents with hematuria as well as
Metastasis:
dysuria and polyuria.
• Lungs
• Bone
Microscopy: Clear Cell Carcinoma has cells that are vacuolated with lipids or glycogen. The tissue structure
becomes disorganized, forming abortive tubules or cluster into cords. The stroma becomes scant but is
highly vascularized.

Renal 199
Hydronephrosis
Enlargement of the kidney due to • Renal atrophy
impedement of urine flow. This is more of a o Decreased GFR
secondary condition to other diseases. o Renal insufficiency/failure

Congenital • Unilateral can be asymptomatic in early
• Atresia of urethra stages
• Valve formation in urethra or ureter • Bilateral has anuria
• Compression of the ureter • Polyuria with impartial obstruction
o Such as by the renal artery • Pain
Acquired
• Obstructive Nephropathy Complications
o Kidney Stones
o Other foreign bodies
• Renal Failure
o BPH
• Inflammation
• Bladder paralysis
• Pregnancy
Pathogenesis
• Impeded flow of urine

o Obstruction/blockage
• Urine accumulates
• Filtrate diffuses into renal interstitium
o Some returns to lymph or veins
• Impaired concentrating ability of
tubules
• Increased pressure in renal pelvis
Gross: Enlargement of the kidney and distended renal pelvis and calyces. A normal calyx is about 1-2 cm.
The medullary pyramids have been flattened and the parenchyma is compressed with atrophy.

Renal 200
Horseshoe Kidney
Fusion of the inferior poles of the kidneys.
Signs & Symptoms
Etiology
• Asymptomatic
• Otherwise may have:
• Commonly seen in Turner’s & Edwards
o Nausea
Syndrome (Trisomy 18).
o Abdominal discomfort
• Can also be an isolated anomaly.
Pathogenesis Complications
• Kidney Stones
• Fusion of the inferior poles during
• UTI
development.
Gross: The two kidneys are fused at the inferior pole by an isthmus of renal parenchyma or fibrous tissue.
This isthmus is usually located anterior to the great vessels and will catch the inferior mesenteric artery,
halting the kidneys ascent and leave them lower in the abdomen. The renal pelvis will face anteriorly.

Renal 201
Minimal Change Disease

Nephrosis due to small changes in the
filtration unit with minimal change. This is the Complications
most common cause of nephrosis in children
between 1 and 7. Can be referred to as Lipoid
• Resolves well with corticosteroids.
Nephrosis.
• Can recur, leading to steroid
dependency.
Etiology • May progress to FSGS
• Unknown Differentials
• Lymphoma or renal cell carcinoma
Minimal Change Disease is a mid
Pathogenesis disorder that typically occurs in children. It will
have nephrotic syndrome but without
hypertension and relatively normal renal
Unknown. May be autoimmune.
function. On biopsy, the only notable change is
on EM with effacement and detachment of foot
Signs & Symptoms processes.
Nephrotic Syndromes:
Nephrotic Syndrome • FSGS
• Proteinuria • Membranous Nephropathy
• Hypoalbuminemia/Edema • Diabetic Nephropathy
• There is no hypertension • Amyloidosis
• Renal function is preserved • MPGN
Labs:
• Low albumin
• Normal creatinine
Biopsy:
• LM: Normal
• IF: Normal
• EM: Podocyte effacement and
detachment from GBM
Electron Micrograph: Fusion of the foot processes

of podocytes with subsequent effacement and
detachment.

Renal 202
Focal Segmental Glomerulosclerosis

Sclerosis of the glomeruli, affecting only Biopsy:
some of them (focal) and only part of each • LM: Focal Segmental Sclerosis of the
affected (segmental). glomeruli
• IF: Normal or non-specific IgM or C3
Etiology • EM: Patchy fusion of foot processes
with effacement
Is secondary:
• HIV
Complications
• Heroin abuse
• Morbid obesity • Renal Insufficiency/Failure
• Chronic reflux nephropathy
Degree of proteinuria indicates prognosis
• Malignancies (lymphoma)
Or can be primary - unknown

Differentials
Pathogenesis FSGS is a more severe form of Minimal
Change Disease. It will have nephrotic
• Unknown. syndrome and maybe some hematuria. On
• Thought to be initiated by injury to the biopsy, there is the characteristic segmental
podocyte. sclerosis of the glomeruli.
• Increased glomerular permeability
• Massive proteinuria
• Minimal Change Disease
• No immune-complex deposition
• Membranous Nephropathy
• Diabetic Nephropathy
Signs & Symptoms • Amyloidosis
• Nephrotic Syndrome
o Proteinuria
o Hypoalbuminemia/Edema
o Hypertension
• Hematuria
Microscopy: Segmental sclerosis of the glomeruli that doesn’t affect all of them. The sclerosis is seen as
thickening of the mesangial matrix, obliterating the capillary lumens with deposition of hyaline.

Renal 203
Membranous Glomerulopathy
Thickening of the basement membrane
with subeptithelial depostion of immune Signs & Symptoms
complexes. Tends to occur between 20 and 50.
• Nephrotic syndrome
Etiology o Hypoalbuminemia/Edema
o Hypertension
o Renal Insufficiency
Idiopathic (85%)
• Microhematuria
Secondary to: • Renal vein thrombosis
• Infection (HBV, syphilis, malaria,
Biopsy:
schistosomiasis)
• LM: Diffuse thickening of GBM
• Malignant tumors
• IF: Deposits of IgG & C3 in GBM
• SLE
• EM: Subepithelial immune complex
• Inorganic salts (Gold, Mercury)
deposition with spikes of GBM growth
• Drugs: NSAIDs, penicillamine, captopril
• Persistent proteinuria
• Subepithelial Antigen & Antibody
• ESRD
reaction with podocytes
• Complement activation Poor prognosis with:
• MAC complex formation in podocyte • Male
membrane • Over 50
• Effacement & Detachment of podocytes • >10 g proteinuria
• Activation of epithelial and mesangial
cells to produce GBM growth leading to
spike and dome formation
• The damage to the GBM increases
permeability leading to proteinuria
Microscopy: Thickening of the GBM, seen here

with a PAS stain.

Renal 204
Immunofluorescence: Granular pattern

Differentials showing immune complex deposition.
Membranous Glomerulopathy a diffuse

thickening of the basement membrane. It
thickens in a characteristic manner due to
immune complex deposition, forming spikes
and domes visible on EM. Other clues include a
history of infection, malignant tumors, SLE,
inorganic salts, or certain drugs.
• Minimal Change Disease
• FSGS
• Amyloidosis
Electron Micrograph: Presence of subepithelial deposits causing growth of new basement membrane. This
produces a spike and dome formation. Also note the effacement of the foot processes.

Renal 205
IgA Nephropathy
Episodic nephritic syndrome that is
associated with respiratory or GI illness. Signs & Symptoms
Commonly seen in Asians and caucasians, but
rarely in african americans.
• Episode of hematuria and proteinuria
Aka Mesangioproliferative Glomerulonephritis every few months.
• Mild proteinuria between episodes.
Etiology Labs:
• Normal C3/4 Compliment
Unknown, may be genetic. Biopsy:

• LM: Segmental areas of increased
Also associated with:
mesangial matrix with hypercellularity
• Hepatic cirrhosis
• IF: Mesangial and subendothelial
• Gluten enteropathy
deposits of IgA and C3
• HIV
• EM: Mesangial and subendothelial
• Minimal change disease
deposits
• Wegener’s
• Ankylosing spondylitis
Pathogenesis
• Abnormal production & clearance of IgA

• Increased serum IgA following RTI
• IgA glycosylation contributes to
decreased clearance and mesangial
deposition
• Activation of alternative compliment
pathway
Microscopy: Diffuse mesangial proliferation and hypercellularity.

Renal 206
Nephritic Syndromes:
Complications • IgA Nephropathy
• Henoch-Schonlein Purpura
• Chronic Renal Failure • Post-Streptococcal Glomerulonephritis
o EM: Humps
• Membranoproliferative
Glomerulonephritis
Differentials o LM: Tram Track
• Rapidly Progressive Glomerulonephritis
o LM: Crescents
IgA Nephropathy is usually associated • Lupus Nephritis
with a recent respiratory or GI illness, but there • Alport’s Syndrome
are other associations as well. The biopsy itself o Hearing Loss
will help distinguish from other disorders. Look o Eye Problems
for deposition of IgA and increased mesangial
matrix. Normal C3/C4 compliment will help
distinguish from Post-Streptococcal and MPGN.
If they mention IgG it is going to be

PSGN or Membranous Glomerulopathy. IgM
would most likely be FSGS.
Henoch-Schonlein Purpura is similar

but with extra-renal symptoms such as arthritis,
vasculitis, and non-thrombocytopenic purpura
(skin rash).
Immunofluorescence: Shows deposition of IgA in the mesangium and subendothelium..

Renal 207
Post-Streptococcal Glomerulonephritis
Glomerulonephritis symptoms following Labs:
a streptococcal infection. Can also be called • Elevated ASO
Acute Diffuse Proliferative Glomerulonephritis • Elevated anti-DNAse B
• Low complement
Etiology Biopsy:
• LM: Hypercellular glomeruli &
• Follows a streptococcal infection, such proliferation of mesangial endothelium.
as pharyngitis. • IF: Granular deposits of IgG & C3
• Common in children 6-10 • EM: Humps in subepithelial space
• Initial streptococcal infection • Irreversible Renal Failure (<1%)

• Antibodies form against streptococcal • Renal Insufficiency 10-40 yrs post illness
antigens
• 10 days – 3 weeks symptoms appear
• Immune complexes deposit in the sub-
epithelium
• Complement activation & inflammation
• Subepithelial humps causes epithelial
damage and proteinuria
• Resolution begins at 1-2 months
Signs & Symptoms

Nephritic Syndrome
• Hematuria
• Proteinuria
• Hypertension
• Edema
Microscopy: Hypercellular glomeruli with proliferation of the mesangial endothelium. This will cause
closure of the capillary loops. Also note the swelling and lymphocytic infiltration.

Renal 208
Differentials
PSGN will likely have the streptococcal
infection history. Otherwise they may indicate
as such with the elevated ASO or anti-DNAse B.
Another feature they could mention is the
humps seen on EM or IgG deposits.
Mention of IgA indicates IgA

Nephropathy, while IgM may indicate FSGS.
Membranous Nephropathy also has IgG
deposits, but is more nephrotic.
• IgA Nephropathy
• Post-Streptococcal Glomerulonephritis
o EM: Humps
• Membranoproliferative
Glomerulonephritis
o LM: Tram Track
o LM: Crescents
• Lupus Nephritis
• Alport’s Syndrome
o Hearing Loss
o Eye Problems
Immunofluorescence: IF stain showing granular deposition of IgG, C3, and fibrin in the mesangium.
Electron Micrograph: Characteristic “humps” in the subepithelial space (arrow).

