16
MELANOMA MELANOMA
MELANOMA MELANOMA
CURRENT CLINlCAL ONCOLOGY
Maurie Markman, MD, SERIES EDITOR
Melanoma: Biologically Targeted Therapeutics, edited by ERNEST C. BORDEN, 2002
Breast Cancer: A Guide to Detection and Multidisciplinary Therapy, edited by MICHAEL H. TOROSIAN, 2002
Colorectal Cancer: Multimodality Management, edited by LEONARD B. SAL1Z,2002
Chronic Leukemias and Lymphomas: Clinical Management, edited by GARY J. SCHIUER, 2003
Cancer of the Lung: From Molecular Biology to Treatment Guidelines, edited by ALAN B. WEITBERG, 2002
Renal Cell Carcinoma: Molecular Biology, Immunology, and Clinical Management, edited by RONALD M. BUKOWSKI AND ANDREW NOVICK, 2000
Current Controversies in Bone Marrow Transplantation, edited by BRIAN J. BOLWELL, 2000
Regional Chemotherapy: Clinical Research and Practice, edited by MAURIE MARKMAN, 2000
Intraoperative Irradiation: Techniques and Results, edited by L. L. GUNDERSON, C. G. WILLETT, L. B. HARRIsON, AND F. A. CALVO, 1999
CURRENT CLINlCAL ONCOLOGY
Maurie Markman, MD, SERIES EDITOR
Melanoma: Biologically Targeted Therapeutics, edited by ERNEST C. BORDEN, 2002
Breast Cancer: A Guide to Detection and Multidisciplinary Therapy, edited by MICHAEL H. TOROSIAN, 2002
Colorectal Cancer: Multimodality Management, edited by LEONARD B. SAL1Z,2002
Chronic Leukemias and Lymphomas: Clinical Management, edited by GARY J. SCHIUER, 2003
Cancer of the Lung: From Molecular Biology to Treatment Guidelines, edited by ALAN B. WEITBERG, 2002
Renal Cell Carcinoma: Molecular Biology, Immunology, and Clinical Management, edited by RONALD M. BUKOWSKI AND ANDREW NOVICK, 2000
Current Controversies in Bone Marrow Transplantation, edited by BRIAN J. BOLWELL, 2000
Regional Chemotherapy: Clinical Research and Practice, edited by MAURIE MARKMAN, 2000
Intraoperative Irradiation: Techniques and Results, edited by L. L. GUNDERSON, C. G. WILLETT, L. B. HARRISON, AND F. A. CALVO, 1999
MELANOMA BIOLOGlCALLY T ARGETED THERAPEUflCS
Edited by
ERNEST C. BORDEN, MD
Center for Cancer Drug Discovery and Development Taussig Cancer Center The Clevekmd Clinic Foundation Cleveland, OH
SPRINGER SCIENCE+BUSINESS MEDIA, LLC 1l0TOVVA, ~EVVJERSEY
MELANOMA BIOLOGlCALLY T ARGETED THERAPEUflCS
Edited by
ERNEST C. BORDEN, MD
Center for Cancer Drug Discovery and Development Taussig Cancer Center The Clevekmd Clinic Foundation Cleveland, OH
SPRINGER SCIENCE+BUSINESS MEDIA, LLC 1l0TOVVA, ~EVVJERSEY
© 2002 Springer Science+Business Media New York 2002 Originally published by Humana Press lnc. 2002 Softcover reprint of the hardcover 1 st edition 2002
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Library of Congress Cataloging-in-Publication Data
Melanoma : biologically targeted therapeutics / edited by Ernest C. Borden p. ; cm. -- (Current clinical oncology)
Includes bibliographical references and index. ISBN 978-1-4684-9668-0 ISBN 978-1-59259-159-6 (eBook)
DOI 10.1007/978-1-59259-159-6 1. Melanoma--Immunotherapy. 2. Biological products--Therapeutic use. 3. Proteins--Therapeutic
use. 1. Borden, Ernest. II. Current clinical oncology (Totowa, N.J.) [DNLM: 1. Melanoma--therapy. 2. Biological Therapy. 3. Gene Therapy. QZ 200 M51785 2002] RC280.M37 M446 2002 616.99'47706--dc21
2001039468
INTRODUCTION
Strategies of treatment involving therapeutic proteins, immune cells, or cellular protein targets are those of greatest potential for further reducing mortality from melanoma. Therapeutic proteins or cells may inhibit melanoma cell growth either by augmentation of immune cell function or by inhibition of angiogenesis. Cytokines and melanoma antigens may be used either in vivo as a vaccine to stimulate immune cell function or ex vivo to stimulate or proliferate cells for infusion. Alternatively, alteration in melanoma cell growth can occur through inhibition of protein signal transduction pathways within melanoma cells or in the endothelial cells constituting the necessary angiogenic support for tumor growth. The great promise of these therapies and their cellular targets constitutes the basis for Melanoma: Biologically Targeted Therapeutics.
