Background

The treatment of malignant melanoma has undergone a revolution just within this past decade. Even metastatic melanoma, once thought to be hopeless, has vaccine and genetically modified immunomodulatory agents which may provide hope for these patients. It must be remembered that melanoma is still a totally curable disease if caught early enough. Thus, vigilence and self examination are critical in identifying any suspicious moles. For more on the basic identification and background of the disease, please visit the following link.

Malignant Melanoma

OUTLINE

Treatment	Overview National Comprehensive Cancer Network Guidelines 2004 (NCCN)
Mohs Micrographic Surgery
Radiation Therapy
Surgery and margin adequacy
Sentinel lymph node dissection
Immunotherapy and Chemotherapy	Gleevac Dacarbazine (DTIC) Phase III trials Phase II trials Thalidomide/Temozolomide Phase III trials Phase II trials Phase I trials
Vaccine therapy
Commonly Used Terms

 

TREATMENT	Early stage melanoma, confined to the skin, complete excision
GENERAL
Primary cutaneous malignant melanoma and its precursor lesions: Diagnostic and therapeutic overview Matthew H. Kanzler, MD Serena Mraz-Gernhard, MD Stanford, California	J Am Acad Dermatol 2001;45:260-76 Abstract quote During the past few decades, scientific data relating to melanoma have flourished. New information regarding acquired nevi, dysplastic nevi (atypical nevi), and congenital nevi has given us a better understanding of these precursor lesions and their relationships to malignant melanoma. The roles of laboratory testing, photography, and newer diagnostic tools (eg, epiluminescence) to evaluate patients for melanoma or precursor lesions have fallen under close scrutiny. Traditional surgical therapeutic interventions continue to be replaced by less aggressive protocols based on prospective randomized studies. Many new interventions such as sentinel lymph node procedures are currently being evaluated at research/referral centers around the world. We present clinicians with an evidence-based summary of the current literature with regard to primary cutaneous melanoma, its diagnosis, precursor lesions, and therapy.

 

MOHS MICROGRAPHIC SURGERY	CHARACTERIZATION
Cutaneous head and neck melanoma treated with Mohs micrographic surgery. Bricca GM, Brodland DG, Ren D, Zitelli JA. Skin Cancer Surgery Center, Sacramento, CA 95816, USA.	J Am Acad Dermatol. 2005 Jan;52(1):92-100. Abstract quote BACKGROUND: Previous studies show that Mohs micrographic surgery is a viable treatment option for cutaneous melanoma. The head and neck region represents an anatomic location of historically high recurrence/metastasis rates and poor survival rates. OBJECTIVE: Our purpose was to determine the safety and efficacy of Mohs micrographic surgery for the treatment of primary cutaneous melanoma of the head and neck. METHODS: A consecutive sample of 625 patients referred for treatment of primary cutaneous melanoma of the head and neck comprised the study group. Mean follow-up for the group was 58.0 months. All melanomas were excised using Mohs micrographic surgery and surgical margin examination was performed using frozen section tissue in all cases. After stratification using updated American Joint Commission for Cancer (AJCC) Breslow thickness criteria, the Kaplan-Meier method was used to calculate 5-year local recurrence rates, metastasis rates, and disease specific survival rates. Tumors were then re-stratified by earlier Breslow thickness criteria for comparison to historical controls for local recurrence rates, metastasis rates, and disease-specific survival rates. Recommendations for predetermined excision margins were proposed and were based on the surgical margin widths that achieved complete melanoma removal in 97% of the cases in this study. RESULTS: Mohs micrographic surgery for the treatment of head and neck melanoma achieved five-year local recurrence rates, metastasis rates, and disease specific survival rates comparable to or better than historical controls after Breslow thickness stratification. The size of the surgical margin required for complete excision was significantly related to tumor thickness but not tumor size or specific location. CONCLUSION: Mohs micrographic surgery is an effective treatment modality for primary cutaneous melanoma, and may contribute to favorable outcomes especially on the head and neck where extensive sub-clinical spread is relatively common.
Dermoscopic patterns of benign volar melanocytic lesions in patients with atypical mole syndrome. Malvehy J, Puig S. Department of Dermatology, Hospital Clinic, Institut de Investigacions Biomediques August Pi i Sune, Barcelona, Spain	Arch Dermatol. 2004 May;140(5):538-44. Abstract quote   BACKGROUND: Acral benign melanocytic lesions in white populations, particularly in subjects with atypical mole syndrome, have been poorly characterized until recently. The advent of dermoscopy has enabled more specific diagnoses of these pigmented skin lesions. OBJECTIVE: To evaluate the clinical and dermoscopic features of benign volar lesions in a group of white patients with atypical mole syndrome. SETTING: A private medical center specializing in early diagnosis of malignant melanoma and a melanoma unit in a university hospital. METHODS: Acral melanocytic lesions in 511 patients with atypical mole syndrome were studied using standard clinical assessment and dermoscopy. RESULTS: Two hundred ten acral melanocytic lesions were observed in 156 of the patients: 165 lesions were present on the soles of 121 patients and 45 lesions on the palms of 35 patients. No acral malignant lesions were detected. We observed the following patterns of lesions: parallel furrow in 111 lesions (52.9%), latticelike in 26 lesions (12.4%), fibrillar or filamentous in 13 lesions (6.2%), and nontypical in 29 lesions (13.8%). In 31 lesions (14.8%), we observed 3 previously undefined patterns: a globular pattern in 11 lesions (5.2%), a homogeneous pattern in 15 lesions (7.1%), and an acral reticular pattern in 5 lesions (2.4%). CONCLUSIONS: We observed a greater number of benign melanocytic lesions in glabrous skin than expected, probably related to our cohort selection of patients with atypical mole syndrome, although the lesions generally exhibited patterns on dermoscopy similar to those seen in Japanese studies. We defined 3 new benign dermoscopic patterns, which will enable better characterization of acral lesions.
Are en face frozen sections accurate for diagnosing margin status in melanocytic lesions? Prieto VG, Argenyi ZB, Barnhill RL, Duray PH, Elenitsas R, From L, Guitart J, Horenstein MG, Ming ME, Piepkorn MW, Rabkin MS, Reed JA, Selim MA, Trotter MJ, Johnson MM, Shea CR. Dept of Pathology, Box 85, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.	Am J Clin Pathol. 2003 Aug;120(2):203-8. Abstract quote   To assess the diagnostic accuracy of margin evaluation of melanocytic lesions using en face frozen sections compared with standard paraffin-embedded sections, we studied 2 sets of lesions in which en face frozen sections were used for analysis of surgical margins (13 from malignant melanomas [MMs] and 10 from nonmelanocytic lesions [NMLs]). Routine permanent sections were cut after routine processing. The slides were mixed and coded randomly. Fifteen dermatopathologists examined the cases separately. Margin status was categorized as positive, negative, or indeterminate. Kappa statistics were calculated per dermatopathologist and per case. One case from each group was excluded because epidermis was not available in the routine sections. Of 330 evaluations (22 cases, 15 dermatopathologists), there were 132 diagnostic discrepancies (40.0%): 66 each for MM and NML (mean per case for both diagnoses, 6). In 9 instances (6.8%), the change was from positive (frozen) to negative (permanent) and in 43 (32.6%), from negative (frozen) to positive (permanent). There was poor agreement between frozen and permanent sections (kappa range per dermatopathologist, -0.1282 to 0.6615). If permanent histology is considered the "gold standard" for histologic evaluation, en face frozen sections are not suitable for accurate surgical margin assessment of melanocytic lesions.
Histopathologic recognition of involved margins of lentigo maligna excised by staged excision: an interobserver comparison study. Florell SR, Boucher KM, Leachman SA, Azmi F, Harris RM, Malone JC, Martignoni G, Bowen GM, Gerwels JW, Hood AF. Department of Dermatology and the Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City.	Arch Dermatol 2003 May;139(5):595-604 Abstract quote Objectives To assess interobserver and intraobserver concordance for identifying positive and negative margins in staged excisions of lentigo maligna and lentigo maligna melanoma and to determine if control biopsy specimens are useful to improve concordance. DESIGN: Retrospective, randomized interobserver and intraobserver comparison study of archived pathologic specimens. The study was conducted in 3 phases, and slides were evaluated blindly and independently by 5 pathologists: in phase 1, all slides were randomized and diagnosed as positive or negative. In phase 2, every third slide was evaluated again and diagnosed as positive or negative. In phase 3, slides were organized into cases, allowing evaluation of each margin in the context of the positive control (tumor from the center of the lesion) and negative control (control biopsy specimen), if available. SETTING: University referral center.Study Material A total of 301 glass microscopic slides from 27 patients who underwent staged excision for lentigo maligna or lentigo maligna melanoma from March 1997 to April 2001. MAIN OUTCOME MEASURES: Interobserver and intraobserver concordance between original diagnoses and study diagnoses rendered on all slides by 5 pathologists. RESULTS: Phase 1 and 3 agreement was moderate (kappa range, 0.4-0.5). Phase 2 (intraobserver) agreement was moderate to good for all pathologists (kappa range, 0.6-0.9). Subset analysis revealed a statistically significant increase in agreement with the use of a control strip biopsy specimen for difficult slides. CONCLUSIONS: Interobserver concordance for margin analysis in lentigo maligna and lentigo maligna melanoma is moderate, and intraobserver concordance is moderate to good. A control strip biopsy specimen may improve concordance in some cases.
Accuracy of frozen section measurements for the determination of Breslow tumour thickness in primary malignant melanoma. Kiehl P, Matthies B, Ehrich K, Volker B, Kapp A. Department of Dermatology and Allergology, Hannover Medical University, Germany.	Histopathology 1999 Mar;34(3):257-61 Abstract quote AIMS: Microstaging of primary malignant melanoma (MM) and the width of surgical margins depend mainly on Breslow tumour thickness (BTT). The use of frozen section (FS) measurements of BTT has been doubted, and previous reports have shown conflicting results regarding the comparability to paraffin sections (PS). To look for significant differences of BTT due to freezing or paraffin embedding, we evaluated a larger series of melanocytic lesions as far as possible excluding other technical influences. METHODS AND RESULTS: Paired 'mirror sections' of 112 melanocytic lesions (33 MM and 79 melanocytic naevi) were measured according to Breslow on single corresponding PS and FS of the same tumour specimen. Comparing measurements on FS and PS, we found very small differences of BTT on average and an almost equal distribution of BTT in the two sets of values with no statistically significant difference by applying the Wilcoxon signed rank test. Concerning the clinically most important 1 mm-threshold of BTT, 110 (98.2%) of the lesions gave equal measurements in FS and PS. CONCLUSIONS: Frozen sections can be used for accurate measurements of Breslow tumour thickness. Consequently, intraoperative frozen section diagnosis of thick melanoma immediately followed by excision with wide surgical margins is possible in experienced centres.
Immunohistochemical staining of lentigo maligna during Mohs micrographic surgery using MART-1 Larisa C. Kelley, MD Laurie Starkus, MHT Boston and Worcester, Massachusetts	J Am Acad Dermatol 2002;46:78-84 Abstract quote Background: Lentigo maligna (LM) often displays extensive subclinical spread. Mohs micrographic surgery (MMS) has been proposed to help delineate the true histologic margin; however, visualizing atypical melanocytes on frozen section is challenging and often requires confirmatory permanent paraffin sections. Objective: Our aim was to use a monoclonal antibody to rapidly stain frozen sections during MMS to facilitate better visualization of atypical melanocytes. Methods: Frozen sections of LM during MMS were stained with MART-1 (melanoma antigen recognized by T cells) and compared with paraffin-embedded sections. Results: We found 100% correlation between frozen sections stained with MART-1 and paraffin-embedded sections. Conclusions: Atypical melanocytes can be better visualized on frozen sections of LM by using MART-1 rather than hematoxylin and eosin. This allows for easier identification during MMS and better chance of complete removal of LM lesions.