Renal 209
Membranoproliferative Glomerulonephritis (MPGN)
Disorder with basement membrane

thickening, mesangial proliferation, and Pathogenesis
infiltration by inflammatory cells.
Two important types: • Immune complex deposition

• Type I: Subendothelial immune • Activation of compliment pathways
complex deposition. Classical pathway.
• Type II: Dense Deposit Disease. Signs & Symptoms
Intramembranous immune complex
deposition. Alternative pathway.
Presents before 30 in one of these ways:
1) Hematuria or proteinuria
Etiology 2) Nephritic Syndrome with hypertension
and edema
Primary is idiopathic 3) Recurrent gross hematuria
4) Insidious onset of nephrotic syndrome
Secondary:
• SLE Labs
• Cryoglobulinemia • Low C3
• Endocarditis • Low C3 convertase (Type II)
• Parasites
• HBV/HCV (Type I)
• Renal Transplant (Type II)
Microscopy: On the left we have a PAS stain depicting thickening of the GBM with lymphocytic infiltration,
mesangial expansion, and hypercellularity. On the right we have a silver stain which gives a better view of
the GBM, which is split to give a “tram track” appearance (arrows).

Renal 210
Biopsy: which will help distinguish it from IgA

• LM: Mesangial expansion & Nephropathy. Otherwise look to the biopsy.
hypercellularity. Splitting of GBM give a
“tram track” appearance.
• IgA Nephropathy
• EM:
o Type I: subendothelial deposits • Henoch-Schonlein Purpura
o Type II: Dense material in GBM • Post-Streptococcal Glomerulonephritis
• Lupus Nephritis
Complications • Alport’s Syndrome
• Renal Insufficiency
• FSGS
• End Stage Renal Failure
• Membranous Nephropathy
Differentials • Amyloidosis
• MPGN
MPGN’s most characteristic feature is

the “tram track” appearance given by the Additional Info
duplication of the GBM, best seen with a silver
stain. They main use one of the underlying
• Type I has a poor prognosis
conditions. It will also have low complement,
• Type II has a worse prognosis.
Electron Micrograph: Type I MPGN has subendothelial immune complex deposition (Left). Type II MPGN
has intramembranous immune complex deposition (Right).

Renal 211
Rapidly Progressive Glomerulonephritis (RPGN)

A group of disorders with rapid decline in
renal function leading to renal failure. Signs & Symptoms
Three types:
• Type I: Anti-GBM - Goodpasture Nephritic Syndrome
• Type II: Immune complex – PSGN & SLE • Hematuria
• Type III: Pauci immune – Wegner’s • Proteinuria (Low)
Granulomatosis & Churg-Strauss • Oliguria
• RBC Casts
• Hypertension
Etiology • Edema
Other symptoms related to underlying disease

• Goodpasture Syndrome
• PSGN Biopsy:
• Wegener’s Granulomatosis • LM: Proliferation of parietal epithelial
• Churg-Strauss Syndrome cells and presence of crescents of fibrin
and macrophages.
• IF Patterns:
Pathogenesis o Type I: Linear
o Type II: Granular
• Immunologically mediated glomerular o Type III: Negative response
injury
• Crescent formation
o Fibrin deposition
o Proliferation of parietal
epithelial cells in response to
plasma proteins
o Migration of monocytes into
Bowman’s space
• Obliteration of Bowman’s space
• Compression of glomeruli
Immunofluorescence: Linear pattern of staining found in Anti-GBM disease, the prototype being
Goodpasture’s Syndrome which also involves the lungs.

Renal 212
Renal Failure • Post-Streptococcal Glomerulonephritis
o EM: Humps
Poor Prognosis • Membranoproliferative
• 75% die or on dialysis within 2 years Glomerulonephritis
o LM: Tram Track
Differentials • Rapidly Progressive Glomerulonephritis
o LM: Crescents
• Lupus Nephritis
RPGN is a collection of disorders that • Alport’s Syndrome
cause rapid renal failure, including diseases o Hearing Loss
such as Goodpasture’s, Wegener’s, SLE, and o Eye Problems
Churg-Strauss. The most notable characteristic
being crescent formation seen on LM.
Microscopy: Crescent formation, seen here on the bottom left, in Bowman’s space. They are comprised of
fibrin and macrophages.
Electron Micrograph: GBM ruptures (arrows) are seen, but no deposits.

Renal 213
Alport Syndrome
Hereditary disorder of Type IV collagen
leading to nephritic syndrome, eye problems, Signs & Symptoms
and hearing loss.
Nephritic Syndrome
Etiology • Hematuria
• Proteinuria
• Hypertension
X-Linked: (80%)
• Edema
• α5 chain of Type IV Collagen
• COL4A5 gene Sensorineural Deafness
AD or AR: (20%) Eye Disorders

• α3 or α4 chains of Type IV Collagen • Lens dislocations
• COL4A3 or COL4A4 genes • Posterior cataracts
• Corneal dystrophy
Pathogenesis Biopsy:
• EM: Foci of GBM thickening
• Mutation in α3, α4, or α5 chain
Skin Biopsy: Analysis of α5 collagen
o These three chains comprise
Type IV collagen Labs: Normal complement levels
o Type IV collagen is found in the
glomerulus, lens capsule,
cochlea, lungs, and Bruch &
Descemet membranes
• Defective chains are degraded
o Thinning of GBM
• Accumulation with other collagen types
o Mainly the fetal isotypes α1/α2
o Thickening of the GBM
Electron Micrograph: Late course will have irregular foci of thickening (attenuation) of the GBM with
splitting of the lamina densa, giving the basket-weave appearance. Early in the course (not shown) may
have a thin basement membrane.

Renal 214
Renal Failure – 20 to 50 years of age • Post-Streptococcal Glomerulonephritis
o EM: Humps
Leiomyomatosis • Membranoproliferative
• Esophageal or tracheobronchial Glomerulonephritis
• Can occur with XLAS o LM: Tram Track
• If mutation spans into COL4A6 • Rapidly Progressive Glomerulonephritis
o LM: Crescents
• Lupus Nephritis
• Alport’s Syndrome
Differentials o Hearing Loss
o Eye Problems
Alport Syndrome is a hereditary

disorder, being X-linked, recessive, or dominant.
Clinically may have hearing loss or eye problems
such as cataracts or lens dislocations. With
biopsy, look for irregular foci of GBM thickening
and splitting of the lamina densa. Key words
may also include “basket weave appearance.”
This disorder will also have normal

complement levels, which is the same as IgA
Nephropathy. PSGN and MPGN will both have
low complement.
There are no deposits in the GBM, so

any mention of IgA, IgG, immune-complexes,
etc, will not be describing Alport Syndrome.

Endocrine 215
Endocrine
General Endocrine
Simple Physiological Hormone Map 216
Diabetes Mellitus 217
Acromegaly 220
Grave’s Disease 221
Hashimoto’s Thyroiditis 223
Neoplastic
Thyroid Adenoma 225
Follicular Carcinoma 227
Papillary Carcinoma of the Thyroid 229
Medullary Thyroid Cancer 231
Cushing Syndrome 233
Adrenal Cortical Adenoma 234
Pheochromocytoma 235

Endocrine 216

Endocrine 217
Diabetes Mellitus
A disease of glycemic control in relation
to the action insulin. Pathogenesis
There are two types:
• Type I: Insulin Deficiency Type I:
• Type II: Insulin Resistence • Destruction of β-islet
islet cells via Type IV
hypersensitivity
• Decreased production of insulin
Etiology • Hyperglycemia
Type II:
Type I:
• Insulin resistance
• Genetic
• β-islet
islet cell hyperplasia
• Associated with HLA-DR3/44
• Increased insulin production
• Possible viral induced hypersensitivity
• β-islet
islet cell exhaustion/destruction
Type II: • Decreased insulin
• Obesity • Hyperglycemia
• Genetic Predisposition
Microscopy: (Left) Here you can see the remains of a islet of Langerhans with lymphocytic infiltration.
(Right) There is a reduction in islet cell mass and deposits of amyloid (pink homogenous material). Some
fibrosis is present. Late stage diabetes may have the islets completely obliterated.

Endocrine 218
Non-enzymatic Glycosylation:
• Glucose binds to proteins, creating Signs & Symptoms
advanced glycosylation end products
(AGE)
• Polyuria/Nocturia
• Pro-inflammatory • Polydipsia
• Increased GBM • Polyphagia
• Implicated in: • Weight Loss
o Diabetic microangiopathy
• Fatigue
o Atherosclerosis
• Blurry Vision
o Diabetic retinopathy
o Diabetic nephropathy Type I has early onset (before 18)
Accumulation of Polyol: Type II has late onset (>40)

• Polyol (sugar alcohol) accumulates in
tissues that do not require insulin for
uptake Labs:
• Normally glucose → sorbitol→ fructose • Fasting Glucose > 126 mg/dL
• Sorbitol creates osmotic effects and • Random Glucose > 200 mg/dL
depletes myoinositol, amino acids, and
• HbA1c >6.5%
potassium
• Implicated in: Urine:
o Diabetic neuropathy • Microalbuminuria ->
> Albuminuria
o Cataracts
o Blurry vision (lens) Oral Glucose Tolerance Test
Activation of Protein Kinase C:

• Intracellular hyperglycemia can activate
the PKC pathway.
• Produces VEGF (pro-angiogenic)
angiogenic)
o Diabetic retinopathy
• Produces TGF-β
o Increased extracellular matrix
and basement membrane
o Microangiopathy
Microscopy:: This is a picture of glomerular complications. The mesangial matrix is expanding, seen as
a the
nodular pink regions spotted throughout the glomerulus.

Endocrine 219
• Diabetic Neuropathy
Complications o Sensory & Motor
o Symmetric in lower extremities
Acute: o Impotence
• Ketoacidosis (Type I) • Diabetic Microangiopathy
o Can lead to coma • Foot Ulceration
• Hyperosmolar Coma (Type II) o Ischemia
o Neuropathy
• Lactic Acidosis (Type II)
o Painless
less trauma
• Hypoglycemia
o Infections
o Insulin overdose
Long Term:
Differentials
o ESRD
o Expansion of mesangial matrix Diabetes mellitus is a fairly
o GBM Thickening characteristic set of symptoms, the most
• Diabetic Macrovascular notable being hyperglycemia.
o Atherosclerosis
Polyuria/Nocturia
o IHD
• Prostate (BPH/Carcinoma)
o Stroke
• Chronic Renal Failure
o Peripheral vascular disease
• Diabetes Insipidus
• Diabetic Retinopathy
o Blindness • SIADH
o Proliferative or non
non-
proliferative
• Cataracts
• Glaucoma
Microscopy:: These images show proliferative retinopathy. On the left we see normal pericytes surrounding
the capillaries. On the right we see a large increase in vasculature with several micro aneurysms. There is
also a retinal infarct, seen in the on the left middle as a homogenous sphere, termed cotton wool exudate.

