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Benign melanocytic lesions mimicking melanomas
Pathology (October 2004) 36(5), pp. 414–418
MELANOCYTIC PATHOLOGY
Benign melanocytic lesions mimicking melanomas MARTIN G. COOK Department of Histopathology, Royal Surrey County Hospital, and Postgraduate Medical School, University of Surrey, Guildford, UK
Summary Review of problematic melanocytic consultation cases has enabled identification of the most common variants of benign melanocytic proliferations which can be confused with melanoma. Apart from Spitz naevus, the most common in this group of lesions are pigmented spindle cell naevus and atypical dermal nodule. Potentially the most problematic but less common are pseudomelanoma following incomplete removal of a naevus and ‘activated’ benign naevus cells in sentinel lymph nodes. By considering the overall architecture and the degree of nuclear atypia of the lesions, all of these problems can usually be resolved. Nuclear or architectural abnormalities by themselves are insufficient and must be assessed together. In addition, the combinations of pattern and cytological change in most of the lesions described here are distinctive and have become recognised as known variations of benign entities. Key words: Melanoma, histology, benign naevi, benign nevi, pseudomelanoma. Received 29 February, revised 11 May, accepted 12 May 2004
INTRODUCTION Any variant of benign naevus may have a malignant counterpart and therefore a list of benign simulants of melanoma could be very long. In practice, there are a smaller number of lesions which show some degree of architectural or cytological atypia which regularly present a diagnostic problem. Table 1 lists those which present frequently as well as those which are mentioned in this context in the literature1 but which in our experience are
TABLE 1
not often problematic. This last group will not be discussed further. Analysis of the referrals for consultation opinion reveals that it is more common for the presenting diagnosis to be changed on review from melanoma or uncertain towards a benign naevus than the reverse (39 and 26%, respectively). This confirms benign simulation of malignancy as a common problem in melanoma diagnosis. In our experience, the most frequent entity in this group of lesions is the compound melanocytic naevus with junctional dysplasia. Despite its frequency it is not going to be expanded on in this review, since this lesion is a precursor of melanoma rather than a simulant and discussing it would enter into the semantic argument of what atypia is sufficient to qualify a lesion as melanoma and what constitutes significant invasion. This is the common pathology in the development of most melanomas and we subscribe to the concept of phases of melanoma progression put forward by Clark et al.2 We have shown that there is very poor agreement in recognition of subdivisions of early melanoma from severe dysplasia though melanoma in situ to early invasion.3 We showed marked improvement in diagnostic accuracy by general pathologists if they used a simpler classification, namely melanocytic intraepidermal neoplasia (MIN) and microinvasion (no vertical growth phase).4 Not only does this avoid unnecessary splitting of a single phase of melanoma progression but it solves the diagnostic dilemma. All of these cases are readily recognised for what they are: early melanoma not yet capable of metastasis and therefore cured by complete excision. Spitz naevus is the next most frequent lesion which simulates melanoma but since this is to be extensively covered later it too will not be described further here.
Benign melanocytic lesions simulating melanoma.
Major or frequent
Minor or infrequent
Compound naevus with junctional ‘dysplasia’ Spitz naevus Atypical blue naevus Pigmented spindle cell naevus Atypical dermal nodule Halo naevus Deep penetrating naevus Plantar naevus Post-surgery pseudomelanoma Benign ‘metastasis’ in SLN Proliferative nodules in congenital naevus of neonates
Genital naevus Combined naevus Ancient naevus Balloon cell naevus Cellular solar lentigo Melanocytic atypia in solar keratosis
ISSN 0031-3025 printed/ISSN 1465–3931 # 2004 Royal College of Pathologists of Australasia DOI: 10.1080/00313020412331283842
BENIGN MIMICS OF MELANOMA
415
Suffice it to say that in our opinion there is a tendency among general pathologists to use the label spitzoid for any cellular compound melanocytic naevus which is a diagnostic problem. This may lead to a conceptual dilution of the entity which has been already well and tightly described decades ago.5
PIGMENTED SPINDLE CELL NAEVUS (PSCN) OF REED6 PSCN has some features of a Spitz naevus in that the cells are usually large and spindly and their features raise in the mind of the pathologist the differential diagnosis of an early invasive melanoma. They are also similar to many Spitz naevi in having a predominantly vertical arrangement of the cells adjacent to the rete ridges and are associated with diffuse epidermal thickening and hypergranulosis. They differ in that, by definition, PSCN contains pigment both in the cytoplasm of the melanocytes and in accompanying melanophages. The cells are compactly arranged overriding the junctional zone with little upward extension of melanocytes (Fig. 1). However, there can be a minor dermal component which shows a reduction in size of cells in the deeper parts but without the poorly defined extension into the dermis characteristic of Spitz naevus. Some degree of horizontal arrangement of cells may be seen and the features of PSCN may merge with the more common type of junctional naevus. They are seen typically on the limbs of children and young adults.
