Until recently, the prevailing paradigm in classification

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1 Nevus/Melanocytoma/Melanoma An Emerging Paradigm for Classification of Melanocytic Neoplasms? Artur Zembowicz, MD, PhD; Richard A. Scolyer, MD, FRCPA, FRCPath N Context. Until recently, the prevailing paradigm in classification and clinical management of melanocytic proliferations mandated dichotomous classification of all melanocytic lesions as either entirely benign (nevus) or entirely malignant (melanoma). However, some diagnostically challenging lesions cannot be unequivocally classified as nevus or melanoma by histologic evaluation of the primary tumor. Such lesions have been referred to as borderline or melanocytic tumors of uncertain malignant potential. Objective. To review and update the problem of diagnostically difficult melanocytic proliferations and recent concepts regarding borderline melanocytic tumors. Data Sources. Published literature and personal experience of the authors. Until recently, the prevailing paradigm in classification and clinical management of melanocytic proliferations mandated dichotomous classification of all melanocytic lesions as either entirely benign (nevus) or entirely malignant (melanoma). This paradigm still allows the accurate classification of the vast majority of melanocytic tumors and remains the basis of current clinical management algorithms. Furthermore, pathologists are expected to be able to distinguish between benign and malignant lesions. However, in everyday practice, even experienced pathologists are unable to reproducibly classify a small subset of melanocytic proliferations into established nosologic categories and, in some cases, may not be able to accurately predict prospectively the biologic behavior of the tumor. Such difficult lesions are often reported Accepted for publication May 19, From the Department of Pathology, Lahey Clinic, Burlington, Massachusetts, Boston, Massachusetts, the Department of Pathology, Harvard Vanguard Medical Associates, Boston, Massachusetts, and the Department of Pathology, Tufts University Medical School, Boston, Massachusetts (Dr Zembowicz); and the Department of Pathology, Melanoma Institute Australia, Sydney, NSW, Australia, Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia, Discipline of Pathology, Sydney Medical School, The University of Sydney, NSW, Australia, and the Cancer Institute New South Wales Clinical Research Fellow, NSW, Australia (Dr Scolyer). The authors have no relevant financial interest in the products or companies described in this article. Reprints: Artur Zembowicz, MD, PhD, Department of Pathology, 6th Floor, 133 Brookline Ave, Boston, MA ( com). Conclusions. Preliminary evidence indicates that it may be appropriate to expand the classification scheme of melanocytic neoplasms to include a third diagnostic category of melanocytic lesions of intermediate malignant potential that are capable of metastasis to regional lymph nodes but have limited potential for distant spread. We propose the term melanocytoma for this group of lesions. We believe that a nevus/melanocytoma/melanoma paradigm may provide a useful intellectual framework to understand, research, and clinically manage borderline melanocytic tumors. (Arch Pathol Lab Med. 2011;135: ) descriptively as a melanocytic tumor of uncertain malignant potential, severely atypical melanocytic proliferation, borderline melanocytic tumor, nevomelanocytic tumors of undetermined risk, or other similar terms. The goal of this article is to review the problem of difficult/borderline melanocytic lesions in the context of our recent suggestion to consider expanding the current classification of melanocytic lesions to include an intermediate-potential/low-malignant-potential diagnostic category of melanocytic tumors ( melanocytomas ), 1 which are characterized by their limited capacity to involve regional lymph nodes and rare systemic spread. BACKGROUND Histologic diagnosis of melanocytic proliferations is inherently difficult, as it requires integration of multiple architectural and cytologic criteria. No single feature is diagnostic of a particular entity. Futhermore, similar features can be found in both benign nevi and melanomas. Ancillary studies (such