De novo intraepidermal epithelioid melanocytic dysplasia as a marker of the atypical mole phenotype -- a clinical and pathological study of 75 patients

BACKGROUND: We encountered a distinctive pattern of dysplastic intraepidermal melanocytic proliferation, which defies classification as a dysplastic melanocytic nevus, but in which the morphologic features fall short of a diagnosis of melanoma in situ. We designate such lesions as de novo intraepidermal epithelioid melanocytic dysplasia. METHODS: From 75 patients, 82 skin biopsies were encountered that showed this distinctive morphology. Hematoxylin- and eosin-stained histologic sections were studied and the features were correlated with personal and family histories of dysplastic nevi and melanoma. RESULTS: The diagnosis of de novo melanocytic dysplasia was made in 27 male patients and 48 female patients (mean age: 44 years). The histologic hallmark was a pagetoid (single-cell) array of moderately to severely atypical epithelioid melanocytes within the epidermis. Seventy-three lesions were located on sun-exposed skin and nine on sun-protected skin. In 41 patients, there was an atypical mole phenotype, whereas 20 patients had a prior or subsequent diagnosis of melanoma with five of 16 patients questioned revealing a family history of melanoma. CONCLUSIONS: De novo intraepidermal epithelioid melanocytic dysplasia is a distinct entity associated with an atypical mole phenotype and a personal and/or family history of melanoma.     

De novo intraepidermal epithelioid melanocytic dysplasia: a review of 263 cases

Background: De novo intraepidermal epithelioid melanocytic dysplasia (DNIEMD) is a newly characterized lesion that is associated with a personal and/or family history of malignant melanoma (MM) and/or dysplastic nevi (DN). However, the biological significance is still uncertain and the persons predisposed to this lesion have not been adequately described. Methods: Clinicopathologic data of 258 patients, from 263 biopsies diagnosed with DNIEMD, was obtained. A brief voluntary questionnaire was used to obtain demographic, risk factor and disease history. Results: There is an 82% (n=263) predominance of women with DNIEMDs. For men and women, the distributions of these lesions occur on the lower extremities (71%), the upper extremities (24%) and trunk (5%). Thirty‐one percent of the 258 patients responded to the questionnaires. 48% of the 60 respondents had green or blue eyes. 26% of 62 respondents had a history of non‐melanoma skin cancer (NMSC). Combined data revealed that 68% of 134 patients had a history of DN. As well, 24% of 89 patients had personal histories of melanoma, while 24% of 72 patients had a family history of melanoma. Conclusion: Most of these DNIEMD lesions are found on the lower extremities of women and men, and they have an increased association with MM, DN and NMSC. Jessup CJ, Cohen LM. De novo intraepidermal epithelioid melanocytic dysplasia: a review of 263 cases.     

The intermediate filament peripherin is expressed in cutaneous melanocytic lesions

Peripherin is an intermediate filament involved in growth and development of the peripheral nervous system and is localized to neurons, some other cells derived from neural tube and neural crest, and some neuroendocrine cells (e.g. β cells of islets of Langerhans). Peripherin also has been demonstrated in neuroblastomas and cutaneous neuroendocrine (Merkel cell) carcinomas. The expression of peripherin by other cells derived from the neural crest is unknown. We evaluated by immunohistochemistry 74 cutaneous melanocytic lesions including primary invasive malignant melanoma (IMM), melanoma in situ (MIS), atypical nevus (nevus with architectural disorder and cytologic atypia of melanocytes) (AN), spindle and epithelioid cell nevus (Spit/nevus) (SN), blue nevus (BN), and common intradermal benign melanocytic nevus (BMN) for expression of peripherin. Peripherin was detected in a cytoplasmic distribution within tumor cells in 14/14 IMM and 8/10 MIS. For IMM, peripherin localised to both the intraepidermal and invasive dermal components. Peripherin was detected in 10/10 AN and 9/9 SN, being localized to the intraepidermal component and, focally, to the superficial dermal component of the lesions. The dendritic nevus cells in 15/15 BN also expressed peripherin. For most of the BMN, expression of peripherin was absent or limited to rare, scattered cells in the superficial portion of the lesions. Melanocytes in adjacent normal skin were not labeled in any of the lesions studied. These results indicate that expression of peripherin is common in both benign and malignant melanocytic lesions, but not in normal resting adult melanocytes. Among benign lesions, expression of peripherin in the dermal component is rare except in the dendritic cells of BN. These findings provide evidence that the expression of peripherin, a marker of neuronal differentiation, is maintained by IMM, MIS, and BN, but is lost in the normal maturational sequence of the dermal component of other melanocytic lesions.     

Melanoma associated with a dermatofibroma

BACKGROUND: Dermatofibromas are common benign cutaneous fibrohistiocytic neoplasms, whereas melanomas are potentially aggressive malignancies. Differentiating these two entities can occasionally be difficult. METHODS: We report the case of a 56-year-old female presenting with a firm pink papule on the left thigh. RESULTS: Histopathology revealed atypical melanocytes in the epidermis and papillary dermis with numerous mitotic figures and intraepidermal pagetoid spread. Within the dermis was a poorly demarcated collection of epithelioid and spindled cells with intermixed keloidal collagen. The atypical melanocytes stained for MART-1 and S-100, whereas the underlying fibrohistiocytic tumor took up factor XIIIa immunostain, confirming the diagnosis of invasive malignant melanoma occurring in association with a dermatofibroma. CONCLUSIONS: This case emphasizes the role of immunohistochemical stains in correctly diagnosing melanocytic and histiocytic neoplasms.     