ATYPICAL DERMAL NODULES IN BENIGN MELANOCYTIC NAEVI7 Atypical dermal nodule is one name for a lesion which has also been referred to as inverted type A naevus,8 melanocytic naevi with focal atypical epithelioid cell components9 and more recently anecdotally as clonal naevus. This can be one of the lesions most easily mistaken
Fig. 2 An atypical dermal nodule in a benign naevus is not associated with atypia in the junctional zone. Lobulated groups of melanocytes with abundant cytoplasm but showing no nuclear atypia contrast with adjacent small intradermal naevus cells (H&E, original magnification, 640).
for an invasive melanoma arising in a pre-existing naevus. It occurs in a wide age range and in virtually all sites. It presents most often as a domed pale brown nodule within which is a dark brown spot occupying a variable proportion of the lesion as a whole. Microscopically, the lesions have a background of intradermal or compound naevus with no junctional atypia. The small type B cells of the dermal component usually surround a group of larger cells which are accompanied by melanophages (Fig. 2). The group of larger cells may be sharply circumscribed or a loosely scattered aggregate of smaller groups. The large size of the cells is due to abundant cytoplasm with fine melanin pigment rather than increased nuclear size. The nuclei show little pleomorphism and virtually no mitotic activity. The lack of junctional activity, nuclear atypia, mitoses or sign of infiltration enables confident recognition despite the apparent intralesional transformation which has been advocated in some contexts as a criterion of malignancy. In one sense the lesion is a variant of combined naevus, but its clinical and histological features are sufficiently distinctive to warrant, in our opinion, a specific name. Clinically, it is worrying because new, central, dark pigmentation develops in what appears otherwise to be a benign mole. Histologically, the extra component, usually central, in the benign naevus is difficult to classify since it does not have consistent features of other entities, although it could be said to have some resemblance to a component of cellular blue naevus.
ATYPIA IN BLUE NAEVI
Fig. 1 PSCN is typified by vertically orientated nests of large spindle cells overriding the junctional zone with little upward extension in the thickened epidermis. The melanocytes contain fine melanin pigment but there is more prominent melanin in macrophages (H&E, original magnification, 6200).
A diagnostic feature of cellular blue naevi is usually a biphasic pattern with heavily pigmented, dendritic shaped cells and fibrosis in the same lesion as confluent sheets of plump spindle cells with large nuclei. Also, there may be occasional mitoses, but atypical mitoses, necrosis and an infiltrative pattern are needed to confirm malignant change in a cellular blue naevus.10 Atypia in common blue naevi
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Fig. 3 Atypia in blue naevi is seen in its extreme form in the bizarre blue naevus. In this there is great variation in cell outline with severely pleomorphic nuclei and multinucleation. There is still a background of heavily pigmented dendritic melanocytes (H&E, original magnification, 6400).
may be pronounced and in practice is as likely to be confused with melanoma as that seen in cellular blue naevi. The pleomorphism may take the form of giant cells with severely irregular and large nuclei and gross variability in the outline of the cytoplasm, so much so that the term ‘bizarre blue naevus’ has been used.11 Paradoxically, the extreme pleomorphism (Fig. 3) is a clue to the diagnosis of a variant of benign blue naevus. The heavily pigmented dendritic background to the lesion in the superficial dermis is usually apparent.
HALO PHENOMENON The intense lymphocytic infiltrate of naevi showing the histological halo phenomenon occasionally presents a problem in distinguishing the lesion from melanoma because of the obscuring of the dermal melanocytes and the frequent mild-to-moderate dysplasia in the overlying junctional component (Fig. 4). The latter, when seen in the context of the usual young age of the patient, is not sufficient to confirm a diagnosis of melanoma and careful examination of the dermal infiltrate will reveal small type B melanocytes, although sometimes showing mild reactive atypia.12 An occasional mitosis can be seen, as in any benign intradermal naevus, and is insufficient to alter the diagnosis. A clinical halo may be seen occasionally around melanomas as well as benign naevi and may not always be associated with a lymphocytic infiltrate. The converse, namely an intense lymphocytic infiltrate without a clinical halo, also occurs.