as comparative genomic hybridization and fluorescence in situ hybridization) have the potential to assist in the categorization of melanocytic tumors; however, they require further validation and are not widely available for routine use. In some cases, the clinical context, such as the age of the patient, location of the lesion, its duration and appearance, have to be taken into account before arriving at a histologic diagnosis. It is probably impossible and perhaps unnecessary to precisely define what constitutes a difficult melanocytic lesion. The frequency of difficult melanocytic lesions obviously depends on the experience of the observer. However, a small but not insignificant number of melanocytic lesions cannot be precisely or reproducibly classified into an 300 Arch Pathol Lab Med Vol 135, March 2011 Nevus/Melanocytoma/Melanoma: An Emerging Paradigm Zembowicz & Scolyer

2 Histologic Categories of Borderline Melanocytic Lesions a Histologic Category Differential Diagnosis 1 Severely atypical dermoepidermal nevomelanocytic proliferation with borderline features of radial-growth-phase malignant melanoma Dysplastic nevus versus superficial spreading or lentigo maligna melanoma 2 Severely atypical dermoepidermal nevomelanocytic proliferation with borderline features of early vertical-growth-phase melanoma Dysplastic nevus versus superficial spreading or lentigo maligna melanoma 3 Severely atypical intraepidermal epithelioid cell melanocytic dysplasia mimicking superficial spreading melanoma Dysplastic nevus versus superficial spreading or lentigo maligna melanoma 4 Atypical lentiginous melanocytic proliferation/de novo melanocytic Dysplastic nevus versus lentigo maligna melanoma dysplasia mimicking lentigo maligna 5 Severely atypical superficial compound Spitz tumor mimicking superficial Spitz nevus versus spitzoid melanoma spreading melanoma in radial or early vertical growth 6 Severely atypical spitzian proliferation (atypical Spitz tumor) mimicking spitzian Atypical Spitz nevus versus spitzoid melanoma melanoma 7 De novo dermal-based epithelioid melanocytic dysplasia Nevus versus melanoma arising in a nevus 8 Borderline lesions mimicking nevoid melanoma Nevus versus nevoid melanoma versus nodular melanoma 9 Severely atypical dermal-based melanocytic proliferation without criteria for nevoid melanoma/minimal deviation melanoma, spitzian type Deep-penetrating nevus, blue nevus, clonal nevus versus melanoma a Derived from data in Crowson et al. 7 established category even by experienced pathologists. This notion was confirmed by a number of concordance studies that showed significant disagreements between melanoma experts in classification of difficult melanocytic lesions. 2 6 In our experience, melanocytic lesions are probably the most common group of lesions submitted for a second opinion/consultation in pathology. In some instances, the diagnostic difficulty is caused by technical issues, such as inadequate sampling, suboptimal orientation of tissue, poor fixation, or faulty processing of the sample. Regrettably, some of these cases can never be precisely classified, even after reprocessing of the tissue. In the remaining difficult lesions, the diagnostic dilemma reveals limitations of the current knowledge and experience of the observer and/or more fundamental limitations of the morphologic method of classification of melanocytic lesions. With careful study and experience, most difficult melanocytic lesions can be classified as more or less unusual variants of a nevus or a melanoma. Many of the problematic lesions appear to show overlapping histologic features of known entities. If the histologic differential diagnosis is between 2 variants of a nevus, there are unlikely to be any clinical consequences of inaccurate classification. However, often the precise classification is of critical importance for patient prognosis and management, as diagnostic considerations include both a benign nevus and melanoma. We refer to this group of lesions as borderline melanocytic tumors. HISTOLOGIC CATEGORIES OF BORDERLINE MELANOCYTIC PROLIFERATIONS Crowson et al 7 and Magro et al 8 compiled a comprehensive list of borderline melanocytic lesions according to histologic features. Their classification can accommodate most, if not