Seminars in Surgical Oncology 8:358-365 (1992)
Precursor Lesions of Melanoma: Do They Exist? MARTIN C. MIHM, JR.,
RAYMOND L. BARNHILL, MD, ARTHUR J. SOBER, MD, AND MANUEL HOWE HERNANDEZ From the Dermatopathology Division and Dermatology Service, Massachusetts General HospitallHarvard Medical School, Boston, Massachusetts MD,
The question of whether definite precursors to melanoma exist is answered in the affirmative. Three cutaneous lesions likely to be such precursors are described and discussed as to their clinical and histologic appearance and incidence. Additionally, a type of conjunctival melanosis that has been associated with malignant melanoma of the conjunctiva is discussed and an attempt is made to define it; a proposed classification of this entity is reviewed. Basic approaches to management and analysis of precursor lesions are elaborated. @
1992 Wiley-Liss. Inc ~~
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KEY WORDS:melanoma precursor, dysplastic nevus, congenital nevus, lentigo maligna, melanocytic hyperplasia, malignant melanoma
INTRODUCTION Tumorigenesis in the skin, as in most other organ systems, often takes place in premalignant hyperplasias [ 11. Specifically, a proportion of melanomas develop with some degree of predictability from precursor lesions that cannot themselves be diagnosed as melanoma [2]. This is not controversial. What is at issue is whether these precursors can be identified reliably, using clinical or histologic criteria, so that the likelihood of progression to the stage favoring metastasis is reduced. This is a critically important question because melanoma detected early responds much better to therapy than do its later stages [ 3 ] . While the reported incidence of malignant melanoma has increased, so have survival rates from the disease. Greater knowledge about, and increased public attention to, the character of the disease and its precursors may be responsible for both trends [4]. The identification and description of the dysplastic nevus [5],an important precursor and marker for melanoma in patients with familial melanoma, has led to continuing research to more precisely define its significance in individuals with “sporadic” dysplastic nevi. The description of this lesion may be considered to build on the 1969 distinction of the diagnostic subtypes of malignant melanoma [6]. 0 1992 Wiley-Liss, Inc.
Histopathologic confirmation of diagnosis of any pigmented lesion, whether benign or a precursor lesion, such as the dysplastic nevus, is the definitive test, much as it is for melanoma. This article reviews the criteria for diagnosis in the precursor lesions capable of evolving into malignant melanoma and attempts to clarify what is known about their development and distinction from other lesions. Clarity of definition can help determine relationships among other factors that are more easily subjected to statistical analysis, such as genetic markers and environmental factors. Although these precursors vary a great deal in character, incidence, and risk of melanoma, the most important cutaneous lesions are the dysplastic nevus, congenital nevus, and lentigo maligna. This paper reviews the clinical and histopathologic features of these lesions and also reviews mucosal and paramucosal lesions that appear to increase melanoma risk, especially those affecting the conjunctiva. In addition, a spectrum of benign lesions are discussed, some of which clinically resemble malignant melanoma or one of its precursors. Address reprint requests to Martin C. Mihm, M.D., Dcrmatopathology Division, Massachusetts General Hospital / Harvard Medical School. Fruit Street, Boston, M A 021 14.
Do Melanoma Precursors Exist? 359
BENIGN LESIONS
Dysplastic Nevus
Lentigo and Other Common Acquired Benign Lesions Significance of familial and sporadic lesions. The Certain cutaneous lesions exhibit hypermelanosis dysplastic nevus, a precursor of and marker for heritawithout melanocytic hyperplasia. A hypermelanosis ble malignant melanoma, may occur at any site on the of special interest occurs on the vulva. This lesion, body. Clinically, while varying descriptions have been called vulvar melanosis, may vary in size from a few proposed [9,lo], most descriptions agree that the dysmillimeters to a few centimeters across and may ex- plastic nevus is usually greater than 5 mm across, has hibit irregularities in pigmentation and border con- irregular coloration, and usually includes some pinktour. It may therefore be confused with vulvar mela- ish hue in an otherwise tan to brown lesion. Marked irregularities in color distribution and in the contour noma, and is discussed in detail below [7]. of the border are common (Figs. 1,2). A similar variaBenign acquired nevomelanocytic proliferations are bility exists in size. Some lesions, especially in a patient not usually difficult to recognize, usually less than 5 with familial dysplastic nevus syndrome, may be only mm across. They include lentigines and nevi that are a few millimeters across, yet exhibit histologic features usually symmetrical, well demarcated, and stable. They vary in color from tan to dark brown, although some dermal nevi may be flesh colored. These lesions have specific histologic characteristics. Lentigines are associated with a proliferation of nevomelanocytes along the dermoepidermal junction in hyperplastic rete ridges. Some slight stromal proliferation may be noted, and dermal melanophages are often present. The word “lentiginous” derives from the distribution of melanocytes in lentigo, but is used more broadly to refer to a similar single-cell proliferation in a normal, hyperplastic, or atrophic epidermis. The common acquired nevus is a lesion, often clinically tan and slightly raised or exhibiting a papule with a symmetrical rim of pigmentation around its edges. Histologically, the common acquired junctional nevus shows well-defined nests of nevomelanocytes with cytoplasm that is often fusiform and rather uniform, spindle-shaped nuclei containing tiny dotlike nucleoli Fig. 1. Rectangular appearance of this dysplastic nevus contrasts in coherent nests at the tips of the rete ridges. A dermal strikingly with round or oval shapes of benign acquired nevi. component, when present, is confined to the papillary dermis, without significant reticular -dermal involvement. In the common acquired nevus, the junctional component often extends beyond its dermal counterpart. Any such extension, however, is usually symmetrical. There may be a proliferation of obviously benign single cells between the nests. In sum, common benign acquired nevi are architecturally distinct and do not show cytologic atypia. They do not involve the reticular dermis to any significant extent. Some congenital nevi cannot be distinguished clinically or histologically from acquired nevi, as discussed in detail in the sections below [8]. CUTANEOUS MELANOCYTIC LESIONS WITH SIGNIFICANT PREMALIGNANT POTENTIAL The most common precursor lesions to malignant melanoma are the dysplastic nevus, the congenital nevus, and lentigo maligna.
Fig. 2. This dysplastic nevus exhibits the “pebbly” surface common to many such lesions. A pink-tan color and irregular border are features commonly seen in dysplastic nevi.
