The Clinical Recognition and Prognostic Factors of Primary Cutaneous Malignant Melanoma

Cutaneous Oncology

The Clinical Recognition and Prognostic Factors of Primary Cutaneous Malignant Melanoma ]oseph]. Chanda, M.D.*

Malignant melanomas occupy a position of central importance in the field of cutaneous oncology. Although accounting for only 3 per cent of all primary cutaneous malignancies, melanomas are responsible for two-thirds of deaths attributed to skin cancers. 52 In addition, both the incidence of and mortality from malignant melanoma have increased significantly in recent years. 13, 53 Public awareness of "black mole cancer" is prominent, and the subject of melanoma has received much recent attention in the nonmedical press. Current medical information indicates that early recognition and proper treatment of melanoma can lead to long-term survival and even cure. Consequently, it is of paramount importance for the clinician to be aware of the clinical features and prognostic factors of melanoma, in order to make a rapid accurate diagnosis and recommend proper treatment. GENERAL FEATURES

Melanomas are malignant tumors derived from melanocytes. 6o Melanocytes are found in the skin, meninges, uveal tract of the eye, and ectodermal mucosae. 60 Most melanomas derive from cutaneous epidermal melanocytes but some melanomas definitely arise in preexisting nevi. 17 . 21, 48 The exact percentages are controversial. 17, 21. 48 Malignant melanocytic change may develop in other noncutaneous locations populated by melanocytes. This review will concentrate on cutaneous melanomas. The incidence of melanomas is increasing in all recently reported series. 4o • 52 Geographic locations closer to the equator show higher incidences and more rapid rates of increase in incidence than more distant locations. 4o Exact current incidence figures for the United States are not available but are probably significantly higher than the 4.2 per 100,000 per year incidence reported in 1977. 52 *Consultant, Division of Dermatology, Holmes Regional Medical Center, Melbourne, Florida

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JOSEPH J. CHANDA

Malignant melanoma may develop anywhere on the cutaneous surface. Truncal and extremity locations predominate. 50 Males and females have been affected with equal frequency in most series. 40 Most cases of melanoma develop in adults between 40 and 70 years of age, but there has been a recent significant increase in melanoma in young adults aged 20 to 40. 40 Melanomas are rare in adolescence and extremely rare in children. The etiology of malignant melanoma is probably multifactorial. A detailed discussion of these causes is beyond the scope of this review. Sunlight,!' 54, 57 trauma,58 oncogenic viruses, 7, 18.66 heredity, 19, 38 endocrinologic factors, 21, 47, 63, 72, 81 and preexisting nevi (both congenital and acquired l7, 19,21,48) have all been etiologically implicated in the development of malignant melanoma. The recent description of a dysplastic nevus syndrome with a high frequency of melanomatous degeneration is also of significant etiologic importance. 36, 38

CLINICAL FEATURES All melanomas, regardless of their site of origin, begin, evolve, and progress according to similar principles of developmental biology.20 Melanomas demonstrate either a radial or a vertical growth phase. These phases refer to the biological stage of development of the lesion. 20 During th~ radial growth phase the net direction of tumor growth is centrifugal or parallel to the surface of the skin, whereas in the vertical growth phase the net direction of tumor progression is downward through the dermis and into the subcutis,20 The growth phase of the lesion correlates roughly with its propensity for invasion and eventual metastasis. The clinical features that call attention to the development of melanoma center on two characteristics, irregula,rity and change, 15, 16,62, 78 All melanomas hav~ either an irregular color, an irregular border, an irregular topography, or combinations of these features. These figures are illustrated in Figures 1 through 6. In preexisting lesions, change from a' uniform color, border, or topography to an irregular one may herald melanomatous degeneration. 15, 16,62,78 Development of symptoms-change in size, pain, burning, itching, swelling, or bleeding-in a new or preexisting lesion may also indicate melanoma. 62, 78 Specific colors that strongly suggest melanoma are blue, red, white, and ink.black shades. 62 Variegation of color (e,g" blue, black, and red in one lesion) or a mottling disarray of pigmentation62 (e. g., different shades or degrees of blackness within a lesion) also suggests melanoma. A scalloped, angled, notched, or indented border may indicate a melanoma. 62, 78 Changes in topography-a flat lesion that develops a papule or nodule in it, or a papular or nodular lesion that develops a stain around it-suggest melanoma. 15, 16, 62, 78 Satellite lesions may also indicate melanoma, Changes in skin markings may also be of diagnostic importance. ll Melanomas in vertical growth phases uniformly have absence of normal skin markings, whereas melanomas in radial growth phases may have accentuated skin markings. ll Several different clinical types of melanoma have been described,20 but the large majority of cutaneous melano.