all, borderline lesions encountered in consultation practice (Table). The lesions are grouped under descriptive diagnostic terms, which reflect the types of lesions prone to cause diagnostic problems, their different morphologic features, and histologic differential diagnoses. The individual categories do not represent distinct clinicopathologic entities and do not provide precise prognostic information to guide clinical management. This classification was not intended to serve as a nosologic scheme, but it nevertheless provides a practical framework for the histologic assessment of difficult melanocytic tumors. It is also a useful foundation for further clinicopathologic and molecular research aimed at identification of new variants or formulation of better diagnostic criteria for the existing entities. The first 4 Crowson/Magro/Mihm histologic categories (1 4) include lesions raising a histologic differential diagnosis of severely atypical/dysplastic nevus or nevus of special anatomic site (genital, milk-line, acral, etc), and superficial spreading or lentigo maligna melanoma (categories 1 4) are by far the most common examples of histologically borderline melanocytic tumors encountered in routine practice. The second most common group of borderline melanocytic tumors is spitzoid neoplasms (Crowson/Magro/ Mihm histologic categories 5 and 6). They include superficial and deep melanocytic proliferations with features reminiscent of Spitz nevus. The least frequent and the most heterogenous group of borderline melanocytic tumors are predominantly dermal, nonspitzoid lesions (Crowson/Magro/Mihm histologic categories 7 9). They include nevi that feature focal highgrade cytologic atypia, atypical proliferative nodules, focal mitotic activity in the context of otherwise benign architectural features, and growth pattern (category 7) and lesions raising histologic differential diagnosis between atypical dermal nevus and nevoid melanoma (category 8). Finally, the rarest of all borderline melanocytic proliferations are histologically distinct dermal tumors that do not fit into any of the above categories. This group (category 9) includes borderline deep-penetrating tumors (atypical lesions reminiscent of deep-penetrating nevus), borderline blue nevi, and other otherwise unclassifiable dermal melanocytic tumors. Tumors currently classified as pigmented epithelioid melanocytoma were also included in the latter category, but in the most recent classification they were separated as a distinct category. 8 CONCEPTS OF BORDERLINE TUMORS IN PATHOLOGY To understand the problem of a difficult melanocytic lesion, it is important to reflect on the nature of diagnostic uncertainties and the use of borderline diagnostic terms in pathology. Borderline diagnostic terms are used in 2 distinct contexts. In the first context, they intend to express the indeterminate nature of the diagnosis. They express a Arch Pathol Lab Med Vol 135, March 2011 Nevus/Melanocytoma/Melanoma: An Emerging Paradigm Zembowicz & Scolyer 301

3 degree of uncertainty about the diagnosis and mean tumor of uncertain malignant potential, unclassifiable or difficult to classify, with overlapping histologic features between benign or malignant, challenging, controversial, equivocal, etc. Formal recognition of the existence of indeterminate lesions can be useful in clinical practice, as proven by the widely accepted concept of atypical squamous cells of uncertain significance in Papanicolaou smears of cervical cytology. In the second context, the borderline diagnostic category means intermediate, a distinct nosologic category, a specific disease or clinicopathologic entity of intermediate or low malignant potential between traditional benign and malignant categories. The concept of borderline ovarian carcinoma and the categorization of some soft tissue tumors (such as plexiform fibrohistiocytic tumor, socalled angiomatoid fibrous histiocytoma, and some types of hemangioendothelioma) are examples of established intermediate borderline diagnostic categories. This is further emphasized by the inclusion of a formal intermediate biologic potential category in the World Health Organization classification of soft tissue tumors published in Within the framework of the melanoma or not