S entinel lymph node (SLN) biopsy was first described by Morton et al. (1) node pick. The lymph node field should be subjected to an elective dissection or left alone.’’ Since publi- tions (1,14,15). They did find an inverse correlation between the num- ber of peritumoral intradermal in- in 1992 in patients with malignant cation in the Archives of Surgery, jections given and the number of melanoma. Many others over almost however, this article has become one excised SLNs. This will need to be 100 y had made significant scientific of the most frequently cited in surgical confirmed before a recommendation contributions that ultimately led to the oncology. for more peritumoral injections can be development of the technique (2–4); An unexpected consequence of SLN made. however, it was Morton’s group from biopsy when applied to large numbers Despite the rapid clinical accep- the John Wayne Cancer Center that of patients with melanoma was the tance of SLN biopsy and the apparent condensed the principle of the tech- discovery that lymphatic drainage of ease with which it can be performed nique now used around the world. the skin was much more variable accurately in many different institu- SLN biopsy allows the accurate stag- in individuals than was previously tions and countries, some controver- ing of regional lymph node fields by thought. In fact, several new lymphatic sies remain. surgical removal and targeted histo- drainage pathways were discovered. logic examination of only those lymph These included drainage from the skin IS SLN BIOPSY ACCURATE IN of the back to triangular intermuscular STAGING REGIONAL NODE See page 234 space nodes (7); drainage through the FIELDS? posterior body wall to nodes in the The original method described by retroperitoneal, intercostal, paraverte- Morton et al. (1) required many oper- nodes receiving direct lymph drainage bral, and paraaortic regions (8); and ations to be performed before the from the tumor site and, on average, frequent drainage to interval nodes surgeon became competent. Two of only 1 or 2 nodes need to be removed that lay outside standard node fields the 3 surgeons in the study who had to achieve this. It has become the (9,10). When this variability in in- performed 36 and 46 procedures, standard of care in melanoma (5) and dividual lymphatic drainage is consid- respectively, were able to locate the breast cancer (6) and is increasingly ered it becomes apparent that in SLN in the regional node field only being applied to other solid cancers previous trials of elective dissection 75% of the time. Since then, however, that have the propensity to metastasize of draining lymph nodes in patients with the introduction of the g-probe to to the regional lymph nodes. with melanoma (11,12), the wrong be used intraoperatively (16 ) and Despite this rapid acceptance into field was being dissected in up to preoperative lymphoscintigraphy (LS) clinical practice, SLN biopsy was 30% of patients. that allows the surgeon to be directed controversial at its conception and The article by Rossi et al. (13) in right to the location of the SLN (17 ), uncertainties remain. When the initial this issue of The Journal of Nuclear identification rates have risen so that description of SLN biopsy by Morton Medicine is further evidence of the SLNs are found in close to 100% of et al. (1) was presented for publica- robust nature of SLN biopsy when patients and the results of the Italian tion, it was rejected by major surgical used in clinical practice to stage the multicenter trial are typical in this journals. It can only be presumed that regional lymph nodes in melanoma regard. A further very important, but this occurred because, in the opinion patients. In this Italian multicenter sometimes overlooked, advantage of of the reviewer, SLN biopsy went study there were regional differences SLN biopsy is that a histopathologist against standard teaching in surgical in the activity injected, the timing faced with only 1 or 2 nodes to ex- oncology at the time—that is, ‘‘Do not of injections before surgery, and the amine, rather than the contents of a number of peritumoral injections whole node field, can use serial given intradermally—yet a very high sections and immunohistochemical Received Oct. 14, 2005; revision accepted Nov. rate of SLN node identification was staining methods to significantly in- 11, 2005. achieved. There was also a true-posi- crease the detection rate for micro- For correspondence or reprints contact: Roger F. Uren, MD, Nuclear Medicine and Diagnostic tive SLN rate for metastasis of 16.9% metastasis (18). Reverse transcription Ultrasound, Suite 206, RPAH Medical Centre, 100 and a false-negative rate of 14%, both polymerase chain reaction (RT-PCR) Carillon Ave., Newtown, New South Wales, 2042, Australia. results similar to previous studies methods have also been adapted for E-mail: rogeruren@optushome.com.au including those from single institu- use in lymph node sections (19) and