THE CLINlCAL PROBLEM
More than four million people will be diagnosed with melanoma in the first decade of the 21st century. Half of those who will die will be individuals who would otherwise have had a life expectancy of another 25 years or more. These individuals will die of systernic metastases, which are present at the time of primary surgery. Despite use of sunscreens, incidence continues to increase in developed countries worldwide. To reduce mortality, there must continue to be a focus on prevention and earlier detection through public education. Early interventions are always preferable to treatment of disseminated metastatic disease. Too frequently, patients at highest risk-those with a prior melanoma andlor a family his tory-are not counseled by their healthcare providers regarding sun exposure and skin protection. Cure is directly related to the microscopic thickness of the primary lesion. Thus, for early detection and excision of thin lesions, public and professional education should continue to be emphasized. The many excellent public and professional education materials, illustrated with dear color photographs, available through the American Cancer Society, the U.S. National Cancer Institute, other national health agencies, and dermatologic organizations should be more widely used.
Once melanoma is detected, precise staging and appropriate surgery are essential (Chapters 2 and 3). Surgery remains essentially the only curative treatment at this time. The surgical research community has contributed very substantially over the past two decades to reducing both morbidity and mortality, once melanoma is diagnosed (1-3). Initial diagnosis remains excisional biopsy. Adequate (1-2 cm) free margins must be established by re-excision. Effectiveness of lirnited, potentially curative excision has been established over the past two decades by large international multi-institutional studies (4-5). This has reduced morbidity associated with the wider, deeper excisions of 25 or more years
v
INTRODUCTION
Strategies of treatment involving therapeutic proteins, irnrnune cells, or cellular protein targets are those of greatest potential for further reducing mortality from melanoma. Therapeutic proteins or cells may inhibit melanoma cell growth either by augmentation of immune cell function or by inhibition of angiogenesis. Cytokines and melanoma antigens may be used either in vivo as a vaccine to stimulate irnrnune cell function or ex vivo to stimulate or proliferate cells for infusion. Alternatively, alteration in melanoma cell growth can occur through inhibition of protein signal transduction pathways within melanoma cells or in the endothelial cells constituting the necessary angiogenic support for tumor growth. The great promise of these therapies and their cellular targets constitutes the basis for Melanoma: Biologically Targeted Therapeutics.
THE CLINlCAL PROBLEM
More than four million people will be diagnosed with melanoma in the first decade of the 21st century. Half of those who will die will be individuals who would otherwise have had a life expectancy of another 25 years or more. These individuals will die of systemic metastases, which are present at the time of primary surgery. Despite use of sunscreens, incidence continues to increase in developed countries worldwide. To reduce mortality, there must continue to be a focus on prevention and earlier detection through public education. Early interventions are always preferable to treatment of disseminated metastatic disease. Too frequent1y, patients at highest risk-those with a prior melanoma and/or a family history-are not counseled by their healthcare providers regarding sun exposure and skin protection. Cure is directly related to the microscopic thickness of the primary lesion. Thus, for early detection and excision of thin lesions, public and professional education should continue to be emphasized. The many excellent public and professional education materials, illustrated with c1ear color photographs, available through the American Cancer Society, the U.S. National Cancer Institute, other national health agencies, and dermatologie organizations should be more widely used.