CLINICAL RECOGNITION OF PRIMARY CUTANEOUS MALIGNANT MELANOMA

Figure 1.

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Melanoma showing irregular color.

mas can be classified into five distinct clinical forms. 15, 16, 78 These are outlined in Table 1. Lentigo maligna melanoma, superficial spreading melanoma, and acral lentiginous melanoma originate with a radial growth phase and then progress to a vertical growth phase. The nodular melanoma has no radial growth phase and begins with a vertical growth ph(lse. Any of these clinical types may present as amelanotic variants. Lentigo maligna

Figure 2.

Melanoma showing irregular color

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JOSEPH J.

Figure 3.

Melanoma showing irregular border.

Figure 4.

Melanoma showing scalloped, notched border.

CHANDA

CLINICAL RECOGNITION OF PRIMARY CUTANEOUS MALIGNANT MELANOMA

Figure 5.

Figure 6. stain.

43

Melanoma showing irregular torqgraphy: flat lesion with a nodule.

Melanoma showing irregular topography: nodular lesion with a surrounding

Table 1.

Clinical Types of Cutaneous Melanomas Superficial spreading melanoma Nodular melanoma Lentigo maligna melanoma Acrallentiginous melanoma Amelanotic melanoma

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JOSEPH J. CHANDA

melanoma is a slowly evolving pigmented lesion that occurs predominantly on sun-exposed areas and typically develops in elderly patients (Figs. 7 and 8).15,16,20,78 Noninvasive premalignant lesions-lentigo maligna-may antedate lentigo maligna melanoma. These precursor lesions are tan, flat macules varying in color. Malignant degeneration is heralded by changes in size, color, or topography. The most common site of occurrence for a

Figure 7.

Lentigo maligna melanoma.

Figure 8.

Lentigo maligna melanoma.

CLINICAL RECOGNITION OF PRIMARY CUTANEOUS MALIGNANT MELANOMA

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lentigo maligna melanoma is the face. Lentigo maligna melanoma accounts for 4.9 percent of melanomas. 20 Nodular melanoma (Figs. 9 and 10) is a rapidly developing nodule or plaque that may occur anywhere on the body,15, 16, 20 It accounts for 14,7

Figure 9.

Figure 10.

Nodular melanoma,

Nodular melanoma.

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J.

CHANDA

per cent of melanomas 2o and is characterized by aggressive behavior with significant potential for early metastasis. Ulceration and dense pigmentation are common. Acral lentiginous melanomas (Figs. 11 and 12) comprise melanomas of the palms, soles, subungual areas, and mucous membranes (oral, anal, vaginal, and nasal mucosa).43, 55, 56, 65, 67 They are the most common melan-

Figure 11.

Acrallentiginous melanoma.

Figure 12.

Acrallentiginous melanoma.

CLINICAL RECOGNITION OF PRIMARY CUTANEOUS MALIGNANT MELANOMA

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omas seen in blacks. 56 Because of their somewhat inapparent body locations they frequently present in advanced stages and with large size and, consequently, tend to have a poor prognosis despite the fact that they initiate with a radial growth phase and are somewhat slow growing .. Superficial spreading melanoma (Figures 13 through 15) is the most

Figure 13.

Superficial spreading melanoma.

Figure 14.

Superficial spreading melanoma.

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JOSEPH J. CHANDA

Figure 15.