Pathology (2004), 36(5), October
Fig. 4 The halo phenomenon is recognised histologically by an intense lymphocytic infiltrate among dermal melanocytes of a compound melanocytic lesion. There is some nuclear enlargement and variability with nucleolar prominence. In this case only focal junctional proliferation is seen (H&E, original magnification, 6100).
The overall pattern is distinctive but is not exclusive to deep penetrating naevus. It can also be seen in nodular melanoma, the correct diagnosis sometimes being only achieved when metastasis occurs. Therefore, it is essential to check the cytology of the melanocytes in the putative deep penetrating naevus. They are usually large but not pleomorphic and mitoses are uncommon. There are a small number of DPN which have an epithelioid cell type14 and others, which although spindle celled, are less deeply penetrating and show conspicuous extension along the neurovascular bundles. These have been termed ‘plexiform spindle cell naevi’.15 All of these variants show some similarity to cellular blue naevi and like them may be seen combined with other variants of naevi.
DEEP PENETRATING NAEVUS (DPN) DPN13 shares some features with deeply invasive nodular melanoma. It extends in an irregular wedge often at least into the deep reticular dermis and is associated with a junctional proliferation of melanocytes (Fig. 5). However, these junctional melanocytes do not show significant dysplasia. The dermal melanocytes are large fusiform cells arranged in fascicles tending to be vertically orientated and associated with intervening melanophages.
Fig. 5 Deep penetrating naevus is recognised in part by its outline, a deeply extending wedge of melanocytes with the base at the epidermis (right) where there are some nests of benign naevus cells. The apex of the lesion, in this case adjacent to a hair follicle, (left) extends into deep reticular dermis. The cells are arranged in fascicles of spindle cells with intervening pigment-laden macrophages (H&E, original magnification, 6100).
BENIGN MIMICS OF MELANOMA
417
PLANTAR MELANOCYTIC LESIONS In general, melanocytic lesions are recognisable irrespective of their anatomical location but some of the naevi on the sole of the foot do present a site specific pattern which can be confused with early melanoma.16 This probably relates to the thickness of the epidermis and the density of the dermal collagen in this site. Some plantar lesions are composed of large, irregular, but well circumscribed nests along the junctional zone. In addition, these nests often show extension into the upper epidermis and stratum corneum simulating transepidermal elimination but should not be confused with pagetoid infiltration of the epidermis. The nests may bulge slightly into the superficial dermis and this area also shows active fibroplasia and a scanty lymphocytic infiltrate. The melanocytes do not show severe cytological atypia but, along with the irregularity of the nests, may show a slightly dishevelled arrangement (Fig. 6). The lack of severe atypia and the circumscription of the nests are most helpful in excluding melanoma but the transepidermal elimination of intact nests is the strongest pointer to the benign nature of these lesions.
PSEUDOMELANOMA FOLLOWING INCOMPLETE REMOVAL OF A BENIGN NAEVUS The lesions so far described have been presented in order of decreasing incidence in referral practice. The pseudomelanoma17 following incomplete excision of a benign naevus is most uncommon, which is fortunate since it can closely simulate a melanoma in situ. The original partially excised lesion was either a junctional or compound naevus. The recurrent (persistent) naevus may show irregularly distributed nests and single melanocytes in the epidermis (Fig. 7). These melanocytes can show some variation in size and shape amounting to moderate pleomorphism and they are not confined to the basal layer or junctional zone. Furthermore, the underlying dermis typically shows fibrosis and inflammation related to the previous surgery, but simulating the host response commonly seen in early
Fig. 7 Recognition of pseudomelanomatous features following incomplete excision of a benign compound naevus are facilitated by identifying the underlying fibrosis as post-surgical scarring. The junctional component shows marked hyperplasia of large melanocytes with occasional cells reaching the mid-epidermis. The presence of epidermal thickening and hypergranulosis represent clues to the diagnosis. Without the adjacent benign lesion and the scarring, this would be indistinguishable from melanoma in situ (H&E, original magnification, 6200).
melanoma. A clue to the benign nature of the lesion may be given by benign naevus cells beneath the layer of scarring but these may have been removed initially or the original lesion may have been entirely junctional. In diagnosing these cases, knowledge of an earlier procedure is highly desirable as is review of the histology of the initial lesion. The latter is important to confirm that the original diagnosis was correctly benign as well as correlating with the features of the subsequent specimen. In the absence of dermal naevus cells, the history of a previous benign lesion is crucial, but additional benign clues are the lack of extension of the recurrent intraepidermal naevus cells beyond the dermal scarring and the absence of severe atypia.