Once melanoma is detected, precise staging and appropriate surgery are essential (Chapters 2 and 3). Surgery remains essentially the only curative treatment at this time. The surgical research cornrnunity has contributed very substantially over the past two decades to reducing both morbidity and mortality, once melanoma is diagnosed (1-3). Initial diagnosis remains excisional biopsy. Adequate (1-2 cm) free margins must be established by re-excision. Effectiveness of limited, potentially curative excision has been established over the past two decades by large international multi-institutional studies (4-5). This has reduced morbidity associated with the wider, deeper excisions of 25 or more years
v
vi Introdnction
previous. Unless the primary is <1-1.5 mm in thiekness when measured by the surgical pathologist, re-excision should include sentinel node biopsy.
Prognostie factors are increasingly able to discriminate those patients at highest risk for recurrent disease (Chapters 2 and 3). Lesion microscopie thickness remains the strongest predictor of outcome (Chapter 2). However, pathologie loss of epidermal continuity (ulceration) and nodal involvement are other critieal elements in identifying those patients at highest risk of recurrence. Precise staging by sentinel node biopsy can determine whieh patients may have residual nodal disease demanding regional node dissection and systemic adjuvant therapies and whieh patients will not. Nodal involvement is being defined with greater accuracy by sentinel node lymphoscintigraphy (6), whieh is a surgieal innovation of substantial value in primary staging. Since regional nodes are key prognostie factors for survival, the pathologic assessment of the first lymph node draining the site of primary melanoma (sentinell ymph node) is proving to be an important prognostic factor for the prediction of the presence of melanoma in the lymphatic basin. Lymphoscintigraphy, with vital dye blue injection and radiolymphoscintigraphy, showed that a negative sentinellymph node biopsy virtually eliminates the presence of lymphatic metastases when multiple histologie sections of the sentinel node are examined (6,7).
BIOLOGICAL AND TARGETED THERAPIES
Interest in stimulating host immune response for therapy of melanoma dates back to observations with the nonspecific immunostimulant, Bacillus CalmetteGuerin (BCG). When injected intralesionally into cutaneous metastatic melanoma nodules, tumor regression resulted in injected nodules, and sometimes in uninjected metastases (8). This clinieal approach was well-grounded in animal studies, which had demonstrated antitumor effects and augmentation of T cell and partieularly macrophage function (9). Other studies began to identify immunologie factors involved in response to murine melanomas (10). Subsequent clinical studies identified only rare effects ofBCG on visceral metastases and no effects on preventing recurrence after primary resection in melanoma patients ( 11). Large clinical studies in other tumors, except local bladder carcinomas, also failed to show clinical effectiveness (12-13). When coupled with difficulties in defining the most potent strains and key chemically defined constituents, interest in BCG as immunotherapy for melanoma waned. However, when coupled with knowledge that melanoma metastases could occasionally spontaneously regress for sometimes months or years, suggesting a host response to tumor ( 14), these initial studies provided a basis that continues to result in the definition of immunologie response to melanoma.
Essentially concomitant with studies ofBCG, aT cell response to melanoma was demonstrated (15). Melanoma-associated antigens began to be defined and
Introduction vii
led to melanoma being among the first tumors to which monoclonal antibodies were produced (16-17). Studies with interferons (IFNs) and interleukin (IL)-2 demonstrated regressions of metastatic disease ( 18-19). This substantial progress over the past 20 years has led to a focus on biological and targeted therapies for melanoma, which are the topics of the chapters which follow.