paradigm, it was widely assumed that all difficult melanocytic lesions belonged to the indeterminate group of lesions, and with further study and expertise they could be categorized as either entirely benign or melanoma. Different terms are applied to histologically ambiguous lesions. Probably the most consistently used is the term melanocytic tumor of uncertain malignant potential. PIGMENTED EPITHELIOID MELANOCYTOMA: A PROTOTYPICAL BORDERLINE MELANOCYTIC TUMOR OF INTERMEDIATE MALIGNANT POTENTIAL Almost a decade ago, the authors independently recognized that a subset of darkly pigmented melanocytic metastasizing tumors histologically reminiscent of melanomas occurring in animals, sometimes referred to as socalled animal-type melanomas, are histologically very similar to benign epithelioid blue nevus described in patients with Carney complex and also occurring sporadically, unassociated with the syndrome. 10 In light of this and the subsequent recognition of apparently irreconcilable, conflicting information about the biologic potential of these tumors the authors began interpreting these lesions as borderline melanocytic tumors of uncertain malignant potential rather than outright melanomas and recommended sentinel lymph node sampling for diagnostic purposes rather than for staging the tumor, based on the probably flawed hypothesis that the presence of sentinel lymph node metastasis would establish evidence that a tumor was malignant. The assumption that the sentinel lymph node tumor harboring status might help to identify histologic criteria that would enable distinction of benign epithelioid blue nevi from their malignant counterparts reflected the generally accepted understanding of the biology of melanocytic tumors at the time these studies were initiated. We prospectively collected a series of 46 such lesions and realized that in spite of frequent sentinel lymph node metastases, with the exception of 1 case, these tumors did not appear to spread beyond lymph nodes, albeit with limited follow-up (median 32 months). Importantly, we compared histologic features of lesions in our series with those of epithelioid blue nevi from the original series of epithelioid blue nevus reported by Dr Carney and confirmed that they are histologically indistinguishable. Based on that study, we proposed that epithelioid blue nevus of Carney complex, and most lesions previously considered to be so-called animal-type melanoma, constitute a distinct clinicopathologic entity, which we called pigmented epithelioid melanocytoma (PEM). 11 An example of PEM is illustrated in Figure 1, A through C. The authors subsequent series of studies 1,11 13 established that PEM has characteristic demographics, clinical presentation, histologic and molecular features, and biologic behavior. Pigmented epithelioid melanocytoma can occur in a syndromic setting of Carney complex (a familial lentiginosis and low-grade neoplasia syndrome) but is more frequently seen as a sporadic lesion in patients without the complex. Pigmented epithelioid melanocytoma is a tumor of young people, with the median age of onset in the third decade of life. It can occur in all races and its epidemiology does not appear to correlate with a history of sun exposure. Pigmented epithelioid melanocytoma has generalized site distribution and can arise in the genital mucosa and the conjunctiva. It usually presents clinically as a slowly growing darkly pigmented skin nodule. Rarely, PEM can present clinically as a lymph node metastasis. The concept of PEM as a distinct clinicopathologic entity was further validated by a recent study 12 showing that PEM frequently shows loss of expression of cyclic AMP dependent protein kinase 1 regulatory subunit 1a (R1a), a product of a gene mutated in families with Carney complex. Cyclic AMP signaling is critically involved in the regulation of melanocyte proliferation and pigment synthesis. 14 Therefore, loss of R1a expression is consistent with its pathogenic role in PEM and provides an explanation for the dark pigmentation of this tumor. Long-term clinical follow-up (median, 67 months) of 26 patients with PEM from the United States and Australia showed no adverse outcomes, even in patients with metastatic deposits in sentinel lymph nodes. 