Endocrine 220
Acromegaly
Excessive lateral growth of the bones. • Hypertension
• Arthritis
Etiology • Menstrual disturbances
• Loss of libido
• Loss of potency in men
• Hyperpituitarism of anterior pituitary • Diabetes mellitus
releasing GH. Usually an adenoma. • Other symptoms of underlying disease
• Rarely due to ectopic GHRH o Headaches
Labs: Elevated GH & IGF1

Pathogenesis
Glucose Tolerance Test with GH measurements
• Excess production of growth hormone

(GH). Differentials
• Persistently high GH causes liver to
secrete IGF-1
Gigantism is similar in process and
• IGF-1 acts to cause most of the
general appearance, however with the inclusion
symptoms
of increased height. The only real difference is
the pathology began prior to closure of
Signs & Symptoms epiphyseal plates.
• Increased growth of bones and some

soft tissue
• Prognathism (Enlargement of the Jaw)

Endocrine 221
Grave’s Disease
The most common cause of • Accumulation of extracellular matrix
hyperthyroidism that affects mostly women • Proliferation of adipocytes
(7:1) and has a peak incidence at 20-40 years of o Protrudes eye (exophthalmos)
age. o Impaired extra-ocular muscles

Autoimmune disorder • Goiter
• Ophthalmopathy
The autoimmune trigger is not certain:
• Pretibial myxedema/Dermopathy
• Environmental
• Weight loss
o High stress events
• Increased appetite
o Infections
• Heat intolerant/sweating
o Yersinia enterolytica
• Tachycardia
• Genetic
o HLA-B8 & HLA-DR3 • Tremor
o Polymorphisms of CTLA-4 & • Anxiety
PTPN22 • Diarrhea
• Lid lag/lid retraction
• Hypocholesterolemia
Pathogenesis • Hyperglycemia
• Hypercalcemia
• IgG binds to TSH receptor
• Stimulates synthesis and release of
T3/T4
• Hypertrophy and hyperplasia of thyroid
follicular epithelial cells
• Negative feedback lowers TSH
Ophthalmopathy
• Infiltration of retro-orbital space by T-
cells
• Inflammatory edema and swelling of
extra-ocular muscles
Gross: Presentation of goiter (enlarged thyroid)

and exophthalmos.

Endocrine 222
Labs:
• Elevated T3/T4
• Low TSH
• TBII/TGI/TSI
Radioiodine Scans
Ultrasound
Differentials
Grave’s disease is a hyperthyroidism
disorder that is characteristically autoimmune.
Clinically they can all present similarly, except
Grave’s usually has the complete triad.
Hyperthyroidism
• Toxic Adenoma
• Toxic Multinodular Goiter
• Thyroiditis
• Struma ovarii
• Functional Thyroid Cancer
o Follicular carcinoma
o Papillary carcinoma
Gross: Presentation of pretibial myxedema. This is part of the characteristic triad of goiter, ophthalmopathy
(including exophthalmos), and pretibial myxedema found in Grave’s Disease.

Endocrine 223
Hashimoto’s Thyroiditis
Autoimmune disorder that leads to • Fatigue
hypothryodism. Usually affects women (10- • Flat affect
20:1) between 45-60 years of age. • Cold intolerance
• Hoarseness
Etiology • Coarse Hair
• Bradycardia
• Decreased reflexes
• Polymorphisms in immune regulation • Psychosis
genes • Menstrual disturbance
• Most notably CTLA4, a negative • Infertility
regulator of T-cell response
• PTPN22 Labs:
• HLA-DR5 • Low T3/T4
• Elevated TSH
Pathogenesis
Complications
• Autoimmune destruction of thyrocytes
o Cell-mediated cytotoxicity B-cell non-Hodgkin’s Lymphoma
o Injury to thyroid by activated • Marginal Zone Lymphoma of MALT
macrophages
Heart failure – decreased contractility
o Antibody dependent cell
mediated cytotoxicity Cretinism – in children with hypothyroidism
• Destruction of follicular cells release
T3/T4, leading to hyperthyroidism
• Eventually enough thyroid is destroyed
and hypothyroidism sets in
Signs & Symptoms
• Painless symmetric enlargement of

thyroid
• Weight gain
Microscopy: Lymphocytic infiltration in well developed germinal centers. The surrounding thyroid follicles
have Hürthle cells, which have abundant eosinophilic granular cytoplasm. They signify metaplastic response
to the germinal center and are present in several thyroid pathologies.

Endocrine 224
Differentials Additional Info

Hashimoto’s is hypothyroidism due to Associated:
autoimmune destruction and is characterized • Type I Diabetes
by lymphocytic infiltration, goiter, and HLA • Autoimmune adrenalitis
association. • SLE
• Myasthenia Gravis
Hypothyroidism
• Sjögren Syndrome
• Iatrogenic – due to treatment
• Iodine deficiency
• Congenital
• Secondary to pituitary/hypothalamic
Gross: Before (Left) and after (Right) treatment for Hashimoto’s Thyroiditis. Note the change in affect (sad
to happy), the change in hair, and some thinning, especially in the neck region.

Endocrine 225
Thyroid Adenoma
Benign tumor of the thyroid follicular hyperthyroidism
cells. This is the most common thyroid tumor,
Labs (Toxic Adenoma):
and occurs more often in females.
• Low TSH
• High T3/T4
Etiology
Iodine Scan
• Hot or Cold nodule
Unclear, possibly due to radiation.
• Toxic type tends to be hot
Gain of function mutation in TSH receptor • Non-functioning type tends to be cold
• Malignancies tend to be cold
About 20% of have these mutations:
• RAS Fine Needle Aspiration
• PAX8/PPARG
Biopsy: no invasion
• PIK3CA
Pathogenesis
Toxic (Functioning) Adenoma
• Mutation in TSH receptor or a-subunit
of Gs
• Hyperplasia of follicular cells
• Constitutively release of T3/T4
Non-functioning Adenoma
• Mutation leads to proliferation of cells
Signs & Symptoms
• Asymptomatic
• Toxic adenoma may cause
thyrotoxicosis presenting as
Gross: Large single mass with a yellow color

location within the thyroid.

Endocrine 226
Complications
Thyrotoxicosis – excessive release of T3/T4
Differentials
Thyroid adenoma is non-invasive, which
is the best and most used clue to differentiate
with Follicular carcinoma.
Thyroid Neoplasm:
• Follicular carcinoma
o Will be invasive
o Thick capsule
o Males 40-60 or middle aged
women
• Papillary carcinoma
o Ground glass nuclei (Orphan
Annie nuclei)
o Nuclear grooves
• Medullary carcinoma
o Proliferation of parafollicular
cells
o Elevated calcitonin
o Amyloid deposits
o No hyperthyroidism
o Can be multicentric/bilateral
Hyperthyroidism:
• Grave’s disease
• Thyroiditis
• Struma ovarii
Microscopy: Uniform follicles that contain colloid material. It is important to note that the capsule is still
intact (arrows). This is the main difference between adenoma and follicular carcinoma. Hürthle cells are
also present.

Endocrine 227
Follicular Carcinoma
Malignant tumor of the follicular cells in
the thyroid. More common in men 40 40-60s or Complications
middle aged women.
Metastasis:: homogenous spread to liver, lungs,
Etiology and bone
• Associated with iodine deficiency. Differentials
Pathogenesis Follicular carcinoma is invasive, which is

the best and most used clue to differentiate
with thyroid adenoma.
• 50% have a RAS mutation
• 30% have PAX8-PPAR-γ-1 Thyroid Neoplasm:
• Thyroid adenoma
o Will be non-invasive
invasive
Signs & Symptoms o Thin capsule
o Females
• Solitary “cold” mass
• Typically asymptomatic
• Possible hyperthyroid symptoms
o Rare
Labs (If thyrotoxicosis):

• Low TSH
• High T3/T4
Iodine Scan
• Cold nodule
• Malignancies tend to be cold
Fine Needle Aspiration
Biopsy: no invasion
Gross:: Singular mass in the thyroid that appears

well demarcated.

Endocrine 228
Annie nuclei)
o Nuclear grooves
cells
o Amyloid deposits
o Can an be multicentric/bilateral
Microscopy:: Uniform follicles that contain colloid mate

material.
rial. It is important to note that the capsule is no
longer intact (zoom box) and the neoplasm invades the capsule. This is the main difference between
adenoma and follicular carcinoma. Hürthle cells are also present.

Endocrine 229
Papillary Carcinoma
Cancer of the follicular cells of the • Psammoma bodies
thyroid. More common in women. Most
common carcinoma of the thyroid. Labs:
• Elevated T3/T4
o Not enough for
Etiology hyperthyroidism
Ionizing radiation Complications

• Particularly when exposed in the first 20
years of life
• Nuclear radiation (Japan/Chernobyl) Metastasis:
• Cervical lymph nodes (50% of cases)
• Distal sites rare: Lungs & bone.
Pathogenesis • Even with metastasis this has a good
prognosis.
Point mutations (33-50%):
• BRAF Differentials
Chromosomal Rearrangements:
• RET/PTC (20%) Papillary carcinoma is a common
• NTRK1 (10%) thyroid cancer with its most distinguishing
feature being it’s histology with ground glass
All mutations involve activating MAP kinase nuclei (Orphan Annie Eyes), nuclear grooves,
signaling pathway. and psammoma bodies. May or may not have
papillae.
Signs & Symptoms
Painless mass in the neck
• Thyroid
• Cervical lymph nodes (with metastasis)
Biopsy:
• Ground glass nuclei
Gross: This singular exophytic and irregular mass has papillae (which are not always present). Papillary
carcinomas can also be multifocal, and well-circumscribed or infiltrative. There are regions of fibrosis and
calcification.

Endocrine 230
Thyroid Neoplasm:
• Thyroid adenoma
o Non-invasive & benign
o Thin capsule
o Women
o Will be invasive
o Thick capsule
women
cells
o Amyloid deposits
o Can be multicentric/bilateral
Microscopy: The image on the left highlights the papillary structure as well as the psammoma bodies (the
dark sphere). On the right highlights the ground glass appearance, which is due to clear nuclei with finely
dispersed chromatin (this is the diagnostic criteria). Also present are the nuclear grooves (dark lines).