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the result is an unprecedented level of metastasis was seen in patients un- tion of the field and this has been accuracy for detecting metastatic de- dergoing elective node dissection after borne out in practice (28). Postopera- posits in the regional nodes. These a positive SLN biopsy compared with tive complications occur in about 40% approaches when combined with SLN a therapeutic dissection when clinical of patients after elective dissection of biopsy mean the regional node field metastasis became evident in the a node field, whereas SLN biopsy will be accurately staged in about 98% lymph node field (23). In-transit me- causes postoperative complications in of patients (14,15). tastasis occurred in 23% and 8% of only 10%. The most severe complica- In the case of patients with breast these patients, respectively. It is im- tions such as lymphedema are also cancer there is no evidence that SLN portant to note, however, that the mean much less common. In fact, the re- biopsy is associated with an increase thickness of the melanomas in the duced morbidity associated with SLN in local recurrence in the regional SLN biopsy–positive group was sig- biopsy is one of the major factors node field (20). Rates of 0.25% are nificantly greater than that in the other that have driven its acceptance by typical and this has not been changed group (3.8 vs. 2.9 mm; P 5 0.023). patient advocates, because 70%–80% by the introduction of SLN biopsy to Increasing Breslow thickness is a ma- of patients have normal SLNs (13–15) patient management. Patients with jor cause of higher rates of in-transit and require no further lymph node breast cancer, however, frequently re- disease and it can only be presumed surgery. ceive adjuvant chemotherapy or radi- that differences in the patient popula- ation therapy to the node field that is tions studied such as this resulted in likely to eliminate any residual cancer the findings observed. Four large DOES SLN BIOPSY IMPROVE remaining in a missed SLN or lying in studies have since shown no increase SURVIVAL? the interstitial tissues of the node field. in the incidence of in-transit metasta- There is some evidence that early With melanoma, where there is cur- sis. Over a 10-y period, 2,018 patients excision of regional lymph node rently no reliably effective therapy for at the Sydney Melanoma Unit were metastasis confers a slight survival disseminated disease, if a melanoma treated by wide local excision of the benefit in patients with melanoma metastasis is missed it is likely to melanoma site alone or wide local (29). Preliminary results of MSLT I declare itself and this is reflected in excision plus SLN biopsy. In-transit were presented recently (27). This the false-negative rates for SLN bi- metastasis occurred in 4.9% and 3.6% trial compared SLN biopsy, followed opsy in melanoma of 10%–15% (13– of these patients, respectively (24). A by immediate elective dissection of 15). These rates of local recurrence are separate study at the MD Anderson the node field if the SLN was positive, similar to those seen after elective Cancer Center in Houston showed in- to a delayed therapeutic node dissec- dissection of a lymph node field in transit metastasis occurred in 12% of tion when a clinical metastasis was melanoma. Despite this false-negative patients who had a positive SLN found in the node field. A disease-free rate, node staging using SLN biopsy biopsy and 3.5% of patients in whom survival benefit was found over 5 y in remains more accurate than the old the SLN biopsy was negative (25). the SLN biopsy group (78% vs. 73%; method of elective node dissection Further work at the John Wayne P 5 0.01) and there may be a survival because the routine examination of Cancer Center has confirmed these benefit in the SLN biopsy–positive the large number of lymph nodes in findings (26 ), and the preliminary group compared with the group who such a specimen using hematoxylin– results of the prospective randomized developed a clinical recurrence. Five- eosin staining was associated with multicenter selective lymphadenec- year survival was 71% after immediate a false-negative histologic examina- tomy trial (MSLT I) (27 ) also showed elective lymph node dissection when tion in up to 10%–16% of patients no increase in the incidence of in- the SLN biopsy was positive and 55% compared with immunohistochemisty transit metastasis associated with SLN in the patients who had a delayed staining of the nodes (21,22). biopsy. It would seem, therefore, that therapeutic lymph node dissection for the nature of the individual patient’s clinical nodal recurrence (P 5 melanoma determines the likelihood 0.0033). There is argument about DOES SLN BIOPSY INCREASE of in-transit metastasis and not the whether these are matched patient THE RATE OF IN-TRANSIT SLN biopsy procedure. groups but the trial is ongoing and its RECURRENCE? results may eventually answer this Because it is imperative for any question. At the Sydney Melanoma physician when managing a patient to IS SLN BIOPSY LESS MORBID Unit the surface location of SLNs is ‘‘first do no harm,’’ this question must THAN ELECTIVE LYMPH marked on the skin with a permanent be answered in the negative before we NODE DISSECTION? tattoo of carbon black ink and clinical can comfortably adopt SLN biopsy as Removal of just 1 or 2 SLNs to follow-up includes periodic targeted a standard technique. There was a re- stage a lymph node field should cause ultrasound examination of these SLNs. port in a small number of patients that fewer postoperative complications It has been our experience that when a significant increase in in-transit compared with a full elective dissec- a clinical recurrence does appear in the