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of the dysplastic nevus. When occurring in association with a pre-existing benign nevus, the lesion appears as an irregular flare, either macular or slightly raised, surrounding the papular nevic portion. When the flare and papule are both present, they are the clinical manifestation of the "shoulder" effect, which histologically describes the atypical melanocytic hyperplasia extending beyond the pre-existing benign nevic component. Marked variability from lesion to lesion is characteristic. Some patients may exhibit hundreds of dysplastic nevi, occurring frequently on the scalp, doubly covered areas of the body (breasts in women and buttocks) and the legs [5,1 I]. The incidence of dysplastic nevi varies from 2% to 9% [12,13]. The presence of the lesion marks an increased risk of developing malignant melanoma, often in the lesion itself [14]. Clark and group have found that as many as 92OA of melanomas in patients with familial dysplastic nevus syndrome arose in extant dysplastic nevi. A patient is considered to have the dysplastic nevus syndrome, inherited as an autosomal dominant trait with variable penetrance, when found to have multiple dysplastic nevi and at least two family members with melanoma [5,9]. In the general population, absent a family history of dysplastic nevi or melanoma, sporadic dysplastic nevi have been found in 18-430/0 of patients with malignant melanoma [I 5, 161 with variation in risk dependent on solar exposure, cutaneous sensitivity, and other factors. It is clear, then, that the dysplastic nevus is a marker for the heritable trait to develop malignant melanoma. Likewise, it is clear that an individual dysplastic nevus can be a precursor for malignant melanoma. Actual
risk is dependent on a variety of factors, including clinical atypia of the lesion [ 171, sun sensitivity, solar exposure, genetic predisposition, and possibly others, with a cumulative and variable effect [4]. Histologic character, The dysplastic nevus has characteristic histologic features, which include both architectural and cytologic atypia [5,18,19]. The Melanoma Programme of the World Health Organization (WHO) sponsored a concordance study proposing the clinical and histopathologic criteria for diagnosis. Table I reviews the histologic criteria [20]. In this study, dysplastic nevi were diagnosed only when both the major and at least two of the minor criteria were met. Other studies have shown reliable histopathologic concordance [22,23]. In our practice, if a lesion exhibits cytologic atypia without the architectural features, it is diagnosed as a junctional or compound nevus with cytologic features suggestive of the dysplastic nevus. Conversely, if all the architectural features are present without cytologic atypia, the lesion is diagnosed as a compound or junctional nevus with the architectural features of the dysplastic nevus. Both types of lesion may occur sporadically or in the setting of the familial dysplastic nevus syndrome [21]. Differential diagnosis. Common benign acquired nevi are usually no greater than 5 mm across. The ordinary freckle is commonly associated with sun exposure in childhood, but any lesion appearing in adult life on sun-exposed skin, or any lesion with greatest diameter of more than 5 mm, must raise the differential diagnosis of dysplastic nevus, lentigo maligna, or a pigmented seborrheic keratosis. The congenital nevus may assume a size larger than
TABLE I. Criteria for Diagnosis of a Dvsolastic Nevus Major Criteria 1. A basilar proliferation of nevomelanocytes along the dermoepidermal junction. usually extending beyond any pre-existing dermal
component by three rete ridges or more. 2. Cells disposed in one of the two following patterns, or a combination thereof: Lentiginous melanocytic hyperplasia: dyshesive cells in irregular nests are scattered along and between elongate rete. These cells show marked irregularities in nuclear size. shape, and hyperchromasia. Epithelioid-cell dysplasia: epithelioid cells disposed in prominent junctional nests, and often also in single-cell array, along the dermoepidermal junction of a normal or hyperplastic epidermis. The cells have large nuclei with irregular chromatin distribution and prominent nucleoli. Their cytoplasm exhibits fine melanin granularity. Minor Criteria 1. Collagen disposition in one or both of two definite patterns: concentric eosinophilic fibrosis. in which a dense zone of acellular,
brightly eosinophilic collagen entraps rete ridges; and lamellar fibroplasia, in which delicate layers of collagen, interspersed with fibroblasts, lie beneath the ends of hyperplastic rete in parallel array. 2. Lymphocytic infiltrates occurring in the papillary dermis. especially beneath areas of remarkable cytologic atypia of mclanocytes. 3. Vascularization in the form of prominent vessels that may be newly formed or existing vessels showing hypertrophied endothelial cells. 4. Fusion or bridging of rete ridges by nests of melanocytes." "We have found this last criterion to be particularly helpful in supporting the diagnosis of dysplastic
nevus.?'
Do Melanoma Precursors Exist? 361
5 mm; however, history and/or histology may help establish its congenital origin (see discussion of congenital nevus). Congenital dysplastic nevi have been observed, although seldom; they give a complicated histologic picture [24]. Early malignant melanoma differs from the dysplastic nevus in its striking degree of discoloration, better-defined contours, and irregularly palpable areas. The lentiginous junctional nevus and lentiginous compound nevus are clinically indistinguishable from the common acquired junctional nevus and compound nevus. Histopathologically, the similarity remains, but there are added nevomelanocytes forming nests, and in single-cell array, in the basal layer of the epidermis. There is no cytologic atypia, and there is a symmetrical distribution around the dermal nests. The pigmented spindle-cell nevus is a lesion that usually occurs on the dorsal surfaces, predominantly on the lower extremities of young women; but it may occur at any time of life, in either sex, and anywhere on the body. Characteristically, the lesions are clinically tan to dark brown, although pigmentation may be slight; they may be flat or raised. The pigmented spindle cell nevus has intraepiderma1 and compound variants [25].The intraepidermal variant is composed of discrete nests of uniform spindle-shaped cells resembling the cells of the compound nevus of Spitz. The cells exhibit varying degrees of pigmentation. Dermal melanophages are frequently present. The compound type of pigmented spindle cell nevus has discrete intraepidermal nests, but also a central dermal mass or expansile nest that widens the papillary dermis. The pigmented spindle cell nevus may resemble histologically the dysplastic nevus, but is distinguished by the absence of pleomorphism and characteristic stromal changes. Congenital Nevus The normal congenital nevus and its variants. The congenital nevus and its many variants are usually clinically stable; they may be expected to follow a benign course. However, some variations may presage malignancy or be malignant, including minimal-deviation melanomas and frank melanomas. The congenital nevus encompasses a broad category, both clinically and histologically. Pigmented lesions present at birth may vary in size from a few millimeters to many centimeters, and some congenital nevi extend over much of the body surface. These lesions may vary in color from tan to dark brown. At birth, they are often flat or slightly raised, becoming increasingly raised and darker with age. Two distinct categories deserve recognition. These are the giant hairy nevus, or garment nevus, and the
small congenital nevus. The garment nevus may in rare cases extend to cover almost the entire body surface; or it may be limited to the back or an extremity or large portions thereof (Fig. 3). While less dramatic clinically, the so-called small congenital nevus is usually a few centimeters in size (Fig. 4).It is practical to consider any lesion larger than 1.5 centimeters that does not exhibit dysplastic features as a small congenital nevus [3,26]. Some congenital nevi may be only a few millimeters across and indistinguishable from benign acquired nevi. Histologically, the presence of nevic cells in appendages in the lower third of the reticular dermis is characteristic when present. The cells are distributed in single-cell array. They often infiltrate the subcutaneous fat and its septa. Nevus cells may be found in the papillae and epithelium of hair follicles, in multiple arrectores pili, and sometimes in sebaceous glands
Fig. 3. A giant congenital nevus exhibits "bathing-trunk" distribution.
Fig. 4. Oval, centrally dark brown lesion with irregular border was noted at birth on the trunk. Note prominence of hairs.
362 Mihm et al.
[27]. Although unusual, these lesions may show nevic cells in a dramatic perivascular array which may resemble a lymphocytic infiltrate. Multiple lymphatic involvement and nevic cells in walls of arteries and veins, in nerves, or in perineurial spaces may be seen [28]. Some congenital nevi affect subcutaneous structures and may extend into muscle, bone, and even, in rare cases, from the skin of the scalp into the brain substance. On the other hand, a congenital nevus may be confined to the papillary dermis and be histologically indistinguishable from a lentigo, a junctional nevus, or an acquired compound nevus. The variant that resembles lentigo is called congenital nevus spilus, and a congenital dysplastic nevus spilus has been documented [24]. Malignant potential. The spectrum of melanocytic atypism in congenital nevi ranges from slightly atypical melanocytic hyperplasia to minimal deviation melanoma to outright, fully evolved malignancy. More rarely, a variety of other malignant tumors may occur in these lesions; these malignancies include a group of soft tissue tumors. Analyses of malignant potential in the congenital nevus have usually distinguished only between small and large nevi. Definite evidence of origin of malignant melanoma in both types exists. As far as malignant potential of giant hairy nevi is concerned, estimates of the association of melanoma with giant nevi diagnosed as congenital by history is 5-58% [29,30]. A lifetime risk has been estimated at 6.3%. Benign and other types of malignant tumors including sarcomas have been reported tooccuringiant hairynevi[3,21,31]. The risk of malignant transformation in small congenital nevi has been estimated at 3-20% [3,26,29,32, 331. I t appears safe to say that there is an increased risk of these small lesions as well. However, as of this time, no statistically documentable prospective study of either small or large congenital nevi and their relationship to the development of melanoma has been carried out. Histology of malignant degeneration. A malignant melanoma arising in a congenital nevus is histologically distinctive. It is very common for nevi biopsied at birth to show atypism of the superficial component; however, this atypism gives way to benign dermalnevic maturation with increasing depth. By contrast, malignant melanoma lacks this gradient of maturation, comprising rather a separate, distinct, invasive nodule. It contains a monomorphous population of atypical cells and may show atypical mitoses, necrosis of single cells or groups of tumor cells, and often an isolated inflammatory response about the malignant portion of the lesion. Malignant melanoma has been noted to arise in a congenital dysplastic nevus spilus,
where it exhibited progressive atypia adjacent to the melanomatous focus [24]. Management. The management of congenital nevi is a problem for the clinician. Most centers recommend conservative observation, including periodic follow-up, with photographic documentation. However, in some cases, surgical intervention is appropriate, especially when suspicious features or changes are seen. The management of each case must be individually considered. Lentigo Maligna Development. Lentigo maligna is a lesion of sunexposed surfaces. Its onset may be noted as early as 20 years of age, but it usually appears in later life. It characteristically begins as a small, tan, freckle-like lesion that progresses both in size and in darkness. It can grow to several centimeters across, all the while exhibiting variations in shades of brown to dark brown to black, often with flecks of dark brown or black. The lesion remains flat throughout, with the appearance of a “stain of varnish” (Fig. 5). Its reflectance of incident light is similar to that of the adjacent skin, usually shiny. This reflectance helps to differentiate it from the duller flat pigmented keratoses. Partial regression of the lesion is a characteristic feature; this change appears as flesh-colored or whitish areas at the edge of or within the macule. The process of enlargement has been noted for more than 50 years in one case [34] before palpable areas
Fig. 5 . This large lesion exhibited the characteristic irregularities in border and variations in tan and brown observed in lentigo maligna. This lesion was present for approximately 10 years before the patient sought advice. Two punch biopsies were performcd, visible as the two round crustcd arcas.
