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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


Treatment Overview
Mohs Micrographic Surgery  
Radiation Therapy  
Surgery and margin adequacy  
Sentinel lymph node dissection  
Immunotherapy and Chemotherapy  
Vaccine therapy  
Commonly Used Terms  



Early stage melanoma, confined to the skin, complete excision


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.



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.



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.



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

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.



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

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 sectioned and examined by routine H&E histology and S-100 immunohistochemistry. The other half of each specimen was analyzed by a nested RT-PCR assay.

RESULTS: Hematoxylin and eosin histology detected metastatic disease in 36 (16%) of the 233 patients tested. S-100 immunohistochemistry detected micrometastatic disease in another 16 patients, and 114 (63%) of 181 patients with histology-negative nodes had positive findings on RT-PCR. There were significant differences between PCR-positive and PCR-negative patient groups in Breslow thickness, Clark level, and the presence of ulceration of the primary tumor, factors that have been shown to correlate with recurrence and survival.

CONCLUSIONS: These results suggest that RT-PCR can increase the sensitivity of detection of metastatic melanoma cells in SLNs over the current standard methods, including H&E histology and S-100 immunohistochemistry. Further long-term follow-up is needed to detect actual differences in recurrence and overall survival.

HMB-45 Immunohistochemical Staining of Sentinel Lymph Nodes A Specific Method for Enhancing Detection of Micrometastases in Patients With Melanoma

Blaire L. Baisden, M.D.; Frederic B. Askin, M.D.; Julie R. Lange, M.D.; William H. Westra, M.D.

From the Departments of Pathology (B.L.B., F.B.A., W.H.W.) and Surgery (J.R.L.), The Johns Hopkins Medical Institutions, Baltimore, Maryland

Am J Surg Pathol 2000;24:1140-1146 Abstract quote

Despite the profound therapeutic and prognostic implications of nodal metastases in patients with melanoma, there is no consensus strategy for the optimal detection of metastases in sentinel lymph node biopsies. Traditional microscopic examination may be too crude to detect scattered, individual tumor cells. Conversely, molecular genetic techniques are prone to false-positive results.

The authors evaluated the ability of HMB-45 immunohistochemistry to enhance detection of melanoma cells in histologically negative sentinel lymph nodes.

Ninety-six sentinel lymph nodes, collected over a 25-month period from 66 consecutive patients with melanoma, were processed routinely and sectioned serially. Slides 1, 3, and 5 were stained with hematoxylin and eosin. HMB-45 staining was performed on an intervening slide in histologically negative nodes. To assess the background incidence of HMB-45-positive cells in lymph nodes draining the skin, the authors stained 244 cervical and axillary lymph nodes from patients without melanoma. Metastases were apparent microscopically in 12 (18%) of the 66 patients with melanoma. Of the remaining 54 patients, four patients (7%) had lymph nodes harboring individual, scattered HMB-45-positive cells. Benign nevocellular aggregates were present in four of the 96 sentinel lymph nodes (4% nodal incidence), but they were HMB-45-negative. The authors did not observe a single HMB-45-positive cell in the 244 lymph nodes from patients without melanoma.

Immunohistochemistry appears to represent a specific means of enhancing tumor detection in sentinel lymph nodes from patients with melanoma.

Sentinel node biopsies in melanoma patients: a protocol for accurate, efficient, and cost-effective analysis by preselection for immunohistochemistry on the basis of Tyr-PCR.

van der Velde-Zimmermann D, Schipper ME, de Weger RA, Hennipman A, Borel Rinkes IH.

Department of Surgery, University Hospital, Utrecht, The Netherlands.

Ann Surg Oncol 2000 Jan-Feb;7(1):51-4 Abstract quote

BACKGROUND: Immunohistochemistry (IHC) of serial sectioning is considered the gold standard for detection of melanoma activity in sentinel node (SN) biopsies. However, this is cost and labor intensive. In contrast, tyrosinase reverse transcription-polymerase chain reaction (RT-PCR) is simple and quick, but it is hampered by its extreme sensitivity. This study was performed to test whether a strategy that combines the two methods, using tyrosinase RT-PCR to preselect nodes for IHC, could be accurate and cost effective.

METHODS: In 36 patients, SNs were identified by scintigraphy and patent blue uptake. Of each SN, one cross section was analyzed first by hematoxylin and eosin staining. Next, all nodes were examined by serial sectioning and IHC of one-half and tyrosinase RT-PCR of the other. Before comparison, all results were documented in a blinded manner. Material costs and workload estimates were noted per SN.

RESULTS: Fifty-five SNs were retrieved from the 36 patients. Hematoxylin and eosin staining of the first cross section revealed tumor positivity in 3 patients (6 SN). Tyrosinase RT-PCR was positive in 11 of the remaining 33 patients (19 of 49 SN). Of these same 11 patients, only 5 were shown to have tumor-positive SNs by using IHC on serial sections (7 SN). All these nodes had been positive for tyrosinase on PCR. For IHC, an average of 40 sections were prepared and examined per SN at a cost of $200(U.S.)/SN. In contrast, routine tyrosinase RT-PCR costs $37(U.S.)/SN, and takes 5% of the time necessary for IHC. A strategy including hematoxylin and eosin staining on the first cross section, followed by tyrosinase RT-PCR on half of each negative (half) node, could preselect nodes to be taken through serial sectioning. In these series, such a strategy would have prevented serial sectioning and IHC of 30 SN from 22 patients. Apart from a considerable gain in efficiency, this would have reduced material costs by a minimum of $6000 (U.S.). This discrepancy would be even higher if work intensity of analysts and pathologists were considered.

CONCLUSIONS: In routine analysis of SN biopsies in melanoma patients, tyrosinase RT-PCR can be used effectively to preselect nodes for further IHC of serial sections. This method seems both time and cost effective.

Examination of regional lymph nodes by sentinel node biopsy and molecular analysis provides new staging facilities in primary cutaneous melanoma.

Blaheta HJ, Ellwanger U, Schittek B, Sotlar K, MacZey E, Breuninger H, Thelen MH, Bueltmann B, Rassner G, Garbe C.

Department of Dermatology, Skin Cancer Program, Eberhard-Karls-University, Tuebingen, Germany.

J Invest Dermatol 2000 Apr;114(4):637-42 Abstract quote

Histopathologic parameters of the primary tumor, such as Breslow's tumor thickness and Clark's level of invasion are the current basis for prognostic classifications of primary cutaneous melanoma. Once patients develop regional node metastasis, histopathologic features of the primary melanoma no longer contribute significantly to survival prediction. In this tumor stage, the extent of lymph node involvement is the main prognostic factor.

This study addresses the question whether application of a highly sensitive molecular biology assay for detection of submicroscopic melanoma cells in sentinel lymph nodes may be suitable to improve melanoma staging.

One hundred and sixteen patients with primary cutaneous melanoma with a total of 214 sentinel lymph nodes were enrolled. Sentinel lymph nodes were analyzed by histopathology including immunohistochemistry and by reverse transcription-polymerase chain reaction for tyrosinase. Patients were examined for tumor recurrences during a follow-up period of 19 mo (median). Disease-free survival probabilities were calculated and independent prognostic factors were determined by multivariate analysis. Using histopathology, micrometastatic nodal involvement was detected in 15 patients (13%). Of the 101 patients with histopathologically negative sentinel lymph nodes, 36 were reclassified by positive tyrosinase reverse transcription-polymerase chain reaction and 65 patients were still negative by reverse transcription-polymerase chain reaction. Recurrences were observed in 23 (20%) of 116 patients. These tumor recurrences were demonstrated in 10 patients (67%) with histopathologically positive sentinel lymph nodes, in nine patients (25%) with submicroscopic tumor cells detected by reverse transcription-polymerase chain reaction, and in four patients (6%) negative by both methods. The differences in recurrence rates were statistically significant (p = 0.01). In a multivariate analysis, histopathologic and reverse transcription-polymerase chain reaction status of the sentinel lymph node were demonstrated to be the only significant prognostic factors for predicting disease-free survival.

Tyrosinase reverse transcription-polymerase chain reaction for the detection of minimal residual melanoma in sentinel lymph nodes is a powerful tool to determine patients who are at increased risk for subsequent metastasis. Moreover, a group of patients with high tumor thickness was identified by negative reverse transcription-polymerase chain reaction to be at low risk for recurrent disease. These data may have an impact on future tumor classifications of primary cutaneous melanoma.