 

RADIATION THERAPY

CHARACTERIZATION

A retrospective study of 150 patients with lentigo maligna and lentigo maligna melanoma and the efficacy of radiotherapy using Grenz or soft X-rays. Farshad A, Burg G, Panizzon R, Dummer R. Department of Dermatology, University Hospital Zurich, Gloriastrasse 31, CH-8091 Zurich, Switzerland.

Br J Dermatol 2002 Jun;146(6):1042-6 Abstract quote BACKGROUND: Lentigo maligna (LM) and lentigo maligna melanoma (LMM) are the most common melanocytic neoplasms on sun-exposed skin of elderly patients. OBJECTIVES: To perform a retrospective study of 150 patients with LM and LMM treated with radiotherapy using Grenz or soft X-rays. METHODS: The information recorded and analysed included gender, age, diagnosis, size of the lesion, localization, X-ray treatment, recurrence rate, other skin malignancies and non-dermatological neoplasms. RESULTS: The 150 patients comprised 78 women and 72 men (mean age 70 years). Ninety-three patients had LM, 54 had LMM and three had both neoplasms. Ninety per cent of lesions were located on the face. Treatment was with Grenz rays in 96 patients with LM and 11 with LMM (70%) and with soft X-rays in 46 patients with LMM (30%). Three patients were treated using both modalities. One hundred and one patients were followed up for at least 2 years after radiotherapy (mean 8 years). The mean time to recurrence was 45.6 months, and the recurrence rate was 7% (seven of 101). Other skin malignancies were observed in 65 of 150 patients, including basal cell carcinoma in 23 (35%) and actinic keratosis in 20 (31%). Four patients developed internal cancers. CONCLUSIONS: The study showed that radiotherapy of LM and LMM was curative. In particular, radiotherapy proved to be an excellent treatment for elderly patients. Owing to the high incidence of other skin cancers, LM patients need careful follow-up.

 