BENIGN PROLIFERATIVE NODULES IN GIANT CONGENITAL NAEVI
Fig. 6 Plantar melanocytic naevi often include large irregular nests of mildly atypical naevus cells. Transepidermal elimination of nests is a common but reassuring feature (H&E, original magnification, 6200).
Benign proliferative nodules are very rare. They may present at any age but are more common in children. They raise a very difficult problem in distinguishing these benign nodules from melanoma arising in the dermal component of congenital naevi. They are usually small nodules (less than 5 mm) composed of type B naevus cells more crowded together and slightly larger than those of the adjacent naevus. Some epithelioid and spindle cells may be seen. If necrosis, severe atypia, mitoses and an expansile destructive pattern of growth are seen, melanoma should be considered. On the other hand, if the clone is without severe atypia or necrosis, shows only an occasional mitosis and has a pattern of growth which merges with the adjacent naevus then the lesion is likely to be benign. In neonates (less than 6 months old) marked atypia with numerous mitoses in larger nodules of congenital naevi still appear to behave benignly.18 Even highly disturbing
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component. A MIB-1 may help since these cells have a positive count of less than 1% or zero. Also, they are usually but not always HMB45 negative. Nevertheless, this distinction may be subtle and the learning period for pathological interpretation of SLN for melanoma is at least as important as that said to be necessary for surgeons performing these procedures. Address for correspondence: Professor M. G. Cook, Department of Histopathology, The Royal Surrey County Hospital, Guildford GU2 7XX, UK. E-mail: [email protected]
References
Fig. 8 The capsule of this sentinel lymph node contains a prominent aggregate of enlarged naevus cells, many with obvious nucleoli. There is also a suggestion of naevus cells extending into the underlying subcapsular sinus. These features are not interpreted as metastatic melanoma (H&E, original magnification, 6400).
appearances with ulceration in patients of this age should not be unequivocally diagnosed as malignant.
BENIGN NAEVUS CELLS IN SLN SIMULATING METASTASIS Finally, in these days when sentinel lymph node (SLN) biopsy is becoming a standard procedure in the management of melanoma, the occurrence of benign naevus cells simulating metastases in SLN should be remembered. Usually naevus cells in SLN are confined to a capsular, or less frequently, trabecular site. They are recognised by their exact location actually within the fibrous tissue of the capsule or trabecula and also by their cytology. They are typically melanocytes with scanty cytoplasm and small regular basophilic nuclei-like type B naevus cells. They are seen in one or more nodes of up to 20% of patients who have SLN biopsies.19 In a small proportion of these nodes with capsular or trabecular naevus cells, the collections of cells are much larger so that they extend beyond the capsule or trabecula into the subcapsular sinus or adjacent parenchyma (Fig. 8). In this site they appear to acquire different cytological features. The nuclei become slightly larger and less densely basophilic. This may be accompanied by occasional small nucleoli and some minor variation to the nuclear outline. Features supporting the benign nature of these elements are the lack of severe atypia and the confluence with a capsular or trabecular
1. Ackerman AB, Cerroni L, Kerl H. Pitfalls in Histopathologic Diagnosis of Malignant Melanoma. Philadelphia: Lea and Febiger, 1994. 2. Clark WH, Elder DE, Guerry D, et al. Model predicting survival in stages of melanoma based on tumour progression. J Natl Cancer Inst 1989; 81: 1893–904. 3. Cook MG, Clarke TJ, Humphreys S, et al. The evaluation of diagnostic and prognostic criteria and the terminology of thin cutaneous melanoma. Histopathology 1996; 28: 497–512. 4. CRC Melanoma Pathology Panel. A nationwide survey of observer variation in the diagnosis of thin cutaneous melanoma including the MIN terminology. J Clin Pathol 1997; 50: 1–4. 5. Weedon D, Little JW. Spindle and epithelioid cell naevi in children and adults. A review of 211 cases of Spitz naevus. Cancer 1977; 40: 217–25. 6. Reed RJ, Ichinose H, Clark WH, Mihm MC. Common and uncommon melanocytic naevi and borderline melanomas. Semin Oncol 1975; 2: 119–47. 7. Collina G, Deen S, Cliff S, Jackson P, Cook MG. Atypical dermal nodules in benign melanocytic naevi. Histopathology 1997; 31: 97–101. 8. Mihm MC, Googe PB, Tong AKF. Problematic Pigmented Lesions: A Case Method Approach. Philadelphia: Lea and Febiger, 1990; Variations on the common acquired nevus. 