Evaluation of sentinel lymph node status in spindle cell melanomas

J Am Acad Dermatol 2001;44:451-5

Retrospective database and medical record review from Oct 21, 1993 to Sept 29, 1999. At the University of California at San Francisco Melanoma Center, patients with tumor thickness greater than 1 mm or less than 1 mm with high-risk features are managed with preoperative lymphoscintigraphy, selective SLN dissection, and wide excision.

Results: Of 29 patients diagnosed with spindle cell melanoma and DMM, 28 had negative SLNs and are free of disease except for one patient who experienced splenic, bony, and brain metastases. The mean follow-up in this population was 16.5 and 11 months, respectively.

Conclusion: Our preliminary findings show that SLNs from patients diagnosed with spindle cell melanoma and DMM only rarely harbor micrometastasis despite their relative thickness. A larger number of cases from multicenter databases may further define the true biology of SLNs in this melanoma variant.

Sentinel lymph node micrometastasis and other histologic factors that predict outcome in patients with thicker melanomas

Basil S. Cherpelis, etal.

J Am Acad Dermatol 2001;44:762-6. Abstract quote

Background: In patients with melanoma, lymph node staging information is obtainable by the surgical techniques of lymphatic mapping and sentinel lymph node (SLN) biopsy. Although no survival benefit has been proven for the procedure, the staging information is useful in identifying patients who may benefit from further surgery or adjuvant therapy. Currently, however, it is not being recommended for patients with thick melanomas (>3-4 mm). The risk of hematogenous dissemination is considered too great in these patients. Recent studies indicate, however, that a surprising number of patients with thick melanomas become long-term survivors, and the lymph node status may be predictive. None of the conventional microscopic features used to gauge prognosis in patients with melanoma have proven helpful in distinguishing the survivors with thick melanoma from those who will die of their disease.

Objective: Our purpose was to evaluate the influence of SLN histology and other microscopic parameters on survival of patients with thick melanomas.

Methods: A computerized patient database at the Cutaneous Oncology Clinic at H. Lee Moffitt Cancer Center was accessed to obtain records on patients with melanomas thicker than 3.0 mm (AJCC T3b). A retrospective analysis was conducted with attention paid to histologic variables, sentinel node status, and survival. Survival curves were constructed with the Kaplan-Meier method, and a Cox-Mantel rank testing was used to establish statistical significance.

Results: Between 1991 and 1999, 201 patients were diagnosed with melanoma thicker than 3.0 mm, and 180 were alive at an average follow-up of 51 months. Of these, 166 were alive without disease. The mean overall and disease-free survival rates were 78% and 66%, respectively. There was a statistically significant difference in disease-free survival (3-year) between SLN-positive and SLN-negative patients (37% vs 73%, respectively; P = .02). The overall survival (3-year) for the SLN-positive patients was less than the node-negative patients (70% vs 82%), but it was not statistically significant (P = .08). The disease-free survival for patients with ulcerated lesions was less than for nonulcerated lesions (77% vs 93%, P = .05). None of the other histologic parameters studied, including Breslow thickness, Clark level, mitotic rate, or regression, had an influence on the overall or disease-free survival in this group of patients with thick tumors.

Conclusions: The results indicate that the SLN node status is predictive of disease-free survival for patients with thick melanomas. A surprising number of patients in the study were free of disease after prolonged follow-up. None of the histologic features of the primary tumor were helpful in predicting outcome, except for ulceration. SLN biopsy appears to be justified for prognostic purposes in patients with thick melanomas.

Sentinel Lymph Nodes Show Profound Downregulation of Antigen-Presenting Cells of the Paracortex: Implications for Tumor Biology and Treatment

Alistair J. Cochran, M.D., Donald L. Morton, M.D., Stacey Stern, Ph.D., Ana M.A. Lana, M.D., R. Essner, M.D. and Duan-Ren Wen, M.D.

Departments of Pathology and Laboratory Medicine and Surgery and Jonsson Comprehensive Cancer Center, University of California Los Angeles, School of Medicine, Los Angeles, California (AJC, D-RW); the John Wayne Cancer Institute, Saint John’s Hospital and Health Center, Santa Monica, California (DLM, SS, RE); and Departamento de Anatomia Pathológica, Faculdade de Medicina da Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil (AMAL)

Mod Pathol 2001;14:604-608 Abstract quote

The sentinel lymph node (SN) is the first node on the direct lymphatic drainage pathway from a tumor. Melanoma-associated SNs are the most likely site of early metastases and their immune functions are strikingly down-modulated.

We evaluated histologic and cytologic characteristics of 21 SNs and 21 nonsentinel nodes (NSNs) from melanoma patients who had clinically localized (AJCC Stage I–II) primary cutaneous melanoma.

SNs showed highly significant reductions in total paracortical area and in the area of the paracortical subsector occupied by dendritic cells. The frequency of paracortical interdigitating dendritic cells (IDCs) was dramatically reduced in SNs, and most IDCs (99%) lacked the complex dendrites associated with active antigen presentation.

The release of immunosuppressive factors from the primary melanoma may induce a localized and specific paralysis in the SN, which prevents the recognition of otherwise immunogenic melanoma antigens by IDCs. This immune paralysis may facilitate the implantation and growth of melanoma cells in the SN. Cytokine therapy may be able to reverse this immune paralysis. These findings have an important practical application in the histopathologic confirmation that a node is truly sentinel. They also offer an hypothesis to explain the failure of the immune surveillance mechanisms to identify and respond to a small primary melanoma that expresses immunogenic tumor antigens.

Developing Indications for the Use of Sentinel Lymph Node Biopsy and Adjuvant High-Dose Interferon Alfa-2b in Melanoma

Robert W. Dubois, MD, PhD; Susan M. Swetter, MD; Michael Atkins, MD; Kelly McMasters, MD; Ron Halbert, MD, MPH; Stanley J. Miller, MD; Ronald Shiell, MD; John Kirkwood, MD

Arch Dermatol. 2001;137:1217-1224 Abstract quote

To convene a multidisciplinary panel of dermatologists, surgical oncologists, and medical oncologists to formally review available data on the sentinel lymph node (SLN) biopsy procedure and high-dose adjuvant interferon alfa-2b therapy for patients with melanoma and to rate the "appropriateness," "inappropriateness," or "uncertainty" of the procedure and therapy to guide clinical decision making in practice.

The panel comprised 13 specialists (4 dermatologists, 4 oncologists, and 5 surgeons) from geographically diverse areas who practiced in community-based settings (n = 8) and academic institutions (n = 5). Participants were chosen based on recommendations from the relevant specialty organizations.

A formal literature review was conducted by investigators at Protocare Sciences Inc, Santa Monica, Calif, on the risks and benefits of performing an SLN biopsy in patients with stage I or II melanoma and adjuvant interferon alfa-2b therapy in patients with stage II or III disease. The MEDLINE database was searched from 1966 through July 2000, and supplemental information was obtained from various cancer societies and cancer research groups. Panel participants were queried on additional sources of relevant information. Unpublished, presented data were included in abstract form on 1 recently closed clinical trial.

Consensus Process
The RAND/UCLA Appropriateness Method was used to review and rate multiple clinical scenarios for the use of SLN biopsy and interferon alfa-2b therapy. The consensus method did not force agreement.

The panel rated 104 clinical scenarios and concluded that the SLN biopsy procedure was appropriate for primary melanomas deeper than 1.0 mm and for tumors 1 mm or less when histologic ulceration was present and/or classified as Clark level 4 or higher. The SLN biopsy was deemed inappropriate for nonulcerated Clark level 2 or 3 melanomas 0.75 mm or less in depth and uncertain in tumors 0.76 to 1.0 mm deep unless they were ulcerated or Clark level 4 or higher. Interferon alfa-2b therapy was deemed appropriate for patients with regional nodal and/or in-transit metastasis and for node-negative patients with primary melanomas deeper than 4 mm. The panel considered the use of interferon alfa-2b therapy uncertain in patients with ulcerated intermediate primary tumors (2.01-4.0 mm in depth) and inappropriate for node-negative patients with nonulcerated tumors less than 4.0 mm deep. Specialty-specific ratings were conducted as well.

Detection of micrometastasis in sentinel lymph nodes of patients with primary cutaneous melanoma.

Blaheta HJ, Schittek B, Breuninger H, Garbe C.

Department of Dermatology, Eberhard-Karls-University, Tubingen, Germany.