1 The results illustrate that spread of PEM beyond local lymph nodes is rare and that the prognosis is significantly more favorable than that of conventional melanoma. Importantly, the findings indicate that the presence of lymph node metastases in PEM does not imply a malignant clinical course. However, the follow-up period reported in this study is still too short to allow a definitive statement that biologic behavior of PEM is limited to lymph node metastasis, as it is well known that malignant behavior and metastasis of melanoma may occur many years and even decades after excision of the primary tumor. 2 The molecular relationship of PEM to Carney complex also helps to understand its unique behavior. Carney complex associated PEMs are thought to be entirely benign. However, PEMs are more frequent in patients without the complex. Interestingly, in some instances, most notably in the case of large cell calcifying Sertoli cell tumor, 15 Carney complex associated tumors can metastasize when occurring in patients without the complex, while they appear to be entirely benign when occurring in patients with Carney complex. The available information suggests that PEM is an example of a borderline melanocytic tumor of the intermediate type. Therefore, we concluded that this tumor 302 Arch Pathol Lab Med Vol 135, March 2011 Nevus/Melanocytoma/Melanoma: An Emerging Paradigm Zembowicz & Scolyer

4 Figure 1. Skin biopsy specimen of a deeply pigmented skin lesion on neck from a 46-year-old man, which was diagnosed as pigmented epithelioid melanocytoma. A sentinel node biopsy was not performed. The patient has had no recurrence or metastases at 72 months followup (hematoxylin-eosin, original magnifications 320 [A], 3100 [B], and 3400 [C]). is probably best understood if the traditional dichotomous nevus versus melanoma paradigm is modified to include a third, intermediate category of melanocytic proliferations, capable of regional lymph node metastasis but rare systemic spread with a generally indolent clinical course. 1 We proposed that the term melanocytoma could be applied as a general category for these lesions. According to this proposal, melanocytic proliferations fall into 3 general categories including nevus, melanocytoma, and melanoma. ARE ATYPICAL SPITZ TUMOR AND ATYPICAL DEEP-PENETRATING NEVUS OTHER EXAMPLES OF INTERMEDIATE BIOLOGIC POTENTIAL TUMORS ( MELANOCYTOMAS )? Adoption of nevus/melanocytoma/melanoma classification offers an intellectual framework and rationale for diagnosis and management of borderline melanocytic tumors. There are parallels to the recognition in soft tissue tumor pathology of a group of tumors with intermediate biologic potential that usually have a benign clinical course but may occasionally show aggressive/malignant clinical behavior. Furthermore, in the latter instances, aggressive behavior cannot be recognized prospectively on the basis of histopathologic assessment of the primary tumor. Obviously, an important question is whether other borderline melanocytic proliferations may similarly be better understood by conceptualizing them in the nevus/ melanocytoma/melanoma framework rather than the conventional nevus versus melanoma paradigm. A strong candidate to be considered as a melanocytoma is atypical Spitz tumor. None of the borderline melanocytic tumors has received as much attention as spitzoid neoplasms. It was widely assumed that, with more study and experience, spitzoid neoplasms could be classified histologically into entirely benign Spitz nevi and spitzoid melanoma. Whilst decades of effort, workshops, and consensus conferences 2 6 have to some extent refined diagnostic criteria to accurately separate benign from malignant Spitz tumors, as demanded by the melanomaor-not paradigm, these do not enable prediction of the biologic behavior of all tumors on the basis of morphologic assessment of a small but significant subset of cases. 16 As a result, most consultants adopted descriptive terminology for these lesions, creating a de facto provisional diagnostic category of atypical Spitz tumor (nevus) of uncertain malignant potential. 