SURGERY AND MARGIN ADEQUACY	CHARACTERIZATION
Guidelines of care for primary cutaneous melanoma Arthur J. Sober, MD, Chair Tsu-Yi Chuang, MD, MPH Madeleine Duvic, MD Evan R. Farmer, MD James M. Grichnik, MD Allan C. Halpern, MD Vincent Ho, MD Victoria Holloway, MD, MPH Antoinette F. Hood, MD Timothy M. Johnson, MD Barbara J. Lowery, MPH Guidelines/Outcomes Committee 2001 by the American Academy of Dermatology, Inc.	J Am Acad Dermatol 2001;45:579-86. Abstract quote This report reflects the best data available at the time the report was prepared, but caution should be exercised in interpreting the data; the results of future studies may require alteration of the conclusions or recommendations set forth in this report.
In situ melanoma	0.5 cm
Invasive up to 1mm	1 cm
Invasive >1 mm	2-3 cm
Evaluating invasive cutaneous melanoma: is the initial biopsy representative of the final depth? Ng PC, Barzilai DA, Ismail SA, Averitte RL Jr, Gilliam AC. Department of Dermatology, Case Western Reserve University/University Hospitals of Cleveland, Ohio 44106, USA.	J Am Acad Dermatol 2003 Mar;48(3):420-4 Abstract quote BACKGROUND: An accurate initial biopsy of the deepest portion of the melanoma is vital to the management of patients with melanomas. OBJECTIVE: Our goal was to evaluate the accuracy of preliminary biopsies performed by a group of predominantly experienced dermatologists (n = 46/72). METHODS: A total of 145 cases of cutaneous melanoma were examined retrospectively. We compared Breslow depth on preliminary biopsy with Breslow depth on subsequent excision. Was the initial diagnostic biopsy performed on the deepest part of the melanoma? RESULTS: Of nonexcisional initial shave and punch biopsies, 88% were accurate, with Breslow depth greater than or equal to subsequent excision Breslow depth. Both superficial and deep shave biopsies were more accurate than punch biopsy for melanomas less than 1 mm. Excisional biopsy was found to be the most accurate method of biopsy. CONCLUSIONS: Deep shave biopsy is preferable to superficial shave or punch biopsy for thin and intermediate depth (<2 mm) melanomas when an initial sample is taken for diagnosis instead of complete excision. We found that a group of predominantly experienced dermatologists accurately assessed the depth of invasive melanoma by use of a variety of initial biopsy types.
Thin stage I primary cutaneous malignant melanoma. Comparison of excision with margins of 1 or 3 cm. Veronesi U, Cascinelli N, Adamus J, Balch C, Bandiera D, Barchuk A, Bufalino R, Craig P, De Marsillac J, Durand JC, et al. National Cancer Institute, Milan, Italy.	N Engl J Med 1988 May 5;318(18):1159-62 Abstract quote Although wide surgical excision is the accepted treatment for thin malignant melanomas, there is reason to believe that narrower margins may be adequate. We conducted a randomized prospective study to assess the efficacy of narrow excision (excision with 1-cm margins) for primary melanomas no thicker than 2 mm. Narrow excision was performed in 305 patients, and wide excision (margins of 3 cm or more) was performed in 307 patients. The major prognostic criteria were well balanced in the two groups. The mean thickness of melanomas was 0.99 mm in the narrow-excision group and 1.02 mm in the wide-excision group. The subsequent development of metastatic disease involving regional nodes and distant organs was not different in the two groups (4.6 and 2.3 percent, respectively, in the narrow-excision group, as compared with 6.5 and 2.6 percent in the wide-excision group). Disease-free survival rates and overall survival rates (mean follow-up period, 55 months) were also similar in the two groups. Only three patients had a local recurrence as a first relapse. All had undergone narrow excision, and each had a primary melanoma with a thickness of 1 mm or more. The absence of local recurrence in the group of patients with a primary melanoma thinner than 1 mm and the very low rate of local recurrences indicate that narrow excision is a safe and effective procedure for such patients.
Local recurrence in malignant melanoma: long-term results of the multiinstitutional randomized surgical trial. Karakousis CP, Balch CM, Urist MM, Ross MM, Smith TJ, Bartolucci AA. Department of Surgery, State University of New York, Buffalo, USA.	Ann Surg Oncol 1996 Sep;3(5):446-52 Abstract quote BACKGROUND: In the past, radical margins of excision were prescribed for cutaneous melanoma based on preconceived notions rather than on hard clinical evidence. METHODS: In a prospective study of 742 patients with intermediate-thickness melanoma (1-4 mm), 470 patients with trunk or proximal extremity lesions were randomized into a 2- or 4-cm margin. Patients with distal extremity or head and neck lesions (n = 272) received uniformly a 2-cm margin. RESULTS: The overall rate of local recurrence was 3.8%. This rate in the randomized portion (n = 470) was 2.1% for the 2-cm margin and 2.6% for the 4-cm margin (p = 0.72). A progressive increase in local recurrence rates was observed with thickness: 2.3% for lesions 1.0-2.0 mm, 4.2% for those 2.01-3.0 mm, and 11.7% for those 3.01-4.0 mm thick (p = 0.001). Local recurrence occurred in 1.5% of those without ulceration and in 10.6% of those with ulceration of the primary lesion (p = 0.001). The local recurrence rate was not significantly affected by the margin of resection even among the thicker or ulcerated lesions. It also was not affected significantly by the method of closure of the primary site or management of the regional nodes, or the age or gender of the patients. CONCLUSIONS: A 2-cm margin is as effective as a 4-cm margin in local control and survival of intermediate-thickness melanomas. The local recurrence rate is significantly affected by the thickness of the primary lesion and the presence or not of ulceration.
Long term results of a randomized study by the Swedish Melanoma Study Group on 2-cm versus 5-cm resection margins for patients with cutaneous melanoma with a tumor thickness of 0.8-2.0 mm. Cohn-Cedermark G, Rutqvist LE, Andersson R, Breivald M, Ingvar C, Johansson H, Jonsson PE, Krysander L, Lindholm C, Ringborg U. Department of Oncology-Pathology, Radiumhemmet, Karolinska Hospital, Stockholm, Sweden.	Cancer 2000 Oct 1;89(7):1495-501 Abstract quote BACKGROUND: Large, prospective, randomized trials with long term follow-up are required to obtain an unbiased evaluation of the significance of resection margins in patients with cutaneous melanoma. METHODS: The Swedish Melanoma Study Group performed a prospective, randomized, multicenter study of patients with primary melanoma located on trunk or extremities and with a tumor thickness > 0.8 mm and RESULTS: The crude rate of local recurrence, defined as a recurrence in the scar or transplant, was < 1% (8 of 989 patients). Twenty percent of the patients (194 of 989 patients) experienced any disease recurrence, and 15% (146 of 989 patients) died of melanoma. There were no statistically significant differences between the two treatment arms. In a multivariate Cox analysis with patients allocated to wide excision as the reference group, the estimated relative hazards for overall survival and recurrence free survival among those allocated to a 2-cm resection margin were 0.96 (95% confidence interval, 0.75-1.24), and 1.02 (95% confidence interval, 0.80-1.30), respectively. CONCLUSIONS: In this long term follow-up study, local recurrences were found to be rare among patients with tumors > 0.8 mm thick and
Analysis of local recurrence and optimizing excision margins for cutaneous melanoma. Ng AK, Jones WO, Shaw JH. Auckland Melanoma Unit, Auckland Hospital, Auckland, New Zealand.	Br J Surg 2001 Jan;88(1):137-42 Abstract quote BACKGROUND: Current guidelines for the treatment of melanoma favour conservatism; however there is still uncertainty regarding best practice for lesions of intermediate thickness. Local recurrence, a measure of treatment adequacy, can be used to determine optimum excision margins and give prognostic information for survival. METHODS: An analysis of the Auckland Melanoma Unit database was performed. Patients with local recurrence were identified and stratified by lesion thickness. Optimum excision margins were derived by regression analysis and evaluated against the database population. Survival and prognostic factors were studied. RESULTS: Eighty-four of 1155 patients (7 per cent) developed local recurrence. Median follow-up was 51 months. Margins predicted to give a local recurrence of zero were: 1 cm for lesions < or = 1 mm thick; 1.5 cm for lesions 1-2 mm thick; and 2 cm for lesions > 2 mm thick. Applied to 1155 patients, there were significant differences in both local recurrence and mortality rates between optimally and suboptimally excised lesions, except for those > 4 mm thick. Thirty-three patients (39 per cent) with local recurrence died. Thickness, local recurrence and ulceration were of prognostic significance. CONCLUSION: Development of local recurrence in melanomas < or = 4 mm thick is due to inadequate treatment. It signifies progressive disease and a poor prognosis. Care must be taken to ensure that all such lesions are optimally excised.
Long-term results of a prospective surgical trial comparing 2 cm vs. 4 cm excision margins for 740 patients with 1-4 mm melanomas. Balch CM, Soong SJ, Smith T, Ross MI, Urist MM, Karakousis CP, Temple WJ, Mihm MC, Barnhill RL, Jewell WR, Wanebo HJ, Desmond R; Investigators from the Intergroup Melanoma Surgical Trial. Johns Hopkins Medical Center, Baltimore, Maryland, USA.	Ann Surg Oncol 2001 Mar;8(2):101-8 Abstract quote BACKGROUND: The Intergroup Melanoma Surgical Trial began in 1983 to examine the optimal surgical margins of excision for primary melanomas of intermediate thickness (i.e., 1-4 mm). There is now a median 10-year follow-up. METHODS: There were two cohorts entered into a prospective multi-institutional trial: (1) 468 patients with melanomas on the trunk or proximal extremity who randomly received a 2 cm or 4 cm radial excision margin and (2) 272 patients with melanomas on the head, neck, or distal extremities who received a 2 cm radial excision margin. RESULTS: A local recurrence (LR) was associated with a high mortality rate, with a 5-year survival rate of only 9% (as a first relapse) or 11% (anytime) compared with an 86% survival for those patients who did not have a LR (P < .0001). The 10-year survival for all patients with a LR was 5%. The 10-year survival rates were not significantly different when comparing 2 cm vs. 4 cm margins of excision (70% vs. 77%) or comparing the management of the regional lymph nodes (observation vs. elective node dissection). The incidences of LR were the same for patients having a 2 cm vs. 4 cm excision margin regardless of whether the comparisons were made as first relapse (0.4% vs. 0.9%) or at anytime (2.1% vs. 2.6%). When analyzed by anatomic site, the LR rates were 1.1% for melanomas arising on the proximal extremity, 3.1% for the trunk, 5.3% for the distal extremities, and 9.4% for the head and neck. The most profound influence on LR rates was the presence or absence of ulceration; it was 6.6% vs. 1.1% in the randomized group involving the trunk and proximal extremity and was 16.2% vs. 2.1% in the non-randomized group involving the distal extremity and head and neck (P < .001). A multivariate (Cox) regression analysis showed that ulceration was an adverse and independent factor (P = .0001) as was head and neck melanoma site (P = .01), while the remaining factors were not significant (all with P > .12). CONCLUSION: For this group of melanoma patients, a local recurrence is associated with a high mortality rate, a 2-cm margin of excision is safe and ulceration of the primary melanoma is the most significant prognostic factor heralding an increased risk for a local recurrence.
Mohs' micrographic surgery using frozen sections alone may be unsuitable for detecting single atypical melanocytes at the margins of melanoma in situ. Barlow RJ, White CR, Swanson NA. Department of Dermatology, Oregon Health Sciences University, Portland, OR, USA.	Br J Dermatol 2002 Feb;146(2):290-4 Abstract quote BACKGROUND: It remains questionable whether micrographic surgery with frozen sections is an appropriate technique for excision of melanoma in situ (MIS) of the lentigo maligna type. Advocates of the technique have interpreted MIS as being histologically defined by nests and contiguous atypical melanocytes on the basal layer. Others, however, have viewed the periphery of MIS as consisting of scattered single atypical melanocytes, a finding that may be difficult or impossible to establish on frozen sections. OBJECTIVES: To examine the reliability of micrographic surgery using frozen sections interpreted by an experienced Mohs' surgeon, in the excision of MIS. METHODS: From a total of 154 specimens, frozen sections from the 50 specimens with margins that were considered difficult to interpret were thawed, sent for routine processing and then examined 'blind' by a dermatopathologist. RESULTS: Using the dermatopathologist's report on paraffin-embedded sections as a reference point, the sensitivity and specificity of frozen sections were calculated to be 59% and 81%, respectively. CONCLUSIONS: Using these histological criteria, micrographic surgery with frozen sections alone is unreliable in the excision of MIS.
Histologic evaluation of lentigo maligna with permanent sections: Implications regarding current guidelines. Agarwal-Antal N, Bowen GM, Gerwels JW. Department of Dermatology, University of Utah, Salt Lake City.	J Am Acad Dermatol 2002 Nov;47(5):743-8 Abstract quote BACKGROUND: Obtaining clear margins of resection of lentigo maligna (LM), a subtype of melanoma in situ, from sun-damaged skin of the head and neck continues to be a surgical challenge. The margins may be uncertain both clinically and histologically, causing difficulty in determining the surgical excision perimeter. OBJECTIVE: We sought to determine whether the current National Institutes of Health consensus conference (1992) recommendation of 5-mm margins is adequate for the removal of LM and to evaluate at what stage tumor-free margins are ultimately attained by using polygonal, staged excisions. METHODS: Ninety-two cases of LM were evaluated and treated in a university tertiary care setting. Straight-edge polygonal resections in a staged fashion of LM variants of MIS were evaluated by means of permanent serial histopathologic sections. Each stage of resection used a 5-mm margin. Specimens were color-coded and mapped. Any sites of tumor at resected margins were identified by a dermatopathologist and noted on the map of the excised specimen. Positive margins and areas with markedly atypical melanocytes were further resected, color-coded, mapped, and evaluated as previously described until margins free of tumor were attained. RESULTS: The patient distribution was 37% female and 63% male, with ages ranging from 24 to 100 years (median age, 70 years). Sixty-nine patients had a biopsy-proven diagnosis of LM involving the head and neck (75%), and 23 patients (25%) had LM elsewhere. Thirty-nine patients (42%) were tumor-free after one stage, 25 (27%) required 2 stages, 14 (15%) required 3 stages, 6 (7%) required 4 stages, and 8 (9%) needed 5 or more stages to achieve tumor-free margins. The central portion of the submitted polygonal excisions revealed an invasive component in 16% of cases. CONCLUSIONS: Use of polygonal perimeter excisions with serial histopathologic permanent sections in a staged fashion is an accurate and thorough method of evaluating and treating LM. This study demonstrates that the standard recommendation of 5-mm margins is adequate in less than 50% of cases and reiterates the need for the careful evaluation of peripheral margins in LM. Because an invasive component can be present and would alter recommended surgical depths and margins, all of the tumor should be submitted at the first stage rather than peripheral margins only.