Endocrine 231
Medullary Thyroid Carcinoma

Cancer of the parafollicular cells (C-
cells) of the thyroid. Peak incidence is 50-60s. Signs & Symptoms
Etiology • Mass/Nodules in thyroid

• Goiter
• Diarrhea (VIP)
RET Mutation
• Compression:
Sporadic (80%) o Dysphagia
o Hoarseness
Familial (20%)
• MEN2A or 2B Biopsy:
o Younger patients • Parafollicular cell proliferation
• Familial Medullary Thyroid Carcinoma • Amyloid deposits
o Without other MEN symptoms
Labs: Elevated calcitonin
• Mutation in RET
Metastasis: Liver, lung, bone, & brain
o Tyrosine kinase receptor
o No chromosomal Carcinoid Syndrome: Serotonin release
rearrangements, such as those
seen in papillary carcinoma
(RET/PTC translocations)
• Constitutively activated MAP kinase
signaling pathway
• Uncontrolled proliferation
• Neoplastic cells release calcitonin
o No hypocalcemia
• Also can release:
o Vasoactive Intestinal Peptide
o Serotonin
o Somatostatin
Gross: Well circumscribed single (sporadic) or multicentric (familial) nodule(s). Large nodules may have
necrosis and/or hemorrhaging.

Endocrine 232
Differentials
Medullary Thyroid Carcinoma is the
only thyroid cancer of the stoma (non-
follicular). Also, the only one to have amyloid
deposits and elevated calcitonin. Only this and
papillary thyroid carcinoma can be bilateral or
multicentric.
Thyroid Neoplasm:
• Thyroid adenoma
o Non-invasive & benign
o Thin capsule
o Women
o Will be invasive
o Thick capsule
women
Annie nuclei)
o Nuclear grooves
Microscopy: Proliferation of parafollicular cells (C-cells) in the stroma, which are polygonal or spindle
shaped and are clustered. Amyloid deposits of distorted calcitonin can be seen as homogenous eosinophilic
extracellular material.

Endocrine 233
Cushing Syndrome
Excess cortisol leading to a • Osteopenia/increased risk of fracture
characteristic set of symptoms. • Hyperglycemia/glucosuria
• Hypokalemia
Etiology • Loss of collagen
o Loose skin
o Abdominal striae
• Iatrogenic
o Steroid cortisol treatments Dexamethasone Test
• ACTH-Dependent (80%) • Changes in ACTH in response to low
o Pituitary Adenoma dose or high dose of dexamethasone
o ACTH Carcinoid • Pituitary: Not low, yes high
• ACTH-Independent (20%) • Ectopic: Not low, not high
o Adrenal Adenoma • Adrenal Tumor: Not low, not high, also
o Adrenal Carcinoma will have low ACTH prior to test
• Increased ACTH Pseudo-Cushing is similar to Cushing

• Adrenal cortical hyperplasia syndrome but resolves easily when treating the
o Adrenal neoplasm starts here underlying cause of alcoholism, anorexia,
• Hypercortisolism bulimia, obesity, or depression.
• Atrophy of contralateral adrenal gland
Signs & Symptoms
• Central Obesity/Weight Gain

• Buffalo Hump
• Moon face – Rounded face
• Decreased libido
• Hypertension
• Hirsutism
Diagram showing various symptoms of Cushing

syndrome.
http://www.physio-pedia.com/Cushing's_Syndrome

Endocrine 234
Adrenal Cortical Adenoma

Benign neoplasm of the adrenal glands o Hypertension
that can be non-function or functional. o Increased infections
• Conn’s Syndrome
Functional can produce cortisol or
o Aldosterone releasing
aldosterone.
o Hypertension
o Hypokalemia
Etiology Muscle cramps
o Metabolic alkalosis
o Aldosterone: Renin >900
Association with p53 and p57 mutations.
Cushing syndrome can also be caused
Uncontrolled proliferation
by a pituitary adenoma (Cushing Disease),
Cushing’s Syndrome iatrogenic with cortisol treatments, or other
• ↑ corbsol causes ↓ ACTH & ↓ CRH diseases.
Conn’s Syndrome There is also a malignant variant of

• ↑ aldosterone causes ↓ renin adenocarcinoma, which may present similarly
but also can metastasize.
Signs & Symptoms ACTH, cortisol, or aldosterone can also

be released in paraneoplastic syndromes.
• Cushing’s Syndrome
o Cortisol releasing
o Hyperglycemia
o Central obesity
o Moon Face
o Muscle wasting
o Buffalo hump
o Osteoporosis
o Striae
o Hirsutism
Gross: The adrenal cortex has a large yellow mass that is well circumscribed with a well developed capsule.

Endocrine 235
Pheochromocytoma
Tumor of chromaffin cells and usually
presents in the adrenal medulla and has Signs & Symptoms
episodes of catecholamine secretion.
Episodes of:
Etiology • Paroxysmal hypertension
• Anxiety
• Palpitations
10% Rule:
• Severe headache
• 10% are bilateral
• Sweating
• 10% are malignant
• Tremors
• 10% arise in childhood
• Cardiac arrhythmias
• 10% calcify
• 10% are not associated with Urine: catecholamines & metabolites
hypertension
• 10% are outside of the adrenals Labs: Elevated VMA
(paraganglioma) CT/MRI: Mass in adrenals
o Bladder wall
o Inferior mesenteric artery root
o Carotid body
• 10% are familial
o MEN 2A/B
o Neurofibromatosis
o May no longer be 10%
Pathogenesis
• Formation of neuroendocrine cells that

secrete catecholamines (dopamine,
norepinephrine & epinephrine)
• Catecholamines cause sympathetic
activation
• This leads to the symptoms
Gross: A large tumor that is enclosed in the adrenal cortex. The tumor is yellow or tan with hemorrhagic
necrosis and cystic degeneration. The leftmost arrow points to normal cortex and the middle arrow points
to normal adrenal medulla.

Endocrine 236
Differentials
Neuroblastoma is a tumor that also
arises in the adrenal glands. This usually occurs
in children and releases mostly dopamine with
its metabolite homovanillic acid (HVA).
Additional Info
Can be located outside of the adrenal
medulla. For example, if present in the bladder,
urination will cause release and hypertension.
Microscopy: Nests of neoplastic polygonal or spindle shaped cells surrounded by thin vascular stoma. The
nuclei of the tumor cells are round or oval with a stippled “salt and pepper” appearance that is characteristic
of neuroendocrine tumors.

Bone & Joints 237
Bone & Joints

Bone
Osteoporosis 238
Hyperparathyroidism 240
Osteomalacia/Ricketts 242
Paget’s Disease of the Bone 244
Achondroplasia 246
Osteogenesis Imperfecta 247
Osteopetrosis 248
Pott’s Disease 250
Joints
Osteoarthritis 251
Rheumatoid Arthritis 253
Neoplastic
Osteosarcoma 255
Enchondroma 258
Chondrosarcoma 259
Osteoclastoma 260

Bone & Joints 238
Osteoporosis
Reduced bone mass leading to weaker bones.
Differentials
Etiology
Osteoporosis will mainly be seen as
asymptomatic other than non-traumatic
• Normal process of aging fractures. The patient will most likely be elderly
• Lack of estrogen and a DEXA will show very low bone density. A
• Secondary biopsy will show loss of horizontal trabeculae
o Steroids with normal mineralization and composition.
o Disuse (astronauts)
o Hyperparathyroidism Osteomalacia would have abnormal
o Hyperthyroidism mineralization and excess osteoid material.
Renal Osteodystrophy would behave similarly,
as it is secondary vitamin D deficiency and will
Pathogenesis have renal pathology.
Paget Disease and Osteopetrosis would

• Bone resorption is greater than bone
have fractures and weakened bone, but with an
production
increase in bone mass, not a decrease.
• After peak mass (20s), there is a steady
decline in bone mass Metabolic Bone Disorders:
• Tensile strength and compression • Osteoporosis
strength are decreased • Hyperparathyroidism
• Increased risk of fractures, the most • Renal Osteodystrophy
common being vertebral compression • Osteomalacia/Rickets
and hip fractures • Scurvy
• Paget’s Disease
Signs & Symptoms
Non-traumatic fractures or compression
fractures of the vertebrae.
DEXA: >2.5 std dev below average
Gross: Comparison between normal (Left) and osteoporotic (Right) bone. Note the diminished density with
thinner trabeculae and the loss of horizontal trabeculae.

Bone & Joints 239
Increased Risk of Fractures:

• Osteoporosis
• Vitamin D Deficiency
o Osteomalacia
o Renal Failure
• Paget’s Disease of the Bone
• Osteopetrosis
• Neoplasms
o Osteosarcoma
o Enchondroma
o Osteoclastoma
Additional Info
http://emedicine.medscape.com/article/1948532-overview#a1
It is important to know the RANK signaling

pathway:
1. PTH is released by the parathyroid

2. PTH acts on osteoblasts to:
a. Up regulates RANKL
i. Also by IL-6
b. Down regulates OPG
(osteoprotegerin)
i. OPG binds RANKL
3. RANKL binds to RANK on osteoclast
precursor cells
4. Fusion of osteoclast precursors
5. New osteoclasts begin to reabsorb bone
Microscopy: Reduction in the size and number of trabeculae with a loss of connection between them.

Bone & Joints 240
Hyperparathyroidism
Excessive excretion of PTH by the parathyroid. Labs:
• Elevated PTH
Etiology • Elevated calcium
o Low in renal failure and Vitamin
D deficiency
Primary • Low phosphate
• Parathyroid adenoma o High in renal failure
Secondary XR: Radiolucency

• Chronic hypocalcemia
• Vitamin D deficiency DEXA: Decreased bone density
Tertiary
• Chronic renal failure
Complications
Pathogenesis • Brown tumor
Low Ca2+ causes increased PTH release

•
Differentials
• PTH induces osteoclastic activity
o PTH acts on osteoblasts to
increase RANKL Hyperparathyroidism can be primary or
• Bone resorption secondary to other conditions. The increased
• Increases serum calcium PTH will in general cause a rise of serum
calcium, with the only exception being in
Vitamin D deficiency and renal failure (which
Signs & Symptoms can cause vitamin D deficiency). The elevated
• Most discovered incidentally

• Nephrolithiasis
• Skeletal changes
• GI dysfunction
• Psychiatric dysfunction
• Neuromuscular dysfunction
Gross: Here we see a resected rib with a brown tumor found adjacent to the costal cartilage. Large areas of
bone loss present as lytic lesions in the bone. The brown color comes from increased vascularity,
hemorrhages, and hemosiderin deposition.

Bone & Joints 241
calcium can cause neuromuscular dysfunction Metabolic Bone Disorders:

and can cause mental disturbances. • Osteoporosis
• Hyperparathyroidism
On biopsy, a key word would e
• Renal Osteodystrophy
tunneling resorption or dissecting osteitis,
• Osteomalacia/Rickets
which is osteoclasts reabsorbing bone down the
• Scurvy
middle of the trabeculae, giving it a tunnel or a
tubal appearance.
The decreased bone density is also seen

in osteoporosis and osteomalacia/rickets.
Keep in mind, hyperparathyroidism may be due
to osteomalacia itself.
Microscopy: Osteoclasts eat away at the center of trabeculae, commonly referred to as tunneling resorption
or dissecting osteitis.