6,8,17 As in PEM, sentinel lymph node sampling has been investigated in patients with diagnostically difficult atypical Spitz tumors, not only as a prognostic indicator but also for diagnostic purposes, as an adjunctive test based on the probably flawed assumption that the presence of a sentinel node metastasis would indicate that the tumor was a melanoma. The reported outcomes in 160 patients with atypical Spitz tumors show that sentinel lymph node metastases are found in 29% to 50% of patients All the reported patients were well, without evidence of residual or recurrent disease, within a median follow-up of 37 months. While further study of larger numbers of patients with longer follow-up is required before definitive conclusions can be made, the results raise the possibility that, although they are distinct entities, both atypical Spitz tumors and PEM have similar biologic potential, and at least some tumors may be provisionally considered as members of the same class of melanocytic lesions. Therefore, we recently proposed that it may be appropriate to consider whether atypical Spitz tumors should also be considered as a melanocytoma. 1 Nevertheless, further clinicopatho- Arch Pathol Lab Med Vol 135, March 2011 Nevus/Melanocytoma/Melanoma: An Emerging Paradigm Zembowicz & Scolyer 303

5 Figure 2. Skin biopsy specimen of a pigmented skin lesion on the left thigh from an 11-year-old girl, which was diagnosed as borderline deeppenetrating tumor. A through D, Punch biopsy specimen of a variably pigmented skin lesion in the left thigh. The lesion shows histologic features characteristic of a deep-penetrating nevus. E and F, Sentinel lymph node from the left groin shows intraparenchymal tumor. A completion node dissection showed tumor in an additional 2 of 17 lymph nodes. The patient has had no recurrence or further metastasis at 76 months follow-up (hematoxylin-eosin, original magnifications 320 [A and E], 3100 [B], 3400 [C and D], and 3200 [F]). 304 Arch Pathol Lab Med Vol 135, March 2011 Nevus/Melanocytoma/Melanoma: An Emerging Paradigm Zembowicz & Scolyer

6 logic studies, supplemented by molecular research, will be needed to determine if atypical Spitz tumor is indeed a distinct clinicopathologic entity. In our view, it is likely that, as a group, so-called atypical spitzoid tumors are likely to be heterogeneous and include some benign Spitz nevi, some melanomas, as well as other tumors with intermediate/low malignant properties ( melanocytomas ). If this is true, the challenge remains how to identify the latter subcategory. We believe that it may be appropriate to consider some other tumors as possible melanocytomas among dermal tumors comprising Crawson/Magro/Mihm diagnostic categories 8 and 9. One possible candidate is borderline deep-penetrating tumors (atypical lesions reminiscent of deep-penetrating nevus). Although atypical deep-penetrating tumors are reportedly capable of spreading to regional lymph nodes, they are associated with a more favorable prognosis than conventional melanoma. 24 An example of a borderline tumor that resulted in lymph node metastases but did not spread beyond lymph nodes within a 5-year follow-up is illustrated in Figure 2, A through F. Magro et al 8 recently reported 7 similar cases. NEVUS/MELANOCYTOMA/MELANOMA PARADIGM: NOSOLOGIC IMPLICATIONS The proposed nevus/melanocytoma/melanoma classification scheme does not remove the problem of histologically ambiguous melanocytic lesions, which cannot be classified into 1 of the categories. These lesions will still have to be reported with descriptive terms, such as melanocytic tumor of uncertain malignant potential (MEL- TUMP). 25 Furthermore, it is important to convey to the clinicians and patients that MELTUMP is not a nosologic category and that lesions currently reported as such may have a spectrum of biologic potential ranging from that of benign nevus through melanocytoma to melanoma. It is also critical to emphasize that the term melanocytoma is not synonymous with MELTUMP. In fact, by definition in our proposal, a melanocytoma is not a MELTUMP. The term melanocytoma should only be applied to entities defined by reproducible histologic and/or molecular features, known to metastasize to lymph nodes but with rare spread beyond lymph nodes, and verified by long clinical follow-up of sufficient number of cases. As discussed above, PEM is a prototypical example of melanocytoma and atypical Spitz nevus