The focus of Melanoma: Biologically Targeted Therapeutics is to provide the rationale and background for translating the many promising biological and targeted therapies into new clinical trials and effective therapies. To furnish a framework for the clinical biology of the disease, the first three chapters cover primary identification and management, pathology, and clinical staging. Because outcome from the primary melanoma is, in part, determined by immune and vascular systems of the host, two chapters provide the context from which to better understand specific interventions. This is followed by individual chapters on cytokines, cellular therapies, monoclonal antibodies, targeted inhibitors, and angiogenesis.
IFN s remain the most acti ve adjuvant therapy for melanoma for patients staged as at highest risk for recurrence (Chapters 3 and 9). Additional clinical studies will be required to clarify the role and optimal timing of intervention with IFN in the adjuvant setting. However, one of the most exciting potential areas for adjuvant therapy is the use of vaccines aimed at stimulating T -cell response (Chapters 4-6). Vaccines mayaiso eventually be of benefit for patients with identified sporadic or familial gene mutations. IFN -a2 may additively or synergistically, through for example increase in dendritic cell function, potentiate melanoma antigen recognition or the effect of melanoma vaccine. IL-2, either alone or in combination with other autokines or adoptive cellular therapies, may provide potential to harness the antitumor effectiveness and specificity ofT cells (Chapters 4, 5, 7, and 8). Clinical studies of therapies targeted at abnormal melanoma cell proliferative signaling and angiogenesis inhibitors are just beginning (Chapters 11, 12, and 13). The first part ofthe 21st century should see the beginnings of an understanding ofhow to effectively utilize IFNs, vaccines, and targeted therapies for melanoma, brought together to increase cure and almost eliminate recurrence. Improvements in outcome for patients with metastatic disease, and probably primary disease, will come through a combination of biological and chemotherapies, an era that has just begun (Chapter 10).
FUTURE
This field is rapidly moving and evolving. New cytokines are being discovered that influence dendritic natural killer (NK) and T -cell function (Chapter 4). These include IL-12, IL-15, IL-18, IL-22, and IL-23 (20-25). Clinical activity of adoptive cellular therapies has been suggested by recent studies in renal carcinoma (26-27). Many groups are beginning to plan and initiate dendritic cell trials
viii Introduction
Table 1
Reduction in Melanoma Mortality and Morbidity
• Prevention
• Early detection
• Refine prognostic factors
• New systemic therapies
• eure
in melanoma (28-32). Cellular allogeneic stern cell transplants after immunosuppression and minimal recipient marrow eradication attempt to hamess the graft vs tumorreaction to therapeutic advantage; although to date, this has proven less effective in melanoma than in renal carcinoma, further trials are sure to follow. An allogeneic cellular extract vaccine has been demonstrated in a randomized trial to reduce risk of recurrence from primary disease (33). Angiogenesis may be affected by high constitutive levels of the transcription factor, nuclear factor (NF)KB, and high levels of IL-8 in melanoma (34); both would be potential new targets for anti-angiogenesis therapies. Many of these advances have occurred even since these chapters were written.
Attention to prevention in high risk individuals, more precise staging of primary disease, and the use of biological, cellular and targeted therapies will further reduce mortality from primary melanomas in the first quarter of the 21st century (Table 1). It is the hope of the authors that the approaches and strategies discussed herein will result in an overall reduction in melanoma mortality to less than 5% by the year 2030.
REFERENCES 1. Reintgen D, Balch CM, Kirkwood J, Ross M. Recent advanees in the eare ofthe patient with
malignant melanoma. Ann Surg 1997; 225: 1-14. 2. Mansfield PF, Lee JE, Balch CM. Cutaneous melanoma: current praetiee and surgical eon
troversies. Curr Probl Surg 1994; 31: 253-374. 3. Borden EC, Smith Tl. Melanoma: Adjuvant therapy with interferons. American Soeiety of
Clinieal Oneology Edueational Book, Spring 1999; 120-125. 4. Veronesi U, Cascinelli N. Narrow exeision (I-ern margin). A safe proeedure for thin
eutaneous melanoma. Arch Surg 1991; 126: 438-441. 5. Balch CM, Urist MM, Karakousis CP, et al. Effieaey of 2-em surgieal margins for interme
diate-thickness melanomas (l to 4 mm): results of a multi-institutional randomized surgical trial. Ann Surg 1993; 218: 262-269.
