EDUCATIONAL SECTION - Cutaneous melanocytic naevus versus melanoma: pitfalls, surprises, dilemmas

European Journal of Surgical Oncology 1999; 25: 622–627

EDUCATIONAL SECTION

Cutaneous melanocytic naevus versus melanoma: pitfalls, surprises, dilemmas W. J. Mooi Department of Pathology, Josephine Nefkens Institute, Erasmus University, Rotterdam, The Netherlands

Introduction On occasions the final pathological diagnosis of a melanocytic lesion turns out to be a ‘surprise’. An apparently innocent naevus may prove to be a melanoma, or conversely, a clinically irregular or suspicious-appearing pigmented macule or nodule may turn out to be histologically (and biologically) benign. This brief review describes situations in which the clinician may be faced with a clinically unexpected pathology report. It is hoped that this review of clinicopathological discrepancies that arise in the diagnosis of melanoma will promote closer liaison of clinician and pathologist, in order to critically assess the cause, whenever this occurs in routine practice. While the appearances of some rarer naevi or subtypes of malignant melanoma can be quite misleading, the pathological diagnosis of some melanocytic lesions is also extremely difficult, and the pathologist is, more than usual, prone to error. There is a much greater likelihood of a pathological underdiagnosis of melanoma (the pathologist stating that a malignant lesion is benign) or overdiagnosis (stating that a benign lesion is malignant) when the clinical impression and histological assessment do not match. Therefore, the fact that there is an apparent clinicopathological discrepancy is an indication that the final proffered diagnosis may be in doubt. To solve this dilemma, both clinician and pathologist need to discuss the case and ask themselves the question, can the apparent clinico-pathological discrepancy be explained? For instance, when a benign naevus recurs after incomplete excision, its shape is often irregular but, in this context, this feature is not an indicator of malignancy. Similarly, pathological teaching states that upward intraepidermal spread (‘ascent’) of melanocytes in the epidermis is often

Correspondence to: Prof. Dr W. J. Mooi, Department of Pathology, Josephine Nefkens Institute, Erasmus University Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands. E-mail: [email protected] 0748–7983/99/060622+06 $12.00/0

Fig. 1. Ascent of melanoma cells in melanoma. Solitary pale melanoma cells can be seen scattered at all levels of the epidermis. Ascent of melanocytes is seen in many melanomas and few benign naevi, but this feature is regularly encountered in some well recognized variants of benign naevi. H&E, ×250.

evidence of malignancy (Fig. 1). However, upward spread of naevomelanocytes does not carry any sinister connotation if seen in a small naevus of the interdigital skin of a young adult (the so-called acral naevus). These, and many other examples, illustrate that in problem cases the definitive diagnosis of melanocytic lesions requires not only an evaluation of the clinical and pathological features, but also an interpretation of the interrelationships of these features. It should be emphasized that the clinician should always state the grounds for the clinical suspicion on the pathology request form, so that the pathologist can search for clues to explain them. Below, we shall briefly discuss the main diagnostic entities which give rise to such apparent discrepancies. From each example, the importance of discussion between clinician and pathologist will be obvious. Benign: clinically benign (usually), histologically suspicious Naevus of genital skin and mucous membranes,1 especially in adolescents and young adults, may exhibit some unusual  1999 Harcourt Publishers Ltd

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Table 1. Ascent of solitary melanocytes occurring in benign melanocytic tumours

Table 2. Mitotic activity in intradermal melanocytes occurring in benign melanocytic tumours

1. 2. 3. 4. 5.

1. 2. 3. 4. 5. 6. 7.