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draining node field it occurs in the SLN ment, and prognosis associated with a minor lymph node excision biopsy immediately beneath the skin tattoo, the particular disease and its stage at in the ipsilateral groin and others have which is evidence that, in fact, the 2 presentation. In patients with mela- seen similar patients (39). We have patient groups are matched and that the noma the status of the SLN is the most also seen direct drainage from a mela- survival benefit is in fact real. This is significant prognostic factor (32–36 ). noma site next to the right nipple to the subject of ongoing research at our Five-year survival in patients with a SLN in the right internal mammary institution. For the moment, however, a SLN biopsy positive for melanoma chain in a patient who had undergone it is prudent to regard SLN biopsy as metastasis is 73% compared with 97% an elective dissection of the right axilla primarily an accurate method of staging when the SLN biopsy is negative. The 20 y earlier for lymphoma (40). In the regional lymph nodes. SLN biopsy result, however, con- both of our cases, the SLN in these tributes only marginally to current unexpected locations was positive decisions regarding the treatment of for melanoma metastasis. Therefore, WILL SLN BIOPSY BE NEEDED individual patients with melanoma. though there is no doubt previous WHEN WE HAVE BETTER GENETIC Most patients today are better in- surgery to a node field causes unusual CHARACTERIZATION OF THE formed about their disease than in drainage pathways to be seen in some PRIMARY TUMOR? the past and an accurate estimate of patients, LS and SLN biopsy can Advances in molecular medicine life expectancy is expected and is nevertheless still accurately stage the are beginning to offer the prospect of important knowledge for the majority. draining lymph nodes wherever they a detailed analysis of the metabolic Setting one’s affairs in order and may be located. and genetic changes present in an indi- perhaps taking that ‘‘dream trip’’ with vidual patient’s primary cancer (30). the family are worthwhile goals since This may also give important infor- most patients with melanoma feel well CAN HIGH-RESOLUTION mation as to the tumor’s metastatic physically until very near the end. For ULTRASOUND EXAMINATION potential. In this situation would there the prognostic accuracy SLN biopsy OF THE SLN AND ITS BASIN be any point in performing SLN provides alone, it would seem worth- REPLACE SLN BIOPSY? biopsy? Cure or control of cancer will while offering to your patients with Ultrasound using high-frequency ultimately require addressing the most melanoma. probes in the 10- to 15-MHz range aggressive clones of the cancer in each There is also, however, an increasing now enables the internal structure of patient. The metastatic cancer cells knowledge accumulating on the genetic lymph nodes to be examined in some that lodge in the SLN have, by their changes occurring in melanoma detail. The normal structure of a lymph behavior, identified themselves as such cells when they become malignant node including the hilum and sub- aggressive clones and, therefore, it is (30,31,37 ). This knowledge is opening capsular sinus as well as the surface these metastatic cells that will need to the door to several new therapeutic outline and shape of the node can be be characterized to optimize therapy. approaches that offer the hope of defined. Most of the lymph nodes that It may even be possible to ‘‘disarm’’ controlling the growth of malignant drain the skin can be accessed with the oncogenic mechanisms (31) that melanoma if not curing it. For any new such high-frequency probes though have caused malignant change in an therapy to be proven requires random- there are exceptions such as the deep individual patient’s melanoma as we ized controlled trials of patients who iliac and obturator nodes that can learn more about the biology and have had accurate staging performed. sometimes drain the lower limb and metabolism of this tumor. It seems SLN biopsy is vital to determine the SLNs in the retro-peritoneal, para- plausible, therefore, that in the future status of the regional lymph nodes vertebral, and paraaortic regions that a combination of SLN biopsy and and will be an important part of the are sometimes seen draining the skin genetic techniques to characterize the randomization of