Recent Results Cancer Res 2001;158:137-46 Abstract quote

The technique of sentinel lymph node (SLN) biopsy has been demonstrated to be highly predictive for the detection of melanoma micrometastases in the regional lymph node basin. Therefore, the SLN was proposed to accurately reflect the lymph node status of patients with primary cutaneous melanoma. As the regional lymph node status is one of the most powerful predictors of survival in patients with primary melanoma, the histopathologic assessment is critically important for accurate staging. In approximately 20% (ranging from 9% to 42%) of patients with primary melanoma, the SLN was found to be tumor-positive by histopathology or immunohistochemistry. However, the true incidence of metastatic melanoma cells in (sentinel) lymph nodes is underestimated by histopathologic examination.

Recently, the method of reverse transcription-polymerase chain reaction (RT-PCR) for tyrosinase mRNA has been used as a molecular marker for the presence of melanoma cells. Tyrosinase RT-PCR was demonstrated to significantly increase the detection of melanoma cells in SLNs as compared to histopathology. All lymph nodes positive by histopathology were shown to express tyrosinase by RT-PCR.

Furthermore, tyrosinase transcripts were also detected in 36-52% of stage I and II melanoma patients with SLNs negative by histopathology. Importantly, the recurrence rate was significantly higher in patients with histologically negative SLNs who were found to be positive by RT-PCR than in patients with negative results by both techniques. These findings indicate that RT-PCR status of the SLN is more sensitive for detection of minimal melanoma disease than histopathology.

Therefore, the RT-PCR status of the SLN may be suitable to improve melanoma staging and may serve as a prognostic factor in patients with primary cutaneous melanoma.

Carbon dye histologically confirms the identity of sentinel lymph nodes in cutaneous melanoma.

Haigh PI, Lucci A, Turner RR, Bostick PJ, Krasne DL, Stern SL, Morton DL. Roy E.

Coats Research Laboratories, Division of Surgical Oncology, John Wayne Cancer Institute at Saint John's Health Center, 2200 Santa Monica Blvd., Santa Monica, CA 90404, USA.

Cancer 2001 Aug 1;92(3):535-41 Abstract quote

BACKGROUND: False-negative results from lymphatic mapping and sentinel lymphadenectomy (LM/SL) are associated with technical failures in nuclear medicine and surgery or with erroneous histologic evaluation. Any method that can confirm sentinel lymph node (SN) identity might decrease the false-negative rate. Carbon dye has been used as an adjunct to assist lymphadenectomy for some tumors, and the authors hypothesized that it could be used for the histologic verification of SNs removed during LM/SL. The current study assessed the clinical utility of carbon dye as a histopathologic adjunct for the identification of SNs in patients with melanoma and correlated the presence of carbon particles with the histopathologic status of the SNs.

METHODS: LM/SL was performed using carbon dye (India ink) combined with isosulfan blue dye and sulfur colloid. Blue-stained and/or radioactive lymph nodes (two times background) were defined as SNs. Lymph nodes were evaluated for the presence of carbon particles and melanoma cells. If an SN lacked carbon dye in the initial histologic sections, four additional levels were obtained with S-100 protein and HMB-45 immunohistochemistry. Completion lymph node dissection (CLND) was performed if any SN contained melanoma cells.

RESULTS: One hundred patients underwent successful LM/SL in 120 lymph node regions. Carbon particles were identified in 199 SNs from 111 lymph node regions of 96 patients. Sixteen patients had tumor-positive SNs, all of which contained carbon particles. The anatomic location of the carbon particles within these tumor-positive SNs was found to be correlated with the location of tumor cells in the SNs. The presence of carbon particles appeared to be correlated with blue-black staining (P = 0.0001) and with tumor foci (P = 0.028). All 35 non-SNs that were removed during LM/SL were tumor-negative, and only 2 contained carbon particles. Of the 272 non-SNs removed during CLND, 5 contained metastases; 3 of these 5 were the only non-SNs that had carbon particles. The use of carbon particles during LM/SL was found to be safe and nontoxic.

CONCLUSIONS: Carbon dye used in LM/SL for melanoma permits the histologic confirmation of SNs. Carbon particles facilitate histologic evaluation by directing the pathologist to the SNs most likely to contain tumor. The location of carbon particles within SNs may assist the pathologist in the detection of metastases, thereby decreasing the histopathologic false-negative rate of LM/SL and subsequently reducing the same-basin recurrence rate.

Elective Lymph Node Dissection in Patients With Melanoma: Systematic Review and Meta-analysis of Randomized Controlled Trials.

Lens MB, Dawes M, Goodacre T, Newton-Bishop JA.

Centre for Evidence-Based Medicine, University of Oxford Nuffield Department of Clinical Medicine, the Oxford Radcliffe National Health Service Trust, Oxford OX3 9DU, England.

Arch Surg 2002 Apr;137(4):458-61 Abstract quote

HYPOTHESIS: Elective lymph node dissection does not improve survival in patients with melanoma without clinically detectable lymph node metastases.

OBJECTIVE: To determine whether elective lymph node dissection in patients with melanoma without clinically detectable regional metastases decreases overall mortality.

DESIGN: Systematic review and meta-analysis of randomized controlled trials comparing elective lymph node dissection with delayed lymphadenectomy at the time of clinical recurrence.

SETTING: Randomized controlled trials available by February 2001.

SUBJECTS: The included trials comprised 1533 participants.

INTERVENTION: Elective lymph node dissection compared with delayed lymphadenectomy or no lymphadenectomy in patients with melanoma without clinically detectable regional metastases.

MAIN OUTCOME MEASURE: Overall mortality in treatment groups as compared with control groups at the end of a 5-year follow-up period.

RESULTS: Three randomized controlled trials met the inclusion criteria. The pooled odds ratio for overall mortality for the 3 trials was 0.86 (95% confidence interval, 0.68-1.09). Results are statistically nonsignificant, but they have potential clinical significance.

CONCLUSIONS: This systematic review of randomized controlled trials comparing elective lymph node dissection with surgery delayed until the time of clinical recurrence shows no significant overall survival benefit for patients undergoing elective lymph node dissection. Trials included in this review, however, contain significant bias. The question is not answered for all patients, and the results do not exclude the possibility that some subgroups may benefit from elective lymph node dissection. Further research is required.

Interval sentinel lymph nodes in melanoma.

McMasters KM, Chao C, Wong SL, Wrightson WR, Ross MI, Reintgen DS, Noyes RD, Cerrito PB, Edwards MJ; Sunbelt Melanoma Trial Group.

Division of Surgical Oncology, Department of Surgery, James Graham Brown Cancer Center, University of Louisvill, 529 S Jackson St, Louisville, KY 40202, USA.

Arch Surg 2002 May;137(5):543-7 Abstract quote

HYPOTHESIS: For patients with melanoma, interval or in-transit sentinel lymph nodes (SLNs) have the same risk for nodal metastasis as SLN in traditional (ie, cervical, axillary, and inguinal) nodal basins.

DESIGN: Prospective clinical trial.

SETTING: Multicenter study.

PATIENTS: Eligible patients were aged 18 to 70 years with melanomas of at least 1.0-mm Breslow thickness and nodes with clinically negative findings.

INTERVENTION: Sentinel lymph node biopsy was guided by preoperative lymphoscintigraphy to identify all SLNs.

MAIN OUTCOME MEASURES: We evaluated interval nodal sites, including epitrochlear, popliteal, and subcutaneous or intramuscular nodes outside of traditional basins, for the presence of metastases.

RESULTS: The SLNs were identified in 2332 nodal basins from 2000 patients. In 62 patients (3.1%), interval SLNs were identified. We found SLN metastases in 442 (19.5%) of 2270 conventional nodal basins and 13 (21.0%) of 62 interval sites. In 11 (84.6%) of the 13 cases in which we found an interval node that was positive for metastatic disease, it was the only site of nodal metastasis.

CONCLUSIONS: Although interval SLNs are identified infrequently, they contain metastatic disease at nearly the same frequency as SLNs in cervical, axillary, and inguinal nodal basins. Positive interval SLNs are likely to be the only site of nodal metastasis. Therefore, detailed preoperative lymphoscintigraphy and meticulous intraoperative search for interval nodes should be performed.

Intraoperative evaluation of sentinel lymph nodes for metastatic melanoma by imprint cytology.

Creager AJ, Shiver SA, Shen P, Geisinger KR, Levine EA.

Department of Pathology, Duke University Medical Center, Durham, North Carolina.