6. Ross MI, Reintgen D, Balch CM. Seleetive lymphadeneetomy: emerging role for lymphatie mapping and sentine1 node biopsy in the management of early stage melanoma. Semin Surg OncoI1993;9:219-223.
7. MeMasters KM, Reintgen DS, Ross MI, et al. Sentinellymph node biopsy for melanoma: eontroversy despite widespread agreement. J Clin Onco12001; 19: 2851-2855.
Introduction i:x
8. Morton DL, Eilber FR, Malmgren RA, Wood WC. Immunological factors which influence response to immunotherapy in malignant melanoma. Surgery 1970; 68: 158-164.
9. Hersh EM, Gutterman JV, Mavligit GM. BCG as adjuvant immunotherapy for neoplasia. Ann Rev Med 1977; 28: 489-515.
10. Kripke ML. Antigenicity of murine skin tumors induced by ultraviolet light. J Natl Cancer Inst 1974;53: 1333-133~
11. Veronesi V, Adamus J, Aubert C, et al. A randomized trial of adjuvant chemotherapy and immunotherapy in cutaneous melanoma. N Eng J Med 1982; 307: 913-916.
12. Morton DL. Active immunotherapy against cancer: present status. Sernin Oncol 1986; 13: 180-185.
13. Borden EC, Hawkins MJ. Biologic response modifiers as adjuncts to othertherapeutic modalities. Sernin Onco11986; 13: 144-152.
14. Cole WH. Efforts to explain spontaneous regression of cancer. J Surg Oncoll981; 17: 201-209.
15. Golub SH, Morton DL. Sensitisation of Iymphocytes in vitro against human melanomaassociated antigens. Nature 1974; 251: 161-163.
16. Shiku H, Takahashi T, Oettgen HF. Cell surface antigens ofhuman malignant melanoma. 11. Serological typing with immune adherence assays and definition of two new surface antigens. J Exp Med 1976; 144: 873-881.
17. Dippold WG, Lloyd KO, Li LT, IkedaH, Oettgen HF, Old LJ. Cell surface antigens ofhuman malignant melanoma: definition of six antigenic systems with mouse monoclonal antibodies. Proc Natl Acad Sei USA 1980; 77; 6114-6118.
18. Krown SE, Burk MW, Kirkwood JM, Kerr D, Morton DL, Oettgen HF. Human leukocyte (alpha) interferon in metastatic malignant melanoma: the American Cancer Society phase 11 trial. Cancer Treat Rep 1984; 68: 723-726.
19. Rosenberg SA, Mule 11, Spiess PJ, Reichert CM, Schwarz SL. Regression of established pulmonary metastases and subcutaneous tumor mediated by the systemic administration of high-dose recombinant interleukin 2. J Exp Med 1985; 161: 1169-1188.
20. Tanaka F, Hashimoto W, Okamura H, Robbins PD, Lotze MT, Tahara H. Rapid generation ofpotent and tumor-specific cytotoxic T Iymphocytes by interleukin 18 using dendritic cells and natural killer cells. Cancer Res 2000; 60: 4838-4844.
21. Vidal-Vanaclocha F, Fantuzzi G, Mendoza L, et al. IL-18 regulates IL-beta-dependent hepatic melanoma metastasis via vascular cell adhesion molecule-l. Proc Natl Acad Sci USA 2000;97: 734-739.
22. Xie MH, Aggarwal S, Ho WH, et al. Interleukin (lL)-22, a novel human cytokine that signals through the interferon receptor-related proteins CRF2-4 and IL-22R. J Biol Chern 2000; 275: 31,335-31,339.
23. Kotenko SV, Izotova LS, Mirochnitchenko OV, et al. Identification ofthe functional IL-TIF (IL-22) receptor complex: the IL-lOR chain (IL-lOR (beta}) is a shared component ofboth IL-10 and IL-TIF (IL-22) receptor complexes. J Biol Chern 2000; 276:2725-2732.