Do Melanoma Precursors Exist? 363
coincident with invasive melanoma supervened. takes on the appearance of fully evolved melanoma Throughout its macular phase, the lesion is biologi- cells, with the more characteristic spindle or epithelically innocuous, with no evidence of metastatic poten- oid shapes, in large aggregates and in pagetoid array, tial, and is considered a clinical precursor to malignant and can be clearly diagnosed as malignant melanoma melanoma. Lentigo maligna melanoma accounts for a in situ. We consider this lesion, lentigo maligna, a small percentage, variably estimated as high as lo%, precursor until it has taken one of these two paths to of melanomas in the Caucasian population [33- 361. melanoma. The incidence of melanoma supervening in lentigo OTHER POSSIBLE CUTANEOUS maligna is unknown but has been estimated to be as PRECURSORS high as 33% [34]. However, a much lower risk of develAtypical Cutaneous Melanocytic Hyperplasia opment of malignant melanoma has been described: In addition to the lesions described above, a prithe incidence of lentigo maligna in a normalized sample of the population of the United States in the age mary proliferation of atypical nevomelanocytes may range of 1-74 years was compared with the actual occur anywhere in the skin without any of the spenumber of lentigo maligna melanomas among patients cific histologic architectural features. This process with cutaneous malignant melanoma. On the basis of clinically is an irregularly shaped macule with irreguthis study, the lifetime risk of developing melanoma in lar coloration. In our experience, this lesion histolentigo maligna was estimated to be 5% or slightly less logically exhibits cells of varying degrees of atypism, which we have in cases noted in association with WI. Gradient of histology. Histologically, lentigo melanoma. The melanoma may occur either within maligna exhibits a proliferation of melanocytes that or contiguous to the atypical hyperplasias. We desigvary in size and shape in an atrophic epidermis. Ini- nate such lesions as atypical melanocytic hyperplasia tially, there is a normal (if enlarged) appearance to and consider that they may be precursors to maligthese melanocytes, which appear randomly disposed. nant melanoma. As the lesion evolves the basilar region undergoes rePRECURSOR LESIONS OF MALIGNANT placement by lentigo maligna’s pleomorphic cells, MELANOMA, AND THEIR SIMULANTS, with some giant cells discernible. Nests appear, usually AFFECTING MUCOSAL AND PARAMUCOSAL composed of spindle-shaped cells, and taking the SURFACES shape of a “swallow’s nest.” Cells also extend along Hypermelanosis and Hyperplasia of Melanocytes the external root sheaths of hair follicles, even into the Mucosal melanoses occur in the conjunctiva, the papillae and sometimes eccrine ducts. With the advent of nesting, a tendency for single-cell invasion appears, oral cavity, and the mucosa and paramucosa of the sometimes as pagetoid spread (single-cell and occa- vulva. They may be found with or without adjacent sionally nested spread upward into the epidermis). An melanocytic hyperplasia. Vulvar melanosis: a simulant of melanoma. The inflammatory infiltrate is commonly present with or without the presence of single-cell invasion. The der- vulvar melanoses are of particular interest, because mis involved by lentigo maligna usually demonstrates they may mimic clinically the radial growth phase of vulvar melanoma. These lesions usually are tan to significant solar elastosis. Progression to melanoma. Clark’s classification in- dark brown and may vary in size up to several centicludes lentigo maligna among the diagnostic types of meters. Histologically, there is usually marked hyperradial growth phase melanoma [6]. We, however, con- melanosis without hyperplasia of melanocytes. N o resider that there is a distinct precursor phase of lentigo lationship to malignant melanoma has been maligna composed of a heterogeneous population of heretofore shown, but insufficient series of cases have atypical cells that are discontiguous and randomly dis- been prospectively studied. Benign nevi and benign posed. There is virtually no propensity for invasion melanocytic hyperplasias occur. However, an atypical before the stage of striking contiguity and marked melanocytic hyperplasia can involve the vulva and pleomorphism. As the histologic picture progresses to may be premalignant. Clinically, it forms a macule of this contiguity, there is formation of nests or forma- variable size and has irregular variations in color, with tion of a “sheet” of atypical melanocytes that appears a range from tan to dark brown to black. Borders are to replace keratinocytes in the the basilar region. Such irregular. Histologically, these lesions usually show lentigichange is often associated with single-cell invasion, which is usually detected only after multiple sections. nous melanocytic hyperplasia with evidence of atypia. Indeed, this change may represent an in situ compo- The cells, at first randomly disposed, become contigunent; however, at times the intraepidermal process ous as the cellular atypia appears to become more
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severe. The more atypical lesions may show prominent nesting of pleomorphic cells. Conjunctival melanosis: when is it a precursor? The hypermelanosis associated with non-nevoid melanocytic hyperplasia of the conjunctiva has been a subject of much discussion, with various terms proposed to describe it, including diffuse hypermelanosis, precancerous melanosis, or cancerous melanosis. We have addressed this question in a review and proposed a classification [38]. The lesion presents as a flat pigmented conjunctival flare, usually in middle-aged persons. It is almost always unilateral, although bilateral diffuse melanoses have been observed. Its course is one of progressive evolution, but often associated with partial regression. In some cases, the pigmentation is present for decades before nodules of melanoma appear. Histologically, the macules may exhibit hypermelanosis only or melanocytic hyperplasia that is benign or atypical. The hypermelanoses with atypia are very much like those of lentigo maligna, which may be characterized as a cutaneous atypical melanocytic hyperplasia. Our proposed classification of non-nevoid pigmented lesions of the conjunctiva includes (1) conjunctival hypermclanosis without melanocytic hyperplasia, (2) conjunctival melanosis with benign melanocytic hyperplasia, and (3) atypical melanocytic hyperplasia of a lentiginous or transepithelial type [38]. We know of documented cases in which melanoma has supervened in lesions containing basilar hypermelanosis without evidence of associated atypical melanocytic hyperplasia. However, it is unclear to us whether these lesions truly represent a precursor or if the melanomatous event is coincidental. We propose that until more evidence is accumulated concerning the melanoses without melanocytic hyperplasia, the designation of precursor be reserved for those described in (3) and possibly also those in (2). In fact, an evolutionary state may exist in these lesions from (2) to (3). To our knowledge, no statistically documented, prospective, randomized studies have addressed this point. Nevertheless, we must include at least pigmented conjunctival lesions with atypical melanocytic hyperplasia as precursor lesions to malignant melanoma. SAMPLING AND REMOVAL OF PRECURSOR LESIONS The clinical diagnosis of a nevomelanocytic tumor has little validity until a pathologic confirmation has been made. That confirmation requires a full, clear histologic picture. To obtain that picture, any lesion suspected of being an atypical melanocytic proliferation, and particularly a precursor to malignant mela-