Superficial spreading melanoma.

common type of melanoma, accounting for almost 70 per cent of all melanomas. 15, 16, 20 They occur anywhere on the body but are mostly commonly seen on the trunk in men and the extremities in women. They typically begin as small pigmented lesions that slowly enlarge and develop the typical irregular features of melanoma. Color variegation is quite common in these lesions. Nonpigmented or amelanotic melanomas constitute approximately 2 per cent of all melanomas (Fig. 16).75 These lesions are composed of histologically authentic melanocytes with complete absence of melanin pigmtmta,tiQn at both the primary and the metastatic sites. Amelanotic melanomas may occur anywhere on the body.75 They occur predominantly in females. 75 Since formation of melanin is a form of cellular differentiation, it~ould be expected that amelanotic melanomas would be more rapidly growing, aggressive, and apt to metastasize. 75 Consistent with this fact is that 75 per cent of amelanotic melanomas present with either regionaJ or distant metastasis and approximately 33 per cent of patients with amelanotic melanpma.are first seen with an unknown primary site, compared with about 7 per cent of patients with pigmented melanomas. 75

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS The clinical diagnosis Qf malignant melanoma is confirmed only by histopathological examination. Even with careful attention to the previously described clinical features, there are numerous benign lesions that can closely approximate melanoma. 15, 16, 22, 37 These are outlined in Table 2, Most pigmented lesions in which a change or a symptom develops are not melanoma. However, any pigmented lesion that raises suspicion of mela-

CLINICAL RECOGNITION OF PRIMARY CUTANEOUS MALIGNANT MELANOMA

Figure 16.

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Amelanotic nodular melanoma.

noma should be biopsied. The aim of the biopsy is twofold: to provide both diagnostic information and prognostic information. These aims can be best achieved by excisional biopsy. Because of variations of thickness of melanomas and because of the presence of areas of regression, shave biopsies and punch biopsies may not provide accurate diagnositc and prognostic information and should not be done. In the case of large lesions when excisional biopsy is not possible, or in cases in which anatomic location makes excisional biopsy unfeasible, an incisional biOpsy of the thickest portion of the lesion should be performed. 2, 14. 39. 59. 71. 83 Previous concerns that incisional biopsy of the melanoma might lead to dissemination have not been documented and are not supported by evidence in the literature.41. 42. 49. 51 Table 2.

Differential Diagnosis of Cutaneous Melanomas

Junctional nevus

Irritated compound nevus Seborrheic keratosis Angiokeratoma Pigmented basal cell carcinoma Pyogenic granuloma Spitz nevus Blue nevus Dermatofibroma Hemorrhage into a cyst Talon noir Angioma Varices

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J.

CIIA:-.IDA

PROGNOSIS

The prognosis for patients with melanoma is not so bleak as once thought. 23 Despite increases in the absolute numbers of patients dying of disseminated melanoma over the past several years, today most patients with melanoma survive for 5 years or more. 17, 23 This improved survival reflects diagnosis at an earlier biological stage of development when dissemination is less likely to have occurred and the primary melanoma is localized. 17 Much recent work has been done on prognostic factors in melanoma resulting in vastly improved information on which parameters are of importance in predicting survival of melanoma. ,1--5. 8. 9. 24-31, 35. 61. 62. 73, 74, 76, n, 79, 80 Most prognostic information in melanoma is used with reference to patients with clinical stage 1 disease-that is, localized cutaneous melanoma. Patients with disseminated melanoma at the time of diagnosis-clinical stage 2 and clinical stage 3 disease-usually succumb to their disease within 5 years or sooner. Basically, prognostic factors for melanoma can be divided into clinical and histological groups. These are outlined in Tables 3 and 4. Of these, the histologic parameters of tumor thickness and level of invasion are the most important and form the foundation on which survival data are based. In 1969 Clark et al. 17 first categorized malignant melanoma into five histological levels, based on vertical depth of tumor invasion, and related these levels to prognosis. They showed that the higher the numerical level of invasion, the poorer was the prognosis for long-term survival. However, because of subjective difficulties in classifying certain melanomas with this method (i. e., was a lesion a deep level 2 or a shallow level 3, a deep level 3 or a shallow level 4, and so forth), Breslow l2 • 13 offered a modification using measurement in millimeters of maixmal vertical tumor thickness measured with a micrometer from the top of the granular cell layer of the tumor to the deepest level of invasion of the melanoma. This parameter of tumor thickness has become the single most important prognostic index for melanoma. Current survival data for melanoma based on tumor thickness are outlined in Table 5. These data show that patients with thin melanomas, 0.76 mm or less, have an excellent prognosis, and that patients with thicker melanomas, greater than 1.5 mm, have a poorer prognosis. Patients with melanomas between 0.76 mm and 1.5 mm have a variable prognosis. Certain other histologic factors have been claimed to affect prognosis and affect it adversely. These include a high mitotic index,73, 74 lack of lymphocytic infiltrate (immune response) at the base of the tumor,61 and histologic evidence of regression. 45 The accu-

Table 3.