24. Oppmann B, Lesley R, BIom B, et al. Novel p19 protein engages IL-12p40 to form acytokine, IL-23, with biological activities similar as weil as distinct from IL-12. Irnrnunity 2000; 13: 715-725.
25. Cooper MA, Fehniger TA, Turner SC, et al. Human natural killer cells: a unique innate immunoregulatory role for the CD56 (bright) sub set. Blood 2001; 97: 3146-3151.
26. Childs RW, Clave E, Tisdale J, Plante M, Hensel N, Barrett 1. Successful treatment of metastatic renal cell carcinoma with a nonmyeloablative allogeneic peripheral-blood progenitorcell transplant: evidence for a graft-versus-tumor effect. J Clin Oncoll999; 17: 2044-2049.
27. Kugler A, Stuhler G, Waiden P, et al. Regression of human metastatic renal cell carcinoma after vaccination with tumor cell-dendritic cell hybrids. Nat Med 2000; 6: 332-336.
x Introduction
28. Schuler-Thurner B, Dieckmann D, Keikavoussi P, et al. Mage-3 and influenza-matrix peptide-specific cytotoxic T cells are inducible in terminal stage HLA-A2.1 + melanoma patients by mature monocyte-derived dendritic cells. J Immunol2000; 165: 3492-3496.
29. Mackensen A, Herbst B, Chen JL, et al. Phase I study in melanoma patients of a vaccine with peptide-pulsed dendritic cells generated in vitro from CD34 (+) hematopoietic progenitOf cells. Int J Cancer 2000; 86: 385-392.
30. Thurner B, Haendle I, Roder C, et al. Vaccination with mage-3A1 peptide-pulsed mature, monocyte-derived dendritic cells expands specific cytotoxic T cells and induces regression of some metastases in advanced stage IV melanoma. J Exp Med 1999; 190: 1669-1678.
31. Lotze MT, Hellerstedt B, Stolinski L, et al. The role of interleukin-2, interleukin-12, and dendritic cells in cancer therapy. Cancer J Sci Am 1997; 3: SI09-114.
32. Baggers J, Ratzinger G, Young JW. Dendritic cells as immunologic adjuvants for the treatment of cancer. J Clin Onco12000; 18: 3879-3882.
33. Sosman JA, Unger JM, Liu P, et al. Significant impact of HLA Class I alleles on outcome in T3NO melanoma patients treated with melacine (MEL), an allogeneic melanoma celllysate vaccine: prospective analysis of Southwest Onoclogy Group (SWOG)-9035. Proc Am Soc Clin OncoI2001;20:35Ia.
34. Huang S, DeGuzman A, Bucana CD, Fidler H. Nuclear Factor-kB activity correlates with growth, angiogenesis, andmetastasis ofhuman melanoma cells in nude mice. Clin Cancer Res 2000;6: 2573-2581.