noma, should be excised. We do not recommend incisional biopsies or trephine (punch) biopsies, except in cases of lesions so large that excision would require extensive surgery to areas such as the face. We do not recommend the shave-biopsy technique in pigmented lesions of any sort. The reasons for this recommendation are obvious to us: any atypical process that may underlie the area of a shave biopsy is lost to evaluation. In dealing with any atypical lentiginous proliferation of melanocytes, whether of a dysplastic nevus, lentigo maligna, or others, a shave biopsy almost always leaves residual melanocytic proliferation in the appendages. If the lesion is indeed a malignant melanoma, the shave-biopsy technique often makes difficult the clear assessment -even after re-excision-of the level and depth of invasion. The management of congenital nevi poses special problems. We have dealt with these in the discussion of this precursor. We emphasize here that any area in a congenital nevus that is suspected of malignant degeneration should be excised with a margin appropriate to the site. CONCLUSION In this review, we answer the question of whether precursor lesions exist to malignant melanoma; the answer is affirmative. We describe lesions as the dysplastic nevus, the congenital nevus, lentigo maligna, and the hypermelanosis of the conjunctiva with melanocytic atypia. Suggestions for handling precursor lesions are proposed. REFERENCES 1. Foulds L: “Neoplastic Development.” London: Academic Press. 1969, pp 69-75. 2. Gruber SB, Barnhill RL, Stenn KS, Roush GC: Nevomelanocytic proliferations in association with cutancous malignant melanoma: A multivariate analysis. J Am Acad Dermatol 21: 773-780, 1989. 3. Balch CM. Soong S-J, Shaw HM: A comparison of worldwide melanoma data. In Balch CM, Milton GW (eds): “Cutaneous Melanoma: Clinical Management and Treatment.” Philadelphia: JB Lippincott, 1985, pp 507-518. 4. Rhodes AR, Weinstock MA, Fitzpatrick TB, et al: Risk factors for cutaneous melanoma: A practical method of recognizing predisposed individuals. JAMA 258: 3146- 31 54, 1987. 5 Clark WH Jr, Reimer RR, Greene MH, et al: Origin of familial melanomas from heritable melanocytic lesions: The “B-K syndrome.” Arch Dermatol 114: 732-738, 1978. 6 Clark WH Jr, From L, Bernardino E, Mihm MC Jr: The histogenesis and biologic behavior of primary human malignant melanoma of the skin. Cancer Rcs 29: 705-726, 1969. 7 Sison-Torre EQ, Ackerman AB: Melanosis of the vulva: A clinical simulator of malignant melanoma. Am J Dermatopatho1 ~ ( s u P P ~51-60, ): 1985. 8 Mihm MC Jr, Googe PB: “Problematic Pigmented Lesions: A Case Method Approach.” Philadelphia: Lea & Febiger, 1990, pp 3-23 9. Elder DE, MacKie RM: Dysplastic melanocytic nevi: Their nature and significance. In Cascinelli N, Veronesi U, Santinami M (eds): “Cutaneous Melanoma: Biology and Management,” Milan: Masson, 1990, pp 93-104.
Do Melanoma Precursors Exist? 365 10. Lynch HT, Frichot BC, Lynch JF: Familial atypical multiple mole-melanoma syndrome. J Med Genet 15: 352-356, 1978. 11. Elder DE, Goldman LI, Goldman SC, et al.: The dysplastic nevus syndrome: A phenotypic association of sporadic cutaneous melanoma. Cancer 46: 1787-1794, 1980. 12. Nordlund JJ, Kirkwood J, Forget BM, et al: Demographic study of clinically atypical (dysplastic) nevi in patients with melanoma and comparison subjects. Cancer Res 45: 18551861, 1985. 13. Crutcher WA, Sagebiel RW: Prevalence of dysplastic naevi in a community practice. [Letter.] Lancet 1: 729, 1984. 14. Clark WH Jr, Elder DE, Guerry D IV, et al: A study of tumor progression: The precursor lesions of superficial spreading and nodular melanoma. Hum Pathol 15: 1147-1 165, 1984. 15. Grob JJ, Andrac L, Romano MH, et al: Dysplastic naevus in non-familial melanoma. A clinicopathological study of 101 cases. Br J Dermatol 118: 745-752, 1988. 16. Halpern AC, Guerry D IV, Elder DE, et al: Case-control study of dysplastic nevi and melanoma. Clin Res 37:869A, 1989 (abst). 17. Swerdlow AJ, Green A. Melanocytic naevi and melanoma: An epidemiological perspective. Br J Dermatol 117: 137- 146, 1987. 18. Rhodes AR, Mihm M C Jr, Weinstock MA: Dysplastic melanocytic nevi: A reproducible histologic definition emphasizing cellular morphology. Mod Pathol, 2: 306-319, 1989. 19. Barnhill RL, Roush GH, Duray PH: Correlation of histologic architectural and cytoplasmic features in atypical (dysplastic) nevomelanocytic nevi. Hum Pathol 21: 51 -58, 1990. 20. Clemente C, Cochran A, Elder DE, et al: Histopathologic correlation in the diagnosis of dysplastic nevi: A concordance study. Hum Pathol 22:313-319, 1991. 21. Mihm MC Jr, Googe PB: “Problematic Pigmented Lesions: A Case Method Approach.” Philadelphia: Lea & Febiger, 1990, p 254. 22. Steijlen PM, Bergman W, Hermans J, et al: The efficacy of histopathological criteria required for diagnosing dysplastic naevi. Histopathology 12: 289-300, 1988. 23. Black WC, Hunt WC: Histologic correlations with the clinical diagnosis of dysplastic nevus. Am J Surg Pathol 14: 44-52, 1990. 24. Rhodes AR, Mihm MC Jr: Origin of cutaneous melanoma in a congenital dysplastic nevus spilus. Arch Dermatol 126: 500505, 1990.
25. Barnhill RL, Mihm MC Jr: Pigmented spindle-cell nevus and its variants: Distinction from melanoma. Br J Dermatol 121: 717-726, 1989. 26. Illig L, Widener F, Hundeiker M, et al: Congenital nevi 5 10 cm as precursors to melanoma: 52 cases, a review, and a new conception. Arch Dermatol 121: 1274-1281, 1985. 27. Mihm MC Jr, Googe PB: “Problematic Pigmented Lesions: A Case Method Approach.” Philadelphia: Lea & Febiger, 1990. pp 127-142. 28. Mark GM, Mihm MC Jr, Liteplo MG, et al: Congenital melanocytic nevi of the small and garment type: Clinical, histological, and ultrastructural studies. Hum Pathol 4: 395-418. 1973. 29. Rhodes AR, Sober AJ, Day CL, et al: The malignant potential of small congenital nevocellular nevi: An estimate of association based on a histologic study of 234 primary cutaneous melanomas. J Am Acad Dermatol 60: 230-241, 1982. 30. Reed WB, Becker SW Jr, Nickel WR: Giant pigmented nevi, melanoma, and leptomenigeal melanocytosis. AMA Arch Dermatol 91: 100-119, 1965. 31. Rhodes AR, Wood WC, Sober AJ, et al: Non-epidermal origin of malignant melanoma associated with a giant congenital nevocellular nevus. Plast Reconstr Surg 67: 782-790. 1981. 32. Rhodes AR, Melski JW: Small congenital nevocellular nevi and the risk of cutaneous melanoma. J Pediatr 100: 219-224. 1982. 33. Rhodes AH: Neoplasm: benign neoplasias, hyperplasias and dysplasias of melanocytes. In Fitzpatrick TB, Eisen AZ, Wolff K, et a1 (eds): “Dermatology in General Medicine.” New York: McGraw Hill, 1987, p 877. 34. Clark WH Jr, Mihm MC Jr: Lentigo maligna and lentigo maligna melanoma. Am J Pathol 55: 39-67, 1969. 35. McGovern VJ: “Malignant Melanoma, Clinical and Histological Diagnosis.” New York: John Wiley & Sons, 1976, p 55. 36. Murphy GF, Mihm MC Jr: Histologic reporting of malignant melanoma. In Mihm MC Jr, Murphy GF, Kaufman N (eds): “Pathobiology and Recognition of Malignant Melanoma.” Baltimore: Williams & Wilkins, 1988, pp 79-93. 37. Weinstock MA, Sober AJ: Risk of progression of lentigo maligna to lentigo maligna melanoma. Br J Dermatol 16: 303310, 1987. 38. Guillen FJ, Albert DM, Mihm MC Jr: Pigmented melanocytic lesions of the conjunctiva-A new approach to their classification. Pathology 17: 275-280, 1985.