Spitz naevus (especially in young patients) Reed naevus (pigmented spindle cell naevus) Naevus of acral skin Recurrent naevus after incomplete removal Congenital naevus in early infancy

histological features, which sometimes lead to an erroneous diagnosis of genital melanoma. In most cases, the clinical appearances are not worrying, so that a ‘surprise’ diagnosis of acral or genital melanoma should lead to critical reassessment of the diagnosis. However, the reverse may also apply with this lesion, as some genital naevi are usually large and have irregular contours, giving rise to clinical suspicion of melanoma although the pathology is, of course, benign.2,3 Acral naevus4 may exhibit unusual histological features roughly similar to those of genital naevi. Typically, acral naevus presents as a small, darkly pigmented macule on the skin of non-weight-bearing parts of the foot, for example between the toes. Many of the patients are young adults. This is in contrast to acral lentiginous melanoma, which is rare in this age group and most commonly affects the plantar weight-bearing areas, including the big toe, or the nail bed. Histologically, acral naevus consists of a proliferation of melanocytes which is architecturally irregular and which often exhibits some solitary melanocytes ascending into the upper layers of the epidermis, a feature often associated with melanoma. However, ascent of melanocytes is also seen in a number of benign naevus subtypes (Table 1). For this reason, ascent of melanocytes is recognized as an important cause of melanoma overdiagnosis and, conversely, its absence is an important cause of melanoma underdiagnosis. In order to avoid this potential error the pathologist should be aware of ascent, that is intraepidermal migration of naevus cells, as a feature of benign entities. In addition, subtle microscopic differences in the appearance of the ascending cells are of help in some instances. Ascending melanoma cells often retain larger nuclei with a vesicular nuclear appearance and ample cytoplasm, whereas ascending benign naevus cells tend to become smaller as they migrate to the upper layers of the epidermis. Ascending melanoma cells often involve the epidermis across the entire width of the lesion, whereas benign ascending naevus cells are more often located in the lesional centre (except in congenital naevus in early infancy, see below). Congenital naevi in early infancy may exhibit ascent of melanocytes, intradermal mitotic activity and the emergence of multiple small superficial ill-defined mitotically active nodules.5 The diagnosis of melanoma should not be made on the basis of these findings. It should be borne in mind that clinically proven melanoma arising in congenital naevi is really quite rare; in the past its incidence has been much overestimated. Some mitotic activity can be seen in the intradermal part of some specific naevus subtypes (Table 2). Spitz naevi6 are often not suspicious clinically, so an erroneous pathological diagnosis of melanoma in this context is unexpected. The histological features, which

Blue naevus (especially cellular blue naevus) Combined naevus Deep penetrating naevus Halo naevus Spitz naevus (superficial!) Congenital naevus in infancy Naevi of genital skin (occasional)

Fig. 2. So-called ‘ancient naevus’, showing scattered, often multinucleated benign naevus cells within a fibrosed dermis. This lesion should be distinguished from regressing melanoma, where the remaining tumour cells within the fibrosed dermis tend to form compact little nodules, and which is generally associated with epidermal flattening. H&E, ×260.

sometimes lead to overdiagnosis, include exuberant proliferation of large melanocytes, ascent of intraepidermal melanocytes, mitotic activity (superficial part of the lesion) and reactive epidermal and dermal changes which add to the subjective impression of ‘irregularity’. These features are often most striking in Spitz naevi of childhood. Spitz naevi of adulthood are generally more compact and largely, or entirely, intradermal in location, and are commonly associated with some fibrosis, resulting in a firm, usually skin-coloured papule or nodule. The problem of distinguishing between Spitz naevus and melanoma is compounded by the occurrence of the rare so-called ‘Spitzoid’ melanoma, which closely resembles Spitz naevus.7–9 Important distinguishing features are found in the deeper parts of the tumour: Spitzoid melanoma, while generally extending deeply into the dermis, usually retains a compact architecture, a large cell type and mitotic activity. For this reason, the diagnosis of Spitz naevus based on a superficial shave biopsy is not always safe. In difficult cases examination of the base of the lesion is essential. ‘Ancient naevus’ is a term recently proposed for a naevus with fibrosis and low cellularity, but with cytological atypia and pleomorphism of a type reminiscent of the cytological changes seen in so-called ancient schwannoma, a benign tumour of peripheral nerves (Fig. 2).14 Whether the atypia in this naevus is indeed similar in pathogenesis remains to be substantiated and, importantly, an occasional mitotic figure is seen in some of these naevi. The precise histological