Cancer 2002 Jun 1;94(11):3016-22 Abstract quote

Sentinel lymph node (SLN) biopsy has revolutionized lymph node staging in patients with malignant melanoma. Intraoperative evaluation is a new addition to the SLN procedure that allows for a one-step regional lymph node dissection to be performed when the SLN biopsy findings are positive. To date, several studies have evaluated the use of intraoperative frozen sectioning to evaluate the SLN in patients with melanoma. The literature pertaining to the use of intraoperative imprint cytology (IIC) to evaluate the SLN in melanoma patients is scant and to the authors' knowledge studies published to date are relatively small. The purpose of the current study was to evaluate the utility of IIC in patients undergoing SLN for melanoma.

A total of 235 SLN biopsies from 93 patients with malignant melanoma and 3 patients with atypical Spitz nevi were examined by IIC after SLN biopsy using a double indicator technique. The SLNs were bisected and a pair of imprints were made from each half. One imprint from each half was stained with hematoxylin and eosin (H & E) whereas its counterpart was stained with Diff-Quik. Paraffin-embedded permanent sections were examined using multiple H & E stained sections from the SLNs in conjunction with immunohistochemical staining for S-100 and HMB-45 proteins.

A total of 235 SLNs were excised from 93 patients (2.5 SLNs per patient). On a per patient basis, metastases were identified in 21 patients (23%) on permanent section evaluation. Of these 21 patients, 8 were detected by IIC (sensitivity of 38%). The negative predictive value was 85%. No false-positive results were identified (specificity of 100%). The positive predictive value was 100%. The overall accuracy of the intraoperative evaluation was 86%. Patients found to have positive SLNs by IIC went on to undergo lymphadenectomy under the same anesthetic.

The sensitivity and specificity of IIC are similar to those of intraoperative frozen-section evaluation. Therefore, IIC appears to be a viable alternative to frozen sectioning when intraoperative evaluation is required. IIC evaluation of SLN makes a single surgical procedure possible for patients with malignant melanoma who are undergoing SLN.

Processing of sentinel lymph nodes for detection of metastatic melanoma.

Prieto VG, Clark SH.

Departments of Pathology and Dermatology, The University of Texas M. D. Anderson Cancer Center, Houston, TX.

Ann Diagn Pathol 2002 Aug;6(4):257-64 Abstract quote

Within the last years, evaluation of sentinel lymph nodes (SLN) has become the most popular method of early staging of several malignancies, including breast carcinoma and melanoma. Because SLN are reportedly the lymph nodes most likely to contain metastatic deposits, identification of such nodes allows pathologists to examine the tissue in a much more intense manner than with the usual lymphadenectomy specimens containing multiple lymph nodes. However, there is not a universally accepted standard protocol for pathologic processing of the SLN.

Initially, the most popular protocols called for bisection of the SLN and examination of serial sections, with or without routinely performed immunohistochemistry. Lately, other protocols have been proposed to try to simplify the histologic analysis while providing at least equivalent results.

Here we review the different protocols used for the evaluation of SLN and describe the protocol currently in use at M. D. Anderson Cancer Center (Houston, TX).


GENERAL J Clin Oncol 1996;14:410
Chang etal. Cancer Invest 1992;10:357.
Rosenberg SA JNCI 1994;86:1159-1166.

Interferon (IFN)-IFN alpha-2b

High dose regimens with lymphadenectomy yielded 10% survival advantage

Significant toxicity High cost ($30,000/yr)

Currently approved for stage III disease and melanoma>4mm with negative LNs

IL-2 combined with LAK cells
Overall response rate of 16% (3% CR 13% PR n=190)
IL-2 combined with TIL Tumor regression in 35%

A phase II study of interferon-alpha 2b with dacarbazine, carmustine, cisplatin and tamoxifen in metastatic melanoma.

Schultz MZ, Buzaid AC, Poo WJ.

Yale Comprehensive Cancer Center, New Haven, CT, USA.

Melanoma Res 1997 Apr;7(2):147-51 Abstract quote

A phase II trial was conducted to determine the efficacy and toxicity of the addition of interferon-alpha 2b (IFN-alpha) to the chemotherapy combination of dacarbazine (DTIC), carmustine (BCNU), cisplatin and tamoxifen (DBCT), in patients with stage III or IV melanoma.

Treatment consisted of DTIC 220 mg/m2 and cisplatin 25 mg/m2 intravenously on days 1-3, BCNU 100 mg/m2 IV on day 1 only, tamoxifen 20 mg orally twice daily and IFN-alpha 5 x 10(6) units/m2 subcutaneously on days 1-5. Cycles were repeated every 4 weeks. All patients received a loading dose of tamoxifen 100 mg orally twice daily for 5 days before the first course of therapy. Of the 24 patients treated, three (13%) achieved a complete response (CR) and six (25%) a partial response (PR), for an overall response rate of 38% (95% confidence interval, 17-58%). Two patients, one who achieved a clinical CR and one a PR, had pathologically confirmed complete responses. Severe myelosuppression occurred in 47% of cycles and constitutional symptoms were common.

Overall, the addition of IFN-alpha to the DBCT regimen did not appear to enhance the response rate and may have increased toxicity.

A phase II study of carboplatin, cisplatin, interferon-alpha, and tamoxifen for patients with metastatic melanoma.

Gause BL, Sharfman WH, Janik JE, Curti BD, Steis RG, Urba WJ, Smith JW 2nd, Alvord WG, Longo DL.

National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland, USA.

Cancer Invest 1998;16(6):374-80 Abstract quote

The purpose of this trial was to determine the toxicity and antineoplastic activity of cisplatin, carboplatin, tamoxifen, and interferon-alpha (IFN-alpha) in patients with advanced melanoma.

Eleven patients with metastatic melanoma were enrolled. The patients received carboplatin 400 mg/m2 i.v. on day 0; cisplatin 25 mg/m2 i.v. on days 7, 14, and 21; tamoxifen 20 mg p.o. b.i.d. on days 0-27; and interferon-alpha 5 million units/m2 subcutaneously 3 times per week. Cycles were repeated every 28 days. Patients were assessed for tumor response at the end of 2 cycles. Toxicity was severe, with 14 of 24 cycles given requiring some form of dose reduction. Carboplatin dose reductions were related to bone-marrow toxicity, whereas IFN-alpha caused fatigue, arthralgias, myalgias, and fever.

The overall response rate was 18% (2 partial responses [PRs]). The combination of cisplatin, carboplatin, tamoxifen, and IFN-alpha is active in advanced melanoma; however, the toxicity is unacceptable.

Randomized trial of treatment with cisplatin and interleukin-2 either alone or in combination with interferon-alpha-2a in patients with metastatic melanoma: a Federation Nationale des Centres de Lutte Contre le Cancer Multicenter, parallel study.

Dorval T, Negrier S, Chevreau C, Avril MF, Baume D, Cupissol D, Oskam R, de Peuter R, Vinke J, Herrera A, Escudier B.

French Cancer Centers' Immunotherapy Group, Institut Curie, Paris.

Cancer 1999 Mar 1;85(5):1060-6 Abstract quote

BACKGROUND: The objective of the current study was to evaluate the response rate, survival, and toxicity of treatment with cisplatin and high dose intravenous continuous infusion interleukin-2 (IL-2) with or without interferon-alpha-2a (IFN) in patients with metastatic melanoma.

METHODS: One hundred and seventeen patients with metastatic melanoma randomly were assigned to receive cisplatin, 100 mg/m2, followed after a 3-day rest period by IL-2, 18 x 10(6) IU/m2, on Days 3-6 and Days 17-21 (Arm 1) or cisplatin and IL-2 using an identical schedule plus subcutaneous IFN, 9 x 10(6) U, 3 times a week during IL-2 administration (Arm 2). In the absence of disease progression or undue toxicity, the cycle could be repeated on Day 29. Patients who responded after two cycles eventually could receive a third cycle. One hundred and one patients were evaluable for toxicity and efficacy.

RESULTS: On treatment Arm 1, 3 patients (6%) achieved a complete response (CR) and 5 patients (10%) achieved a partial response (PR) with a median response duration of 3.8 months for the CRs and 8.7 months for the PRs. On treatment Arm 2, 2 patients (3%) achieved a CR (durations of 5.9 and 33.1 months, respectively) and 11 patients (21%) a PR with a median response duration of 8.3 months. The median durations of overall survival were 10.4 months (range, 1.1-39.7+ months) and 10.9 months (range, 0.5-38.1+ months) for treatment Arms 1 and 2, respectively. The toxicity profile was consistent with the known side effects of this IL-2 intravenous regimen combined with cisplatin chemotherapy and IFN. Toxicity was more pronounced in treatment Arm 2 compared with treatment Arm 1. There were 2 and 4 patients, respectively, in treatment Arms 1 and 2 who died within 28 days after completion of treatment.