patients into future of the back (8). The closer the node is metastatic cancer cells will be the therapy trials for melanoma. to the skin surface the easier is its approach followed. examination with high-frequency ul- trasound and thus the best lymph node CAN SLN BIOPSY BE PERFORMED images are obtained in the groin of AT A TIME WHEN WE HAVE NO ACCURATELY AFTER PREVIOUS thin patients and the cervical chains. RELIABLY EFFECTIVE THERAPY SURGERY OF THE EXPECTED The axilla is a more difficult region to FOR DISSEMINATED MELANOMA DRAINING NODE FIELD? examine with ultrasound. There is no WHAT IS THE POINT OF DOING It is well known that previous sur- doubt that ultrasound is more accurate SLN BIOPSY? gery to lymph nodes can alter lym- than clinical palpation in detecting When dealing as medical practi- phatic drainage pathways. We have metastatic disease in lymph nodes tioners with a patient who presents seen drainage from a leg melanoma (41) and this is particularly so when with any disease there are several as- site to a SLN in the contralateral groin used as part of clinical follow-up in pects to address—the diagnosis, treat- (38) in a patient who had undergone patients with melanoma (42), but how
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well does ultrasound detect metastasis anoma and breast cancer and is moving space lymph nodes in melanoma on the back. J Nucl Med. 1996;37:964–966. in the SLN compared with histologic toward this in many other cancers. 8. Uren RF, Howman-Giles R, Thompson JF. Lym- examination after excision biopsy of Despite rapid advances in the mo- phatic drainage from the skin of the back to the SLN? In this role ultrasound lecular characterization of cancer, retroperitoneal and paravertebral lymph nodes in melanoma patients. Ann Surg Oncol. 1998;5: does not perform well because of the SLN biopsy is likely to remain a part 384–387. simple fact that most melanoma of patient management as it allows the 9. Uren RF, Howman-Giles R, Thompson JF, et al. metastasis at presentation is micro- most aggressive clones of the tumor Interval nodes: the forgotten sentinel nodes in patients with melanoma. Arch Surg. 2000;135: scopic and current ultrasound ma- (those that have metastasized) to be ex- 1168–1172. chines have a resolution limit for amined. Future management is likely 10. McMasters KM, Chao C, Wong SL, et al. Interval metastasis of 2–4 mm, depending on to involve a combination of surgical sentinel lymph nodes in melanoma. Arch Surg. 2002;137:543–547. the depth of the node from the skin and molecular techniques. 11. Reintgen DS, Cox EB, McCarty KS Jr, Volmer RT, (43,44). SLN biopsy is safe and does not Seigler HF. Efficacy of elective lymph node False-negative rates of 61%–79% increase the chance of local recurrence dissection in patients with intermediate thickness primary melanoma. Ann Surg. 1983;198:379–385. were recorded in 2 prospective studies in the node field or in-transit recur- 12. McCarthy W, Shaw H, Milton G. Efficacy of in which preoperative ultrasound was rence between the primary site and the elective lymph node dissection in 2,347 patients followed by biopsy and histologic draining node field. with clinical stage I malignant melanoma. Surg Gynecol Obstet. 1985;161:575–580. examination of the SLN (43,44). Both Disease-free survival does seem to 13. Rossi CR, De Salvo GL, Trifirò G, et al. The impact of these studies had a specificity of be improved by SLN biopsy and there of lymphoscintigraphy technique on the outcome of 100% so that a positive ultrasound for may be some improvement in overall sentinel node biopsy in 1,313 patients with cuta- metastasis in this situation could be survival but this is yet to be definitively neous melanoma: an Italian multicentric study (SOLISM–IMI). J Nucl Med. 2006;47:234–241. used to anticipate an elective dissec- proved. Its use, however, even in 14. Reintgen D, Cruse CW, Wells K, et al. The orderly tion of the field once the SLN has been cancers that have no currently effective progression of melanoma nodal metastases. Ann removed. Ultrasound will not replace therapies for disseminated disease, can Surg. 1994;220:759–767. 15. Thompson JF, McCarthy WH, Bosch CM, et al. SLN biopsy to stage the SLN as be justified on the basis of providing Sentinel lymph node status as an indicator of the external scanning methods will never the most accurate prognostic informa- presence of metastatic melanoma in regional be capable of detecting a small cluster tion and staging for entry into thera- lymph nodes. Melanoma Res. 1995;5:255–260. 16. Alex JC, Weaver DL, Fairbank JT, Rankin BS, of metastatic cells in a lymph node, peutic trials of new treatments. Krag DN. Gamma-probe-guided lymph node something that can be quite obvious Ultrasound of the SLNs cannot localization in malignant melanoma. 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Individualized Prophylactic Neck Irradiation in Patients With cN0 Head and Neck Cancer Based On Sentinel Lymph Node(s) Identification: Definitive Results of A Prospective Phase 1-2 Study