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Fig. 3. Macroscopic appearance of a resected deeply pigmented benign cellular blue naevus. A mass lesion with compact architecture and deep pigmentation is evident. The multinodular appearance, which results from extension into periadnexal and subcutaneous fatty tissue, mimicks melanoma satellitosis. As is the case with many of such large cellular blue naevi, this lesion was located on the buttock. ×5.

and clinical features of this recently proposed entity remain to be investigated further. Some variants of blue naevi, especially cellular blue naevus10 and combined naevus (which combines the histological features of common acquired naevus with deep portions of blue naevus),11 may sometimes have worrying histological appearances, because of deep pigmentation, deep dermal penetration and high cellularity (Figs 3 and 4).12 Most of these lesions are not obviously suspicious clinically, so that a histological misdiagnosis of melanoma usually comes as a surprise. Again, a detailed knowledge of macroscopic and microscopic features of these rare entities is essential. For some unknown reason, large cellular blue naevi are most commonly located in the gluteal or intergluteal fold area, which is an important clue to the diagnosis. Deep penetrating naevus, originally considered to represent a separate entity,13 is now regarded as a subtype of blue naevus, with an epithelioid rather than a spindle cell type. A combination of lesions, with an overlying or adjacent naevus of common acquired naevus type, is especially common. When the two components are arranged side by side, asymmetry may result and may lead to either a clinical or histological suspicion of malignancy.

Benign: clinically suspicious, histologically benign A number of well-known and less well-known phenomena may account for a spurious clinical suspicion of melanoma.15 Folliculitis within or underneath a melanocytic naevus may result in swelling and a burning sensation. This

folliculitis may not be apparent in the initial slides cut from the block. Inflammatory regression of a naevus (halo naevus, Sutton naevus16) in its early phase, before the tell-tale concentric, symmetrical and centripetally spreading depigmentation has developed, may also give rise to perilesional erythema and an itching or burning sensation. Histologically, the naevus is widely infiltrated by a diffuse dense lymphohistiocytic inflammatory infiltrate. In contrast to regressing melanoma, where the infiltrate varies between different parts of the lesion and often alternates with areas of fibrosis devoid of melanocytes and inflammatory infiltrate, the infiltrate is similar in character throughout the lesion. Intradermal melanocytes may be slightly larger than in most naevi and an occasional intradermal melanocyte may be in mitosis. Recurrent naevi may be histologically easily recognizable as such, but since they are also sometimes difficult to interpret histologically, these are considered in the next section. Finally, it should be borne in mind that some nonmelanocytic lesions may imitate the clinical features of melanoma. Examples include seborrhoeic keratosis, cutaneous haemangiomas of angiokeratoma or pyogenic granuloma type and dermatofibroma. Traumatic subungual haematoma may closely mimic acral lentiginous melanoma (or vice versa). Generally, these entities do not cause problems in histological differential diagnosis.

Clinically suspicious, histologically suspicious, but benign nonetheless A number of uncommon types of naevi may have worrying appearances clinically and histologically, but are benign. The best known of these is the recurrent naevus after previous incomplete removal, most commonly by way of shave biopsy.17,18 Typically, such recurrent naevi become apparent after a few months (paradoxically, most locally recurrent melanomas need more time to manifest themselves clinically!), usually in the form of an irregularly shaped pigmented macule. Histologically, a superficial scar is covered by flattened epidermis. Within the epidermis and scar, irregular groups of melanocytes may be seen, often slightly larger and more pleomorphic than the usual naevus cells. Ascent of these cells into upper parts of the epidermis is not uncommon. There may be some lateral spread into non-scarred skin but, generally, this is minimal. Underneath the intradermal scar, groups of monomorphic naevus cells are often seen. Histological re-evaluation of the initial shave biopsy is of great importance to aid in the exclusion of melanoma. If only for this reason, it is essential that all removed skin lesions are investigated histologically. It is extremely frustrating to be confronted with a recurrent melanocytic lesion, which cannot be diagnosed with certainty as a recurrent benign naevus, because the initially removed lesion was not submitted for pathological assessment. Reed naevus (pigmented spindle cell naevus) commonly presents as a jet-black papule or nodule, which may be indistinguishable macroscopically from heavily pigmented nodular melanoma. Histologically, there is often an