CONCLUSIONS: The observed overall response rates of 16% and 25% in treatment Arms 1 and 2, respectively, is lower than that expected with biochemotherapy; despite the fact that the objective of the trial was not to show any difference between the 2 treatment arms, our results indicate that the addition of IFN, at the dose and schedule used in this trial, fails to improve the activity of a cisplatin/IL-2 regimen significantly in patients with metastatic melanoma. Although response rates were relatively low, the median overall survival was nearly 1 year in both groups.

Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma.

Chapman PB, Einhorn LH, Meyers ML, Saxman S, Destro AN, Panageas KS, Begg CB, Agarwala SS, Schuchter LM, Ernstoff MS, Houghton AN, Kirkwood JM.

Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.

J Clin Oncol 1999 Sep;17(9):2745-51 Abstract quote

PURPOSE: Several single-institution phase II trials have reported that the Dartmouth regimen (dacarbazine, cisplatin, carmustine, and tamoxifen) can induce major tumor responses in 40% to 50% of stage IV melanoma patients. This study was designed to compare the overall survival time, rate of objective tumor response, and toxicity of the Dartmouth regimen with standard dacarbazine treatment in stage IV melanoma patients.

PATIENTS AND METHODS: In this multicenter phase III trial, 240 patients with measurable stage IV melanoma were randomized to receive the Dartmouth regimen (dacarbazine 220 mg/m(2) and cisplatin 25 mg/m(2) days 1 to 3, carmustine 150 mg/m(2) day 1 every other cycle, and tamoxifen 10 mg orally bid) or dacarbazine 1, 000 mg/m(2). Treatment was repeated every 3 weeks. Patients were observed for tumor response, survival time, and toxicity.

RESULTS: Median survival time from randomization was 7 months; 25% of the patients survived > or = 1 year.There was no difference in survival time between the two treatment arms when analyzed on an intent-to-treat basis or when only the 231 patients who were both eligible and had received treatment were considered. Tumor response was assessable in 226 patients. The response rate to dacarbazine was 10.2% compared with 18.5% for the Dartmouth regimen (P =.09). Bone marrow suppression, nausea/vomiting, and fatigue were significantly more common in the Dartmouth arm.

CONCLUSION: There was no difference in survival time and only a small, statistically nonsignificant increase in tumor response for stage IV melanoma patients treated with the Dartmouth regimen compared with dacarbazine. Dacarbazine remains the reference standard treatment for stage IV melanoma

Multi-institutional phase II randomized trial of integrated therapy with cisplatin, dacarbazine, vindesine, subcutaneous interleukin-2, interferon alpha2a and tamoxifen in metastatic melanoma. BREMIM (Biological Response Modifiers in Melanoma).

Sertoli MR, Queirolo P, Bajetta E, DelVecchio M, Comella G, Barduagni L, Bernengo MG, Vecchio S, Criscuolo D, Bufalino R, Morabito A, Cascinelli N.

Italian Cooperative Group, Istituto Nazionale Tumori, Milan.

Melanoma Res 1999 Oct;9(5):503-9 Abstract quote

The aim of this study was to evaluate the toxicity and efficacy of a monochemotherapy regimen of dacarbazine (DTIC), tamoxifen , interferon-alpha2a and interleukin-2 (IL-2) and two polychemotherapy regimens of cisplatin, DTIC, vindesine, tamoxifen, interferon-alpha2a with or without IL-2 in patients with metastatic melanoma.

Consecutive patients with metastatic melanoma were enrolled in this trial and were randomized to arm A, consisting of DTIC 800 mg/m2 every 21 days, IL-2 9 MIU subcutaneously days 1-5 and 8-12, arm B, consisting of cisplatin 30 mg/m2 days 1-3, DTIC 250 mg/m2 days 1-3 and vindesine 2.5 mg/m2 day 1 every 28 days (CVD), or arm C, consisting of CVD plus IL-2 6 MIU days 1-5 and 8-12 every 28 days. In all three arms Interferon 3 MU subcutaneously three times a week and tamoxifen 20 mg orally were given throughout. Ninety-two patients were included in this study. Patient characteristics in the three groups were well balanced. The three regimens were delivered on an outpatient basis without major toxicity. The toxicities that did occur consisted primarily of flu-like symptoms in the IL-2 arms (A and C) and haematological toxicities in the CVD arms (B and C). No grade IV toxicities were encountered and no treatment-related deaths occurred. The total response rate was 13% in arm A, 35% in arm B and 37% in arm C. The median duration of response was 6 months and the median survival was 11 months.

According to this phase II randomized trial polychemoimmunotherapy with CVD has an objective response rate of 35-36%, while monochemoimmunotherapy with DTIC has a response rate of 13%.

A randomized phase III study comparing dacarbazine, BCNU, cisplatin and tamoxifen with dacarbazine and interferon in advanced melanoma.

Middleton MR, Lorigan P, Owen J, Ashcroft L, Lee SM, Harper P, Thatcher N.

CRC Department of Medical Oncology, Christie Hospital NHS Trust, Manchester, UK.

Br J Cancer 2000 Mar;82(6):1158-62 Abstract quote

The purpose of this study was to compare the response rate, overall and 1-year survival in patients with advanced melanoma treated with a standard therapy, dacarbazine and interferon-alpha (DTIC/IFN), or combination chemotherapy, consisting of dacarbazine, BCNU, cisplatin and tamoxifen (DBCT).

Treatment toxicity and time spent in hospital were secondary end points. One hundred and five patients (of whom 100 were eligible) were randomized to receive either DTIC/IFN or DBCT. The trial was designed to detect a 25% absolute difference in response rate or in 1-year survival with 80% power. There was no significant difference in response rate: this was 17.3% with DTIC/IFN and 26.4% with DBCT. Median overall survival was similar at 199 and 202 days respectively. One-year survival rate favoured standard treatment (30.6 vs 22.6%), but did not differ significantly between arms. DBCT was associated with significantly greater haematological toxicity, and a greater need for time spent in hospital (5.75 days/treatment cycle vs 2.29 with dacarbazine and interferon).

DBCT combination therapy cannot be recommended as standard treatment for advanced melanoma. Dacarbazine remains the standard chemotherapy for this condition.

Cisplatin, dacarbazine, and fotemustine plus interferon alpha in patients with advanced malignant melanoma. A multicenter phase II study of the Italian Cooperative Oncology Group.

Daponte A, Ascierto PA, Gravina A, Melucci MT, Palmieri G, Comella P, Cellerino R, DeLena M, Marini G, Comella G;

Italian Cooperative Oncology Group. Division of Medical Oncology A, National Tumor Institute, Naples, Italy.

Cancer 2000 Dec 15;89(12):2630-6 Abstract quote

BACKGROUND: In a previous study, the authors tested the combination of fotemustine (FM) 100 mg/m(2) intravenously (i.v.) on Day 1, dacarbazine (DTIC) 250 mg/m(2) i.v. on Days 2-5, and interferon alpha (IFNalpha) 3 MIU intramuscularly three times per week in 43 patients with advanced melanoma. An overall response rate of 40% and a median survival of 40 weeks were obtained. To evaluate whether the addition of cisplatin (CDDP) to this regimen could improve these results, the authors conducted a preliminary Phase I study and concluded that CDDP 25 mg/m(2) i.v. for 2 days can be combined safely with DTIC, FM, and IFNalpha. Herein, the authors report the results of a Phase II trial with this regimen.

METHODS: From June 1996 to February 1999, 64 patients with metastatic melanoma who were not amenable to surgery were enrolled in this study. Sixty eligible patients (32 males and 28 females; median age, 53 years) were treated with a combination of FM 100 mg/m(2) i.v. on Day 1, DTIC 300 mg/m(2) i.v. on Days 2-4, and CDDP 25 mg/m(2) i.v. on Days 3 and 4 recycled every 3 weeks. IFN alpha2b was administered at a dose of 3 MIU intramuscularly 3 times per week until disease progression.

RESULTS: A total of 189 courses were administered, with a median number of 3 courses per patient (range, 1-8 courses per patient). Eleven complete responses and 12 partial responses were observed, for an overall response rate of 38.3% (95% exact confidence interval, 26.1-51.8%). The median survival was 36 weeks. Neutropenia and thrombocytopenia affected 85% of patients and 68% patients and was World Health Organization Grade 3-4 in 40% and 50%, respectively. The side effects attributable to IFN alpha2b were mild and manageable. The other side effects were moderate and well controlled by supportive therapy.