9. Ball NJ, Golitz LE. Melanocytic nevi with focal atypical epithelioid cell components. J Am Acad Dermatol 1994; 30: 724–9. 10. Tran TA, Carlson JA, Basaca PC, Mihm MC. Cellular blue naevus with atypia (atypical cellular blue naevus). J Cutan Pathol 1998; 25: 252–8. 11. Youngberg GA, Rasch EM, Douglas HL. Bizarre blue naevus. J Am Acad Dermatol 1986; 15: 336–41. 12. Mooney MA, Barr RJ, Burton MG. Halo nevus or halo phenomenon? J Cutan Pathol 1995; 22: 342–8. 13. Seab JA, Graham JH, Helwig EB. Deep penetrating naevus. Am J Surg Pathol 1989; 13: 39–44. 14. Crowson AN, Magro SM, Mihm MC. The Melanocytic Proliferations. New York: Wiley Liss, 2001; Deep penetrating naevus. 15. Barnhill RL, Mihm MC, Magro CM. Plexiform spindle cell naevus. Histopathology 1991; 18: 243–7. 16. Fallowfield ME, Collina G, Cook MG. Melanocytic lesions of the palm and sole. Histopathology 1994; 24: 463–7. 17. Kornberg R, Ackerman AB. Pseudomelanoma. Recurrent melanocytic naevus following partial surgical removal. Arch Dermatol 1975; 111: 1588–90. 18. Elder DE, Murphy G. Melanocytic Tumours of the Skin. AFIP Atlas of Tumor Pathology. 3rd Series, Fascicle 2. Washington, DC: AFIP, 1991; 70. 19. Carson KF, Wen DR, Li PX, et al. Nodal nevi and cutaneous melanomas. Am J Surg Pathol 1996; 20: 834–40.
MELANOCYTIC PATHOLOGY
Benign melanocytic lesions mimicking melanomas MARTIN G. COOK Department of Histopathology, Royal Surrey County Hospital, and Postgraduate Medical School, University of Surrey, Guildford, UK
Summary Review of problematic melanocytic consultation cases has enabled identification of the most common variants of benign melanocytic proliferations which can be confused with melanoma. Apart from Spitz naevus, the most common in this group of lesions are pigmented spindle cell naevus and atypical dermal nodule. Potentially the most problematic but less common are pseudomelanoma following incomplete removal of a naevus and ‘activated’ benign naevus cells in sentinel lymph nodes. By considering the overall architecture and the degree of nuclear atypia of the lesions, all of these problems can usually be resolved. Nuclear or architectural abnormalities by themselves are insufficient and must be assessed together. In addition, the combinations of pattern and cytological change in most of the lesions described here are distinctive and have become recognised as known variations of benign entities. Key words: Melanoma, histology, benign naevi, benign nevi, pseudomelanoma. Received 29 February, revised 11 May, accepted 12 May 2004
INTRODUCTION Any variant of benign naevus may have a malignant counterpart and therefore a list of benign simulants of melanoma could be very long. In practice, there are a smaller number of lesions which show some degree of architectural or cytological atypia which regularly present a diagnostic problem. Table 1 lists those which present frequently as well as those which are mentioned in this context in the literature1 but which in our experience are
TABLE 1
not often problematic. This last group will not be discussed further. Analysis of the referrals for consultation opinion reveals that it is more common for the presenting diagnosis to be changed on review from melanoma or uncertain towards a benign naevus than the reverse (39 and 26%, respectively). This confirms benign simulation of malignancy as a common problem in melanoma diagnosis. In our experience, the most frequent entity in this group of lesions is the compound melanocytic naevus with junctional dysplasia. Despite its frequency it is not going to be expanded on in this review, since this lesion is a precursor of melanoma rather than a simulant and discussing it would enter into the semantic argument of what atypia is sufficient to qualify a lesion as melanoma and what constitutes significant invasion. This is the common pathology in the development of most melanomas and we subscribe to the concept of phases of melanoma progression put forward by Clark et al.2 We have shown that there is very poor agreement in recognition of subdivisions of early melanoma from severe dysplasia though melanoma in situ to early invasion.3 We showed marked improvement in diagnostic accuracy by general pathologists if they used a simpler classification, namely melanocytic intraepidermal neoplasia (MIN) and microinvasion (no vertical growth phase).4 Not only does this avoid unnecessary splitting of a single phase of melanoma progression but it solves the diagnostic dilemma. All of these cases are readily recognised for what they are: early melanoma not yet capable of metastasis and therefore cured by complete excision. Spitz naevus is the next most frequent lesion which simulates melanoma but since this is to be extensively covered later it too will not be described further here.