Bone & Joints 242
Osteomalacia & Rickets

Impaired bone mineralization causing
Rickets in children or Osteomalacia in adults. Signs & Symptoms
Etiology • Bone pain

• Osteopenia
• Increased risk of fractures
Vitamin D Deficiency
• Limited sun exposure Rickets:
• Diet/Malnutrition • Bowing of legs
• Malabsorption syndrome • Lumbar lordosis
• Drugs • Frontal bossing
• Liver failure • Rachitic rosary
• Renal failure o Overgrowth of cartilage at
costochondral junction
Pathogenesis • Harrison’s groove
• Pigeon chest
• Vitamin D deficiency XR: Bowing

• Decreased calcium absorption Biopsy: Excessive osteoid material
• Hypocalcemia
• Increased PTH Labs:
• Increased bone resorption • Low calcium
• Increased phosphate excretion • Low phosphate
• Impaired bone mineralization • High PTH
o Osteopenia • High alkaline phosphatase
o Increased risk of fractures
• In children:
o Inadequate calcification of
epiphyseal plate
o Bowing of legs
Microscopy: Excessive osteoid material, which is un-mineralized bone matrix, seen here as the pink
material.

Bone & Joints 243
Metabolic Bone Disorders:

Differentials • Osteoporosis
• Hyperparathyroidism
Osteomalacia & Rickets are similar in • Renal Osteodystrophy
pathology; the major difference between the • Osteomalacia/Rickets
two is the age of onset, with osteomalacia in • Scurvy
adults and Rickets in children. Due to children • Paget’s Disease
being in the middle of development, their
symptoms tend to be more severe than those
• Osteoporosis
would develop the disease in adulthood.
Any mention of vitamin D deficiency is o Osteomalacia
likely to be pointing to these diseases. It may o Renal Failure
be secondary to things like chronic renal failure • Paget’s Disease of the Bone
(renal osteodystrophy) or a malabsorption • Osteopetrosis
syndrome, which will have their own additional • Neoplasms
presentations. A physical indicator that is o Osteosarcoma
commonly used in bowing of the legs in o Enchondroma
children. o Osteoclastoma
Osteomalacia has an increased risk of

pathological fractures due to a decrease in bone
mass. Osteoporosis also has this, but will have
normal mineralization on biopsy and normal lab
values. Paget’s disease also has fractures, but
with excess bone mass that is abnormally
remodeled, making the bone weaker.
Osteopetrosis is another disease with fractures,
but like Paget’s it has increased bone mass.

Bone & Joints 244
Paget’s Disease of the Bone

Abnormal remodelling of bone Mixed Lytic and Blastic Stage
• More active bone formation
Etiology • Compensatory blastic activity
overcomes lytic activity
Sporadic or familial Osteosclerotic Stage

• Dense abnormally remodeled bone
Common in Europeans • Not strong, prone to fracture
• Cells are “burnt out”
Associated Mutations:
• RANKL
• p62 Signs & Symptoms
• NF-κB
• No RANK mutations
Usually Asymptomatic
Also thought to have a viral component
(Paramyxovirus), but no complete infectious
virus has been isolated from affected bone.
Pathogenesis
Osteolytic Stage
• Osteoclast activation
• Bone is excessively resorbed
Radiology: The XR of the skull shows patchy areas of varying lucency (osteolytic) and opacity (sclerosis). The
XR of the leg shows bowing of the tibia with radio-opaque and radiolucent areas. Note that the fibula
remains straight.

Bone & Joints 245
A very characteristic feature of Paget’s

Complications is the cement lines forming the mosaic
appearance on biopsy.
• Bone pain Osteopetrosis will have the increase in
• Skeletal deformities – change in hat size fractures and increased bone mass as well;
• Chalk stick fractures however it is due to defective osteoclastic
o Fractures transverse to long activity. The growth will be symmetric and
axis of bone diffuse, unlike Paget’s, and may have the
• Spinal stenosis – back pain characteristic Erlenmeyer flask shape. It may
• Headaches also present with anemia.
• Hearing loss
• Osteoarthritis Osteosclerosis:
• Cardiac Failure • Osteoarthritis
o With pre-existing heart disease • Osteoma
• Sarcoma/tumors • Osteopetrosis
Labs: Metabolic Bone Disorders:

• Elevated ALP • Osteoporosis
• Normal Calcium, Phosphate, PTH, Vit D • Hyperparathyroidism
• Renal Osteodystrophy
Urinalysis: • Osteomalacia/Rickets
• Elevated hydroxyproline • Scurvy
Differentials
Paget’s disease of the bone is normally
asymptomatic, found incidentally while looking
for something else on XR. However, it can have
a myriad of presentations. Most notably, it can
have chalk stick fractures, sarcomas, or cardiac
failure in someone whom already has a heart
condition. Other key symptoms can be a tight
hat, headaches, or hearing loss, all which have
to do with thickening of the skull.
Most labs will be normal, with the only

elevations being markers for bone remodeling:
serum ALP and urine hydroxyproline.
Microscopy: Here we see a mosaic pattern of lamellar bone, similar to a jigsaw puzzle, with prominent
cement lines that haphazardly connects units of lamellar bone. The white areas are resorption pits with
osteoclastic activity.

Bone & Joints 246
Achondroplasia
The most common form of dwarfism.
Differentials
Etiology
There are many other causes of dwarfism, but
this is the only one covered in class.
Autosomal dominant mutation of FGFR3
Most are de novo mutations (sporadic) Additional Info

Pathogenesis Homozygous mutations are lethal in utero
• Over activation of FGFR3

• Inhibition of chondrocyte proliferation
at epiphyseal plate
• Shortened long bones
Signs & Symptoms
• Short extremities
• Short stature
Complications
• Spinal cord compression at foramen

magnum
• Spinal stenosis
Gross: A person of abnormally low height with shortened limbs and digits. The head and torso are of normal
size. The legs are slightly bowed due to shortening of the tibia more than the fibula.

Bone & Joints 247
Osteogenesis Imperfecta
Collection of disorders of collagen Skin biopsy: check collagen
synthesis. Also known as Brittle Bone Disease.
There are 8 types of OI, the most Complications

important to know are types I & II.
• Type I: Mild, normal life span
Etiology • Type II: Most severe, death in utero
Mutations in Type I collagen synthesis Differentials

Pathogenesis OI type I usually presents early in life
with a history of multiple fractures. A clear
indicator is blue sclera of the eyes. There may
Type I:
also be hearing loss.
• Loss of expression of one of the α1
chains OI type II is severe and commonly
• Less α1 chains produced results in death in the uterus.
• Loss of structural integrity
Child abuse must be considered, so look
Type II: for bruising, especially in areas that are subject
• Defect in α1/ α2 chains to normal childhood injuries such as the chest.
• Defective chain incorporated into
collagen
• Disruption of collagen structure
• Degradation of collagen
• Loss of structural integrity
Signs & Symptoms
• History of multiple fractures

• Blue Sclera (Typical in Type I OI)
• Hearing loss
• Small/misshapen teeth
Radiology: Presence of multiple fractures and also some

bowing defects. There is also osteoporosis and thin
diaphysis.

Bone & Joints 248
Osteopetrosis
Unopposed osteoblastic activity due to
a defect in osteoclasts. Complications
Etiology Most common cause of death is infections.
• Deficient osteoclastic activity
Pathogenesis
• Not well understood

• Mutations:
o C-src
o C-fos
• Carbonic Anhydrase II Deficiency
o Osteoclast hydrogen ion
excretion
o No excretion means no
resorption
Signs & Symptoms
• Compression of marrow:
o Recurrent Infections
o Anemia
o Hepatosplenomegaly &
extramedullary hematopoiesis
• Cranial Nerve Dysfunction
o Hearing loss
• Increased risk of fractures
Radiology: The bones are very radiopaque with widening of the metaphysis, giving it the characteristic
“Erlenmeyer flask” appearance. On a spinal XR, the vertebrae would have a “rugger jersey” appearance due
to sclerosis beneath the endplates.

Bone & Joints 249

Differentials • Osteoporosis
Osteopetrosis will most o Osteomalacia
characteristically have the Erlenmeyer flask o Renal Failure
appearance of the bones, in addition to the loss • Paget’s Disease of the Bone
of marrow symptoms, fractures, and CN • Osteopetrosis
deficits. • Neoplasms
o Osteosarcoma
Paget’s disease of the bone is similar o Enchondroma
with the enlarged bones that are prone to o Osteoclastoma
fractures. However, it will be patchy, not
diffuse. Paget’s may also have the CN deficits,
but not the marrow symptoms.
Microscopy: Un-reabsorbed primary spongiosa fills the metaphysis and the bone trabeculae are composed
of calcified cartilage surrounded by bone.

Bone & Joints 250
Pott’s Disease
Complication of tuberculosis. Aka
Tuberculous Osteomyelitis of the vertebrae. Differentials
Etiology Osteomyelitis is the general term for

any infections of the bone, with tuberculosis
being just one of the possibilities. More
Infection of vertebrae with M. tuberculosis or common is S. aureus, followed by Streptococcus
M. bovis. and Enterococcus species. Can be either acute
or chronic, following normal inflammation
Pathogenesis conventions (acute has infiltrates, chronic has
fibrosis, etc)
• Initial infection with tuberculosis

• 15-20 years post infection Additional Info
• Bacteria invade vertebrae or long bones
o Pott’s is specific to vertebrae Cold Abscess: skin over abscess is not warm
• Caseous necrosis
• Type IV Hypersensitivity
• Vertebrae deformity and collapse
Signs & Symptoms
• Low grade fever

• Back pain
• Neurological deficits
Complications
• Gibbus deformity (kyphosis)

• Psoas abscess
o Spread from vertebrae into
psoas muscle
Gross: Abscess formation and deterioration of the

lumbar spine. The abscess is compressing the spinal
cord.

Bone & Joints 251
Osteoarthritis
The most common form of arthritis and
involves the loss of articular cartilage in the Signs & Symptoms
joint. Generally considered a non-inflammatory
arthritis. Primary OA tends to affect people in
• Deep aching pain
their 50-60s.
• Morning stiffness (within 15 minutes)
that gets worse
Etiology • Limited range of movements
• Crepitus
• Nerve root compression
Breakdown of articular cartilage
o Radicular pain
• Age related
o Muscle spasms
• Trauma to joint
o Muscular atrophy
• Symptoms are usually asymmetric
• Obesity
XR:
Pathogenesis • Joint Space Narrowing
• Osteophytes
• Sclerosis
• Chondrocytes lost to wear and tear
• Inadequate regeneration
• Gradual loss of matrix
• Most commonly affects large joints in
the lower extremities, spine, and hand
joints (DIP/PIP).
Microscopy: Here we see the articular cartilage with vertical and horizontal fibrillation as well as cracking of
the matrix.