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Fig. 4. Combined naevus, the superficial portion corresponding to the usual type of intradermal naevus, and a much more extensive deeper part with the histology of cellular blue naevus. In this context, deep pigmentation and the presence of a few deep mitoses do not indicate malignancy. H&E, ×90.

Fig. 5. Pigmented spindle cell naevus (Reed naevus). A compact and highly cellular lesion, with confluent large nests of melanocytes, associated with epidermal hyperplasia and hyperkeratosis. This benign lesion, which most typically occurs on an extremity of a young adult female, often presents as a jet-black papule or nodule, raising a suspicion of nodular melanoma. H&E, ×45.

exuberant proliferation of large oval to elongated melanocytes, associated with transepidermal spread of melanocytic nests and ascent of some melanocytes (Fig. 5). In addition, mitoses are commonly present.19,20 These features may be misinterpreted as indicative of malignancy. However, Reed naevi are entirely benign. Agminate Spitz naevi are rare. These consist of a group of papules with the histology of Spitz naevi.21 This may be the primary presentation of the naevus, or it may follow previous incomplete resection of a Spitz naevus. Although

this form of recurrence, as multiple benign papules of Spitz naevus mimicking melanoma satellites, is very rare, it may present formidable diagnostic problems. As a routine, we advise re-excision (with narrow margins) of all incompletely removed Spitz naevi, in order to avoid this diagnostic pitfall. Again, it is of paramount importance that the initial excision specimen is submitted for pathological diagnosis. Dysplastic naevus is a subtype of melanocytic naevus which is associated with a familial syndrome, familial dysplastic naevus, where it is associated with a markedly

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increased risk of malignant melanoma,22,23 although it rarely occurs in large numbers in affected family members. Most dysplastic naevi occur sporadically, outside this specific and rare context, and do not imply a clinically significant increase in melanoma risk. Both macroscopically and histologically, the dysplastic naevus shares some features with thin melanoma,24 so that the distinction is occasionally problematic. Recently, it has been proposed that the ‘dysplastic phenotype’ may also be seen in other naevus subtypes.25

Clinically not (very) suspicious, histologically melanoma As a group, amelanotic melanoma is the main cause of clinical underdiagnosis of melanoma. Several variants of amelanotic melanoma can be distinguished. Quickly growing tumours, often with an epithelioid cell type, generally produce exophytic ulcerating nodules which resemble so-called pyogenic granuloma. In contrast, spindle cell amelanotic melanoma more commonly has an endophytic growth pattern, invading underlying tissues and often inducing a fibrotic response, resulting in a firm nodule or area of induration. Very rarely, a skin lesion clinically indistinguishable from Spitz naevus turns out to be an amelanotic melanoma. When this occurs in an adolescent, or even a child, and the histology is that of a Spitzoid melanoma, the differential diagnostic problems are especially formidable. Suffice to say that young age per se is no proof of benignity; we have seen several examples of such melanomas leading to metastasis and tumour-related death.