and, perhaps, atypical deep-penetrating tumors are additional candidates. NEVUS/MELANOCYTOMA/MELANOMA PARADIGM: MANAGEMENT IMPLICATIONS Experience with PEM and atypical Spitz tumors has significant implications for clinical management of borderline melanocytic lesions. It allows a more conservative approach to tumors previously considered as MELTUMPs but that can be classified as melanocytomas. According to melanoma-or-not paradigm, the safest course of action was to manage all borderline lesions as if they were melanomas of equivalent thickness. This approach, advocating management by assuming the worst case scenario of malignant potential of a lesion, still should remain the cornerstone of management of borderline melanocytic tumors of indeterminate type (MELTUMPs). However, it may not be appropriate for melanocytomas. Excision of the tumor with clear margins is probably mandatory in all borderline melanocytic lesions. However, wide local excision of a melanocytoma site as for a melanoma may be unnecessary if the lesion involves a cosmetically sensitive area, such as the face; there is no evidence documenting the utility of such an approach. Physicians have to use their best judgment, as there are no hard data to determine the optimal width of reexcision of melanocytomas. It is difficult to argue against performing sentinel lymph node sampling in borderline tumors of indeterminate type/meltumps, which are suspected to have the ability to metastasize, or are known to metastasize to lymph nodes, and whose actual risk of distant spread has not been established by rigorous clinical follow-up studies. Many pathologists still consider any lesion capable of metastasis as malignant. However, in our opinion, recent experience of series of patients with PEM and atypical Spitz tumors supports the viewpoint that histologically ambiguous melanocytic neoplasms with lymph node metastases should not be automatically reclassified as melanomas, as it is questionable whether sentinel lymph node biopsy provides important evidence of the individual lesion s risk of progression to clinically significant metastatic disease. Ideally, these patients should be enrolled in prospective or retrospective clinicopathologic correlation studies with long-term follow-up, aiming to group the tumors into histologically and/or molecularly recognizable subsets and then trying to determine if they behave as melanocytomas or melanomas. It is less clear whether patients with PEM or atypical Spitz tumors, or other melanocytomas, will benefit from sentinel lymph node procedure. A potential benefit of the procedure would appear to be that any tumor within the sentinel node is removed. Regional node field clearance and biologic therapy and chemotherapy should probably be avoided, unless bulky nodal or other metastases develop. For patients with disease that is apparently clinically localized to the primary tumor site, identifying the sentinel lymph nodes by lymphoscintigraphy for subsequent close monitoring by clinical examination and ultrasonography appears to offer an alternative, noninvasive strategy to sentinel lymph node biopsy that may allow early detection of growing metastases. A. Z. and R. A. S. would like to thank their respective mentors, Martin C. Mihm Jr, MD (Massachusetts General Hospital, Boston) and Stanley W. McCarthy, AO, MBBS, FRCPA (Royal Prince Alfred Hospital, Sydney, Australia) for years of teaching, sharing challenging cases, collaboration, and support. Many of the concepts presented in this review have been developed during the 8-year tenure of A. Z. in Dr Mihm s second-opinion consultation practice at the Massachusetts General Hospital and the ongoing close working relationship of R. A. S. with Prof McCarthy. The authors also thank John F. Thompson, MD (Royal Prince Alfred Hospital, Sydney, Australia) for his critical appraisal of the manuscript. References 1. Mandal R, Murali R, Lundquist K, et al. Pigmented epithelioid melanocytoma: favorable outcome after 5 year follow-up. Am J Surg Pathol. 2009;33(12): Barnhill RL, Argenyi Z, Berwick M, et al. Atypical cellular blue nevi (cellular blue nevi with atypical features): lack of consensus for diagnosis and distinction from cellular blue nevi and malignant melanoma ( malignant blue nevus ). Am J Surg Pathol. 