Bone & Joints 252
Osteoarthritis Rheumatoid Arthritis
Joint Large – knees, spine Small – fingers, wrists
Symmetry Asymmetrical Symmetrical/global
Pathology Loss of cartilage Pannus and fusion
Inflammation Small role Autoimmune

Begins rapidly (about 15-30 minutes) and
Morning Stiffness Slow onset (over an hour)
gets worse
Exercise Exacerbates Alleviates pain
Skin nodules, baker cyst, vasculitis, pleural
Extra-articular None
effusions
may have tophi. Acute attacks are heavily
Differentials inflamed and mimics septic arthritis.
The two main arthritis disorders are

osteoarthritis and rheumatoid arthritis, which
are compared in the above chart.
Seronegative Arthritis is a group of

arthritic disorders which is similar in
histopathology to rheumatoid arthritis, but with
involvement of ligaments, tendons, and
cartilage. The most common of this group is
Ankylosing Spondylitis, which is known for
fusion of the vertebrae.
Septic Arthritis is an infection of the

synovial fluid, commonly affecting young
patients. The organisms that cause this are
similar to osteomyelitis, such as S. aureus, but
also include N. gonococcus and Lyme disease.
Histologically similar to RA.
Gout is deposition of urate crystals in

the synovium and articular cartilage. The
patient will have elevated uric acid levels and
Radiology: In this hip XR it is important to note the narrowing of the joint space , some osteosclerosis (seen
as denser areas of bone) and osteophyte formation (mushroom shaped bony outgrowths, shown at the
arrows).

Bone & Joints 253
Rheumatoid Arthritis
Autoimmune arthitis that symmetrically o Subcutaneous
affects small joints. o Heart valves
o Lung pleura
o Pericardium
Etiology o Spleen
• Low grade fever, malaise, fatigue,
Type III Hypersensitivity lymphadenopathy
Risk Factors: Labs: Rheumatoid factor positive

• Female (4:1) • IgM against Fc of IgG
• 20-50 years of age
XR: Decreased joint space
• HLA-DR4
Synovial fluid:
Pathogenesis • Increased proteins
• Increased WBC – neutrophils
• Low mucin
• Non-specific inflammation
• Diffuse proliferative synovitis
• Pannus formation
o Proliferation of synovium and
granulation tissue over the
articular cartilage
• Fibrous and bony ankylosis
o Joint fusion
Signs & Symptoms
• Warm, swollen, and painful joints

o Gets better with exercise
o Starts 1 hour after awakening
o Symmetrical and bilateral
o Affects mostly small joints
• Rheumatoid nodules
Microscopy: Here we see a joint that has profuse pannus formation, seen as the pink material within and
surrounding the joint space. The cartilage itself has been destroyed and replaced with fibrous tissue.

Bone & Joints 254
Complications
• Swan-Neck/Boutonniere
Neck/Boutonniere Finger
Deformities
• Vasculitis in medium sized arteries
o Myocardial Infarctions
o Renal Failure
• End Stage Lung Disease
• Amyloidosis
Differentials
The two main arthritis disorders are
osteoarthritis and rheumatoid arthritis, which
are compared in a table within the
osteoarthritis profile.
Seronegative Arthritis is a group of

arthritic disorders
ers which is similar in
histopathology to rheumatoid arthritis, but with
involvement of ligaments, tendons, and
cartilage. The most common of this group is
Ankylosing Spondylitis, which is known for
fusion of the vertebrae.
Septic Arthritis is an infecti

infection of the
synovial fluid, commonly affecting young
patients. The organisms that cause this are
similar to osteomyelitis, such as S. aureus
aureus, but
also include N. gonococcus and Lyme disease.
Histologically similar to RA.
Gout is deposition of urate crysta

crystals in
the synovium and articular cartilage. The
patient will have elevated uric acid levels and
may have tophi. Acute attacks are heavily
inflamed and mimics septic arthritis.
Gross:: Here we see the long term effects of RA, with the wrists deviated med
medially
ially (radial deviation) and the
fingers showing ulnar deviation.

Bone & Joints 255
Osteosarcoma
Bone producing malignant tumor. This
is the most common primary bone tumor and Signs & Symptoms
mostly affects people under 20 years of age.
The rest tend to be the elderly. Tends to affect
• Pathological fractures
men more than women.
• Painful enlarging mass
Etiology XR: Codman’s triangle
Biopsy:
Mutations: • Stoma cells with nuclear pleomorphism
• Complex karyotypes • Mitotic activity
o Amplification of MDM2
• Rb Complications
o Retinoblastoma increases risk
by a thousand fold
• p53, cyclins, cyclin-dependent kinases Metastasis: Lung
• Uncontrolled proliferation Osteosarcoma is a malignant tumor

found at the metaphysis of the long bones and
• Most commonly affects metaphysis
may infiltrate the epiphyseal plate or even the
• Destroys surrounding cortices
joint space. Look for Codman’s triangle on XR.
• Spreads into medullary canal
• Replaces bone marrow
• Arises in metaphysis
• Can infiltrate epiphyseal plate or enter
the joint space
Occurs in the:
• Knee – 60%
• Hip – 15%
• Shoulder – 10%
• Jaw – 8%
Microscopy: Coarse, lace like pattern of neoplastic bone formation arising from anaplastic tumor cells.
These tumor cells will be pleomorphic with large hyperchromatic nuclei, giant cells, and mitotic activity
There may also be cartilage and fibrous tissue.

Bone & Joints 256
The benign tumors are: Osteoclastoma, aka Giant Cell Tumor of

• Osteoid Osteoma Bone, is a tumor of mesenchymal cells that
• Osteoma activate osteoclasts. Tends to form in the
• Osteochondroma epiphysis and extends into the metaphysis. The
• Enchondroma bones commonly affected are distal femur,
• Osteoclastoma proximal tibia, (knee) and distal radius. These
lesions are painful and lytic. Generally
Osteoid Osteoma is a benign tumor considered benign but can metastasize to the
that has a limited growth potential. It is a bone lungs.
forming tumor with an age of onset of 5-25
years of age. They tend to occur in the
diaphysis of long bones of the lower
extremities. A biopsy will show irregular
trabeculae of woven bone with plump
osteoblasts. The lesion may have local
tenderness. These tumors respond well to
NSAIDs.
Osteoma, also called a bone island, is a

benign proliferation of cortical bone. It typically
affects the paranasal sinus or the skull. There
may be no symptoms but may contribute to
sinusitis. XR will show radiodense regions that
are well circumscribed.
Osteochondroma is a benign outgrowth

of plate-like cartilage and bone. It tends to
arise in the metaphysis. The presentation will
be asymptomatic but may have some pain or
pathological fractures.
Enchondroma is a benign growth of

hyaline cartilage. May be singular or multiple,
with multiple being part of Ollier’s disease or
Mafucci syndrome. This is a lytic lesion that is
well circumscribed. It is likely to be
asymptomatic and an incidental finding.
Radiology: Codman’s triangle, which is the region between the edges of broken cortex and shows the raised
periosteum. Look for the two extra triangles protruding from the left side of the bone (right side of image).

Bone & Joints 257
The malignant tumors are: Increased Risk of Fractures:

• Osteosarcoma • Osteoporosis
• Chondrosarcoma • Vitamin D Deficiency
• Ewing Sarcoma o Osteomalacia
o Renal Failure
Chondrosarcoma is a malignant tumor • Paget’s Disease of the Bone
of the cartilage. Usually affects the pelvic and
• Osteopetrosis
flat bones (such as the ribs) with occasional
• Neoplasms
presence in long bones. Patients usually
o Osteosarcoma
present with pain. On XR lytic lesion is seen.
o Enchondroma
Biopsy will shoe hyaline or myxoid cartilage
o Osteoclastoma
matrix.
Ewing Sarcoma is an odd neoplasm in

that is de-differentiates into a cell that isn’t
found anywhere else in the body. The tumor
cells are primitive round cells and grow in the
diaphysis and/or metaphysis. The lesions are
lytic and painful. This tumor tends to grow in
younger people (10-20). There is elevation of
the periosteum that form an onion skin or sun-
burst pattern. This neoplasm has a
translocation of t(11;22) involving EWS and Fli-1
genes.
Metastasis from elsewhere:
• Breast
• Lung
• Prostate
• Kidney
• Thyroid
First Aid for the USLME Step 1: 2011 Edition

Bone & Joints 258
Enchondroma
Benign growth of cartilage within the bones.
Signs & Symptoms
Three main presentations:
• Singular Tumor
o Phalanges Asymptomatic
o Long bones XR: Radiolucent regions with O-ring sign
• Ollier’s Disease
o Unilateral with multiple
chondromas Complications
• Mafucci Syndrome
o Multiple chondromas with • Limited growth potential
hemangiomas • Pathological fractures
o Almost certain to have extra-
skeletal carcinomas
Differentials
Tends to affect people 20-50 years old.
Enchondroma is likely to be an
Etiology incidental finding. Look for benign lytic lesions
of the hands.
Arises from hyaline cartilage A detailed bone neoplasm differential is
Ollier’s disease is weakly associated with PTHR1 found under osteosarcoma.
Pathogenesis
• Uncontrolled proliferation
• Lytic lesion
• Located in the diaphysis
Tend to occur: Phalanges, both hand & foot
Radiology: Radiolucent regions in the diaphysis/metaphysis region of the middle phalanges of the hand.
Each radiolucency is surrounded by a ring of radiodense bone, termed the O-ring sign.

Bone & Joints 259
Chondrosarcoma
Malignant tumor of neoplastic cartilage.
Complications
Etiology
Metastasis: Lungs and other bones
Tend to affect men more than women (2:1) and

those over 40 years old. Differentials
Pathogenesis Chondrosarcoma will have the typical

bone neoplasm presentation, with the
combination of lytic lesions and arises from the
• A variety of tumors all with proliferation cartilage. Tends to metastasize to the lungs.
of neoplastic cartilage.
• Tumor can invade or entrap pre-existing A detailed bone neoplasm differential is
bone found under osteosarcoma.
• May arise from an enchondroma.
Tends to affect: Additional Info

• Pelvic bones
• Flat bones (ribs) Treated with surgery.
• Long bones
Signs & Symptoms
• Painful enlarging mass

• Reactive thickening of cortex
XR: Lytic lesion with ring like calcifications
Biopsy: Variably formed cartilage, either hyaline

or myxoid, with varying cellularity.
Microscopy: Neoplastic cartilage with anaplastic chondrocytes and excessive matrix. The malignant
chondrocytes are in various stages of maturity.