Precursor Lesions of Melanoma: Do They Exist? MARTIN C. MIHM, JR.,
RAYMOND L. BARNHILL, MD, ARTHUR J. SOBER, MD, AND MANUEL HOWE HERNANDEZ From the Dermatopathology Division and Dermatology Service, Massachusetts General HospitallHarvard Medical School, Boston, Massachusetts MD,
The question of whether definite precursors to melanoma exist is answered in the affirmative. Three cutaneous lesions likely to be such precursors are described and discussed as to their clinical and histologic appearance and incidence. Additionally, a type of conjunctival melanosis that has been associated with malignant melanoma of the conjunctiva is discussed and an attempt is made to define it; a proposed classification of this entity is reviewed. Basic approaches to management and analysis of precursor lesions are elaborated. @
1992 Wiley-Liss. Inc ~~
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KEY WORDS:melanoma precursor, dysplastic nevus, congenital nevus, lentigo maligna, melanocytic hyperplasia, malignant melanoma
INTRODUCTION Tumorigenesis in the skin, as in most other organ systems, often takes place in premalignant hyperplasias [ 11. Specifically, a proportion of melanomas develop with some degree of predictability from precursor lesions that cannot themselves be diagnosed as melanoma [2]. This is not controversial. What is at issue is whether these precursors can be identified reliably, using clinical or histologic criteria, so that the likelihood of progression to the stage favoring metastasis is reduced. This is a critically important question because melanoma detected early responds much better to therapy than do its later stages [ 3 ] . While the reported incidence of malignant melanoma has increased, so have survival rates from the disease. Greater knowledge about, and increased public attention to, the character of the disease and its precursors may be responsible for both trends [4]. The identification and description of the dysplastic nevus [5],an important precursor and marker for melanoma in patients with familial melanoma, has led to continuing research to more precisely define its significance in individuals with “sporadic” dysplastic nevi. The description of this lesion may be considered to build on the 1969 distinction of the diagnostic subtypes of malignant melanoma [6]. 0 1992 Wiley-Liss, Inc.
Histopathologic confirmation of diagnosis of any pigmented lesion, whether benign or a precursor lesion, such as the dysplastic nevus, is the definitive test, much as it is for melanoma. This article reviews the criteria for diagnosis in the precursor lesions capable of evolving into malignant melanoma and attempts to clarify what is known about their development and distinction from other lesions. Clarity of definition can help determine relationships among other factors that are more easily subjected to statistical analysis, such as genetic markers and environmental factors. Although these precursors vary a great deal in character, incidence, and risk of melanoma, the most important cutaneous lesions are the dysplastic nevus, congenital nevus, and lentigo maligna. This paper reviews the clinical and histopathologic features of these lesions and also reviews mucosal and paramucosal lesions that appear to increase melanoma risk, especially those affecting the conjunctiva. In addition, a spectrum of benign lesions are discussed, some of which clinically resemble malignant melanoma or one of its precursors. Address reprint requests to Martin C. Mihm, M.D., Dcrmatopathology Division, Massachusetts General Hospital / Harvard Medical School. Fruit Street, Boston, M A 021 14.
Do Melanoma Precursors Exist? 359
BENIGN LESIONS
Dysplastic Nevus
Lentigo and Other Common Acquired Benign Lesions Significance of familial and sporadic lesions. The Certain cutaneous lesions exhibit hypermelanosis dysplastic nevus, a precursor of and marker for heritawithout melanocytic hyperplasia. A hypermelanosis ble malignant melanoma, may occur at any site on the of special interest occurs on the vulva. This lesion, body. Clinically, while varying descriptions have been called vulvar melanosis, may vary in size from a few proposed [9,lo], most descriptions agree that the dysmillimeters to a few centimeters across and may ex- plastic nevus is usually greater than 5 mm across, has hibit irregularities in pigmentation and border con- irregular coloration, and usually includes some pinktour. It may therefore be confused with vulvar mela- ish hue in an otherwise tan to brown lesion. Marked irregularities in color distribution and in the contour noma, and is discussed in detail below [7]. of the border are common (Figs. 1,2). A similar variaBenign acquired nevomelanocytic proliferations are bility exists in size. Some lesions, especially in a patient not usually difficult to recognize, usually less than 5 with familial dysplastic nevus syndrome, may be only mm across. They include lentigines and nevi that are a few millimeters across, yet exhibit histologic features usually symmetrical, well demarcated, and stable. They vary in color from tan to dark brown, although some dermal nevi may be flesh colored. These lesions have specific histologic characteristics. Lentigines are associated with a proliferation of nevomelanocytes along the dermoepidermal junction in hyperplastic rete ridges. Some slight stromal proliferation may be noted, and dermal melanophages are often present. The word “lentiginous” derives from the distribution of melanocytes in lentigo, but is used more broadly to refer to a similar single-cell proliferation in a normal, hyperplastic, or atrophic epidermis. The common acquired nevus is a lesion, often clinically tan and slightly raised or exhibiting a papule with a symmetrical rim of pigmentation around its edges. Histologically, the common acquired junctional nevus shows well-defined nests of nevomelanocytes with cytoplasm that is often fusiform and rather uniform, spindle-shaped nuclei containing tiny dotlike nucleoli Fig. 1. Rectangular appearance of this dysplastic nevus contrasts in coherent nests at the tips of the rete ridges. A dermal strikingly with round or oval shapes of benign acquired nevi. component, when present, is confined to the papillary dermis, without significant reticular -dermal involvement. In the common acquired nevus, the junctional component often extends beyond its dermal counterpart. Any such extension, however, is usually symmetrical. There may be a proliferation of obviously benign single cells between the nests. In sum, common benign acquired nevi are architecturally distinct and do not show cytologic atypia. They do not involve the reticular dermis to any significant extent. Some congenital nevi cannot be distinguished clinically or histologically from acquired nevi, as discussed in detail in the sections below [8]. CUTANEOUS MELANOCYTIC LESIONS WITH SIGNIFICANT PREMALIGNANT POTENTIAL The most common precursor lesions to malignant melanoma are the dysplastic nevus, the congenital nevus, and lentigo maligna.
Fig. 2. This dysplastic nevus exhibits the “pebbly” surface common to many such lesions. A pink-tan color and irregular border are features commonly seen in dysplastic nevi.