Histopathological underdiagnosis of melanoma The recent recognition of a number of benign melanoma simulators, the most important ones having been briefly referred to above, may sometimes lead to a tendency to downplay the importance of architectural and cytological features previously considered diagnostic of melanoma. It is, however, of crucial importance that the diagnostic significance of certain features which may indicate malignancy, such as ascent and Pagetoid intraepidermal spread of atypical melanocytes, deep mitotic activity, irregular architecture, unequal distribution of reactive changes etc., is not disregarded just because these features also occur in some specific and well-defined benign naevus subtypes. Naevoid melanoma26 is not really a specific entity, but the term is useful to indicate a group of melanomas which at first glance closely resemble melanocytic naevi of some type. Spitzoid melanomas have been briefly referred to above; some other melanomas have a treacherous resemblance to common acquired naevi, often of the papillomatous compound naevus type (so-called verrucous naevoid melanoma).27,28 A helpful feature to call attention to the possible malignant nature of the lesion is its size: most papillomatous naevoid melanomas are larger than 1 cm across by the time they are resected, whereas most compound naevi are smaller.

Histopathological overdiagnosis of ‘early’ melanoma: a problem of unknown magnitude In contrast to underdiagnosis of melanoma, in which case follow-up data points to the correct diagnosis when metastases become apparent, the diagnosis of small, thin, presumably ‘early’ melanoma is impossible to disprove in individual instances. There is reason for concern that the marked increase in melanoma incidence, paralleled by an ever increasing survival rate,29 is in part caused by histopathological overdiagnosis of melanoma rather than by the success of early melanoma detection and treatment. It should be realized that the histological diagnosis of small and thin melanomas is based on criteria which have been corroborated largely on the basis of data derived from the evaluation of thicker melanomas. This by itself can never provide conclusive proof. Indeed, the histology of a naevus changes markedly during the lesion’s life. Very similar problems apply to many areas of tumour diagnosis, when harmless cancer-simulators, cancer precursor lesions and early full-fledged malignant tumours need to be distinguished. A full discussion of this important and problematic area falls, however, outside the scope of this brief review.

The diagnosis of melanocytic tumours: the importance of a ‘splitter’s’ approach From the above, it will be clear that the pathologist needs to be familiar with a large number of naevus and melanoma variants, in order to be able to reach a correct diagnosis in exceptional cases. The pathologist has to be aware, for example, when deep mitotic activity is insignificant (e.g. in a cellular blue naevus) and when it is indicative of malignancy (in a thick ‘Spitzoid’ melanocytic tumour); when differences in cell type and architecture in different parts of the same lesion are acceptable (combined naevus, deep penetrating naevus) and when it is a sign of malignancy (compact intradermal nodules in melanoma). Because of this, it is a practical impossibility to readily distinguish between benign and malignant melanocytic tumours on the basis of universally applicable histological criteria. In each individual case, the specific differential diagnosis determines which histological findings are diagnostically relevant and how they should be interpreted. Any apparent discrepancy should be analysed on the basis of a detailed knowledge of the relevant subtypes of naevus and melanoma, in order to avoid the important and sometimes grave consequences of under or overdiagnosis of melanoma. A detailed discussion between clinician and pathologist is often an essential and indispensable part of the final diagnostic pathway for melanocytic lesions.

Acknowledgement The author is grateful to Dr D. N. Poller for helpful suggestions during the finalization of this manuscript.