Histologic Prognostic Pammeters for Melanomas Tumor thickness Level of invasion Microscopic satellites Mitotic index Lymphocytic infiltration Regression

CLINICAL RECOG;\IITION OF PRIMARY CUTANEOUS ",'ALIG;\IANT MELANOMA

Table 4.

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Clinical Prognostic Parameters for Melanomas Age Sex Clinical type of melanoma Ulceration Anatomic site Anatomic subsite (BANS, HF)

racy and reproducibility of these parameters are uncertain, and they do not, at present, approach the reliability of tumor thickness or level of invasion as prognostic indicators. One recently described histologic parameter does, however, appear to be important and may prove to be a prognostic modifier for tumor thickness and level of invasion. This is a concept of microscopic satellitosis as advocated by Day et al. 32 and Harrist et al. 46 They define microscopic satellites as tumor mass greater than 0.05 mm in diameter in the reticular dermis, panniculus, or vessels beneath the principal invasive tumor mass but distinctly separated from the tumor mass by normal tissue. Clinical stage 1 patients with these microscopic satellites have decreased 5-year survival rates and increased frequency of occult regional lymph node metastasis when compared with patients with melanomas of similar tumor thickness but without microscopic satellites. Clinical prognostic parameters are patients' age, sex, clinical type of melanoma, presence of ulceration, and anatomic site and subsite of the melanoma. Most studies in the literature indicate that when matched f(1r age, clinical type of melanoma, level of invasion, and tumor thickness, female patients have a better prognosis than male patients. 1.5, 16 The reasons for this are unclear but may reflect hormonal influences on the rate of melanoma growth. In addition, younger patients with melanoma generally tend to fare better than older patients when similarly matched. 21. 23 The presence of significant (greater than 3 mm in width) ulceration has correlated with a poor prognosis in several studies. 6 , 33 This probably reflects the fact that most tumors that ulcerate are rapidly growing and probably in a vertical growth phase and thereby at higher risk for dissemination. The clinical type of melanoma is also a prognostic influence, probably indicating different intrinsic biologic behavior among varying clinical types. In most clinical series nodular melanomas tend to have the worse prognosis Table 5. TUMOR THICKNESS

0--0.75 mm 0.76-1.49 mm 1.50--2.25 mm 2.26-3.00 mm > 3.00 mm

Survival Data for Clinical Stage 1 Melanomas* NUMBER OF PATIENTS

5-YEAR DISEASE FREE SURVIVAL

71 4.5 32 19 38

100% 66% 69%

37% 23%

*From Balch, C. M., et al.: A multifactorial analysis of melanoma: Prognostic and histological features comparing Clark's and Breslow's staging methods. Ann. Surg., 188:732--742, 1978.

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CHANDA

when considered as a group, lentigo maligna melanoma the best prognosis, and superficial spreading melanomas and acral lentiginous melanomas intermediate prognoses.l 7. 52 Amelanotic melanomas also tend to have a worse prognosis than their pigmented counterparts. 75 Anatomic location has long been recognized as somehow influencing prognosis, with extremity lesions having a good prognosis, truncal lesions a poor prognosis, and head and neck lesions having an intermediate prognosis. 12, 13. 60 The notion of specific anatomic subsites of melanoma having a distinct adverse effect on prognosis when matched for tumor thickness was initially proposed by Day and Lew34 and confirmed and reinforced by Rogers et aL 70 They found that melanomas of the hands and feet (HF) and melanomas of an area referred to by the acronym BANS (B-interscapular area of the upper back; A-posterior upper arms; N-posterior and lateral neck; S-scalp) had a poor prognosis when matched for tumor thickness and compared to similarly located melanomas (hands and feet vs. extremities; interscapular area of the upper back vs. the lower back; posterior neck vs, the anterior neck; the scalp vs. the face). The reasons for these differences are unclear but may reflect regional differences in lymphocytic drainage and microcirculation. CONCLUSION