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of the dysplastic nevus. When occurring in association with a pre-existing benign nevus, the lesion appears as an irregular flare, either macular or slightly raised, surrounding the papular nevic portion. When the flare and papule are both present, they are the clinical manifestation of the "shoulder" effect, which histologically describes the atypical melanocytic hyperplasia extending beyond the pre-existing benign nevic component. Marked variability from lesion to lesion is characteristic. Some patients may exhibit hundreds of dysplastic nevi, occurring frequently on the scalp, doubly covered areas of the body (breasts in women and buttocks) and the legs [5,1 I]. The incidence of dysplastic nevi varies from 2% to 9% [12,13]. The presence of the lesion marks an increased risk of developing malignant melanoma, often in the lesion itself [14]. Clark and group have found that as many as 92OA of melanomas in patients with familial dysplastic nevus syndrome arose in extant dysplastic nevi. A patient is considered to have the dysplastic nevus syndrome, inherited as an autosomal dominant trait with variable penetrance, when found to have multiple dysplastic nevi and at least two family members with melanoma [5,9]. In the general population, absent a family history of dysplastic nevi or melanoma, sporadic dysplastic nevi have been found in 18-430/0 of patients with malignant melanoma [I 5, 161 with variation in risk dependent on solar exposure, cutaneous sensitivity, and other factors. It is clear, then, that the dysplastic nevus is a marker for the heritable trait to develop malignant melanoma. Likewise, it is clear that an individual dysplastic nevus can be a precursor for malignant melanoma. Actual
risk is dependent on a variety of factors, including clinical atypia of the lesion [ 171, sun sensitivity, solar exposure, genetic predisposition, and possibly others, with a cumulative and variable effect [4]. Histologic character, The dysplastic nevus has characteristic histologic features, which include both architectural and cytologic atypia [5,18,19]. The Melanoma Programme of the World Health Organization (WHO) sponsored a concordance study proposing the clinical and histopathologic criteria for diagnosis. Table I reviews the histologic criteria [20]. In this study, dysplastic nevi were diagnosed only when both the major and at least two of the minor criteria were met. Other studies have shown reliable histopathologic concordance [22,23]. In our practice, if a lesion exhibits cytologic atypia without the architectural features, it is diagnosed as a junctional or compound nevus with cytologic features suggestive of the dysplastic nevus. Conversely, if all the architectural features are present without cytologic atypia, the lesion is diagnosed as a compound or junctional nevus with the architectural features of the dysplastic nevus. Both types of lesion may occur sporadically or in the setting of the familial dysplastic nevus syndrome [21]. Differential diagnosis. Common benign acquired nevi are usually no greater than 5 mm across. The ordinary freckle is commonly associated with sun exposure in childhood, but any lesion appearing in adult life on sun-exposed skin, or any lesion with greatest diameter of more than 5 mm, must raise the differential diagnosis of dysplastic nevus, lentigo maligna, or a pigmented seborrheic keratosis. The congenital nevus may assume a size larger than
TABLE I. Criteria for Diagnosis of a Dvsolastic Nevus Major Criteria 1. A basilar proliferation of nevomelanocytes along the dermoepidermal junction. usually extending beyond any pre-existing dermal
component by three rete ridges or more. 2. Cells disposed in one of the two following patterns, or a combination thereof: Lentiginous melanocytic hyperplasia: dyshesive cells in irregular nests are scattered along and between elongate rete. These cells show marked irregularities in nuclear size. shape, and hyperchromasia. Epithelioid-cell dysplasia: epithelioid cells disposed in prominent junctional nests, and often also in single-cell array, along the dermoepidermal junction of a normal or hyperplastic epidermis. The cells have large nuclei with irregular chromatin distribution and prominent nucleoli. Their cytoplasm exhibits fine melanin granularity. Minor Criteria 1. Collagen disposition in one or both of two definite patterns: concentric eosinophilic fibrosis. in which a dense zone of acellular,
brightly eosinophilic collagen entraps rete ridges; and lamellar fibroplasia, in which delicate layers of collagen, interspersed with fibroblasts, lie beneath the ends of hyperplastic rete in parallel array. 2. Lymphocytic infiltrates occurring in the papillary dermis. especially beneath areas of remarkable cytologic atypia of mclanocytes. 3. Vascularization in the form of prominent vessels that may be newly formed or existing vessels showing hypertrophied endothelial cells. 4. Fusion or bridging of rete ridges by nests of melanocytes." "We have found this last criterion to be particularly helpful in supporting the diagnosis of dysplastic
nevus.?'
Do Melanoma Precursors Exist? 361
5 mm; however, history and/or histology may help establish its congenital origin (see discussion of congenital nevus). Congenital dysplastic nevi have been observed, although seldom; they give a complicated histologic picture [24]. Early malignant melanoma differs from the dysplastic nevus in its striking degree of discoloration, better-defined contours, and irregularly palpable areas. The lentiginous junctional nevus and lentiginous compound nevus are clinically indistinguishable from the common acquired junctional nevus and compound nevus. Histopathologically, the similarity remains, but there are added nevomelanocytes forming nests, and in single-cell array, in the basal layer of the epidermis. There is no cytologic atypia, and there is a symmetrical distribution around the dermal nests. The pigmented spindle-cell nevus is a lesion that usually occurs on the dorsal surfaces, predominantly on the lower extremities of young women; but it may occur at any time of life, in either sex, and anywhere on the body. Characteristically, the lesions are clinically tan to dark brown, although pigmentation may be slight; they may be flat or raised. The pigmented spindle cell nevus has intraepiderma1 and compound variants [25].The intraepidermal variant is composed of discrete nests of uniform spindle-shaped cells resembling the cells of the compound nevus of Spitz. The cells exhibit varying degrees of pigmentation. Dermal melanophages are frequently present. The compound type of pigmented spindle cell nevus has discrete intraepidermal nests, but also a central dermal mass or expansile nest that widens the papillary dermis. The pigmented spindle cell nevus may resemble histologically the dysplastic nevus, but is distinguished by the absence of pleomorphism and characteristic stromal changes. Congenital Nevus The normal congenital nevus and its variants. The congenital nevus and its many variants are usually clinically stable; they may be expected to follow a benign course. However, some variations may presage malignancy or be malignant, including minimal-deviation melanomas and frank melanomas. The congenital nevus encompasses a broad category, both clinically and histologically. Pigmented lesions present at birth may vary in size from a few millimeters to many centimeters, and some congenital nevi extend over much of the body surface. These lesions may vary in color from tan to dark brown. At birth, they are often flat or slightly raised, becoming increasingly raised and darker with age. Two distinct categories deserve recognition. These are the giant hairy nevus, or garment nevus, and the
small congenital nevus. The garment nevus may in rare cases extend to cover almost the entire body surface; or it may be limited to the back or an extremity or large portions thereof (Fig. 3). While less dramatic clinically, the so-called small congenital nevus is usually a few centimeters in size (Fig. 4).It is practical to consider any lesion larger than 1.5 centimeters that does not exhibit dysplastic features as a small congenital nevus [3,26]. Some congenital nevi may be only a few millimeters across and indistinguishable from benign acquired nevi. Histologically, the presence of nevic cells in appendages in the lower third of the reticular dermis is characteristic when present. The cells are distributed in single-cell array. They often infiltrate the subcutaneous fat and its septa. Nevus cells may be found in the papillae and epithelium of hair follicles, in multiple arrectores pili, and sometimes in sebaceous glands
Fig. 3. A giant congenital nevus exhibits "bathing-trunk" distribution.
Fig. 4. Oval, centrally dark brown lesion with irregular border was noted at birth on the trunk. Note prominence of hairs.
362 Mihm et al.
[27]. Although unusual, these lesions may show nevic cells in a dramatic perivascular array which may resemble a lymphocytic infiltrate. Multiple lymphatic involvement and nevic cells in walls of arteries and veins, in nerves, or in perineurial spaces may be seen [28]. Some congenital nevi affect subcutaneous structures and may extend into muscle, bone, and even, in rare cases, from the skin of the scalp into the brain substance. On the other hand, a congenital nevus may be confined to the papillary dermis and be histologically indistinguishable from a lentigo, a junctional nevus, or an acquired compound nevus. The variant that resembles lentigo is called congenital nevus spilus, and a congenital dysplastic nevus spilus has been documented [24]. Malignant potential. The spectrum of melanocytic atypism in congenital nevi ranges from slightly atypical melanocytic hyperplasia to minimal deviation melanoma to outright, fully evolved malignancy. More rarely, a variety of other malignant tumors may occur in these lesions; these malignancies include a group of soft tissue tumors. Analyses of malignant potential in the congenital nevus have usually distinguished only between small and large nevi. Definite evidence of origin of malignant melanoma in both types exists. As far as malignant potential of giant hairy nevi is concerned, estimates of the association of melanoma with giant nevi diagnosed as congenital by history is 5-58% [29,30]. A lifetime risk has been estimated at 6.3%. Benign and other types of malignant tumors including sarcomas have been reported tooccuringiant hairynevi[3,21,31]. The risk of malignant transformation in small congenital nevi has been estimated at 3-20% [3,26,29,32, 331. I t appears safe to say that there is an increased risk of these small lesions as well. However, as of this time, no statistically documentable prospective study of either small or large congenital nevi and their relationship to the development of melanoma has been carried out. Histology of malignant degeneration. A malignant melanoma arising in a congenital nevus is histologically distinctive. It is very common for nevi biopsied at birth to show atypism of the superficial component; however, this atypism gives way to benign dermalnevic maturation with increasing depth. By contrast, malignant melanoma lacks this gradient of maturation, comprising rather a separate, distinct, invasive nodule. It contains a monomorphous population of atypical cells and may show atypical mitoses, necrosis of single cells or groups of tumor cells, and often an isolated inflammatory response about the malignant portion of the lesion. Malignant melanoma has been noted to arise in a congenital dysplastic nevus spilus,
where it exhibited progressive atypia adjacent to the melanomatous focus [24]. Management. The management of congenital nevi is a problem for the clinician. Most centers recommend conservative observation, including periodic follow-up, with photographic documentation. However, in some cases, surgical intervention is appropriate, especially when suspicious features or changes are seen. The management of each case must be individually considered. Lentigo Maligna Development. Lentigo maligna is a lesion of sunexposed surfaces. Its onset may be noted as early as 20 years of age, but it usually appears in later life. It characteristically begins as a small, tan, freckle-like lesion that progresses both in size and in darkness. It can grow to several centimeters across, all the while exhibiting variations in shades of brown to dark brown to black, often with flecks of dark brown or black. The lesion remains flat throughout, with the appearance of a “stain of varnish” (Fig. 5). Its reflectance of incident light is similar to that of the adjacent skin, usually shiny. This reflectance helps to differentiate it from the duller flat pigmented keratoses. Partial regression of the lesion is a characteristic feature; this change appears as flesh-colored or whitish areas at the edge of or within the macule. The process of enlargement has been noted for more than 50 years in one case [34] before palpable areas
Fig. 5 . This large lesion exhibited the characteristic irregularities in border and variations in tan and brown observed in lentigo maligna. This lesion was present for approximately 10 years before the patient sought advice. Two punch biopsies were performcd, visible as the two round crustcd arcas.