CONCLUSIONS: The schedule used in this study demonstrated significant activity in patients with advanced, untreated melanoma. The addition of CDDP in the management of the patients in this series seemed to increase significantly both the proportion of patients who achieved a complete response and the probability of long term survival compared with a previous series of patients who were treated by the authors. However, considering the currently available therapies, this regimen does not seem to offer a special advantage in the treatment of patients with this disease. New agents and new protocols are needed.

Cohort study of metastatic melanoma patients in the Dermatology Institute of Florence 1990/1997

. Moretti S, Carli P, Biggeri A, Volpi V, Pimpinelli N.

U.O. Dermatologia II, Ospedale Santa Maria Nuova, Firenze, Italy.

J Eur Acad Dermatol Venereol 2001 Jan;15(1):30-3 Abstract quote

BACKGROUND: Chemotherapy and immunotherapy are treatments currently employed in advanced melanoma, but responses obtained are poor, and metastatic melanoma patients with visceral localization rarely survive for more than 6 months. Thus, different therapeutic regimens are used in metastatic melanoma and no standardized therapy exists so far.

METHODS: We report a retrospective survival study involving 80 patients with metastatic melanoma who were treated either with chemotherapy [dacarbazine (DTIC) alone or DTIC in monotherapeutic or polychemotherapeutic regimen] or immunochemotherapy [interferon (IFN)-alpha at low doses added to chemotherapy]. Survival of patients was statistically evaluated in an actuarial curve taking into account as predictive variables sex, age, marital status, site of primary tumour, histological type, Clark level, sites of metastases, and the different therapeutic regimens (i.e. DTIC alone, DTIC plus IFN-alpha, or others, with or without IFN-alpha).

RESULTS: Site of primary melanoma, histological type, Clark level and therapy regimen appeared to exhibit a prognostic significance in survival; when a multivariate analysis was performed to obtain a mutual adjustment of survival values for each variable, only the therapeutic regimen was found to be significant as an independent prognostic variable. Patients treated with immunochemotherapy, i.e. DTIC plus IFN-alpha, showed a probability of dying of 0.41 (95% confidence interval 0.2-0.8) compared with patients treated with DTIC alone.

CONCLUSIONS: In our study immunochemotherapy, comprised of DTIC plus IFN-alpha at low doses, was associated with a significantly longer survival of patients, in comparison with chemotherapy comprised of only DTIC.

Phase II randomized study of dacarbazine, carmustine, cisplatin and tamoxifen versus dacarbazine alone in advanced melanoma patients.

Chiarion Sileni V, Nortilli R, Aversa SM, Paccagnella A, Medici M, Corti L, Favaretto AG, Cetto GL, Monfardini S.

Department of Medical Oncology, Padova Hospital, Azienda Ospedaliera, Italy.

Melanoma Res 2001 Apr;11(2):189-96 Abstract quote

This randomized phase II trial was performed to define the activity and toxicity of the combination of dacarbazine (DTIC), carmustine (BCNU), cisplatin (DDP) and tamoxifen (DBDT regimen) versus DTIC alone in patients with metastatic melanoma. Sixty patients with metastatic melanoma were randomly assigned to receive BCNU 150 mg/m2 intravenously (i.v.) on day 1, cisplatin 25 mg/m2 i.v. daily on days 1 to 3, DTIC 220 mg/m2 i.v. daily on days 1 to 3 and tamoxifen 160 mg orally daily for 7 days prior to chemotherapy (DBDT arm; arm A). Treatment cycles were repeated every 28 days, while BCNU was given every two cycles. The DTIC arm (arm B) patients received DTIC alone 1200 mg/m2 i.v. on day 1, repeated every 21 days. Patients were evaluated every two cycles; responding patients continued the treatment for a maximum of 12 cycles. The overall response rate was 26% in the DBDT arm and 5% in the DTIC arm. Complete responses were 2.5% for DBDT and 0% for DTIC. The median progression-free survival and the median survival were 4 and 9 months, respectively for DBDT, and 2 and 7 months for DTIC. DBDT was associated with significant haematological toxicity: 33% of the patients experienced a grade III or IV neutropenia and 28% a grade III or IV thrombocytopenia. In conclusion, the overall response rate obtained with DBDT was greater than that obtained with DTIC alone; however, this combination increases toxicity with limited impact on overall survival.

Dacarbazine and interferon alpha with or without interleukin 2 in metastatic melanoma: a randomized phase III multicentre trial of the Dermatologic Cooperative Oncology Group (DeCOG).

Hauschild A, Garbe C, Stolz W, Ellwanger U, Seiter S, Dummer R, Ugurel S, Sebastian G, Nashan D, Linse R, Achtelik W, Mohr P, Kaufmann R, Fey M, Ulrich J, Tilgen W.

Department of Dermatology, Christian-Albrechts-University, Kiel.

Br J Cancer 2001 Apr 20;84(8):1036-42 Abstract quote

In several phase II-trials encouraging tumour responses rates in advanced metastatic melanoma (stage IV; AJCC-classification) have been reported for the application of biochemotherapy containing interleukin 2.

This study was designed to compare the efficacy of therapy with dacarbazine (DTIC) and interferon alpha (IFN-alpha) only to that of therapy with DTIC and IFN-alpha with the addition of interleukin 2 (IL-2) in terms of the overall survival time and rate of objective remissions and to provide an elaborated toxicity profile for both types of therapy.

290 patients were randomized to receive either DTIC (850 mg/m(2)every 28 days) plus IFN-alpha2a/b (3 MIU/m(2), twice on day 1, once daily from days 2 to 5; 5 MIU/m(2)3 times a week from week 2 to 4) with or without IL-2 (4.5 MIU/m(2)for 3 hours i.v. on day 3; 9.0 MIU/m(2) i.v. day 3/4; 4.5 MIU/m(2) s.c. days 4 to 7). The treatment plan required at least 2 treatment cycles (8 weeks of therapy) for every patient. Of 290 randomized patients 281 were eligible for an intention-to-treat analysis. There was no difference in terms of survival time from treatment onset between the two arms (median 11.0 months each). In 273 patients treated according to protocol tumour response was assessable. The response rates did not differ between both arms (P = 0.87) with 18.0% objective responses (9.7% PR; 8.3% CR) for DTIC plus IFN-alpha as compared to 16.1% (8.8% PR; 7.3% CR) for DTIC, IFN-alpha and IL-2. Treatment cessation due to adverse reactions was significantly more common in patients receiving IL-2 (13.9%) than in patients receiving DTIC/IFN-alpha only (5.6%).

In conclusion, there was neither a difference in survival time nor in tumour response rates when IL-2, applied according to the combined intravenous and subcutaneous schedule used for this study, was added to DTIC and IFN-alpha. However, toxicity was increased in melanoma patients treated with IL-2. Further phase III trials with continuous infusion and higher dosages must be performed before any final conclusions can be drawn on the potential usefulness of IL-2 in biochemotherapy of advanced 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 thJ Clin Oncol 2002 Mar 1;20(5):1311-8 Related Articles, Books, LinkOut

Quality-of-Life--Adjusted Survival Analysis of High-Dose Adjuvant Interferon Alfa-2b for High-Risk Melanoma Patients Using Intergroup Clinical Trial Data.

Kilbridge KL, Cole BF, Kirkwood JM, Haluska FG, Atkins MA, Ruckdeschel JC, Sock DE, Nease RF Jr, Weeks JC.

University of Virginia, Charlottesville, VA.

PURPOSE: High-dose adjuvant interferon alfa-2b (IFNalpha2b) for high-risk melanoma is a 1-year regimen that improves relapse-free and overall survival but has significant toxicity. A quality-of-life--adjusted survival (QAS) analysis analysis of two cooperative group phase III trials, E1684 and E1690/S9111/C9190, was performed, incorporating patient values (utilities) for the toxicity of IFNalpha2b treatment and melanoma recurrence. PATIENTS AND METHODS: Quality-Adjusted Time Without Symptoms or Toxicity methodology was used with melanoma patient utilities and trial data to estimate the effect of IFNalpha2b on QAS. The increase or decrease in QAS that patients could expect from treatment was estimated based on their utilities. Eleven utility predictor questions were tested to identify patients with utilities that result in decreased QAS. RESULTS: Using E1684 data, IFNalpha2b would result in an increase in QAS for all sets of patient utilities. This benefit was significant (P <.05) for 16% of patients. Using E1690/S9111/C9190 data, 77% of patients would experience a benefit in QAS from IFNalpha2b and 23% would experience a decrease in QAS; neither of these effects was statistically significant. Using utility predictors and the E1690/S9111/C9190 analysis, a decision rule was formulated that helps identify patients in whom IFNalpha2b may detract from QAS. CONCLUSION: Most patients experienced improvement in QAS in both trials, but this benefit was statistically significant in only 16% of patients in E1684. Change in QAS depends more on the utility for IFNalpha2b toxicity than on the utility for melanoma recurrence. Cancer patients probably have higher utilities for IFNalpha2b toxicity than members of the general population and will tend to favor IFNalpha2b treatment as a result.

e 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.