The increased incidence of melanoma and its attendant publicity have heightened patients' awareness of this malignancy. It is to be hoped that this will lead to earlier consultation with a physician for suspicious lesions. It is also hoped that, by being familiar with the clinical features and prognostic factors of melanoma outlined above, the clinician will be able to diagnose melanomas earlier, recommend proper management, and thereby improve survival. REFERENCES 1. Anais, E. D., Steinitz, R., and Ben Hur, N.: Solar radiation: A possible etiologic factor in malignant melanoma in Israel: A retrospective study (1960--1972). Cancer, 42:299304, 1978. 2. Bagley, F. H., Cady, B., Lee, A., et a!.: Changes in clinical presentation and management of malignant melanoma. Cancer, 47:2126-2134, 1981. 3, Balch, C. M., Murad, T. M., Soong, S. J., et al.: A multifactorial analysis of melanoma: Prognostic and histopathological features comparing Clark's and Breslow's staging methods, Ann. Surg., 188:732-742, 1978. 4. Balch, C. M., Karakousis, C., Mettlin, C., et al.: Management of cutaneous melanoma in the United States. Surg. Cynecol. Obstet., 158:311-318, 1984. 5. Balch, C. M., Soong, S. J., Milton, C. W., et al.: Changing trends in cutaneous melanoma over a quarter century in Alabama, USA, and New South Wales, Australia. Cancer, 52:1748-1753, 1983. 6. Balch, C. M., Wilkerson, J. A" Murad, T. M., et al.: The prognostic significance of ulceration of cutaneous melanoma. Cancer, 45:3012-3017, 1980, 7. Balda, B. R., Hehlmann, R., Cho, J. R., et a!.: Oncornavirus-like particles in human skin cancers. Proc. Natl. Acad, Sci. USA, 72:3697-3701, 1975. 8. Blois, M. S., Sagebiel, R. W" Abarbanel, R. M., et al.: Malignant melanoma of the skin. Cancer, 52:1330--1341, 1983.