CONTENTS
Introduction ....................................................................................................... v
Contributors ................................................................................................... xiii
I PERSPECTIVE ON THE CLINICAL DISEASE
1 Management of Primary Malignant Melanoma .................................... 3
Philip L. Bailin, Jon S. Meine, and Christine Poblete-Lopez
2 A Pathologist's Perspective on Prognostic Features of Malignant Melanoma ................................................................... 39
Ralph J. Tuthill
3 Clinical Prognostic Factors and Staging ............................................. 73
Hamed Daw and Thomas Olencki
11 BIOLOGICAL AND TARGETED THERAPEUTICS
4 Principles of Antitumor Immunity and Tumor-Mediated Immunosuppression ............................................. 95
Peter A. Cohen, Suyu Shu, and James H. Finke
5 Immunotherapy of Advanced Melanoma Directed at Specific Antigens ......................................................... 141
Stanley P. L. Leong and Suyu Shu
6 Melanoma Antigens: Vaecines and Monoclonal Antibodies ............ 157
Paul B. Chapman and Jedd D. Wolchok
7 Interleukin-2 ....................................................................................... 183
James W. Mier and Michael B. Atkins
8 Interleukin-12: Immunologie and Antitumor Effeets in Human Malignant Melanoma .................................................... 221
Ronald M. Bukowski and Charles Tannenbaum
9 Interferons: Preclinieal and Clinical Studies in Melanoma ............. 235
Ernest C. Borden
10 B iochemotherapy of Melanoma ......................................................... 259
Lawrence E. Flaherty and Philip Agop Philip
Xl
xii Contents
11 Signal Transduction Abnormalities as Therapeutic Targets ............. 287
Ruth Halaban and Maria C. von Willebrand
12 Tumor Angiogenesis .......................................................................... 325
Bela Anand-Apte and Paul L. Fox
13 Antiangiogenic Therapy for Melanoma ............................................ 361
Vann P. Parker Index .............................................................................................................. 379
CONTRIBUTORS
BELA ANAND-ApTE, MBBS, PhD, Cole Eye Institute, Department of Ophthalmie Research, The Cleveland Clinic Foundation, Cleveland, OH
MICHAEL B. ATKINS, MD, Director of Cutaneous Oncology and Biologie Therapy Programs, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center; Associate Professor of Medicine, Harvard Medical School, Boston, MA
PHILIP L. BAlLIN, MD, FACP, Department of Dermatology, The Cleveland Clinic Foundation, Cleveland, OH
ERNEST C. BORDEN, MD, Director, Center for Cancer Drug Discovery and Development, Taussig Cancer Center, The Cleveland Clinic Foundation, Cleveland, OH
RONALD M. BUKOWSKI, MD, Experimental Therapeutics Program, Taussig Cancer Center, The Cleveland Clinic, Cleveland, OH
PAUL B. CHAPMAN, MD, Clinical Immunology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center and Cornell University Joan and Sanford I. Weilt Medical College, New York, NY
PETER A. COHEN, MD, Center for Surgery Research, The Cleveland Clinic Foundation, Cleveland, OH
HAMED DAW, MD, Moll Cancer Center, The Cleveland Clinic Foundation, Cleveland,OH
JAMES H. FINKE, PhD, Department of Immunology, The Cleveland Clinic Foundation, Cleveland, OH
LAWRENCE E. FLAHERTY, MD, Barbara Ann Karmanos Cancer Institute, Division of Hematology and Oncology, Wayne State University School of Medicine, Detroit, MI
PAUL L. Fox, PhD, Lerner Research Institute, Department ofCell Biology, The Cleveland Clinic Foundation, Cleveland, OH
RUTH HALABAN, PhD, Department of Dermatology, Yale University School of Medicine, New Haven, CT
STANLEY P. L. LEONG, MD, Professor of Surgery, University of California, San Francisco, School of Medicine; Member, UCSF Comprehensive Cancer Center, San Francisco, CA
JON S. MEINE, MD, Surgical Dermatology, The Cleveland Clinic Foundation, Cleveland, OH
JAMES W. MIER, MD, Director of Cancer Immunotherapy Laboratory, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center; Associate Professor of Medicine, Harvard Medical School, Boston, MA
xiii
xiv Contributors
THOMAS OLENCKI, DO, Taussig Cancer Center, The Cleveland Clinic Foundation, Cleveland, OB
VANN P. PARKER, PhD, Clinical Development, Ribozyme Pharmaceuticals, Inc., Boulder, CO
PHILIP Aaop PmLIP, MD, PhD, MRCP, Barbara Ann Karmanos Cancer Institute, Division of Bematology and Oncology, Wayne State University, Detroit, MI
CHRISTINE POBLETE-LoPEZ, MD, Surgical Dermatology, The Cleveland Clinic Foundation, Cleveland, OB
SUYU SHU, PhD, Director, Center for Surgical Research, Division of Surgery, The Cleveland Clinic Foundation, Cleveland, OB
CHARLES TANNENBAUM, PhD, Lerner Research Institute, Department of Immunology, The Cleveland Clinic, Cleveland, OB
RALPH J. TUTHILL, MD, Anatomie Pathology, The Cleveland Clinic Foundation, Cleveland, OB
MARIA C. VON WILLEBRAND, MD, PhD, Department of Dermatology, Yale University School of Medicine, New Baven, CT
JEDD D. WOLCHOK, MD, PhD, Clinical Immunology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center and Cornell University Joan and Sanford I. Weill Medical College, New York, NY
COLOR PLATES
Color Plates follow p. 176.