Benign melanocytic lesions simulating melanoma.
Major or frequent
Minor or infrequent
Compound naevus with junctional ‘dysplasia’ Spitz naevus Atypical blue naevus Pigmented spindle cell naevus Atypical dermal nodule Halo naevus Deep penetrating naevus Plantar naevus Post-surgery pseudomelanoma Benign ‘metastasis’ in SLN Proliferative nodules in congenital naevus of neonates
Genital naevus Combined naevus Ancient naevus Balloon cell naevus Cellular solar lentigo Melanocytic atypia in solar keratosis
ISSN 0031-3025 printed/ISSN 1465–3931 # 2004 Royal College of Pathologists of Australasia DOI: 10.1080/00313020412331283842
BENIGN MIMICS OF MELANOMA
415
Suffice it to say that in our opinion there is a tendency among general pathologists to use the label spitzoid for any cellular compound melanocytic naevus which is a diagnostic problem. This may lead to a conceptual dilution of the entity which has been already well and tightly described decades ago.5
PIGMENTED SPINDLE CELL NAEVUS (PSCN) OF REED6 PSCN has some features of a Spitz naevus in that the cells are usually large and spindly and their features raise in the mind of the pathologist the differential diagnosis of an early invasive melanoma. They are also similar to many Spitz naevi in having a predominantly vertical arrangement of the cells adjacent to the rete ridges and are associated with diffuse epidermal thickening and hypergranulosis. They differ in that, by definition, PSCN contains pigment both in the cytoplasm of the melanocytes and in accompanying melanophages. The cells are compactly arranged overriding the junctional zone with little upward extension of melanocytes (Fig. 1). However, there can be a minor dermal component which shows a reduction in size of cells in the deeper parts but without the poorly defined extension into the dermis characteristic of Spitz naevus. Some degree of horizontal arrangement of cells may be seen and the features of PSCN may merge with the more common type of junctional naevus. They are seen typically on the limbs of children and young adults.
ATYPICAL DERMAL NODULES IN BENIGN MELANOCYTIC NAEVI7 Atypical dermal nodule is one name for a lesion which has also been referred to as inverted type A naevus,8 melanocytic naevi with focal atypical epithelioid cell components9 and more recently anecdotally as clonal naevus. This can be one of the lesions most easily mistaken
Fig. 2 An atypical dermal nodule in a benign naevus is not associated with atypia in the junctional zone. Lobulated groups of melanocytes with abundant cytoplasm but showing no nuclear atypia contrast with adjacent small intradermal naevus cells (H&E, original magnification, 640).
for an invasive melanoma arising in a pre-existing naevus. It occurs in a wide age range and in virtually all sites. It presents most often as a domed pale brown nodule within which is a dark brown spot occupying a variable proportion of the lesion as a whole. Microscopically, the lesions have a background of intradermal or compound naevus with no junctional atypia. The small type B cells of the dermal component usually surround a group of larger cells which are accompanied by melanophages (Fig. 2). The group of larger cells may be sharply circumscribed or a loosely scattered aggregate of smaller groups. The large size of the cells is due to abundant cytoplasm with fine melanin pigment rather than increased nuclear size. The nuclei show little pleomorphism and virtually no mitotic activity. The lack of junctional activity, nuclear atypia, mitoses or sign of infiltration enables confident recognition despite the apparent intralesional transformation which has been advocated in some contexts as a criterion of malignancy. In one sense the lesion is a variant of combined naevus, but its clinical and histological features are sufficiently distinctive to warrant, in our opinion, a specific name. Clinically, it is worrying because new, central, dark pigmentation develops in what appears otherwise to be a benign mole. Histologically, the extra component, usually central, in the benign naevus is difficult to classify since it does not have consistent features of other entities, although it could be said to have some resemblance to a component of cellular blue naevus.
ATYPIA IN BLUE NAEVI
Fig. 1 PSCN is typified by vertically orientated nests of large spindle cells overriding the junctional zone with little upward extension in the thickened epidermis. The melanocytes contain fine melanin pigment but there is more prominent melanin in macrophages (H&E, original magnification, 6200).