 

SENTINEL LYMPH NODE DISSECTION	CHARACTERIZATION
GENERAL	Arch Surg 1997;132:666-73 J Clin Oncol 1999;17:976-83. Often utilized for management of stage I-II malignant melanoma with tumor thickness greater than 1 mm or less than 1 mm with high-risk features (including spindle cell melanoma and DMM) involves preoperative lymphoscintigraphy followed by selective sentinel lymph node (SLN) dissection and surgical re-excision The SLN histology determines whether or not formal lymphadenectomy is warranted
	Surg Oncol Clin North Am 1992;1:247-59. A dye with/without a radioactive tag is injected into the melanoma site Dye is immediately picked up by the body's lymphatic system and drains to the regional lymph nodes-this route is the route that melanoma cells would follow if metastasis were to occur Melanoma tends to spread in succession from one lymph node chain to another but usually involves the first or sentinel node of a chain before spreading to the rest of the lymph nodes within the chain Sentinel node is identified by the dye, the surgeonl removes it and sends it to the pathologist for an intraoperative frozen section If melanoma has spread to this sentinel lymph node, the surgeon will proceed to remove all of the other lymph nodes within that chain If the lymph node is negative and clear of melanoma, the surgeon will stop, sparing the patient the morbidity of a complete lymph node dissection NOTE: This technique is not reliable after wide local excision and interruption of local lymphatics
GENERAL
Sentinel node in melanoma patients: triple negativity with routine techniques and PCR as positive prognostic factor for survival. Denninghoff VC, Falco J, Kahn AG, Trouchot V, Curutchet HP, Elsner B. 1Department of Pathology, Center for Medical Education and Clinical Investigation, Buenos Aires, Argentina.	Mod Pathol. 2008 Apr;21(4):438-44. Abstract quote Lymph node mapping and sentinel lymph node biopsy are currently used to stage patients with cutaneous malignant melanoma. Immunohistochemical stains contribute to the detection of micrometastases; however, molecular biology techniques are associated with better diagnostic sensitivity. Sixty sentinel lymph nodes were included in this study. The primary lesions were malignant melanoma stage I or II, with a follow-up of longer than 2 years. Sentinel lymph nodes were studied with hematoxylin-eosin, immunohistochemistry for S-100 and HMB-45, and molecular biology techniques (reverse transcription (RT)-PCR) for the detection of tyrosinase messenger RNA. In 15 of 60 cases (25%), tyrosinase was detected by RT-PCR; three of these cases were also positive by immunohistochemistry. The population was divided into three groups: (i) hematoxylin-eosin-/immunohistochemistry+/molecular biology techniques+ (3 cases); (ii) hematoxylin-eosin-/immunohistochemistry-/molecular biology techniques+ (12 cases); (iii) hematoxylin-eosin-/immunohistochemistry-/molecular biology techniques- (45 cases). Correlation of the groups with overall survival showed the following: (i) 2 of 3 patients died (67%); (ii) 5 of 12 died (42%), and (iii) all 45 patients are alive, with no lymphadenectomy and a median follow-up of 84 months. The inclusion of molecular biology techniques appears to be of great value for the detection of sentinel lymph node micrometastases in patients with cutaneous malignant melanoma. In our series, those patients who showed negativity with all the three methods had a null recurrence rate. Therefore, this triple negativity could be a positive prognostic factor for overall survival. Our findings suggest the possibility of molecular oncological staging, which would allow the selection of patients with submicroscopic metastases for a complete treatment.
RT in situ PCR detection of MART-1 and TRP-2 mRNA in formalin-fixed, paraffin-embedded tissues of melanoma and nevi. Itakura E, Huang RR, Wen DR, Paul E, Wünsch PH, Cochran AJ. 1Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.	Mod Pathol. 2008 Mar;21(3):326-33. Abstract quote Melanoma antigen recognized by T cells 1 (MART-1) and tyrosinase-related protein-2 (TRP-2) are two useful markers for immunohistochemical detection of melanocytic tumors. However, these markers may be passively acquired (phagocytosed) rather than actively synthesized. Reverse transcriptase in situ polymerase chain reaction (RT in situ PCR) can amplify even small amounts of specific mRNA in cells and therefore confirm the cellular source of a marker. We developed a one-step RT in situ PCR procedure in which Thermus thermophilus DNA polymerase synthesizes and amplifies cDNA from mRNA in a single reaction mixture. To examine its practicability and feasibility with formalin-fixed, paraffin-embedded (FFPE) tissue, we compared the results of one-step RT in situ PCR with those of immunohistochemistry (IHC). MART-1 mRNA was identified in the cytoplasm of lesional cells from 23/26 primary melanomas (92%), 9/9 metastatic melanomas (100%) and 5/6 nevi (83%). MART-1 epitope was detected by IHC in 23/24 primary melanomas (96%), 9/9 metastatic melanomas (100%) and 5/6 nevi (83%). TRP-2 mRNA was identified in the cytoplasm of lesional cells from 17/26 primary melanomas (65%), 6/9 metastatic melanomas (67%) and 4/6 nevi (67%). TRP-2 epitope was detected by IHC in 20/24 primary melanomas (83%), 9/9 metastatic melanomas (100%) and 4/6 nevi (67%). Both techniques detected MART-1 and TRP-2 in FFPE melanoma cell lines. Neither marker was detected in squamous cell carcinomas or basal cell carcinomas by RT in situ PCR or IHC. We conclude that the RT in situ PCR technique can be successfully applied to FFPE tissue to determine the cellular sources of gene expression observed by conventional PCR approaches.
Prognostic Significance of Isolated HMB45 or Melan A Positive Cells in Melanoma Sentinel Lymph Nodes. Satzger I, Völker B, Meier A, Schenck F, Kapp A, Gutzmer R. Department of Dermatology, Skin Cancer Center Hannover, Hannover Medical School, Hannover, Germany.	Am J Surg Pathol. 2007 Aug;31(8):1175-80. Abstract quote The detection of micrometastases (defined as groups of malignant cells) in the sentinel lymph node (SLN) is an important prognostic tool in melanoma. The use of immunohistochemistry with melanocytic markers such as HMB45 and Melan A increases the detection rate of micrometastases but there are also cases with isolated immunohistochemically positive cells (IPC). To determine the prognostic significance of isolated HMB45 and/or Melan A positive cells in melanoma SLN, we compared the clinical course of 47 patients with IPC to 308 patients with negative SLN and to 122 patients with micrometastases. The mean follow-up was 38.1 months. By Kaplan-Meier analyses, relapse free survival and overall survival of patients with IPC were similar to SLN negative patients, whereas patients with micrometastases had a significantly worse relapse free survival and overall survival. In the 47 patients with IPC, 6 relapses (12.8%) and 3 melanoma-related death (6.4%) occurred, in the SLN negative patients 36 relapses (11.7%) and 17 melanoma-related deaths (5.5%), in the patients with micrometastases 46 relapses (37.7%) and 29 melanoma-related deaths (23.8%). Prognosis of patients with IPC in SLN did not correlate with type of positive staining (HMB45, Melan A, or both), capsular involvement, number of cells, presence of cytologic atypias of IPC, or tumor penetrative depth. In conclusion, with short-term follow-up IPC in melanoma SLN are without prognostic significance.
Sentinel node biopsy for early-stage melanoma: accuracy and morbidity in MSLT-I, an international multicenter trial. Morton DL, Cochran AJ, Thompson JF, Elashoff R, Essner R, Glass EC, Mozzillo N, Nieweg OE, Roses DF, Hoekstra HJ, Karakousis CP, Reintgen DS, Coventry BJ, Wang HJ; Multicenter Selective Lymphadenectomy Trial Group. John Wayne Cancer Institute, Santa Monica, CA 90404, USA.	Ann Surg. 2005 Sep;242(3):302-11; discussion 311-3. Abstract quote   OBJECTIVE: The objective of this study was to evaluate, in an international multicenter phase III trial, the accuracy, use, and morbidity of intraoperative lymphatic mapping and sentinel node biopsy (LM/SNB) for staging the regional nodal basin of patients with early-stage melanoma. SUMMARY BACKGROUND DATA: Since our introduction of LM/SNB in 1990, this technique has been widely adopted and has become part of the American Joint Committee on Cancer (AJCC) staging system. Eleven years ago, the authors began the international Multicenter Selective Lymphadenectomy Trial (MSLT-I) to compare 2 treatment approaches: wide excision (WE) plus LM/SNB with immediate complete lymphadenectomy (CLND) for sentinel node (SN) metastases, and WE plus postoperative observation with CLND delayed until the subsequent development of clinically evident nodal metastases. METHODS: After each center achieved 85% accuracy of SN identification during a 30-case learning phase, patients with primary cutaneous melanoma (> or =1 mm with Clark level > or =III, or any thickness with Clark level > or =IV) were randomly assigned in a 4:6 ratio to WE plus observation (WEO) with delayed CLND for nodal recurrence, or to WE plus LM/SNB with immediate CLND for SN metastasis. The accuracy of LM/SNB was determined by comparing the rates of SN identification and the incidence of SN metastases in the LM/SNB group versus the subsequent development of nodal metastases in the regional nodal basin of those patients with tumor-negative SNs. Early morbidity of LM/SNB was evaluated by comparing complication rates between the 2 treatment groups. Trial accrual was completed on March 31, 2002, after enrollment of 2001 patients. RESULTS: Initial SN identification rate was 95.3% overall: 99.3% for the groin, 95.3% for the axilla, and 84.5% for the neck basins. The rate of false-negative LM/SNB during the trial phase, as measured by nodal recurrence in a tumor-negative dissected SN basin, decreased with increasing case volume at each center: 10.3% for the first 25 cases versus 5.2% after 25 cases. There were no operative mortalities. The low (10.1%) complication rate after LM/SNB increased to 37.2% with the addition of CLND; CLND also increased the severity of complications. CONCLUSIONS: LM/SNB is a safe, low-morbidity procedure for staging the regional nodal basin in early melanoma. Even after a 30-case learning phase and 25 additional LM/SNB cases, the accuracy of LM/SNB continues to increase with a center's experience. LM/SNB should become standard care for staging the regional lymph nodes of patients with primary cutaneous melanoma.