Quality-of-Life--Adjusted Survival Analysis of High-Dose Adjuvant Interferon Alfa-2b for High-Risk Melanoma Patients Using Intergroup Clinical Trial Data.

Kilbridge KL, Cole BF, Kirkwood JM, Haluska FG, Atkins MA, Ruckdeschel JC, Sock DE, Nease RF Jr, Weeks JC.

University of Virginia, Charlottesville, VA.


J Clin Oncol 2002 Mar 1;20(5):1311-8 Abstract quote

PURPOSE: High-dose adjuvant interferon alfa-2b (IFNalpha2b) for high-risk melanoma is a 1-year regimen that improves relapse-free and overall survival but has significant toxicity. A quality-of-life--adjusted survival (QAS) analysis analysis of two cooperative group phase III trials, E1684 and E1690/S9111/C9190, was performed, incorporating patient values (utilities) for the toxicity of IFNalpha2b treatment and melanoma recurrence.

PATIENTS AND METHODS: Quality-Adjusted Time Without Symptoms or Toxicity methodology was used with melanoma patient utilities and trial data to estimate the effect of IFNalpha2b on QAS. The increase or decrease in QAS that patients could expect from treatment was estimated based on their utilities. Eleven utility predictor questions were tested to identify patients with utilities that result in decreased QAS.

RESULTS: Using E1684 data, IFNalpha2b would result in an increase in QAS for all sets of patient utilities. This benefit was significant (P <.05) for 16% of patients. Using E1690/S9111/C9190 data, 77% of patients would experience a benefit in QAS from IFNalpha2b and 23% would experience a decrease in QAS; neither of these effects was statistically significant. Using utility predictors and the E1690/S9111/C9190 analysis, a decision rule was formulated that helps identify patients in whom IFNalpha2b may detract from QAS.

CONCLUSION: Most patients experienced improvement in QAS in both trials, but this benefit was statistically significant in only 16% of patients in E1684. Change in QAS depends more on the utility for IFNalpha2b toxicity than on the utility for melanoma recurrence. Cancer patients probably have higher utilities for IFNalpha2b toxicity than members of the general population and will tend to favor IFNalpha2b treatment as a result.

Interferon alfa therapy for malignant melanoma: a systematic review of randomized controlled trials.

Lens MB, Dawes M.

Center for Evidence-Based Medicine, University of Oxford, Oxford, United Kingdom.

J Clin Oncol 2002 Apr 1;20(7):1818-25 Abstract quote

PURPOSE: No standard systemic adjuvant therapy has been proven to increase overall survival in melanoma patients. The effect of interferon alfa (IFNalpha) as a single agent or in combination has been widely explored in clinical trials. The purpose of this study was to assess the benefit of IFNalpha therapy in malignant melanoma.

METHODS: We performed a systematic review of randomized controlled trials comparing regimens with or without IFNalpha adjuvant therapy in melanoma patients. We assessed the effect of IFNalpha therapy on overall survival (OS), disease-free survival (DFS), melanoma recurrences, and toxicity. The quality of each trial was systematically evaluated.

RESULTS: Nine randomized controlled trials (RCTs) of IFNalpha therapy in melanoma patients were identified. Eight were published and one was unpublished. Eight trials comprising 3,178 patients fulfilled our inclusion criteria and were analyzed. Quality assessment scores ranged from 22 to 71, with a mean score of 55.4 (95% confidence interval, 53.8 to 57.0). For OS, only one trial reported a statistically significant benefit for IFNalpha, but our analysis did not confirm it. Two trials reported statistically significant benefit in DFS for the patients treated with IFNalpha, but our analysis confirmed it in only one trial. There was a wide clinical heterogeneity between included trials, making meta-analysis inappropriate.

CONCLUSION: In our review, results from included RCTs demonstrated no clear benefit of IFNalpha therapy on OS in melanoma patients. A large RCT is required to answer whether a full regimen of IFNalpha therapy is effective and to identify the subgroups of patients who might benefit from IFNalpha treatment.

Results from a randomized phase III study comparing combined treatment with histamine dihydrochloride plus interleukin-2 versus interleukin-2 alone in patients with metastatic melanoma.

Agarwala SS, Glaspy J, O'Day SJ, Mitchell M, Gutheil J, Whitman E, Gonzalez R, Hersh E, Feun L, Belt R, Meyskens F, Hellstrand K, Wood D, Kirkwood JM, Gehlsen KR, Naredi P.

Melanoma Center, University of Pittsburgh Cancer Institute, 200 Lothrop Street, Pittsburgh, PA 15213-2582, USA.

J Clin Oncol 2002 Jan 1;20(1):125-33 Abstract quote

PURPOSE: Reactive oxidative species (ROS) produced by phagocytic cells have been ascribed a role in the localized suppression of lymphocyte function within malignant tumors. Histamine has been shown to inhibit ROS formation and possibly synergize with cytokines to permit activation of natural killer cells and T cells. This study was designed to determine whether the addition of histamine to a subcutaneous (SC) regimen of interleukin-2 (IL-2) would improve the survival of metastatic melanoma patients.

PATIENTS AND METHODS: A phase III, multicenter, randomized, parallel group study comparing IL-2 plus histamine with IL-2 alone was conducted in 305 patients with advanced metastatic melanoma. Patients were randomized to IL-2 (9 MIU/m(2) bid SC on days 1 to 2 of weeks 1 and 3, and 2 MIU/m(2) bid SC on days 1 to 5 of weeks 2 and 4) with or without histamine (1.0 mg bid SC days 1 to 5, weeks 1 to 4). The primary end point, survival, was prospectively applied to all randomized patients (intent-to-treat-overall population, ITT-OA) and all patients having liver metastases at randomization (ITT-LM population). Secondary end points included safety of the combined treatment, time to disease progression, and response rate.

RESULTS: Combined treatment with histamine plus IL-2 significantly improved overall survival in the ITT-LM population (P =.004) and showed a trend for improved survival in the ITT population (P =.125). Grade 3 and 4 adverse events were comparable in the two arms.

CONCLUSION: Use of histamine as an adjunct to IL-2 is safe, well tolerated, and associated with a statistically significant prolongation of survival compared with IL-2 alone in metastatic melanoma patients with liver involvement. Further trials to confirm and understand the role of histamine in this combination treatment are underway.



Whole cell vaccine
Tumor lysate vaccine

Melanoma associated antigens (MAA):
MAGE 1 and 3
GAGE 1 and 2
Tyrosinase TRP-1

Potential Peptide Vaccines Antigens encoded by genes that are expressed in various tumors but silent in normal adults

Differentiating antigens encoded by genes in melanoma and normal melanocytes

These MAA are HLA restricted so typing must be performed before enrollment in vaccine protocols

Vaccination with irradiated autologous melanoma cells engineered to secrete human granulocyte-macrophage colony-stimulating factor generates potent antitumor immunity in patients with metastatic melanoma.

Soiffer R, Lynch T, Mihm M, Jung K, Rhuda C, Schmollinger JC, Hodi FS, Liebster L, Lam P, Mentzer S, Singer S, Tanabe KK, Cosimi AB, Duda R, Sober A, Bhan A, Daley J, Neuberg D, Parry G, Rokovich J, Richards L, Drayer J, Berns A, Clift S, Dranoff G, et al.

Department of Adult Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.

Proc Natl Acad Sci U S A 1998 Oct 27;95(22):13141-6 Abstract quote

We conducted a Phase I clinical trial investigating the biologic activity of vaccination with irradiated autologous melanoma cells engineered to secrete human granulocyte-macrophage colony-stimulating factor in patients with metastatic melanoma.

Immunization sites were intensely infiltrated with T lymphocytes, dendritic cells, macrophages, and eosinophils in all 21 evaluable patients. Although metastatic lesions resected before vaccination were minimally infiltrated with cells of the immune system in all patients, metastatic lesions resected after vaccination were densely infiltrated with T lymphocytes and plasma cells and showed extensive tumor destruction (at least 80%), fibrosis, and edema in 11 of 16 patients examined. Antimelanoma cytotoxic T cell and antibody responses were associated with tumor destruction.