A diagnostic feature of cellular blue naevi is usually a biphasic pattern with heavily pigmented, dendritic shaped cells and fibrosis in the same lesion as confluent sheets of plump spindle cells with large nuclei. Also, there may be occasional mitoses, but atypical mitoses, necrosis and an infiltrative pattern are needed to confirm malignant change in a cellular blue naevus.10 Atypia in common blue naevi
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Fig. 3 Atypia in blue naevi is seen in its extreme form in the bizarre blue naevus. In this there is great variation in cell outline with severely pleomorphic nuclei and multinucleation. There is still a background of heavily pigmented dendritic melanocytes (H&E, original magnification, 6400).
may be pronounced and in practice is as likely to be confused with melanoma as that seen in cellular blue naevi. The pleomorphism may take the form of giant cells with severely irregular and large nuclei and gross variability in the outline of the cytoplasm, so much so that the term ‘bizarre blue naevus’ has been used.11 Paradoxically, the extreme pleomorphism (Fig. 3) is a clue to the diagnosis of a variant of benign blue naevus. The heavily pigmented dendritic background to the lesion in the superficial dermis is usually apparent.
HALO PHENOMENON The intense lymphocytic infiltrate of naevi showing the histological halo phenomenon occasionally presents a problem in distinguishing the lesion from melanoma because of the obscuring of the dermal melanocytes and the frequent mild-to-moderate dysplasia in the overlying junctional component (Fig. 4). The latter, when seen in the context of the usual young age of the patient, is not sufficient to confirm a diagnosis of melanoma and careful examination of the dermal infiltrate will reveal small type B melanocytes, although sometimes showing mild reactive atypia.12 An occasional mitosis can be seen, as in any benign intradermal naevus, and is insufficient to alter the diagnosis. A clinical halo may be seen occasionally around melanomas as well as benign naevi and may not always be associated with a lymphocytic infiltrate. The converse, namely an intense lymphocytic infiltrate without a clinical halo, also occurs.
Pathology (2004), 36(5), October
Fig. 4 The halo phenomenon is recognised histologically by an intense lymphocytic infiltrate among dermal melanocytes of a compound melanocytic lesion. There is some nuclear enlargement and variability with nucleolar prominence. In this case only focal junctional proliferation is seen (H&E, original magnification, 6100).
The overall pattern is distinctive but is not exclusive to deep penetrating naevus. It can also be seen in nodular melanoma, the correct diagnosis sometimes being only achieved when metastasis occurs. Therefore, it is essential to check the cytology of the melanocytes in the putative deep penetrating naevus. They are usually large but not pleomorphic and mitoses are uncommon. There are a small number of DPN which have an epithelioid cell type14 and others, which although spindle celled, are less deeply penetrating and show conspicuous extension along the neurovascular bundles. These have been termed ‘plexiform spindle cell naevi’.15 All of these variants show some similarity to cellular blue naevi and like them may be seen combined with other variants of naevi.
DEEP PENETRATING NAEVUS (DPN) DPN13 shares some features with deeply invasive nodular melanoma. It extends in an irregular wedge often at least into the deep reticular dermis and is associated with a junctional proliferation of melanocytes (Fig. 5). However, these junctional melanocytes do not show significant dysplasia. The dermal melanocytes are large fusiform cells arranged in fascicles tending to be vertically orientated and associated with intervening melanophages.
Fig. 5 Deep penetrating naevus is recognised in part by its outline, a deeply extending wedge of melanocytes with the base at the epidermis (right) where there are some nests of benign naevus cells. The apex of the lesion, in this case adjacent to a hair follicle, (left) extends into deep reticular dermis. The cells are arranged in fascicles of spindle cells with intervening pigment-laden macrophages (H&E, original magnification, 6100).
BENIGN MIMICS OF MELANOMA
417
PLANTAR MELANOCYTIC LESIONS In general, melanocytic lesions are recognisable irrespective of their anatomical location but some of the naevi on the sole of the foot do present a site specific pattern which can be confused with early melanoma.16 This probably relates to the thickness of the epidermis and the density of the dermal collagen in this site. Some plantar lesions are composed of large, irregular, but well circumscribed nests along the junctional zone. In addition, these nests often show extension into the upper epidermis and stratum corneum simulating transepidermal elimination but should not be confused with pagetoid infiltration of the epidermis. The nests may bulge slightly into the superficial dermis and this area also shows active fibroplasia and a scanty lymphocytic infiltrate. The melanocytes do not show severe cytological atypia but, along with the irregularity of the nests, may show a slightly dishevelled arrangement (Fig. 6). The lack of severe atypia and the circumscription of the nests are most helpful in excluding melanoma but the transepidermal elimination of intact nests is the strongest pointer to the benign nature of these lesions.
