The Center for Melanoma reflects efforts by physicians and researchers from the Departments of Dermatology, Division of Surgical Oncology (Surgery), Division of Transplant Surgery, Division of Hematology and Oncology (Medicine), and Division of Dermatopathology (Pathology). These specialists come together in the Pigmented Lesion Center (PLC), which provides care for patients who have been diagnosed with cutaneous melanoma and individuals with an elevated risk of developing melanoma.

The Pigmented Lesion Center
The PLC is the oldest continuously operating multidisciplinary melanoma group in the country and one of the first in the world. Established in 1966 by Dr. Thomas B. Fitzpatrick (Dermatology), Dr. John Raker (Surgery), Dr. Wallace Clark, and Dr. Martin C. Mihm (Pathology), the PLC was created to advance understanding of cutaneous melanoma, a relatively rare cancer at that time. Over the ensuing four decades, the incidence of cutaneous melanoma has risen dramatically, and the PLC has become the major center for melanoma patient care in the New England area and a leader in all aspects of melanoma investigation. Given its rich history, the PLC is recognized internationally, sharing a seat on the World Health Organization Melanoma Programme.

As a care center, the PLC evaluates more than 200 new melanoma patients per year and attends to more than 3,000 visits. Additional patients are also treated and managed in the medical and surgical oncology units as well as within surgery. As a teaching site, the PLC trains dermatology residents from Harvard Medical School and other rotating residents and students, postgraduate dermatopathology fellows, and fully trained physicians from around the world interested in melanocytic tumors. As a research unit, investigators from the PLC were among the first to describe the different cutaneous melanoma subtypes, the association between sun exposure and cutaneous melanoma, the various factors that predict outcome from histological markers such as tumor-infiltrating lymphocytes to molecular markers such as melastatin, and the use of sentinel lymph node biopsies in the staging of melanoma patients.

The PLC is currently staffed by dermatologists (Drs. Arthur Sober, Hensin Tsao, and Martin C. Mihm), a rotating surgical oncologist (Drs. Kenneth Tanabe, A. Ben Cosimi, and Michele Gadd), a medical oncologist (Dr. Frank Haluska) and a genetic counselor (Kristin Niendorf). Second pathology opinions are rendered in rotation by a dermatopathologist (Drs. Martin C. Mihm, Thomas Flotte, Lyn Duncan, and Vincent Liu). Although members have research interests, they all contribute to the flow of patient care and the establishment of melanoma care guidelines within MGH. Some recent and ongoing research efforts within the Massachusetts General Hospital melanoma community include:

Programs for advanced melanoma
Research of treatments for advanced stages of melanoma is carried out in the divisions of Surgical Oncology and Hematology/Oncology and the department of Radiation Oncology in the Cancer Center. Surgery is the mainstay of melanoma therapy. Clinical trials designed to improve our ability to predict melanoma outcomes by examining pathology markers in patients undergoing lymph node biopsies are ongoing. Techniques to improve surgical therapy of metastases are also being studied, such as arterial perfusion of the liver with chemotherapy to treat isolated hepatic melanoma metastases.

Investigations of radiation techniques are also in place. Drs. Arnab Chakravarti, John Munzenrider, and Thomas Delaney take special interest in melanoma patients. The use of boron as a radiation sensitizer, and the addition of anti-angiogenesis agents to radiation for the treatment of brain tumors, are both cutting-edge techniques being studied. Metastasis of melanoma to the central nervous system is a special problem with this disease. Drs. Tracy Batchelor and Fred Hochberg of Neurology care for this group of patients. The availability of the Northeast Proton Therapy Center for the treatment of these patients ensures that they have access to the most innovative therapies.

Finally, the medical treatment of patients with metastatic melanoma is undergoing rapid evolution due to advances in the field. Immunologic approaches to therapy constitute one major focus of our research program. Studies of cellular therapies for advanced disease, vaccine approaches, and gene therapy studies have all been investigated at the hospital. Recent advances in our understanding of the genetic causes of melanoma have led to a renewed enthusiasm in the second major research focus-therapies targeted at specific genetic lesions in melanoma. The use of small molecules to treat advanced melanoma holds great promise for the future of this field.