Sentinel Lymph Node Biopsy for Cutaneous Melanoma The Stanford Experience, 1997-2004 David R. Berk, MD; Denise L. Johnson, MD; Alison Uzieblo, MD; Michaela Kiernan, PhD; Susan M. Swetter, MD	Arch Dermatol. 2005;141:1016-1022. Abstract quote Objective  To review sentinel lymph node (SLN) data from Stanford University Medical Center from January 1, 1997, to January 1, 2004, including rates of SLN positivity according to 2002 American Joint Committee on Cancer (AJCC) tumor classification, relation to other clinical and pathologic prognostic factors, and rates and sites of melanoma recurrence. Design  Retrospective case series. Setting  Stanford University Medical Center and Stanford melanoma clinics. Patients  A total of 274 consecutive patients with primary melanoma who underwent SLN biopsy (SLNB) between January 1, 1997, and January 1, 2004, or who were referred to the Stanford melanoma clinics after SLNB and were followed up through March 2005. Interventions  All patients underwent standard wide local excision of their primary tumors and SLNB with intradermal injection of isosulfan blue dye and/or technetium sulfur colloid. Main Outcome Measure  Rates of SLN positivity per 2002 AJCC tumor classification, relation to other clinical and pathologic prognostic factors, and rates and sites of melanoma recurrence in node-negative and node-positive patients. Results  Positive SLNs were detected in 39 (15%) of 260 cases, including 0 (0%) of 45 for cutaneous melanomas 1.0 mm thick or less (T1), 21 (18%) of 115 for melanomas 1.01 to 2.0 mm thick (T2), 12 (19%) of 64 for melanomas 2.01 to 4.0 mm thick (T3), and 5 (16%) of 32 for melanomas thicker than 4.0 mm (T4). Median Breslow depths were 1.89 mm for SLN-positive biopsy specimens and 1.50 mm for SLN-negative biopsy specimens (P = .07). The recurrence rate was 46% among SLN-positive patients, with a median time to recurrence of 8 months. Bivariate analysis revealed SLN positivity to be associated with AJCC tumor classification (P = .02), location on the trunk (P = .03), and presence of ulceration (P = .03). By multivariate logistic regression, ulceration (P = .01) was predictive of SLN positivity, whereas SLN status (P< .001), ulceration (P = .02), and location (P = .03) were predictive of recurrent disease. Conclusion  Data from the past 8 years confirm the accuracy and prognostic value of SLNB in cutaneous melanoma and the low rate of regional nodal recurrence for SLN-negative patients.
The Importance of Total Number of Sentinel Lymph Nodes in Patients With Stage N0 Cutaneous Melanoma Laura E. Stewart, MD, etal.	Am J Clin Pathol 2005;124:77-82 Abstract quote Staging of malignant melanoma now relies routinely on the sentinel node (SN) technique. On average, 2.1 SNs are removed per patient. Nevertheless, despite the success of the SN technique, approximately 10% of patients with negative SNs experience metastatic recurrence. Because a prior theoretical analysis using Poisson and Bayes probability models suggested that limited sampling of SNs could cause false-negative results, we undertook this study to see whether the subset of patients with negative SNs and only 1 or 2 nodes examined have a shorter time to recurrence than patients with 3 or more nodes examined and found to be negative. Our study cases comprised 178 melanoma cases with SN biopsy: positive SN, 47; negative SN and fewer than 3 nodes examined, 68; and negative SN and more than 2 nodes examined, 63. Patients with negative SNs and fewer than 3 examined had disease-free survival intermediate between patients with positive SNs and those with negative SNs and more than 2 examined (P = .013). These results suggest that among patients with negative SNs, those with fewer than 3 nodes examined have greater risk for recurrence.
Analysis of Lymph Nodal Metastases in Malignant Melanoma Using the Poisson Probability Paradigm and Bayes Rule Robin T. Vollmer, MD	Am J Clin Pathol 2005;123:707-715 Abstract quote This article deals with and formalizes 2 notions common to the practice of pathology. The first is that the number of lymph nodes found positive for metastasis relates directly to the total number of lymph nodes examined. The second is that for any patient, there is a chance that the absence of lymph node metastases is a false-negative result. I introduce the Poisson probability density function to deal with the first notion and the Bayes probability rule to deal with the second. To illustrate the insight these 2 models provide, I apply them to data regarding lymph nodal metastases in malignant melanoma. In this preliminary study, the results of these 2 models correlate well with observed survival probabilities in patients with stage N0 melanoma and with observed rates of false-negative results in sentinel lymph node biopsy technology. With further development, the combination of these models should provide a way to estimate the probability of nodal metastasis when, in fact, none have been observed. Thus, these models might provide useful tools for evaluating patients with stage N0 malignant neoplasms.
Characterization of Micrometastatic Disease in Melanoma Sentinel Lymph Nodes by Enhanced Pathology: Recommendations for Standardizing Pathologic Analysis. Spanknebel K, Coit DG, Bieligk SC, Gonen M, Rosai J, Klimstra DS. From the Departments of *Surgery, double daggerEpidemiology and Biostatistics, and parallelPathology, Memorial Sloan-Kettering Cancer Center, New York, NY; daggerDepartment of Surgical Oncology, University of Maryland, Baltimore, MD; and section signDepartment of Pathology, National Cancer Institute, Milan, Italy.	Am J Surg Pathol. 2005 Mar;29(3):305-317. Abstract quote   Lymphatic mapping and sentinel lymph node (SLN) biopsy are widely used as a staging technique for patients with cutaneous malignant melanoma who are at risk for metastases. SLN status has been shown to be a strong predictor of prognosis, and a variety of techniques have been used to identify minimal metastatic disease in SLNs. However, there is no validated consensus method for the optimal histologic analysis of SLNs harvested from melanoma patients. This study was conducted: 1) to assess the yield of metastatic melanoma detected in SLNs deemed negative by initial routine pathologic analysis (RPA) by subjecting them (after review of the original slides) to enhanced pathologic analysis (EPA) that included complete step-sectioning and immunohistochemistry (IHC); 2) to characterize the distribution of metastatic melanoma deposits within the SLNs; 3) to determine a preferred method of pathologic analysis applicable to daily practice; and 4) to attempt to assess the clinical significance of disease detected by EPA. A total of 105 SLNs were harvested from 49 patients who underwent successful SLN biopsy procedures during the period of study. Ten SLNs from 10 patients were positive on initial RPA and were not analyzed further. Ninety-five SLNs from the remaining 39 patients were reviewed and processed with additional hematoxylin and eosin, S-100 protein, and HMB-45 stains at 50-mum intervals for 20 levels or until the SLN tissue was exhausted. A single pathologist reviewed all sections without knowledge of the results of the other stains. Overall, metastatic melanoma was discovered in SLNs from 20 of the 39 patients: SLNs from 6 patients were found to have melanoma on review of the original hematoxylin and eosin slides, and SLNs from 14 patients were positive only after EPA. Twenty-one individual positive SLNs from these 14 patients were detected by EPA; of these, 10 positive SLNs were identified solely by IHC, representing 12% of the patient cohort and 10% of all SLNs studied by EPA. Detection rates were significantly associated with the staining method and the number of levels performed (P < 0.01). S-100 protein staining resulted in the highest yield of SLN positivity (86%), followed by HMB-45 (81%) and hematoxylin and eosin (52%). No single method detected all of the micrometastases. A detailed topographic mapping of metastatic deposits in SLNs was carried out. When using all three staining techniques, all 20 levels were required to identify 100% of the micrometastases; 95% of positive SLNs were identified with 17 levels, 90% with 15 levels, 75% with 10 levels, and 42% with 3 levels. Projected rates of detection for various different sectioning strategies were determined, with alteration of either the number of levels examined, the interval between the levels, or both. Detection of SLN positivity can be increased to 71% by performing three levels at 250-mum intervals, each level being composed of a set of three sections stained with hematoxylin and eosin, S-100 protein, and HMB-45, respectively. Therefore, this is the methodology we propose for the study of SLNs in melanoma patients. After a median follow-up of 87 months (range, 9-134 months), patients with EPA-detected disease and those with negative SLNs by EPA demonstrated improved recurrence-free and disease-specific survival compared with patients with RPA-detected disease in SLNs. Sampling error introduced by variations in pathologic processing should be addressed by standardization of pathologic methods, and the clinical significance of minimal SLN disease should be addressed in prospective studies of homogeneously staged patients.