Bone & Joints 260
Osteoclastoma
Benign tumor that is locally aggressive
and arises from mesenchymal stromal cells. Complications
Tends to affect people 20-40 years old. Aka as
Giant-Cell Tumor of the Bone.
Rarely metastasizes to lungs
Arises from mesenchymal stromal cells Osteoclastoma presents like most of
the bone neoplasms, but will show osteoclast-
Pathogenesis like giant cells on biopsy. Tends to affect the
knee, as does osteosarcoma. Any mention of
RANKL or RANK is likely referring to
• Mesenchymal tumor cell express RANKL osteoclastoma.
• Recruits monocytes and activates them
to osteoclasts. A detailed bone neoplasm differential is
• Osteoclasts clump together to form found under osteosarcoma.
osteoclast-like giant cells.
Tends to affect:
• Distal femur & Proximal tibia (knee)
• Distal radius
Signs & Symptoms
• Painful bone lesion

• Arthritis in knee (or affected joint)
XR: Radiolucency
Biopsy: Osteoclast type giant cells
Microscopy: Uniform oval mononuclear cells with high mitotic activity. Interspersed are osteoclast-type
giant cells. Note the patches of hemorrhage and reactive bone formation.

Neuropathology 261
Neuropathology
General Brain
Hydrocephalus 262
Epidural Hematoma 263
Subdural Hematoma 264
Subarachnoid Hemorrhage 265
Basal Ganglia Hemorrhage 266
Cerebral Infarction 267
Brain Abcess 268
Alzheimer’s Disease 269
Multiple Sclerosis 270
Neoplastic
Glioblastoma Multiforme 272
Meningioma 274
Medulloblastoma 276

Neuropathology 262
Hydrocephalus
Accumulation of excess CSF in the ventricles • Vision disturbance
• Ataxia
Etiology • Incontinence
MRI: Enlarged ventricles

Communicating
• Reduced absorption of CSF Complications
• Meningitis
• Normal Pressure Hydrocephalus
• Loss of brain parenchyma
Non-communicating • Herniation
• Cerebral aqueduct stenosis
• Scar formation in the foramina of
Luschka and Magendie
Differentials
• Tumors & Cysts
Hydrocephalus tends to be a secondary
Ex Vacuo process, so look for evidence of the underlying
• Loss of brain parenchyma/atrophy cause. Mention of enlarged ventricles is likely
• Alzheimer’s referring to hydrocephalus.
Increased ICP:
Pathogenesis • Neoplasms
• Abscesses
• The cycle of CSF production, flow, and • Meningitis
resorption is somehow impeded • Edema
• CSF accumulates
• ICP increases
• Ventricles dilate under the pressure
Signs & Symptoms
• Cognitive deterioration
• Headache/Nausea
• Neck pain
Gross: Note the enlarged ventricles (1,2, & 3 seen
here). The expansion of the right lateral sulcus may
indicate communicating, but more evidence is needed.

Neuropathology 263
Epidural Hematoma
Hemorrhage between the dura mater
and the skull. Differentials
Etiology Both epidural and subdural hematomas

can be due to trauma. Epidural will have the
biconvex shape on CT, as well as a more rapid
• Head trauma onset, due to being an arterial bleed, with a
o Especially in temporal area well defined lucid interval. Any mention of the
middle meningeal artery or pterion is likely to
Pathogenesis be epidural.
The other bleeds won’t have the lucid

• Skull fracture & trauma interval and tend to not be due to trauma.
• Rupture of an artery
o Middle meningeal if in the
temporal region
• Lucid period involves the accumulation
of blood
• Hematoma grows and begins
compressing the brain
Signs & Symptoms

1. Initial loss of conscience with trauma
2. Lucid interval
3. Rapid onset of severe headache,
nausea/vomiting, and/or seizures
4. Decline in mental status
5. Coma
6. Death
CT: Biconvex lens shaped hematoma
Radiology: CT scan with a radiodense region in the right frontal lobe area is a collection of blood between
the skull and the dura mater. Note the characteristic biconvex lens shape, which is due to the skulls sutures
preventing the spread.

Neuropathology 264
Subdural Hematoma
Hemorrhage between the dura and • Severe headaches
arachnoid mater. • Progressive decline in mental status and
function
Etiology CT: Concave hematoma
• Head trauma Differentials

• Shaken Baby Syndrome
At risk groups: Both subdural and epidural hematomas

• Infants are due to trauma, and can present relatively
• Elderly similarly. Subdural will also have a lucid
interval, but is much more likely to over days to
weeks because of the slow venous bleed. The
Pathogenesis crescent shape on CT is a characteristic sign.
Look for elderly patients or a shaken baby.
• Trauma to the head There is a progressive loss of mental
• Rupture of the bridging veins functioning.
• Hemorrhaging between the dura and
The other bleeds won’t have the lucid
arachnoid mater
interval and tend to not be due to trauma.
• Lucid period involves the accumulation
of blood
• Hematoma grows and begins
compressing the brain
Signs & Symptoms
• Initial trauma, likely to be unconscious

• Lucid interval
o Acute (hours)
o Delayed (days to weeks)
• Chronic subdural hematoma may
organize itself and be self-limiting
Radiology: CT scan with a radiodense region along the right side of the skull indicating accumulation of
blood between the dura and arachnoid maters. Note the characteristic crescent shape that is found in
subdural hematomas. Also not the small shift in the midline to the patient’s left.

Neuropathology 265
Subarachnoid Hemorrhage
Hemorrhage into the subarachnoid • Recurrent bleeding
space, which is between the arachnoid and pia • Additional ischemic injury
mater. o vasospasm
• Berry Aneurysm (Saccular Aneurysm) Subarachnoid hemorrhages tend to
• Mycotic aneurysm follow berry aneurysm ruptures, and will
• Neoplasm present with headaches and double vision.
Epidural and subdural hematomas will

Pathogenesis usually follow trauma and have characteristic
shapes on CT.
• Aneurysm ruptures Intraparenchymal hemorrhage and
o Berry aneurysms – 80% Ischemic strokes (infarctions) will also have the
• Blood pools in subarachnoid space sudden onset, but will have more direct loss of
• Compression of the brain functions depending on locale.
• Meningeal fibrosis and scarring
o Obstruction of CSF flow or
resorption
Signs & Symptoms
• Sudden onset
• Severe headache
• Double vision
• Loss of consciousness
Complications
• Death
Gross: There is extensive pooling of blood in the subarachnoid space, extending from the circle of Willis
down the brainstem. This is most likely due to a ruptured berry aneurysm.

Neuropathology 266
Intraparenchymal Hemorrhage
Hemorrhage into the parenchyma.
Most commonly occurs in mid to late adult life Complications
with a peak at 60 years of age.
• Death (15% of HTN patient deaths)
Etiology
Differentials
• Hypertension
o Deep structures
Intraparenchymal hemorrhages are
o Basal ganglia usually a product of chronic hypertension, and
o Hypothalamus will present based on the location of
o Thalamus
hemorrhage. If due to amyloidosis, it will be
• Cerebral Amyloid Angiopathy more lobar. Look for sudden onset of
o More lobar hemorrhage symptoms with specific deficits.
o Cerebral cortex
• Thrombosis/Embolism Other sudden onset disorders include
the cerebral infarcts or subarachnoid
hemorrhage (berry aneurysm rupture).
Pathogenesis
• Rupture of small intraparenchymal

vessel
• Typically occurs in the deep brain
structures
o Basal ganglia
o Thalamus
o Pons
o Also cerebellum
Signs & Symptoms
• Increased ICP symptoms

• Other symptoms based on location
Radiology: Scan showing a mass of blood in the

right basal ganglia with subsequent compression
of the adjacent parenchyma.

Neuropathology 267
Cerebral Infarction
Infarction of the cerebral parenchyma.
Also called an ischemic stroke. Complications
Etiology • Death
• Cerebral arthrosclerosis Differentials

o Larger vessels
o ICA
Cerebral infarctions have a sudden
o MCA onset, similar to subarachnoid and
o Basilar
intraparenchymal hemorrhages. Cerebral
• Emboli infarcts and intraparenchymal hemorrhages can
o Mostly mural be collectively termed “stroke,” which generally
• Vasculitis refers to any sudden neurological defects due
• Trauma to a vascular etiology. Differences include
etiology and the pathology driving the damage.
Pathogenesis Of note, hemorrhaging may increase ICP,
whereas infarction may not.
• Occlusion of the vessel

• Ischemia of parenchyma
• Necrosis
• May have hemorrhage (red infarct)
Signs & Symptoms
• Depends on site of infarction
MRI/CT: Locate infarction
Gross: Several regions of the brain, most notably on the patient’s right, have a yellow/brown color with a
gelatinous appearance. This is an early stage of a cerebral infarction.

Neuropathology 268
Brain Abcess
Liquefactive necrosis in the brain parenchyma. o Seizures
o Papilledema
Mental status change
Etiology o
Lumbar Puncture
• Bacterial Infection • Elevated WBC
o Most commonly hematogenous • Elevated Protein
spread • Normal Glucose
o Direct spread is also possible
MRI/CT
Predisposing conditions
• Acute bacterial endocarditis Complications
• Cyanotic congenital heart disease
• Chronic pulmonary infection
Rupture of abscess:
• Ventriculitis
Pathogenesis • Meningitis
• Venous sinus thrombosis
• Focal infection
• Infected cells digested by hydrolytic Differentials
enzymes
• Formation of pus
Abscesses tend to be associated with a
• Removal of debris
bacterial infection, so any mention of such is a
• Empty abscess formation
good indicator. Also look to the CSF analysis.
• Granulation tissue forms around
abscess Meningitis may present similarly, but
with less of the mental status changes.
Signs & Symptoms
• Progressive focal deficits

• Increased ICP symptoms
o Headaches
o Projectile vomiting
o Nuchal rigidity
Gross: Note the large liquefactive abscess with

the remaining fibrous capsule.

Neuropathology 269
Alzheimer’s Disease
The most common cause of demetia in • Changes in mood, behavior, and
the eldery due to degeneration of the cortex. personality
Etiology Complications
• Most are sporadic Death usually due to infections
• Early onset is hereditary
o Down Syndrome – APP on 21
o Presenilin 1 or 2
Differentials
o Apo-E4
Alzheimer’s is a common cause of
dementia. Diagnosis is confirmed with biopsy
Pathogenesis on autopsy. Imaging may be able to show ex
vacuo hydrocephalus.
• Amyloid precursor protein (APP) is
Normal Pressure Hydrocephalus can
normally cleaved by α and γ secretase.
also cause dementia, but can be relatively cured
• Instead cleaved by β and γ secretase,
with treatment.
producing β-amyloid fragments.
• β-amyloid accumulates.
• Alters neurotransmission, is toxic, and
causes neuronal cell death.
• Also increases risk of hemorrhage.
• Tau proteins accumulate as
neurofibrillary tangles.
Signs & Symptoms
• Slow onset memory loss

• Progressive disorientation
• Aphasia
• Loss of learned motor skills and
language
Gross: Atrophy of the brain parenchyma leading to small gyri and widened sulci. This occurs mostly in the
frontal and temporal lobes.