Other areas of investigation include:

• Second cancers among survivors of cutaneous melanoma
• The effectiveness of sibling education on risk reduction
• The utility of chest radiographs on outcome
• The molecular basis for hereditary melanoma along with its attendant genetic testing issues
• Genetic pathways that are altered during melanoma pathogenesis
• The creation of an integrated database of clinical and pathological information on patients seen at MGH since 1970 in order to delineate patient characteristics and determine the effects of tumor thickness, nodal status, and size of nodal deposit on melanoma survival
• The role of sentinel node biopsy in the management of melanoma
• Molecular and histologic evaluation of sentinel lymph nodes
• Development of genetically engineered vaccines for melanoma
• Novel vascular markers in predicting metastatic behavior
• The histogenic mechanism of tumor rejection in a GM-CSF based vaccine strategy
• The role of tumor-infiltrating lymphocytes in the prognosis of melanoma
• Microarray analysis of benign and malignant melanocytic tumors
• The role of melastatin in predicting outcome
• Establishing novel immune-based strategies for the treatment of metastatic melanoma
• Immunological monitoring of patients undergoing immune based therapies

Selected Clinical Research Protocols

Allelic variants associated with the dysplastic melanocytic nevus phenotype

A randomized phase II trial of immunization with peptide-pulsed DCs vs. DC/tumor fusions for patients with advanced melanoma

A phase II study of vaccination with autologous, lethally irradiated melanoma cells engineered by adenoviral mediated gene transfer to secrete human granulocyte-macrophage stimulating factor

Prospective study of melastatin expression in predicting the risk for developing local regional metastases of primary melanoma

Phase III trial of high-dose interferon alfa-2b versus cisplatin, vinblastine, DTIC plus Il-2 and interferon in patients with high risk melanoma-CALGB 500002

Faculty
Arthur J. Sober, MD
Director

A.B. Cosimi, MD
Lyn Duncan, MD
Thomas Flotte, MD
Michele Gadd, MD
Frank G. Haluska, MD, PhD
James Michaelson, PhD
Martin C. Mihm, MD
Kenneth K. Tanabe, MD
Hensin Tsao, MD, PhD

Selected Publications
Goggins WB, Tsao H. A population-based analysis of risk factors for a second primary cutaneous melanoma among melanoma survivors. Cancer 2003; 97:639-43.

Geller AC, Emmons K, Brooks DR, Zhang Z, Powers C, Koh HK, Sober AJ, Miller DR, Li F, Haluska F, Gilchrest BA. Skin cancer prevention and detection practices among siblings of patients with melanoma. J Am Acad Dermatol 2003; 49:631-8.

Soiffer R, Hodi FS, Haluska F, Jung K, Gillessen S, Singer S, Tanabe K, Duda R, Mentzer S, Jaklitsch M, Bueno R, Clift S, Hardy S, Neuberg D, Mulligan R, Webb I, Mihm M, Dranoff G. Vaccination with irradiated, autologous melanoma cells engineered to secrete granulocyte-macrophage colony stimulating factor by adenoviral-mediated gene transfer augments antitumor immunity in patients with metastatic melanoma. J Clin Oncol 2003; 21:3343-50.

Dadras SS, Paul T, Bertoncini J, Brown LF, Muzikansky A, Jackson DG, Ellwanger U, Garbe C, Mihm MC, Detmar M. Tumor lymphangiogenesis: A novel prognostic indicator for cutaneous melanoma metastasis and survival. Am J Pathol 2003; 162:1951-60.

Tsao H, Millman P, Linette GP, Hodi FS, Sober AJ, Goldberg MA, Haluska FG. Hypopigmentation associated with an adenovirusmediated gp100/MART-1-transduced dendritic cell vaccine for metastatic melanoma. Arch Dermatol 2002; 138:799-802.

Yang S, Linette GP, Longerich S, Haluska FG. Antimelanoma activity of CTL generated from peripheral blood mononuclear cells after stimulation with autologous dendritic cells pulsed with melanoma gp100 peptide G209-2M is correlated to TCR avidity. J Immunol 2002; 169:531-9.

Duncan LM, Deeds J, Cronin FE, Donovan M, Sober AJ, Kauffman M, McCarthy JJ. Melastatin expression and prognosis in cutaneous malignant melanoma. J Clin Oncol 2001; 19(2):568-76.

Greenberg DB, Jonasch E, Gadd MA, Ryan BF, Sober AJ, Mihm MC, Tanabe KK, Ott M, Haluska F. Adjuvant therapy of melanoma with interferon alfa-2b is associated with mania and bipolar syndromes; gabapentin may serve as mood stabilizer. Cancer 2000; 89:356-362.

Tsao H, Zhang X, Kwitkiwski K, Finkelstein DM, Sober AJ, Haluska FG. Low prevalence of germline CDKN2A and CDK4 mutations in patients with early onset melanoma. Arch Dermatol 2000; 136: 1118-1122.

Yu LL, Flotte TJ, Tanabe KK, Gadd MA, Cosimi AB, Sober AJ, Mihm MC Jr, Duncan LM. Detection of microscopic melanoma metastases in sentinel lymph nodes. Cancer 1999; 86:617-27.