Prediction of metastatic melanoma in nonsentinel nodes and clinical outcome based on the primary melanoma and the sentinel node. Cochran AJ, Wen DR, Huang RR, Wang HJ, Elashoff R, Morton DL. Department of Pathology and Laboratory Medicine, School of Public Health at UCLA, Los Angeles, CA 90095-1732, USA.	Mod Pathol. 2004 Jul;17(7):747-55. Abstract quote Lymphatic mapping and sentinel node biopsy are well-established techniques for staging and managing patients with melanoma, breast cancer and other malignancies that spread initially to the regional lymph nodes. Identification of tumor in the sentinel node is the most precise staging technique currently available. The sentinel node is the site of metastatic melanoma in approximately 20% of melanoma patients and if tumor is present in the sentinel node it is customary to perform a complete dissection of the lymph nodes of the affected nodal basin. This may be overtreatment for some patients as tumor is identified in the nonsentinel nodes of only one-third of sentinel node-positive melanoma patients treated by completion lymphadenectomy. If it were possible accurately to identify the minority of patients with tumor in the nonsentinel nodes, the patients most likely to benefit from lymphadenectomy, the remaining patients could be spared a potentially morbid operation that is unlikely to confer clinical advantage. In 90 patients with a melanoma-positive sentinel node, who subsequently had a completion lymphadenectomy, we evaluated and compared the capacity of characteristics of the primary melanoma and of the sentinel node to predict individuals likely to have tumor in nonsentinel nodes. We assessed the Breslow thickness of the primary, the amount of tumor in the sentinel node (relative tumor area) and, as an index of immune modulation of the sentinel node, the density of dendritic leukocytes in the nodal paracortex. The relative area of tumor in the sentinel node and Breslow thickness of the primary melanoma most accurately predicted the presence of tumor in the nonsentinel nodes (P=0.0001 in both cases-Wilcoxon rank sums). The presence of melanoma in the nonsentinel nodes was also predicted by the density of dendritic leukocytes in the paracortex (P=0.008-Wilcoxon rank sums). These three observations assessed alone and in combination predict the presence of tumor in the nonsentinel nodes with high accuracy. The same characteristics also significantly correlated with tumor recurrence (tumor burden, P=0.0001, Breslow, P=0.0001 and dendritic cell density, P=0.0007) and death from melanoma (tumor burden, P=0.0001, Breslow, P=0.0001 and dendritic cell density, P=0.0026).
False-positive Rate of the Immunoperoxidase Stains for MART1/MelanA in Lymph Nodes. Yan S, Brennick JB. Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, NH.	Am J Surg Pathol. 2004 May;28(5):596-600.   MART1 and MelanA are considered sensitive markers of melanocytic differentiation and are used to increase the detection of melanoma micrometastases in sentinel lymph nodes (SLNs). However, the false-positive rates of these two antibodies have not been adequately evaluated. We examined 217 lymph nodes (LNs) from patients with no history of melanoma: 117 SLNs from breast cancer patients, 79 LNs from other nonmelanoma malignancy patients, and 21 reactive LNs. Capsular melanocytic nevi were identified in 5 SLNs from 5 breast cancer patients by both antibodies. Two of these 5 SLNs with capsular nevus also contain MART1- and MelanA-positive cells within the lymph node parenchyma. Individual immunoperoxidase-positive cells were also identified within the parenchyma of lymph nodes without capsular nevus (9 LNs with MART1 and 3 LNs with MelanA). The false-positive rate is 5.1% for MART1 and 2.4% for MelanA. In conclusion, MART1- or MelanA-positive cells may be present in lymph nodes from patients without melanoma. Therefore, MART1- and MelanA-positive cells in SLNs from melanoma patients, without corresponding atypia or hematoxylin and eosin findings, should be interpreted with caution.
Staging workup, sentinel node biopsy, and follow-up tests for melanoma: update of current concepts. Johnson TM, Bradford CR, Gruber SB, Sondak VK, Schwartz JL. Department of Dermatology, University of Michigan Comprehensive Cancer Center, University of Michigan Health System, Ann Arbor 48109-0314, USA.	Arch Dermatol. 2004 Jan;140(1):107-13. Abstract quote   OBJECTIVES: To clarify and update workup and follow-up strategies based on fundamental principles and current data, and to discuss new and current concepts regarding sentinel lymph node biopsy (SLNB), particularly in relation to the staging workup. DATA SOURCES: Studies conducted from 1995 to 2003 were identified by PubMed search. Additional searches included workup for reference lists of retrieved articles when applicable, and PubMed-related articles. STUDY SELECTION: Contemporary studies with good design, conclusions based on sound methods, and results pertaining to staging workup, SLNB, and follow-up tests were critically reviewed. DATA EXTRACTION: Data and conclusions based on the above studies were incorporated into a review. DATA SYNTHESIS: Routine tests have marginal to no efficacy and are not cost-efficient for detecting occult disease in asymptomatic patients with localized melanoma. The only staging test that has relatively high sensitivity and specificity and provides tissue diagnosis is SLNB; moreover, SLNB has revolutionized our understanding of lymphatic pathways. The concepts of interval nodes and unexpected lymphatic drainage pathways have been addressed by several recent reports. There are no data that demonstrate any significant difference in overall survival for detection of asymptomatic vs symptomatic stage IV melanoma. CONCLUSIONS: An initial workup is useful for staging and prognosis to identify occult disease, with potential outcome benefit if treated early; and, by detecting distant occult disease (stage IV), to obviate the need for an extensive surgical procedure and thereby avoid associated increased morbidity. The foundation for the workup and follow-up remains thorough history taking and a physical examination, combined with a low index of suspicion for symptom-directed tests.
Nodal Melanocytic Nevi in Sentinel Lymph Nodes Correlation With Melanoma-Associated Cutaneous Nevi John B. Holt, MD, Omar P. Sangueza, Edward A. Levine, MD, Perry Shen, MD, Simon Bergman, MD, Kim R. Geisinger, MD, and Andrew J. Creager, MD	Am J Clin Pathol 2004;121:58-63 Abstract quote Melanocytic nevi occurring in lymph nodes create diagnostic difficulty by mimicking metastases. Few studies describe nodal nevi in sentinel lymph nodes (SLNs) excised for melanoma. We evaluated 72 cases in which patients had undergone SLN biopsy for melanoma. Lymph nodes and cutaneous melanomas were evaluated according to a standard protocol. Nodal nevi were identified in 8 patients (11%). Of these, 6 (75%) had an associated cutaneous nevus ( P = .006). Of 21 patients with an associated nevus, 4 (19%) with nodal nevi had a cutaneous nevus with congenital features ( P = .01). The incidence of nodal nevus correlated with a Breslow thickness greater than 2.5 mm ( P = .02). Nevi were not seen in non-SLNs. Nodal nevi appear more frequently in patients with melanoma-associated cutaneous nevi, particularly if congenital features are present. The increased frequency of nodal nevi in SLNs relative to non-SLNs suggests an etiology of mechanical transport of nevus cells.
Pathologic review of negative sentinel lymph nodes in melanoma patients with regional recurrence: a clinicopathologic study of 1152 patients undergoing sentinel lymph node biopsy. Li LX, Scolyer RA, Ka VS, McKinnon JG, Shaw HM, McCarthy SW, Thompson JF. Melanoma and Skin Cancer Research Institute, Sydney Melanoma Unit, Royal Prince Alfred Hospital, Camperdown, NWS, Australia.	Am J Surg Pathol. 2003 Sep;27(9):1197-202. Abstract quote   A sentinel lymph node (SLN) that is melanoma negative by pathologic examination implies absence of melanoma metastasis to that regional lymph node field. However, a small proportion of patients develop regional node field recurrence after a negative SLN biopsy. In this study, we reviewed the histopathology of negative SLNs from such patients to determine whether occult melanoma cells were present in the SLNs, to characterize the pathologic features of false-negative SLNs, and to provide recommendations for the histopathologic examination of these specimens. Between March 1992 and June 2001, of 1152 patients who had undergone SLN biopsy for primary melanomas at the Sydney Melanoma Unit, 976 were diagnosed with negative SLNs by initial pathologic examination (using 2 hematoxylin and eosin stained sections, and 2 immunostained sections for S-100 protein and HMB45), and follow-up was available in 957. Of these, 26 (2.7%) developed regional lymph node recurrence during a median follow-up period of 35.7 months. For 22 of them, the original slides and tissue blocks were available for reexamination. The original slides of each block were reviewed. Multiple further sections were cut from each block and stained with hematoxylin and eosin, for S-100, HMB45, and Melan A. Deposits of occult melanoma cells were detected in 7 of the 22 cases (31.8%). In 5 of the 7 cases, deposits of melanoma cells were present only in the recut sections. There were no significant differences in clinical and pathologic variables for those patients in whom occult melanoma cells were found by pathologic reexamination of their SLNs, compared with those in whom no melanoma cells were detected. The detection of melanoma cell deposits in only 7 of 22 false-negative SLNs suggests that mechanisms other than failure of histopathologic examination may contribute to the failure of the SLN biopsy technique in some patients. The failure rate for melanoma detection in SLNs by our routine pathologic examination, using the current protocol at our institution, was <1% (7 of 957 patients). Routinely performing more intensive histopathologic examination of SLNs is difficult to justify from a cost benefit perspective; we therefore recommend examining two hematoxylin and eosin stained sections and two immunostained sections (for S-100 and HMB45) routinely on SLNs from melanoma patients.