Neuropathology 270
Multiple Sclerosis
Idiopathic demylination of the central • Scanning speech
nervous system. • Intention tremor
• Nystagmus
Etiology • Internuclear ophthalmoplegia
• Hemiparesis
• Loss of sensation
Mixed genetic and environmental agents • Bowel, bladder, and sexual dysfunction
causing autoimmunity to central myelin.
Risk Factors: Complications

• Young adults
• Female (3:1)
• Gradual worsening of symptoms with
• Smoking
each episode
• Low Vitamin D
• Caucasians
• EBV Differentials
• HLA-DR15 (includes -DR2)
• Temperate Latitudes (before puberty) Multiple Sclerosis is a difficult diagnosis
• Maternal history given its wide range of possible symptoms that
come and go. They may directly indicate
Pathogenesis central demyelination.
Post Infectious Demyelination is similar

+
• CD4 TH1 activation disorder but will follow a flu-like illness. Can be
• INF-γ activates macrophage and TH17 termed Acute Inflammatory Encephalopathy,
• Targeted destruction against myelin with (AHEM) or without (ADEM) hemorrhage.
• Destruction of oligodendrocytes
Signs & Symptoms

Transient and recurrent episodes of:
• Unilateral vision loss
• Blurred vision
Gross: There are multiple grey-tan plaque lesions

that are well circumscribed and irregular around the
ventricles. These are indicated by the arrows.

Neuropathology 271
Myelinolysis is a demyelination
disorder that can be central pontine or extra-
pontine. It is in response to rapid correction of
hyponatremia (iatrogenic), but the actual
pathogenesis is unknown.
Some of the other degenerative disorders

include Parkinson’s, Huntington’s, and ALS.
Parkinson’s Disease is a triad of

tremor, rigidity, and akinesia. It is due to
atrophy of the substantia nigra and occurs
sporadically.
Huntington’s Disease is the opposite of

Parkinson’s, with chorea and dementia being
the main symptoms. There is atrophy of
caudate and putamen. It is due to a CAG
repeat in the HTT gene (huntingtin protein)
Amyotrophic Lateral Sclerosis, aka Lou

Gehrig’s Disease, is a disease of the anterior
horn of the spinal cord leading to muscle
atrophy. It occurs in middle age and has a poor
prognosis.
Radiology: MRI of the head show a reduction in the white matter, with most of the cortex now being grey
matter.

Neuropathology 272
Glioblastoma Multiforme
Malignant brain neoplasm that arises
from astrocytes and is the worst grade of the Complications
lineage with the least differentiation. Tends to
affect adults 30-50 years of age. Aka fibrillary
Very poor prognosis, life expectancy 1-2 years
astrocytoma
The brain neoplasms tend to present
• Tumor of astrocytes the same, with generalized increase in ICP and
symptoms based on location. Look for
Pathogenesis astrocyte origins and GFAP (indication of
astrocyte origin).
• Unknown Oligodendroglioma is a similar

• Mutations of p53 and Rb neoplasm, but of the oligodendrocytes. It
presents similarly but with a better prognosis.
Signs & Symptoms Ependymomas arise from the

ependyma lining of the ventricles, usually in the
4th ventricle. These occur earlier in life (younger
• Seizures
than 20). Tends to spread to the spinal cord.
• Headaches
Can be seen in neurofibromatosis type 2.
• Focal deficits
MRI/CT: Mass visible
GFAP: Positive, marker for astrocytes
Good prognosis:
• EGFR negative
• IDH-1 positive
• p53 positive
• MGMT methylation positive
Gross: Occluding the lateral ventricles is a large neoplasm with poorly defined borders that infiltrate the
surrounding tissue. Some regions are firm, while others are soft and yellow, giving it the “multiforme”
nomenclature.

Neuropathology 273
Meningiomas are tumors of the

meninges, and will have symptoms of increased
ICP and compression symptoms. It isn’t
attached to the brain.
Schwannomas are tumors of peripheral

nerve sheaths. In the head, they are most
prominent in CN VIII, giving hearing loss. Is a
component of NF.
Medulloblastoma is a tumor of the

cerebellum. They tend to occur in children, but
can occur in adults. There will be symptoms of
cerebellar dysfunction, such as ataxia, and a
common complication is hydrocephalus.
Pituitary adenoma is a tumor that will

eschew the hormone balance, and will give
symptoms mostly based on endocrine changes.
If it becomes large enough, it may interfere with
vision.

• Lung
• Breast
• Melanoma

Neuropathology 274
Meningioma
Tumor of the meninges.
Differentials
Etiology
The brain neoplasms tend to present
the same, with generalized increase in ICP and
Can be singular or multiple. symptoms based on location. Look for
Neurofibromatosis type 2 (NF2): meningeal origins and no direct infiltration of
• Bilateral vestibular schwannomas the parenchyma. They may discuss in relation
to NF2, so keep in mind the association with
• Meningiomas
schwannomas and hearing loss.
• Gliomas
• Cataracts Glioblastoma is a very malignant tumor
• Some cutaneous lesions (more in NF1) arising from astrocytes. GFAP is a marker for
astrocyte origin.
Even if not NF2, may still have a mutation in
NF2 gene Oligodendroglioma is a similar
neoplasm, but of the oligodendrocytes. It
Pathogenesis presents similarly but with a better prognosis.
Ependymomas arise from the

• Arises from meningothelial cells of the ependyma lining of the ventricles, usually in the
arachnoid or from stromal arachnoid 4th ventricle. These occur earlier in life (younger
cells of the choroid plexus in the than 20). Tends to spread to the spinal cord.
ventricles. Can be seen in neurofibromatosis type 2.
• Compression, irritation, vascular
damage, or infiltration (rare) of the
underlying parenchyma.
Signs & Symptoms
• Symptoms are dependent on location
MRI/CT: Visible mass
Gross: Well defined mass attached to the meninges and compresses the brain, but it not attached to the
parenchyma.

Neuropathology 275

component of NF.

vision.
Medulloblastoma is a tumor of the

cerebellum. They tend to occur in children, but
can occur in adults. There will be symptoms of
cerebellar dysfunction, such as ataxia, and a
common complication is hydrocephalus.

• Lung
• Breast
• Melanoma

Neuropathology 276
Medulloblastoma
Childhood malignant tumor of the cerebellum.
Complications
Etiology
Drop Metastases: Infiltrates cortex and pia
mater, then seeds the subarachnoid space.
• Loss of material 17p Forms nodules in the CNS, including the cauda
o Poor prognosis equina.
• MYC amplification
• Sonic Hedgehog gene Hydrocephalus
• WNT
• NOTCH Differentials
Pathogenesis The brain neoplasms tend to present
the same, with generalized increase in ICP and
• Not known symptoms based on location. The location here
will be the cerebellum.
Signs & Symptoms Glioblastoma is a very malignant tumor

arising from astrocytes. GFAP is a marker for
astrocyte origin
• Increased ICP
• Cerebellar disruption
o Ataxia
Better prognosis:
• β-catenin expression
• Tyrosine Receptor Kinase C positive
Worse prognosis:
• Loss of 17p
Gross: Well circumscribed grey neoplasm in the cerebellum. It extends through the surface of the cerebellar
folia and involves the leptomeninges. In children, the tumor will be midline, while in adults it will be more
lateral.

Neuropathology 277
Oligodendroglioma is a similar Metastasis from elsewhere:

neoplasm, but of the oligodendrocytes. It • Lung
presents similarly but with a better prognosis. • Breast
• Melanoma
Ependymomas arise from the
ependyma lining of the ventricles, usually in the
4th ventricle. These occur earlier in life (younger
than 20). Tends to spread to the spinal cord.
Can be seen in neurofibromatosis type 2.
Additional Info
Meningiomas are tumors of the
• Very radiosensitive
meninges, and will have symptoms of increased
ICP and compression symptoms. It isn’t
attached to the brain.

component of NF.

vision.

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Path Profiles

A brief review of the major disorders covered in the pathology course.

By Sean H. – Fall 2012

With that said, good luck, and enjoy.

Path Profiles – Fall 2012

Path Profiles – Major Sections

Gastrointestinal (Not Completed)

Path Profiles – Fall 2012

Sickle Cell Anemia 09

Iron Deficiency Anemia 15

White Blood Cell Disorders

Acute Lymphoblastic Leukemia 27

Chronic Lymphocytic Leukemia 29

Hairy Cell Leukemia 31

Acute Myeloblastic Leukemia 35

Chronic Myeloid Leukemia 37

Answers & Explanations 43

Path Profiles – Fall 2012

These abnormal RBCs get filtered out in

In response to the hemolytic anemia,

Path Profiles – Fall 2012

extravascular hemolytic anemia that involves

The presence of jaundice may indicate a

Also with hemolytic anemias you will

Other hemolytic anemias include:

The most characteristic aspect of HS is

Path Profiles – Fall 2012

Etiology Signs & Symptoms

Alternatively, the membrane can

Path Profiles – Fall 2012

Deficiency is the history of oxidative insult

With hemolytic anemias you will see Additional Info

Decreased serum haptoglobin is indicative

The main distinguishing aspects of G6PD

Path Profiles – Fall 2012

Sickle Cell Anemia

Sickle cells can occlude small capillaries,

Path Profiles – Fall 2012

RBCs causes an extravascular hemolytic anemia.

Path Profiles – Fall 2012

Path Profiles – Fall 2012

There is an increase in dietary iron

Only one mutation (β/β0/+) will lead to

Path Profiles – Fall 2012

Signs & Symptoms Differentials

• Anemia All hemolytic anemias have the

Genotype Disease Symptoms

--/-- Hydrops fetalis Stillborn

-α/-- HbH Disease Severe anemia

-α/-α α-thalassemia May have mild

αα/-α Silent Carrier Asymptomatic

Differences in α and β include:

Path Profiles – Fall 2012

• β-globin is found on chromosome 16.

Affected individuals do not show symptoms

Path Profiles – Fall 2012

Iron Deficiency Anemia

Etiology • Usually asymptomatic

Increased requirements Complications

Plummer-Vinson Syndrome: Difficulty

Iron is absorbed in the duodenum in a

Path Profiles – Fall 2012

Sideroblastic anemia has low

Iron is mostly is found in hemoglobin