Color Plate 1. Lentigo maligna melanoma (Fig. 1, Chapter 1; see discussion on p. 9).
Color Plate 2. Superficial spreading melanoma (Fig. 2, Chapter 1; see full caption discussion on pp. 11-12).
Color Plate 3. Nodular melanoma (Fig. 3, Chapter 1; see discussion on pp. 12-13).
Color Plate 4. Acrallentiginous melanoma (Fig. 4, Chapter 1; see discussion on pp. 13-14).
Color Plate 5. Subungual melanoma (Fig. 5, Chapter 1; see discussion on pp. 14-15).
Color Plate 6. Vertical growth (Fig. 1, Chapter 2; see full caption discussion on pp. 40--41).
Color Plate 7. Variant vertical growth (Fig. 2, Chapter 2; see full caption and discussion on pp. 40--41).
Color Plate 8. Moderate to severe melanocytic dysplasia (Fig. 3, Chapter 2; see full caption and discussion on pp. 42-43).
Color Plate 9. Severe melanocytic dysplasia (Fig. 4, Chapter 2; see full caption and discussion on pp. 42-44).
Color Plate 10. Severe compound melanocytic dysplasia (Fig. 5, Chapter 2; see full caption and discussion on pp. 43-44).
Color Plate 11. Histology of regression (Fig. 6, Chapter 2; see full caption and discussion on p. 45).
Color Plate 12. Thin (0.76 mm) level IV vertical growth with subsequent metastasis and death (Fig. 7, Chapter 2; see full caption and discussion on p. 46).
Color Plate 13. Breslow's tumor thickness measurement (Fig. 8, Chapter 2; see full caption and discussion on pp. 47-48).
Color Plate 14. Ulceration (Fig. 10, Chapter 2; see full caption and discussion on p. 49).
xv
xvi Contributors
Color Plate 15. Tumor infiltrating lymphocytes (Fig. 11, Chapter 2; see full caption and discussion on pp. 50-51).
Color Plate 16. Immune-reactive stroma (incomplete regression) (Fig. 12, Chapter 2; see discussion on p. 53).
Color Plate 17. Micrometastasis in a sentinellymph node. H&E stain shows a small group of atypical cells of uncertain nature (A). Immunostaining with antibodies to Melan-A (Mart-I) supports the interpretation of micrometastasis of malignant melanoma (B). (Figs. 13 A,B, Chapter 2; see discussion p. 60-63.)
Color Plate 18. Putative mechanism by which tumor cells can induce immune dysfunction in T cells and dendritic cells. Tumor cells can produce a variety of immunosuppressive products that inc1ude IL-lO, gangliosides, TGFß, and PGs. These products can affect T cell signaling and can suppress activation of transcription factors such as NFKB. Blocking NFKB may also reduce expression of certain anti-apoptotic genes that would render T cells more sensitive to apoptosis. IL-lO can also inhibit the Ag-presenting function of Des. Moreover, some tumors express Fas ligand (Fas-L) that can induce apoptosis in T cells that express Fas receptor. At the same time, some tumor cells that express Fas receptor may themselves be resistant to apoptosis induced by Fas-L expression on the activated T cells. Such resistance, in some cases, appears related to the tumor cells' reduced expression of molecules such as caspase that are essential for activation of apoptotic pathways. (Fig. 5, Chapter 4; see discussion on p. 122.)