Sentinel lymph node biopsy has no benefit for patients with primary cutaneous melanoma metastatic to a lymph node: an assertion based on comprehensive, critical analysis: part I. Medalie NS, Ackerman AB. Ackerman Academy of Dermatopathology, New York, NY 10021, USA.	Am J Dermatopathol. 2003 Oct;25(5):399-417. Abstract quote   The thesis is set forth in this treatise that there is no place in the routine practice of medicine for the procedure for melanoma known conventionally and universally as sentinel node biopsy. Our assertion is based on assessment of the extensive body of literature devoted to the subject of treatment of melanoma before any metastasis has manifested itself clinically and of that dedicated to therapy for overt metastatic melanoma by a variety of modalities, chief among those addressed here being elective lymph node dissection and sentinel lymph node biopsy. In this era of sentinel lymph node biopsy, elective lymph node dissection has been modified to include only patients with metastasis of melanoma to lymph nodes, a procedure now termed "selective complete lymph node dissection." Among adjuvant medical therapies, the most popular today is interferon alpha-2B. Critical, incisive scrutiny of the literature leads to the conclusion, incontrovertibly, that elective lymph node dissection has no benefit for a patient and that all modifications of it also are devoid of value. The reason, logically, for the lack of utility of elective lymph node dissection becomes apparent by virtue of the route taken by cells of melanoma as they metastasize; those cells proceed in the same fashion as does lymph, bacteria, foreign material (including vital dyes and radioactive tracers), and other kinds of cells, to wit, by passing rapidly through nodes, including the sentinel one, and even bypassing entirely the nodes. In reality, cells of metastatic melanoma are not held up in nodes for any significant period of time, contrary to what is asserted repeatedly, but without any basis in fact, by many students of the subject. Moreover, not a single adjuvant medical therapy available currently is effective against metastatic melanoma and, therefore, none of them should be invoked to justify performance of sentinel node biopsy. Even if the sentinel node is found to house cells of melanoma, which, as a rule, conveys a grim message regarding the future, the finding in an individual patient is meaningless; a particular patient may live in harmony with metastases of melanoma for more than 30 years and even die of an unrelated malady. In short, no surgeon, pathologist, or oncologist is a seer, diviner, or prophet when it comes to predicting accurately the outcome for a patient with metastasis of melanoma; the end could come in weeks, months, or decades. If, however, a sentinel node is found to contain nary a cell of metastatic melanoma, it, too, means nothing for an individual patient because the existence of metastases widely is not excluded by that finding. In short, sentinel node biopsy cannot be considered the standard of care in the daily practice of medicine; it is woefully substandard because it is without benefit. There is no justification, whatsoever, for the procedure, scientifically or practically, and for that reason it should be abandoned, without delay, now.
Significance of dual-basin drainage in patients with truncal melanoma undergoing sentinel lymph node biopsy. Jacobs IA, Chang CK, Salti GI. Department of Surgical Oncology, the University of Illinois, Chicago, IL 60612, USA.	J Am Acad Dermatol. 2003 Oct;49(4):615-9. Abstract quote   BACKGROUND: The number of nodal basins and the number of lymph nodes containing regional metastases are important prognostic factors in patients with truncal malignant melanoma. Because the lymphatic drainage pattern of truncal melanoma often includes more than 1 basin, we designed a study to evaluate whether: (1) patients with dual-basin drainage were at an increased risk of lymph node metastases identified by sentinel lymph node (SLN) biopsy; and (2) the histologic status of an individual basin reliably predicted the status of the other draining basin in patients with dual-basin drainage. METHODS: The records of 269 consecutive patients with melanoma, who were treated primarily with intraoperative lymphatic mapping and SLN biopsy between 1997 and 2002, were reviewed. Of these patients, 122 had primary truncal melanomas. All patients underwent preoperative lymphoscintigraphy, which established the number and location of draining nodal basins. The chi-square and Fisher's exact tests of relevant clinicopathologic factors determined which factors were predictive of the presence of a pathologically positive SLN. RESULTS: At least one SLN was identified in all patients. Dual-basin drainage was present in 39 (32%) patients, and a pathologically positive SLN was found in 12 (31%) of these patients. By chi-square and Fisher's exact tests, dual-basin drainage was not a significant independent risk factor for the presence of at least 1 pathologically positive SLN (P =.846). Tumor thickness (P <.001), Clark level (P =.003), and tumor ulceration (P =.003) were significant independent risk factors for the presence of at least 1 pathologically positive SLN. SLN pathology in one basin did not predict the histology of the other basin in 7 (18%) of 39 patients with dual-basin drainage. CONCLUSIONS: Dual-basin drainage is not independently associated with an increased risk of nodal metastases in patients with truncal melanoma. Because the histologic status of an individual basin did not reliably predict the status of the other draining basins in patients with dual-basin drainage, it is important to adequately identify and completely assess all nodal basins at risk, as defined by lymphoscintigraphy, in patients with truncal melanoma.
Reassessing the role of lymphatic mapping and sentinel lymphadenectomy in the management of cutaneous malignant melanoma. Perrott RE, Glass LF, Reintgen DS, Fenske NA. University of South Florida College of Medicine, Tampa, FL 33612-4719, USA.	J Am Acad Dermatol. 2003 Oct;49(4):567-88; quiz 589-92. Abstract quote   Lymphatic mapping and sentinel lymphadenectomy was developed as a minimally invasive technique to provide regional lymph node staging information for patients at high risk for metastatic melanoma, but without clinically palpable disease. Only patients who demonstrate micrometastases undergo complete regional lymphadenectomy, sparing approximately 80% of patients the expense and morbidity of an elective lymph node dissection. This technique has been widely accepted as the preferred method to determine the pathologic status of the regional lymph nodes and the staging information gained is incorporated into the latest version of the American Joint Committee on Cancer staging system for cutaneous melanoma. Still, there is much controversy as to the use of this technique as a staging procedure and its overall therapeutic benefit in the treatment of patients with melanoma. Currently ongoing clinical trials will determine if lymphatic mapping and sentinel lymphadenectomy directly influences overall survival for patients with malignant melanoma. We review the latest technical aspects of this procedure and discuss the controversies surrounding its use.
Sentinel lymph node biopsy in patients with thin melanoma. Lowe JB, Hurst E, Moley JF, Cornelius LA. Divisions of Dermatology and Surgical Oncology, Washington University School of Medicine, St Louis, Mo.	Arch Dermatol 2003 May;139(5):617-21 Abstract quote OBJECTIVE: To define the percentage of positive sentinel lymph node biopsies and identify risk factors for the presence of lymph node disease in patients with melanomas less than or equal to 1 mm in depth. DESIGN: Retrospective chart review. SETTING: Washington University School of Medicine and Barnes-Jewish Hospital, St Louis, Mo, a melanoma referral center with outpatient surgical care.Patients Forty-six patients with melanomas less than or equal to 1 mm in depth undergoing sentinel lymph node biopsy at our institution between 1996 and 2002. RESULTS: The procedure was well tolerated and there were no reported complications. Of the 46 patients, 3 (7%) (95% exact confidence interval, 1.3%-17.8%) were found to have positive sentinel lymph nodes or micrometastatic disease. The finding of a positive sentinel lymph node was associated with a Clark level of III or more (P</=.07). CONCLUSIONS: Conclusions from this study are limited by the small sample size. The results of our study suggest that sentinel lymph node biopsy of patients with melanomas less than or equal to 1 mm in depth may be indicated when the Clark level is III or more.
Sentinel node biopsy in vulvar and vaginal melanoma: presentation of six cases and a literature review. Abramova L, Parekh J, Irvin WP Jr, Rice LW, Taylor PT Jr, Anderson WA, Slingluff CL Jr. Department of Surgery, University of Virginia Health Science Center, Charlottesville, Virginia 22906, USA.	Ann Surg Oncol 2002 Nov;9(9):840-6 Abstract quote BACKGROUND: Urogenital melanoma is a rare neoplasm with poor prognosis. Its management in the past involved radical vulvectomy and complete bilateral inguinofemoral lymphadenectomy. Sentinel lymph node biopsy is an accurate low-morbidity procedure when used in the context of cutaneous melanoma. However, prophylactic lymphadenectomy has not been shown to improve survival of melanoma patients. We wanted to determine the feasibility of sentinel lymph node biopsy in patients with female urogenital melanoma as a staging procedure. METHODS: Six patients with vulvar or vaginal melanomas underwent preoperative lymphatic mapping with (99m)Tc-labeled sulfur colloid followed by sentinel lymphadenectomy. In addition, we reviewed the literature on the application of sentinel lymph node biopsy in urogenital tract melanomas. RESULTS: One or more sentinel nodes were identified in all six patients by lymphoscintigraphy. All patients underwent sentinel lymphadenectomy, except for one patient with a deep vaginal melanoma that drained to pelvic nodes. The five successful cases had unilateral drainage patterns. None of the sentinel lymph nodes excised had tumor invasion. Combined with five other patients from the published literature, the success rate of localizing sentinel lymph nodes in the patients with urogenital melanoma approaches 100%. CONCLUSIONS: This experience, plus reports of a small number of patients from three similar studies, supports the impression that sentinel lymph node biopsy is feasible for vulvar and vaginal melanoma.
The EORTC melanoma group translational research program on prognostic factors and ultrastaging in association with the adjuvant therapy trials in stage II and stage III melanoma. European Organization for Research and Treatment of Cancer. Eggermont AM, Keilholz U, Testori A, Cook M, Lienard D, Ruiter DJ. EORTC-Melanoma Group, Brussels, Belgium.	Ann Surg Oncol 2001 Oct;8(9 Suppl):38S-40S Abstract quote Last year the Melanoma Group of the European Organization for Research and Treatment of Cancer (EORTC-MG) completed accrual (1418 patients) for trial EORTC 18952, a three-arm phase III trial evaluating adjuvant therapy with two different intermediate doses of interferon (IFN) alfa-2b versus observation for stage IIB-III melanoma. About 25% of the patients entered the trial with tumor-positive sentinel nodes (SNs). Prognosis was significantly better in SN-positive patients than in patients with palpable regional node involvement (P < .00001). Subsequently the EORTC-MG embarked on two large phase III trials of adjuvant therapy based on the tumor status of the SN. In trial EORTC 18961 for stage II melanoma, GM2-KLH/QS-21 vaccination is compared with observation (1300 patients); in trial EORTC 18991 for stage III melanoma, 5-year treatment with pegylated interferon alfa-2b (PEG-Intron) is compared with observation (900 patients). Translational research projects will compare SN assessment by hematoxylin and eosin (H&E) staining, immunohistochemistry (IHC), and reverse transcriptase-polymerase chain reaction (RT-PCR) to determine the relative accuracy of each method and its correlation to relapse and survival of patients with stage II melanoma. In stage III patients, a similar workup of the most proximal nonsentinel node in the full lymph-node dissection specimen will indicate the accuracy of each methodology to detect nodal metastasis beyond the SN and the prognostic significance thereof. These findings will be correlated to the results of sequential blood testing by RT-PCR and by tumor marker assays for S100, TA90, and angiostatin. In addition, tumor-positive and tumor-negative SNs will be assessed for activated cytotoxic T lymphocytes and downregulation of dendritic cell functions.