Do Melanoma Precursors Exist? 363
coincident with invasive melanoma supervened. takes on the appearance of fully evolved melanoma Throughout its macular phase, the lesion is biologi- cells, with the more characteristic spindle or epithelically innocuous, with no evidence of metastatic poten- oid shapes, in large aggregates and in pagetoid array, tial, and is considered a clinical precursor to malignant and can be clearly diagnosed as malignant melanoma melanoma. Lentigo maligna melanoma accounts for a in situ. We consider this lesion, lentigo maligna, a small percentage, variably estimated as high as lo%, precursor until it has taken one of these two paths to of melanomas in the Caucasian population [33- 361. melanoma. The incidence of melanoma supervening in lentigo OTHER POSSIBLE CUTANEOUS maligna is unknown but has been estimated to be as PRECURSORS high as 33% [34]. However, a much lower risk of develAtypical Cutaneous Melanocytic Hyperplasia opment of malignant melanoma has been described: In addition to the lesions described above, a prithe incidence of lentigo maligna in a normalized sample of the population of the United States in the age mary proliferation of atypical nevomelanocytes may range of 1-74 years was compared with the actual occur anywhere in the skin without any of the spenumber of lentigo maligna melanomas among patients cific histologic architectural features. This process with cutaneous malignant melanoma. On the basis of clinically is an irregularly shaped macule with irreguthis study, the lifetime risk of developing melanoma in lar coloration. In our experience, this lesion histolentigo maligna was estimated to be 5% or slightly less logically exhibits cells of varying degrees of atypism, which we have in cases noted in association with WI. Gradient of histology. Histologically, lentigo melanoma. The melanoma may occur either within maligna exhibits a proliferation of melanocytes that or contiguous to the atypical hyperplasias. We desigvary in size and shape in an atrophic epidermis. Ini- nate such lesions as atypical melanocytic hyperplasia tially, there is a normal (if enlarged) appearance to and consider that they may be precursors to maligthese melanocytes, which appear randomly disposed. nant melanoma. As the lesion evolves the basilar region undergoes rePRECURSOR LESIONS OF MALIGNANT placement by lentigo maligna’s pleomorphic cells, MELANOMA, AND THEIR SIMULANTS, with some giant cells discernible. Nests appear, usually AFFECTING MUCOSAL AND PARAMUCOSAL composed of spindle-shaped cells, and taking the SURFACES shape of a “swallow’s nest.” Cells also extend along Hypermelanosis and Hyperplasia of Melanocytes the external root sheaths of hair follicles, even into the Mucosal melanoses occur in the conjunctiva, the papillae and sometimes eccrine ducts. With the advent of nesting, a tendency for single-cell invasion appears, oral cavity, and the mucosa and paramucosa of the sometimes as pagetoid spread (single-cell and occa- vulva. They may be found with or without adjacent sionally nested spread upward into the epidermis). An melanocytic hyperplasia. Vulvar melanosis: a simulant of melanoma. The inflammatory infiltrate is commonly present with or without the presence of single-cell invasion. The der- vulvar melanoses are of particular interest, because mis involved by lentigo maligna usually demonstrates they may mimic clinically the radial growth phase of vulvar melanoma. These lesions usually are tan to significant solar elastosis. Progression to melanoma. Clark’s classification in- dark brown and may vary in size up to several centicludes lentigo maligna among the diagnostic types of meters. Histologically, there is usually marked hyperradial growth phase melanoma [6]. We, however, con- melanosis without hyperplasia of melanocytes. N o resider that there is a distinct precursor phase of lentigo lationship to malignant melanoma has been maligna composed of a heterogeneous population of heretofore shown, but insufficient series of cases have atypical cells that are discontiguous and randomly dis- been prospectively studied. Benign nevi and benign posed. There is virtually no propensity for invasion melanocytic hyperplasias occur. However, an atypical before the stage of striking contiguity and marked melanocytic hyperplasia can involve the vulva and pleomorphism. As the histologic picture progresses to may be premalignant. Clinically, it forms a macule of this contiguity, there is formation of nests or forma- variable size and has irregular variations in color, with tion of a “sheet” of atypical melanocytes that appears a range from tan to dark brown to black. Borders are to replace keratinocytes in the the basilar region. Such irregular. Histologically, these lesions usually show lentigichange is often associated with single-cell invasion, which is usually detected only after multiple sections. nous melanocytic hyperplasia with evidence of atypia. Indeed, this change may represent an in situ compo- The cells, at first randomly disposed, become contigunent; however, at times the intraepidermal process ous as the cellular atypia appears to become more
364 Mihm et al.
severe. The more atypical lesions may show prominent nesting of pleomorphic cells. Conjunctival melanosis: when is it a precursor? The hypermelanosis associated with non-nevoid melanocytic hyperplasia of the conjunctiva has been a subject of much discussion, with various terms proposed to describe it, including diffuse hypermelanosis, precancerous melanosis, or cancerous melanosis. We have addressed this question in a review and proposed a classification [38]. The lesion presents as a flat pigmented conjunctival flare, usually in middle-aged persons. It is almost always unilateral, although bilateral diffuse melanoses have been observed. Its course is one of progressive evolution, but often associated with partial regression. In some cases, the pigmentation is present for decades before nodules of melanoma appear. Histologically, the macules may exhibit hypermelanosis only or melanocytic hyperplasia that is benign or atypical. The hypermelanoses with atypia are very much like those of lentigo maligna, which may be characterized as a cutaneous atypical melanocytic hyperplasia. Our proposed classification of non-nevoid pigmented lesions of the conjunctiva includes (1) conjunctival hypermclanosis without melanocytic hyperplasia, (2) conjunctival melanosis with benign melanocytic hyperplasia, and (3) atypical melanocytic hyperplasia of a lentiginous or transepithelial type [38]. We know of documented cases in which melanoma has supervened in lesions containing basilar hypermelanosis without evidence of associated atypical melanocytic hyperplasia. However, it is unclear to us whether these lesions truly represent a precursor or if the melanomatous event is coincidental. We propose that until more evidence is accumulated concerning the melanoses without melanocytic hyperplasia, the designation of precursor be reserved for those described in (3) and possibly also those in (2). In fact, an evolutionary state may exist in these lesions from (2) to (3). To our knowledge, no statistically documented, prospective, randomized studies have addressed this point. Nevertheless, we must include at least pigmented conjunctival lesions with atypical melanocytic hyperplasia as precursor lesions to malignant melanoma. SAMPLING AND REMOVAL OF PRECURSOR LESIONS The clinical diagnosis of a nevomelanocytic tumor has little validity until a pathologic confirmation has been made. That confirmation requires a full, clear histologic picture. To obtain that picture, any lesion suspected of being an atypical melanocytic proliferation, and particularly a precursor to malignant mela-