PSEUDOMELANOMA FOLLOWING INCOMPLETE REMOVAL OF A BENIGN NAEVUS The lesions so far described have been presented in order of decreasing incidence in referral practice. The pseudomelanoma17 following incomplete excision of a benign naevus is most uncommon, which is fortunate since it can closely simulate a melanoma in situ. The original partially excised lesion was either a junctional or compound naevus. The recurrent (persistent) naevus may show irregularly distributed nests and single melanocytes in the epidermis (Fig. 7). These melanocytes can show some variation in size and shape amounting to moderate pleomorphism and they are not confined to the basal layer or junctional zone. Furthermore, the underlying dermis typically shows fibrosis and inflammation related to the previous surgery, but simulating the host response commonly seen in early
Fig. 7 Recognition of pseudomelanomatous features following incomplete excision of a benign compound naevus are facilitated by identifying the underlying fibrosis as post-surgical scarring. The junctional component shows marked hyperplasia of large melanocytes with occasional cells reaching the mid-epidermis. The presence of epidermal thickening and hypergranulosis represent clues to the diagnosis. Without the adjacent benign lesion and the scarring, this would be indistinguishable from melanoma in situ (H&E, original magnification, 6200).
melanoma. A clue to the benign nature of the lesion may be given by benign naevus cells beneath the layer of scarring but these may have been removed initially or the original lesion may have been entirely junctional. In diagnosing these cases, knowledge of an earlier procedure is highly desirable as is review of the histology of the initial lesion. The latter is important to confirm that the original diagnosis was correctly benign as well as correlating with the features of the subsequent specimen. In the absence of dermal naevus cells, the history of a previous benign lesion is crucial, but additional benign clues are the lack of extension of the recurrent intraepidermal naevus cells beyond the dermal scarring and the absence of severe atypia.
BENIGN PROLIFERATIVE NODULES IN GIANT CONGENITAL NAEVI
Fig. 6 Plantar melanocytic naevi often include large irregular nests of mildly atypical naevus cells. Transepidermal elimination of nests is a common but reassuring feature (H&E, original magnification, 6200).
Benign proliferative nodules are very rare. They may present at any age but are more common in children. They raise a very difficult problem in distinguishing these benign nodules from melanoma arising in the dermal component of congenital naevi. They are usually small nodules (less than 5 mm) composed of type B naevus cells more crowded together and slightly larger than those of the adjacent naevus. Some epithelioid and spindle cells may be seen. If necrosis, severe atypia, mitoses and an expansile destructive pattern of growth are seen, melanoma should be considered. On the other hand, if the clone is without severe atypia or necrosis, shows only an occasional mitosis and has a pattern of growth which merges with the adjacent naevus then the lesion is likely to be benign. In neonates (less than 6 months old) marked atypia with numerous mitoses in larger nodules of congenital naevi still appear to behave benignly.18 Even highly disturbing
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component. A MIB-1 may help since these cells have a positive count of less than 1% or zero. Also, they are usually but not always HMB45 negative. Nevertheless, this distinction may be subtle and the learning period for pathological interpretation of SLN for melanoma is at least as important as that said to be necessary for surgeons performing these procedures. Address for correspondence: Professor M. G. Cook, Department of Histopathology, The Royal Surrey County Hospital, Guildford GU2 7XX, UK. E-mail: [email protected]
References
Fig. 8 The capsule of this sentinel lymph node contains a prominent aggregate of enlarged naevus cells, many with obvious nucleoli. There is also a suggestion of naevus cells extending into the underlying subcapsular sinus. These features are not interpreted as metastatic melanoma (H&E, original magnification, 6400).
appearances with ulceration in patients of this age should not be unequivocally diagnosed as malignant.
BENIGN NAEVUS CELLS IN SLN SIMULATING METASTASIS Finally, in these days when sentinel lymph node (SLN) biopsy is becoming a standard procedure in the management of melanoma, the occurrence of benign naevus cells simulating metastases in SLN should be remembered. Usually naevus cells in SLN are confined to a capsular, or less frequently, trabecular site. They are recognised by their exact location actually within the fibrous tissue of the capsule or trabecula and also by their cytology. They are typically melanocytes with scanty cytoplasm and small regular basophilic nuclei-like type B naevus cells. They are seen in one or more nodes of up to 20% of patients who have SLN biopsies.19 In a small proportion of these nodes with capsular or trabecular naevus cells, the collections of cells are much larger so that they extend beyond the capsule or trabecula into the subcapsular sinus or adjacent parenchyma (Fig. 8). In this site they appear to acquire different cytological features. The nuclei become slightly larger and less densely basophilic. This may be accompanied by occasional small nucleoli and some minor variation to the nuclear outline. Features supporting the benign nature of these elements are the lack of severe atypia and the confluence with a capsular or trabecular
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