2008;32(1): Barnhill RL, Argenyi ZB, From L, et al. Atypical Spitz nevi/tumors: lack of consensus for diagnosis, discrimination from melanoma, and prediction of outcome [comment in Hum Pathol. 1999;30(12): ]. 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7 4. Corona R, Mele A, Amini M, et al. Interobserver variability on the histopathologic diagnosis of cutaneous melanoma and other pigmented skin lesions. J Clin Oncol. 1996;14(4): Cerroni L, Kerl H. Tutorial on melanocytic lesions. Am J Dermatopathol. 2001;23(3): Cerroni L, Barnhill R, Elder D, et al. Melanocytic tumors of uncertain malignant potential: results of a tutorial held at the XXIX Symposium of the International Society of Dermatopathology in Graz, October Am J Surg Pathol. 2010;34(3): Crowson AN, Magro CM, Mihm CMJ. The Melanocytic Proliferations. New York, NY: Willey-Liss; Magro CM, Crowson AN, Mihm MC Jr, Gupta K, Walker MJ, Solomon G. The dermal-based borderline melanocytic tumor: a categorical approach. JAm Acad Dermatol. 2010;62(3): Fletcher CDM, Unni KK, Mertens F, eds. Pathology and Genetics of Tumours of Soft Tissue and Bone. Lyon, France: IARC Press; World Health Organization Classification of Tumours; vol Carney JA, Ferreiro JA. The epithelioid blue nevus: a multicentric familial tumor with important associations, including cardiac myxoma and psammomatous melanotic schwannoma. Am J Surg Pathol. 1996;20(3): Zembowicz A, Carney JA, Mihm MC. Pigmented epithelioid melanocytoma: a low-grade melanocytic tumor with metastatic potential indistinguishable from animal-type melanoma and epithelioid blue nevus. Am J Surg Pathol. 2004; 28(1): Zembowicz A, Knoepp SM, Bei T, et al. Loss of expression of protein kinasea regulatory subunit 1alpha in pigmented epithelioid melanocytoma but not in melanoma or other melanocytic lesions. Am J Surg Pathol. 2007;31(11): Scolyer RAM, Thompson JF, Warnke K, McCarthy SW. Pigmented epithelioid melanocytoma [letter]. Am J Surg Pathol. 2004;28(8): Park HY, Gilchrest BA. Signaling pathways mediating melanogenesis [review]. Cell Mol Biol (Noisy-le-grand). 1999;45(7): Kratzer SS, Ulbright TM, Talerman A, et al. Large cell calcifying Sertoli cell tumor of the testis: contrasting features of six malignant and six benign tumors and a review of the literature [review]. Am J Surg Pathol. 1997;21(11): Paradela S, Fonseca E, Pita S, et al. Spitzoid melanoma in children: clinicopathological study and application of immunohistochemistry as an adjunct diagnostic tool. J Cutan Pathol. 2009;36(7): Barnhill RL. The Spitzoid lesion: rethinking Spitz tumors, atypical variants, Spitzoid melanoma and risk assessment. Mod Pathol. 2006;(19 suppl 2):S21 S Gamblin TC, Edington H, Kirkwood JM, Rao UN. Sentinel lymph node biopsy for atypical melanocytic lesions with spitzoid features. Ann Surg Oncol. 2006;13(12): Lohmann CM, Coit DG, Brady MS, Berwick M, Busam KJ. Sentinel lymph node biopsy in patients with diagnostically controversial spitzoid melanocytic tumors. Am J Surg Pathol. 2002;26(1): Murali R, Sharma RN, Thompson JF, et al. Sentinel lymph node biopsy in histologically ambiguous melanocytic tumors with spitzoid features (so-called atypical spitzoid tumors). Ann Surg Oncol. 2008;15(1): Su LD, Fullen DR, Sondak VK, Johnson TM, Lowe L. Sentinel lymph node biopsy for patients with problematic spitzoid melanocytic lesions: a report on 18 patients. Cancer. 2003;97(2): Urso C, Borgognoni L, Saieva C, et al. Sentinel lymph node biopsy in patients with atypical Spitz tumors : a report on 12 cases [comment in Hum Pathol. 2006;37(7): ]. Hum Pathol. 2006;37(7): Ludgate MW, Fullen DR, Lee J, et al. The atypical Spitz tumor of uncertain biologic potential: a series of 67 patients from a single institution. Cancer. 2009; 115(3): Scolyer RAM, Muramatsu R, McCarthy SW. Atypical deep penetrating nevus forming a component of a combined nevus. In: Zembowicz A, Mihm CMJ, Murphy GF, Tahan SR, eds. Pigmented Skin Lesions. Brisbane, Australia: Knowledge Books and Software; 2009: Elder DE, Xu X. The approach to the patient with a difficult melanocytic lesion [review]. Pathology. 2004;36(5): Arch Pathol Lab Med Vol 135, March 2011 Nevus/Melanocytoma/Melanoma: An Emerging Paradigm Zembowicz & Scolyer

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