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9. Blois, M. S., Sagebiel, R. W., Tuttle, M.S., et al.: Judging prognosis in malignant melanoma of the skin: A problem of inference over small data sets. Ann. Surg., 198:200206, 1983. 10. Boddie, A. W., Smith, J. L., and McBride, C. M.: Malignant melanoma in children and young adults: Effect of diagnostic criteria on staging and results. South. Med. J., 71 :1074, 1978. 11. Bondi, E. K, Elder, D. K, Guerry, B., et al.: Skin markings in malignant melanoma. JAMA, 250:503--505, 1983. 12. Breslow, A.: Thickness, cross sectional area, and depth of invasion in the prognosis of cutaneous melanoma. Ann. Surg., 172:902-908, 1970. 13. Breslow, A.: Tumor thickness, level of invasion, and node dissection in stage 1 cutaneous melanoma. Ann. Surg., 182:572-575, 1975. . 14. Callen, J. P., Chanda, J. J., and Stawiski, M. A.: Malignant melanoma. Arch. Dermatol., 114:369-370, 1978. 15. Chanda, J. J.: Primary cutaneous malignant melanoma: Recognition, properties, and management. Primary Care, 5:325-337, 1978. 16. Chanda, J. J.: Melanoma. In: Callen, J. P. (ed): Cutaneous Aspects of Internal Disease. Chicago, Year Book Medical Publishers, 1980, pp. 223--238. 17. Clark, W. H., From, L., Bernardino, K A., et al.: The histogenesis and biologic behavior of primary human malignant melanoma of the skin. Cancer Res., 29:707~ 726, 1969. 18. Clark, W. H., and ten Heggeler, B.: Nuclear structures suggesting the presence of a virus in the melanocytes of human primary cutaneous malignant melanoma. J. Cell BioI., 55:45A, 1972. 19. Clark, W. H., Reimer, R. R, Green, M., et al.: Origin offamilial malignant melanomas from hereditable melanocytic lesions. B-K mole syndrome. Arch. Dermatol., 114:732738, 1978. 20. Clark, W. H., Ainsworth, A. M., Bernardino, K A., et al.: The developmental biology of primary human malignant melanomas. Semin. Oncol., 2:83--103, 1975. 21. Davis, N. C.: Cutneous melanoma: The Queensland experience. Curr. Probl. Surg., 13:1~63, 1976. 22. Davis, N. C., McLeod, G. R, Beardmore, G. L., et al.: Pigmented skin tumors. CA, 23:160-170, 1973. 23. Davis, N. C., McLeod, G. R., Beardmore, G. L., et al.: Primary cutaneous melanoma: A report from the Queensland melanoma project. CA, 26:80-108, 1976. 24. Day, C. L., Sober, A. J., Lew, R A., et al.: Malignant melanoma patients with positive nodes and relatively good prognosis: Micro staging retains prognostic Significance in clinical stage. 1 melanoma patients with metastases to regional nodes. Cancer, 47:955962, 1981. 25. Day, C. L., Sober, A. J., Kopf, A. W., et al.: A prognostic model for clinical stage melanoma of the upper extremity. Ann. Surg., 193:436-440, 1981. 26. Day, C. L., Sober, A. J., Kopf, A. W., et al.: A prognostic model for clinical stage melanoma of the trunk. Am. J. Surg., 142:247~251, 1981. 27. Day, C. L., Sober, A. J., Kopf, A. W., et al.: A prognostic model for clinical stage melanoma of the lower extremity. Surgery, 89:599-603, 1981. 28. Day, C. L., Mihm, M. c., Sober, A. J., et al.: Prognostic factors for melanoma patients with lesions 0.76 to 1.69 mm in thickness: An appraisal of thin level 4 lesions. Ann. Surg., 195:30-34, 1982. 29. Day, C. L., Mihm, M. C., Lew, R. A., et al.: Prognostic factors for patients with clinical stage 1 melanoma of intermediate thickness (1.51~3. 99 mm). Ann. Surg., 195:35-43, 1982. 30. Day, C. L., Lew, RA., Mihm, M. C., et al.: A multi-variate analysis of prognostic factors for melanoma patients with lesions greater than or equal to 3.65 mm of thickness. Ann. Surg., 195:44-49, 1982. 31. Day, C. L., and Lew, R. A.: Malignant melanoma prognostic factors. 6: Distant mestastases and length of survival. J. Dermatol. Surg. Oncol., 10:686-689, 1984. 32. Day, C. L., Harrist, T. J., Gorstein, F., et al.: Malignant melanoma: Prognostic significance of microscopic satellites in the reticular dermis and subcutaneous fat. Ann. Surg., 194:108-112, 1981. 33. Day, C. L., Lew, R. A., Harrist, T. J., et al.: Malignant melanoma prognostic factors. 4: Ulceration width. J.. Dermatol. Surg. Oncol., 10:23--24, 1984.