noma, should be excised. We do not recommend incisional biopsies or trephine (punch) biopsies, except in cases of lesions so large that excision would require extensive surgery to areas such as the face. We do not recommend the shave-biopsy technique in pigmented lesions of any sort. The reasons for this recommendation are obvious to us: any atypical process that may underlie the area of a shave biopsy is lost to evaluation. In dealing with any atypical lentiginous proliferation of melanocytes, whether of a dysplastic nevus, lentigo maligna, or others, a shave biopsy almost always leaves residual melanocytic proliferation in the appendages. If the lesion is indeed a malignant melanoma, the shave-biopsy technique often makes difficult the clear assessment -even after re-excision-of the level and depth of invasion. The management of congenital nevi poses special problems. We have dealt with these in the discussion of this precursor. We emphasize here that any area in a congenital nevus that is suspected of malignant degeneration should be excised with a margin appropriate to the site. CONCLUSION In this review, we answer the question of whether precursor lesions exist to malignant melanoma; the answer is affirmative. We describe lesions as the dysplastic nevus, the congenital nevus, lentigo maligna, and the hypermelanosis of the conjunctiva with melanocytic atypia. Suggestions for handling precursor lesions are proposed. REFERENCES 1. Foulds L: “Neoplastic Development.” London: Academic Press. 1969, pp 69-75. 2. Gruber SB, Barnhill RL, Stenn KS, Roush GC: Nevomelanocytic proliferations in association with cutancous malignant melanoma: A multivariate analysis. J Am Acad Dermatol 21: 773-780, 1989. 3. Balch CM. Soong S-J, Shaw HM: A comparison of worldwide melanoma data. In Balch CM, Milton GW (eds): “Cutaneous Melanoma: Clinical Management and Treatment.” Philadelphia: JB Lippincott, 1985, pp 507-518. 4. Rhodes AR, Weinstock MA, Fitzpatrick TB, et al: Risk factors for cutaneous melanoma: A practical method of recognizing predisposed individuals. JAMA 258: 3146- 31 54, 1987. 5 Clark WH Jr, Reimer RR, Greene MH, et al: Origin of familial melanomas from heritable melanocytic lesions: The “B-K syndrome.” Arch Dermatol 114: 732-738, 1978. 6 Clark WH Jr, From L, Bernardino E, Mihm MC Jr: The histogenesis and biologic behavior of primary human malignant melanoma of the skin. Cancer Rcs 29: 705-726, 1969. 7 Sison-Torre EQ, Ackerman AB: Melanosis of the vulva: A clinical simulator of malignant melanoma. Am J Dermatopatho1 ~ ( s u P P ~51-60, ): 1985. 8 Mihm MC Jr, Googe PB: “Problematic Pigmented Lesions: A Case Method Approach.” Philadelphia: Lea & Febiger, 1990, pp 3-23 9. Elder DE, MacKie RM: Dysplastic melanocytic nevi: Their nature and significance. In Cascinelli N, Veronesi U, Santinami M (eds): “Cutaneous Melanoma: Biology and Management,” Milan: Masson, 1990, pp 93-104.
Do Melanoma Precursors Exist? 365 10. Lynch HT, Frichot BC, Lynch JF: Familial atypical multiple mole-melanoma syndrome. J Med Genet 15: 352-356, 1978. 11. Elder DE, Goldman LI, Goldman SC, et al.: The dysplastic nevus syndrome: A phenotypic association of sporadic cutaneous melanoma. Cancer 46: 1787-1794, 1980. 12. Nordlund JJ, Kirkwood J, Forget BM, et al: Demographic study of clinically atypical (dysplastic) nevi in patients with melanoma and comparison subjects. Cancer Res 45: 18551861, 1985. 13. Crutcher WA, Sagebiel RW: Prevalence of dysplastic naevi in a community practice. [Letter.] Lancet 1: 729, 1984. 14. Clark WH Jr, Elder DE, Guerry D IV, et al: A study of tumor progression: The precursor lesions of superficial spreading and nodular melanoma. Hum Pathol 15: 1147-1 165, 1984. 15. Grob JJ, Andrac L, Romano MH, et al: Dysplastic naevus in non-familial melanoma. A clinicopathological study of 101 cases. Br J Dermatol 118: 745-752, 1988. 16. Halpern AC, Guerry D IV, Elder DE, et al: Case-control study of dysplastic nevi and melanoma. Clin Res 37:869A, 1989 (abst). 17. Swerdlow AJ, Green A. Melanocytic naevi and melanoma: An epidemiological perspective. Br J Dermatol 117: 137- 146, 1987. 18. Rhodes AR, Mihm M C Jr, Weinstock MA: Dysplastic melanocytic nevi: A reproducible histologic definition emphasizing cellular morphology. Mod Pathol, 2: 306-319, 1989. 19. Barnhill RL, Roush GH, Duray PH: Correlation of histologic architectural and cytoplasmic features in atypical (dysplastic) nevomelanocytic nevi. Hum Pathol 21: 51 -58, 1990. 20. Clemente C, Cochran A, Elder DE, et al: Histopathologic correlation in the diagnosis of dysplastic nevi: A concordance study. Hum Pathol 22:313-319, 1991. 21. Mihm MC Jr, Googe PB: “Problematic Pigmented Lesions: A Case Method Approach.” Philadelphia: Lea & Febiger, 1990, p 254. 22. Steijlen PM, Bergman W, Hermans J, et al: The efficacy of histopathological criteria required for diagnosing dysplastic naevi. Histopathology 12: 289-300, 1988. 23. Black WC, Hunt WC: Histologic correlations with the clinical diagnosis of dysplastic nevus. Am J Surg Pathol 14: 44-52, 1990. 24. Rhodes AR, Mihm MC Jr: Origin of cutaneous melanoma in a congenital dysplastic nevus spilus. Arch Dermatol 126: 500505, 1990.
25. Barnhill RL, Mihm MC Jr: Pigmented spindle-cell nevus and its variants: Distinction from melanoma. Br J Dermatol 121: 717-726, 1989. 26. Illig L, Widener F, Hundeiker M, et al: Congenital nevi 5 10 cm as precursors to melanoma: 52 cases, a review, and a new conception. Arch Dermatol 121: 1274-1281, 1985. 27. Mihm MC Jr, Googe PB: “Problematic Pigmented Lesions: A Case Method Approach.” Philadelphia: Lea & Febiger, 1990. pp 127-142. 28. Mark GM, Mihm MC Jr, Liteplo MG, et al: Congenital melanocytic nevi of the small and garment type: Clinical, histological, and ultrastructural studies. Hum Pathol 4: 395-418. 1973. 29. Rhodes AR, Sober AJ, Day CL, et al: The malignant potential of small congenital nevocellular nevi: An estimate of association based on a histologic study of 234 primary cutaneous melanomas. J Am Acad Dermatol 60: 230-241, 1982. 30. Reed WB, Becker SW Jr, Nickel WR: Giant pigmented nevi, melanoma, and leptomenigeal melanocytosis. AMA Arch Dermatol 91: 100-119, 1965. 31. Rhodes AR, Wood WC, Sober AJ, et al: Non-epidermal origin of malignant melanoma associated with a giant congenital nevocellular nevus. Plast Reconstr Surg 67: 782-790. 1981. 32. Rhodes AR, Melski JW: Small congenital nevocellular nevi and the risk of cutaneous melanoma. J Pediatr 100: 219-224. 1982. 33. Rhodes AH: Neoplasm: benign neoplasias, hyperplasias and dysplasias of melanocytes. In Fitzpatrick TB, Eisen AZ, Wolff K, et a1 (eds): “Dermatology in General Medicine.” New York: McGraw Hill, 1987, p 877. 34. Clark WH Jr, Mihm MC Jr: Lentigo maligna and lentigo maligna melanoma. Am J Pathol 55: 39-67, 1969. 35. McGovern VJ: “Malignant Melanoma, Clinical and Histological Diagnosis.” New York: John Wiley & Sons, 1976, p 55. 36. Murphy GF, Mihm MC Jr: Histologic reporting of malignant melanoma. In Mihm MC Jr, Murphy GF, Kaufman N (eds): “Pathobiology and Recognition of Malignant Melanoma.” Baltimore: Williams & Wilkins, 1988, pp 79-93. 37. Weinstock MA, Sober AJ: Risk of progression of lentigo maligna to lentigo maligna melanoma. Br J Dermatol 16: 303310, 1987. 38. Guillen FJ, Albert DM, Mihm MC Jr: Pigmented melanocytic lesions of the conjunctiva-A new approach to their classification. Pathology 17: 275-280, 1985.