These results demonstrate that vaccination with irradiated autologous melanoma cells engineered to secrete granulocyte-macrophage colony-stimulating factor stimulates potent antitumor immunity in humans with metastatic melanoma.

Immunizing patients with metastatic melanoma using recombinant adenoviruses encoding MART-1 or gp100 melanoma antigens.

Rosenberg SA, Zhai Y, Yang JC, Schwartzentruber DJ, Hwu P, Marincola FM, Topalian SL, Restifo NP, Seipp CA, Einhorn JH, Roberts B, White DE.

Surgery Branch, National Cancer Institute, Bethesda, MD, USA.

J Natl Cancer Inst 1998 Dec 16;90(24):1894-900 Abstract quote

BACKGROUND: The characterization of the genes encoding melanoma-associated antigens MART-1 or gp100, recognized by T cells, has opened new possibilities for the development of immunization strategies for patients with metastatic melanoma. With the use of recombinant adenoviruses expressing either MART-1 or gp100 to immunize patients with metastatic melanoma, we evaluated the safety, immunologic, and potential therapeutic aspects of these immunizations.

METHODS: In phase I studies, 54 patients received escalating doses (between 10(7) and 10(11) plaque-forming units) of recombinant adenovirus encoding either MART-1 or gp100 melanoma antigen administered either alone or followed by the administration of interleukin 2 (IL-2). The immunologic impact of these immunizations on the development of cellular and antibody reactivity was assayed.

RESULTS: Recombinant adenoviruses expressing MART-1 or gp100 were safely administered. One of 16 patients with metastatic melanoma receiving the recombinant adenovirus MART-1 alone experienced a complete response. Other patients achieved objective responses, but they had received IL-2 along with an adenovirus, and their responses could be attributed to the cytokine. Immunologic assays showed no consistent immunization to the MART-1 or gp100 transgenes expressed by the recombinant adenoviruses. High levels of neutralizing antibody were found in the pretreatment sera of the patients.

CONCLUSIONS: High doses of recombinant adenoviruses could be safely administered to cancer patients. High levels of neutralizing antibody present in patients' sera prior to treatment may have impaired the ability of these viruses to immunize patients against melanoma antigens.

Development of a polynucleotide vaccine from melanoma antigen recognized by T cells-1 and recombinant protein from melanoma antigen recognized by T cells-1 for melanoma vaccine clinical trials.

Lee SW, Li H, Strong TV, Moore SE, Conry RM.

Department of Medicine, University of Alabama at Birmingham 35294-3300, USA

J Immunother 2000 May-Jun;23(3):379-86 Abstract quote

MART-1, a melanoma antigen recognized by T cells-1, is a melanocyte lineage-differentiation antigen expressed only in melanocytes and melanoma cells. This protein is recognized by many T-lymphocyte lines that are human leukocyte antigen (HLA)-A2 restricted and melanoma reactive. These observations have culminated in an array of clinical trials of MART-1 immunization using recombinant viruses or MART-1 immunodominant peptides. Polynucleotide immunization is a promising alternative to recombinant viral vaccines that allows delivery of the full-length cDNA encoding all potential peptide epitopes in a vector that is uncompromised by anti-viral immunity.

In preparation for a phase I clinical trial of MART-1 polynucleotide immunization in patients with resected melanoma who were at significant risk for recurrence, the authors constructed a plasmid DNA encoding the MART-1 cDNA under transcriptional regulatory control of the cytomegalovirus immediate early promoter-enhancer and partially deleted intron A. This plasmid directs high-level MART-1 expression in transduced myoblasts and maturing myocytes diffusely throughout the cytoplasm. Immunization of mice with this construct by intramuscular injection elicited MART-1-specific immune responses in all animals. Previous trials of MART-1 immunization have been unable to examine the humoral immune response to MART-1 because of a lack of sufficient, highly purified protein.

We have produced and purified Escherichia coli recombinant MART-1 protein using a glutathione-S-transferase fusion protein expression system. Protein staining of a sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed a band of MART-1 protein at approximately 20 kD; and Western immunoblotting with an anti-MART-1 monoclonal antibody confirmed a doublet at approximately 20 kD. These findings are consistent with previous reports using different expression systems for recombinant MART-1. This protein preparation functioned well in enzyme-linked immunosorbent assays (ELISAs) to detect anti-MART-1 antibody responses in a mouse model; and a panel of healthy donor human sera showed minimal binding to ELISA plates coated with the protein, supporting its utility in monitoring human anti-MART-1 antibody responses. The glutathione-S-transferase fusion method yielded approximately 200 micrograms MART-1 per 2-L bacterial culture, enough to coat 100 ELISA plates.

Phase 1 clinical trial of irradiated autologous melanoma cells adenovirally transduced with human GM-CSF gene.

Kusumoto M, Umeda S, Ikubo A, Aoki Y, Tawfik O, Oben R, Williamson S, Jewell W, Suzuki T.

Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City 66160, USA.

Cancer Immunol Immunother 2001 Sep;50(7):373-81 Abstract quote

The objective of this study was to determine the safety and antitumor activity of an autologous GM-CSF-secreting melanoma cell vaccine that was engineered ex vivo with recombinant replication-incompetent adenovirus harboring a human GM-CSF gene (Adv/hGM-CSF).

Melanoma samples were surgically obtained from 30 patients (15 female and 15 male, ages ranging from 23 to 87) and were processed for vaccine preparation. Due to stringent eligibility criteria, 9 out of 30 patients were enrolled in the phase 1 clinical trial (FDA IND7677). Melanoma cell lines established from surgical specimens of 9 patients were transduced with Adv/hGM-CSF (MOI of 100) and subsequently irradiated at 35 Gy. These cell lines secreted human GM-CSF in vitro at an average rate of 80-424 ng/10(6) cells/24 h. All patients were intradermally and subcutaneously injected at several sites with irradiated autologous melanoma cells (2x10(6)-1x10(7) in 300 microl saline), 2-10 times, at intervals of 4-8 weeks. None of the patients vaccinated showed any serious adverse systemic response. Three patients (nos.1, 6 and 7) demonstrated local reaction (erythema) to the vaccination. Tumor-specific CTL assays performed in the absence of K562 cells showed that the levels of CTLs in peripheral blood of 5 patients increased following vaccination, whereas those in one patient declined. Levels of CTLs assayed in the presence of K562 cells were considerably lower than those assayed in the absence of K562 cells, but were also found to increase following vaccination in the peripheral blood of 6 patients. A patient who had been vaccinated 10 times (patient 1) responded to the vaccination by apparent reduction in size of metastatic tumor in the lung. Immunohistochemical examination of the vaccination sites of patient 1, biopsied after the 3rd and 4th vaccination. showed that the vaccination sites responded with infiltration of inflammatory cells, such as T cells (CD3+, CD8+), macrophages and dendritic cells (CD83+), for a period up to about 8 days.

These data suggest that repeated vaccinations with irradiated autologous GM-CSF-producing tumor cells were well tolerated by patients and led to the activation of an antitumor immune response in some patients.

Hypopigmentation Associated With an Adenovirus-Mediated gp100/MART-1-Transduced Dendritic Cell Vaccine for Metastatic Melanoma.

Tsao H, Millman P, Linette GP, Hodi FS, Sober AJ, Goldberg MA, Haluska FG.

Department of Dermatology, Bartlett 622, 48 Blossom St, Massachusetts General Hospital, Boston, MA 02114.

Arch Dermatol 2002 Jun;138(6):799-802 Abstract quote

BACKGROUND: Reports of vitiligo associated with metastases and rare cases of spontaneous regression of disease have fueled enthusiasm for immunologic approaches to the treatment of advanced melanoma. More recent strategies have focused on using antigen-presenting dendritic cells as vaccines.

OBSERVATIONS: We observed 3 cases of leukoderma associated with a novel adenovirus-mediated gp100/MART-1-transduced dendritic cell (MART indicates melanoma antigen recognized by T cells). All 3 patients had advanced metastatic melanoma. Despite the development of this leukodermic response, all patients experienced disease progression while under treatment.

CONCLUSION: We provide the initial evidence for effective induction of a leukodermic response with a gp100/MART-1-transduced dendritic cell vaccine.

Weedon D. Weedon's Skin Pathology. Churchill Livingstone. 1997.
Fitzpatrick's Dermatology in General Medicine. 5th Edition. McGraw-Hill. 1999.

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