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34. Day, C. L., and Lew, R. A.: Malignant melanoma prognostic factors. 5: Clinical staging. J. Dermatol. Surg. Oncol., 10:351-3.53, 1984. 35. Drzewiecki, K. T, and Anderson, T. K.: Survival with malignant melanoma. Cancer, 49:2414-2419, 1982. 36. Editorial. Per~ursors to malignant melanoma. JAMA, 251 :1864-1866, 1984. 37. Editorial. Clinical atlas of pigmented lesions. J. Dermatol. Surg. Oncol., 5:700-715, 1979. 38. Elder, D. K, Goldman, L. 1., Coldman, F. C., et al.: Dysplastic nevus syndrome. Cancer, 46:1787-1794,1980. 39. Elder, D. K, Cuerry, D. P., Heiberger, R. M., et al.: Optimal resection margins for cutaneous malignant melanoma. Plast. Reconstr. Surg., 71:66-72, 1983. 40. Elwood, J. M., and Lee, J. A.: Recent data on the epidemiology of malignant melanoma. Semin. Oncol., 2:149-154, 1975. 41. Epstein, K, Bragg, K., and Linden, C.: Biopsy and prognosis of malignant melanoma. JAMA, 208:1369-1371, 1969. 42. Epstein, E., and Bragg, K.: Curability of melanoma. A 25 year retrospective study. Cancer, 46:818-821, 1980. 43. Feibleman, C. K, Stoll, H., and Maize, J. C.: Melanomas of the palms, soles and nailbeds: A clinical pathological study. Cancer, 46:2492-2504, 1980. 44. Creeley, P. W., Middleton, A. C., and Curtin, J. W.: Incidence of malignancy in giant pigmented nevi. Plast. Reconstr. Surg., 36:26-33, 1965. 45. Gromet, M. A., Epstein, W. L., and B1ois, M. S.: The regressing thin melanoma: A distinct lesion with metastatic potential. Cancer, 42:2282-2285, 1978. 46. Harrist, T J., Rigel, D. S., Day, C. L., et al.: Microscopic satellites are more highly associated with regional lymph node metastasis than is primary melanoma thickness. Cancer, 53:2183-2187, 1984. 47. Heis, H., and Krementz, KT: Survival experience in patients with malignant melanoma of the skin. 1950-1957. Natl. Cancer Inst. Monogr., 6:69-82, 1961. 48. Helwig, E. B.: Malignant melanoma of the skin in man. Natl. Cancer Inst. Mongr., 10:287-298, 1963. 49. Jones, W. M., Jones-Williams, W., Roberts, N. M., et al.: Malignant melanoma of the skin: Prognostic value of clinical features in the role of treatment of 111 cases. Br. J. Cancer, 22:437-451, 1968. 50. Kaplan, K N.: The risk of malignancy in large congenital nevi. Plast. Reconstr. Surg., 53:421-429, 1974. 51. Knutson, C. 0., Hori, J. M., and Spratt, J. S.: Melanoma. Curr. Probl. Surg., 12:1-55, 1971. 52. Kopf, A. W., Bart, R. S., and Rodriguez-Sains, R. S.: Malignant melanoma: Review. J. Dermatol. Surg. Oncol., 3:41-125, 1977. 53. Kopf, A. W., Rigel, D. S., and Friedman, R. J.: The rising incidence and r;nortality rate of malignant melanoma. J. Dermatol. Surg. Oncol., 8:760-762, 1982. 54. Kopf, A. W., Cripke, M. L., and Steam, R. S.: Sun and malignant melanoma. J. Am. Acad. Dermatol., 11:674-684,1984 . .55. Krementz, KT., Sutherland, C. M., Carter, R. D., et al.: Malignant melanoma in the American black. Ann. Snrg., 183:5.53-554, 1976. 56. Krementz, K T, Reid, R. J., Coleman, W. P., et al.: Acrallentiginous melanoma: A clinical pathological entity. Ann. Snrg., 195:632-645, 1982. 57. Lee, J. A.: Sunlight and the etiology of malignant melanoma: A synthesis. Med. J. Aust., 2:846-851, 1970 . .58. Lee, J. A.: Current evidence about the causes of malignant melanoma. Prog. Clin. Cancer, 6:151-161, 1975. 59. Lee, Y. T: Diagnosis, treatment and prognosis of early melanoma: The importance of depth of micro invasion. Ann. Snrg., 191 :87-97, 1980. 60. Luce, J. K., McBride, C. M., and Frei, K, Ill: Melanoma. In Holland, J. F., and Frei, K, III (eds.): Cancer Medicine. Philadelphia, Lea and Febiger, 1973, pp. 1823-1843. 61. Maize, J. C.: Primary cutaneous malignant melanoma: Analysis of prognostic value of histological characteristics. J. Am. Acad. Dermatol., 8:857-868, 1983. 62. Mihm, M. C., Clark, W. H., and From, L.: The clinical diagnosis, classification, and histogenic concepts of the early stages of cutaneous malignant melanoma. N. Engl. J. Med., 284:1078-1082, 1971. 63. Nathanson, L., Hall, T C., and Farber, S.: Biological aspects of human malignant melanoma. Cancer, 20:6.50-6.58, 1967.

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