Thin < or = 1 mm level III and IV melanomas are higher risk lesions for regional failure and warrant sentinel lymph node biopsy. Corsetti RL, Allen HM, Wanebo HJ. Department of Surgery/Surgical Oncology, Roger Williams Medical Center, Providence, Rhode Island, USA.	Ann Surg Oncol 2000 Jul;7(6):456-60 Abstract quote BACKGROUND: Thin melanomas have become increasingly prevalent, and lesions 1 mm or less in thickness are frequently diagnosed. They are considered highly curable when treated with wide local excision alone with reported 5-year disease free survivals of 95% to 98%. However, thin Clark level III and IV melanomas may have an increased potential for metastasizing and late recurrence because of dermal lymphatics located at the interface of the papillary and reticular dermis. We have addressed this controversial area by reviewing the outcomes of patients with invasive thin (< or = 1.0 mm thick) melanomas. METHODS: We reviewed 415 invasive melanomas from 1983-1995 in the Rhode Island tumor registries which kept records of both tumor thickness and Clark levels. Sixty-eight (16.4%) of the 415 invasive melanomas were thin (< or = 1.0 mm in thickness) and were treated by wide local excision only. In situ lesions were excluded. Thirty-eight (56%) of the 68 thin melanomas were either Clark level III or IV. RESULTS: Seven (18.4%) of the 38 level III and IV thin melanomas had a recurrence at a minimum follow-up of 36 months. Median time to recurrence was 52 months, and the average measured depth of tumor thickness was 0.84 mm. Only one (3.3%) of 30 level II melanomas recurred (P < .05). CONCLUSIONS: Thin level III and IV melanomas are at increased risk for late recurrence when compared with all thin melanomas. Because there is effective adjuvant therapy with alpha interferon for patients with stage III melanoma to treat regional and systemic disease, and because sentinel lymph node biopsy (SLNB) offers minimal morbidity, we suggest using SLNB to accurately stage and treat all patients with thin melanoma that are high Clark levels that are at increased risk for metastases.
ADDITIONAL STUDIES
Lymph node micrometastases of cutaneous melanoma: increased sensitivity of molecular diagnosis in comparison to immunohistochemistry. Blaheta HJ, Schittek B, Breuninger H, Maczey E, Kroeber S, Sotlar K, Ellwanger U, Thelen MH, Rassner G, Bultmann B, Garbe C. Department of Dermatology, Eberhard-Karls-University, Tuebingen, Germany.	Int J Cancer 1998 Aug 21;79(4):318-23 Abstract quote The presence of regional lymph node metastases is one of the most significant prognostic factors for predicting survival in patients with clinical stage I or II cutaneous melanoma. For accurate staging of the primary tumor a sensitive technique is required to detect occult nodal micrometastases. This prospective diagnostic study was designed to evaluate the incidence of nodal micrometastases using nested reverse transcription-polymerase chain reaction (RT-PCR) for tyrosinase in comparison to immunohistochemical examination. Furthermore, the incidence of melanoma micrometastases detected by RT-PCR was analysed in correlation to major prognostic factors. A total of 466 regional lymph nodes from 79 patients with primary cutaneous melanoma (tumor thickness > 0.75 mm) were investigated. In 49 lymph nodes from 31 patients immunohistochemistry demonstrated melanoma metastases. Using tyrosinase RT-PCR, nodal micrometastases were detected in 136 lymph nodes from 52 patients including all lymph nodes positive by immunohistochemical examination. Out of the 417 lymph nodes negative by immunohistochemistry, 87 nodes (21%) were identified to express tyrosinase by the RT-PCR technique. Among the 48 patients negative by immunohistochemical assessment, 21 (44%) had nodal micrometastases (n = 40) using RT-PCR. All 68 lymph nodes from 46 non-melanoma patients serving as negative controls for tyrosinase RT-PCR were negative. The detection of melanocytic nodal micrometastases by tyrosinase RT-PCR is a highly specific method with a sensitivity significantly higher than that achieved by immunohistochemistry (p < 0.0001). Patients with nodal micrometastases identified exclusively by RT-PCR had significantly higher tumor thickness as compared to patients with negative results by RT-PCR (p < 0.01).
Multi-institutional melanoma lymphatic mapping experience: the prognostic value of sentinel lymph node status in 612 stage I or II melanoma patients. Gershenwald JE, Thompson W, Mansfield PF, Lee JE, Colome MI, Tseng CH, Lee JJ, Balch CM, Reintgen DS, Ross MI. Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.	J Clin Oncol 1999 Mar;17(3):976-83 Abstract quote PURPOSE: To compare the effect of pathologic sentinel lymph node (SLN) status with that of other known prognostic factors on recurrence and survival in patients with stage I or II cutaneous melanoma. PATIENTS AND METHODS: We reviewed the records of 612 patients with primary cutaneous melanoma who underwent lymphatic mapping and SLN biopsy between January 1991 and May 1995 to determine the effects of tumor thickness, ulceration, Clark level, location, sex, and SLN pathologic status on disease-free and disease-specific survival. RESULTS: In the 580 patients in whom lymphatic mapping and SLN biopsy were successful, the SLN was positive by conventional histology in 85 patients (15%) but negative in 495 patients (85%). SLN status was the most significant prognostic factor with respect to disease-free and disease-specific survival by univariate and multiple covariate analyses. Although tumor thickness and ulceration influenced survival in SLN-negative patients, they provided no additional prognostic information in SLN-positive patients. CONCLUSION: Lymphatic mapping and SLN biopsy is highly accurate in staging nodal basins at risk for regional metastases in primary melanoma patients and identifies those who may benefit from earlier lymphadenectomy. Furthermore, pathologic status of the SLN in these patients with clinically negative nodes is the most important prognostic factor for recurrence. The information from SLN biopsy is particularly helpful in establishing stratification criteria for future adjuvant trials.
Outcome of patients with melanoma and histologically negative sentinel lymph nodes. Gadd MA, Cosimi AB, Yu J, Duncan LM, Yu L, Flotte TJ, Souba WW, Ott MJ, Wong LS, Sober AJ, Mihm MC, Haluska FG, Tanabe KK. Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston 02114, USA.	Arch Surg 1999 Apr;134(4):381-7 Abstract quote HYPOTHESIS: Patients with melanoma and histologically negative sentinel lymph nodes identified by lymphatic mapping have a very good prognosis. DESIGN: Cohort study with follow-up information obtained from medical records and telephone interviews. SETTING AND PATIENTS: Of all patients with cutaneous melanoma who underwent intraoperative sentinel lymph node mapping between November 15, 1993, and April 18, 1997, at the Massachusetts General Hospital, Boston, 89 were found to have no evidence of melanoma in their sentinel nodes. Forty-six lesions (51%) were on an extremity and 44 (49%) were of axial location. The median tumor thickness was 1.8 mm (range, 0.36-12.0 mm) and 11 tumors (12%) were ulcerated. INTERVENTIONS: Patients underwent intraoperative sentinel lymph node mapping with lymphazurin and radiolabeled sulfur colloid. Sentinel lymph nodes were analyzed by standard hematoxylin-eosin staining. Only 2 patients received adjuvant therapy following wide excision of the primary lesion. MAIN OUTCOME MEASURES: Site of initial recurrence and time to initial recurrence. RESULTS: The median follow-up for all patients was 23 months (range, 2-54 months). Eleven patients (12%) developed melanoma recurrences, and 78 (88%) patients remain disease free. Regional lymph nodes were the initial site of recurrence in 7 (8%) of 89 patients, and 7 (7%) of 106 mapped basins. Four patients had recurrence without involvement of regional lymph nodes: 2 with distant metastases and 2 with in transit metastases. The median time to recurrence was 12 months (range, 2-35 months). Sentinel lymph nodes were reanalyzed using serial sections and immunoperoxidase stains in 7 patients with recurrence and metastatic melanoma was identified in 3 (43%). CONCLUSIONS: The risk for melanoma recurrence is relatively low in patients with histologically negative sentinel nodes identified by lymphatic mapping. Longer follow-up will improve our understanding of the prognostic value of this procedure.
Clinical relevance of molecular staging for melanoma: comparison of RT-PCR and immunohistochemistry staining in sentinel lymph nodes of patients with melanoma. Li W, Stall A, Shivers SC, Lin J, Haddad F, Messina J, Glass LF, Lyman G, Reintgen DS. Cutaneous Oncology Program, H. Lee Moffitt Cancer Center and Research Institute at the University of South Florida, Tampa, Florida 33612, USA.	Ann Surg 2000 Jun;231(6):795-803 Abstract quote OBJECTIVE: To determine the clinical significance of a molecular assay based on the reverse transcriptase polymerase chain reaction (RT-PCR) for the presence of micrometastatic melanoma cells in sentinel lymph nodes (SLNs). SUMMARY BACKGROUND DATA: Routine histologic examination of lymph nodes often underestimates the presence of micrometastatic disease. The authors have previously shown that an RT-PCR assay designed to detect melanocyte-specific expression of the tyrosinase gene could be used to define a population of patients at higher risk for both recurrence and death compared with routine hematoxylin and eosin (H&E) histology. In this study, the authors used the tyrosinase RT-PCR assay in a patient population examined by a more detailed histologic analysis, including S-100 immunohistochemistry. METHODS: Patients underwent lymphatic mapping and SLN biopsy. SLN specimens were bivalved, and half of each specimen was serially sect