Educational section References 1. Christensen WN, Friedman KJ, Woodruff JD, Hood AF. Histologic characteristics of vulvar nevocellular nevi. J Cutan Pathol 1987; 14: 87–91. 2. Sison-Torre EQ, Ackerman AB. Melanosis of the vulva. A clinical simulator of malignant melanoma. Am J Dermatopathol 1985; 7: 51S–60S. 3. Nogita T. Atypical melanosis of the foot. J Dermatol 1996; 23: 825–7. 4. Han KH, Cho KH. Acral lentiginous nevus. J Dermatol 1998; 25: 23–7. 5. Kerl H, Smolle J, Ho¨dl S, Soyer HP. Kongenitales Pseudomelanom. Zeitschr Hautkrankh 1989; 64: 564–8. 6. Spitz S. Melanomas of childhood. Am J Pathol 1948; 24: 591–609. 7. Okun MR. Melanoma resembling spindle and epithelioid cell nevus. Arch Dermatol 1979; 115: 1416–20. 8. Peters MS, Goellner JR. Spitz naevi and malignant melanomas of childhood and adolescence. Histopathol 1986; 10: 1289–302. 9. Walsh N, Crotty K, Palmer A, McCarthy S. Spitz nevus versus spitzoid malignant melanoma: an evaluation of the current distinguishing histopathologic criteria. Hum Pathol 1998; 29: 1105–12. 10. Rodriguez HA, Ackerman LV. Cellular blue nevus. Clinicopathologic study of forty-five cases. Cancer 1968; 21: 393–405. 11. Leopold JG, Richards DB. The interrelationship of blue and common naevi. J Pathol Bacteriol 1968; 95: 37–46. 12. Tran TA, Carlson JA, Basaca PC, Mihm MC. Cellular blue nevus with atypia (atypical cellular blue nevus): a clinicopathologic study of nine cases. J Cutan Pathol 1998; 25: 252–8. 13. Seab JA, Graham JH, Helwig EB. Deep penetrating nevus. Am J Surg Pathol 1989; 13: 39–44. 14. Kerl H, Soyer HP, Cerroni L, Wolf IH, Ackerman AB. Ancient melanocytic nevus. Semin Diagn Pathol 1998; 15: 210–5.

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15. Cerroni L, Kerl H. Simulators of malignant melanoma of the skin. Eur J Dermatol 1998; 8: 388–96. 16. Sutton RL. An unusual variety of vitiligo (leukoderma acquisitum centrifugum). J Cutan Dis 1916; 34: 797–800. 17. Schoenfeld RJ, Pinkus H. The recurrence of nevi after incomplete removal. Arch Dermatol 1958; 78: 30–5. 18. Kornberg R, Ackerman AB. Pseudomelanoma: recurrent melanocytic nevus following partial surgical removal. Arch Dermatol 1975; 111: 1588–90. 19. Reed RJ, Ichinose H, Clark WH, Mihm MC. Common and uncommon melanocytic nevi and borderline melanomas. Sem Oncol 1975; 2: 119–47. 20. Smith NP. The pigmented spindle cell tumor of Reed: an underdiagnosed lesion. Sem Diagn Pathol 1987; 4: 75–87. 21. Paties CT, Borroni G, Rosso R, Vassallo G. Relapsing eruptive multiple Spitz nevi or metastatic Spitzoid malignant melanoma? Am J Dermatopathol 1987; 9: 520–7. 22. Frichot BC, Lynch HT, Guirgis HA, Harris RE, Lynch JF. A new cutaneous phenotype in familial malignant melanoma. Lancet 1977; I: 864–5. 23. Clark WH, Reimer RR, Greene M, Ainsworth AM, Mastrangelo MJ. Origin of familial malignant melanomas from heritable melanocytic lesions. “The B-K mole syndrome”. Arch Dermatol 1978; 114: 732–8. 24. Mooi WJ. The dysplastic naevus. J Clin Pathol 1997; 50: 711–5. 25. Toussaint S, Kamino H. Dysplastic changes in different types of melanocytic nevi. A unifying concept. J Cutan Pathol 1999; 26: 84–90. 26. McNutt NS. “Triggered trap”: nevoid malignant melanoma. Semin Diagn Pathol 1998; 15: 203–9. 27. Levene A. On the histological diagnosis and prognosis of malignant melanoma. J Clin Pathol 1980; 33: 101–24. 28. Suster S, Ronnen M, Bubis JJ. Verrucous pseudonevoid melanoma. J Surg Oncol 1987; 36: 134–7. 29. Dennis LK. Analysis of the melanoma epidemic, both apparent and real: data from the 1973 through 1994 surveillance, epidemiology, and end results program registry. Arch Dermatol 1999; 135: 275–80.