Seasonal variation in dysplastic naevi

There is a relationship between sunlight and the development of melanocytic neoplasms. Because the incidence and excision of melanocytic neoplasms varies according to season, we sought to determine if dysplasia and/or intraepidermal melanocytic expression differed in a cohort of dysplastic naevi (DN) removed in January compared with a similar cohort removed in August. The DN were graded based on the degree of dysplasia, and the number of intraepidermal melanocytes were counted after immunohistochemical staining with HMB-45 and Melan-A. There was no seasonal difference in the grading of the dysplastic naevi in either season (P = 0.08). Comparing 85 cases from August and 86 from January, there was a larger number of Melan-A-positive melanocytes in the August samples (P < 0.02), and a larger number of HMB-45-positive melanocytes in January (P < 0.01). This difference may be related to seasonal variations such as exposure to ultraviolet light exposure; however, there was no difference between the two groups in the degree of atypia seen.     

BAP1‐deficient and VE1‐negative atypical Spitz tumor

Atypical Spitz tumor with loss of BAP1 or Wiesner nevus is a peculiar variant of intradermal spitzoid melanocytic neoplasm composed of epithelioid melanocytes with a sheet‐like growth pattern, abundant infiltrating lymphocytes and rare or absent mitotic activity. This subset of atypical spitzoid tumors is characterized by the BRAF^V600E mutation and loss of BAP1 expression. Recognition of these lesions is important because they can be a marker for a hereditary BAP1‐associated cancer syndrome. We present an unusual case of sporadic Wiesner nevus that had typical histopathologic features and a BAP1 but not a BRAF mutation. The biological significance of Wiesner nevus is controversial, and little is known about prognosis, particularly in atypical cases like this one.     

BRCA1‐associated protein (BAP1)‐inactivated melanocytic tumors

Although discussed using variable terminology, cutaneous BRCA1‐associated protein (BAP1)‐inactivated melanocytic tumor (BIMT) has been considered a discrete diagnostic entity since 2011. Here, we review the initial genomic studies that identified these distinct melanocytic tumors and the clinical and histopathological features that define these tumors. These epithelioid, predominantly dermal, and melanocytic tumors present as erythematous nodules and histopathologically have features that may overlap with Spitz nevi and nevoid melanoma. There is no sex predilection, and cutaneous BIMTs can appear at any age; however, in most familial (germline mutant) cases patients have multiple cutaneous tumors with a first diagnosis in the second or third decade of life; ocular melanoma and other tumors are increasingly identified in these kindreds with germline BAP1 mutation. These tumors have been described with a myriad of terms including: Wiesner nevus, nevoid melanoma‐like melanocytic proliferation (NEMMP), BAP1 mutant Spitz nevus, BAP1 mutant nevoid melanoma, cutaneous BAPoma, and most recently cutaneous BIMT.     

Age distribution and histologic patterns of dysplastic nevi

A total of 676 dysplastic moles collected from 487 patients over a 1-year period were reviewed together with demographic data. The associated nevus in 642 cases (95%) had a superficial, or "acquired," pattern within the papillary dermis, in comparison with the nevus in the remaining 34 cases (5%), which showed a deep, or "congenital," pattern. The dysplasia was graded in severity as mild, moderate, or severe (on a scale of 1 to 3). When patients with mild to severe dysplastic melanocytic nevi were compared with those patients showing atypical intraepidermal melanocytic hyperplasia (also called in situ malignant melanoma) or early invasive malignant melanoma associated with dysplasia, a progression of ages was noted. The average ages in the five diagnostic groups were as follows: 34.8 years, mild dysplasia (group 1); 35.1 years, moderate dysplasia (group 2); 41.5 years, severe dysplasia (group 3); 44.4 years, in situ malignant melanoma (group 4), and 46.9 years, early invasive malignant melanoma (group 5). Statistical analysis revealed that the two younger groups differed significantly in age from the three older groups. Men and women had an equal proportion of acquired and congenital pattern nevi, but men were older in each category and had more severe dysplasia, a greater tendency toward truncal lesions, and more regressive changes. Biopsy of trunk lesions was done in 275 cases (80%), of extremity lesions in 60 cases (17%), and in head and neck sites in 9 cases (3%).(ABSTRACT TRUNCATED AT 250 WORDS)     

De novo myeloid sarcoma in a 4‐month‐old infant: a case report and review of the literature

Myeloid sarcoma is a rare tumor of immature myeloid cells in an extramedullary site. Myeloid sarcoma may present in a variety of locations; skin is one of the common sites. It may precede or occur concurrently with acute myeloid leukemia, chronic myeloid leukemia, other forms of myeloproliferative disorders/myelodysplastic syndrome or de novo. We report a case of a 4‐month‐old female who presented with cutaneous lesions without evidence of leukemia, determined to be de novo myeloid sarcoma. She had erythematous nodules in multiple skin sites. Biopsy revealed a diffuse atypical mononuclear cell infiltrate involving the entire dermis and extending to the subcutis. The infiltrate was diffusely positive for lysozyme, CD43, CD15, CD33, CD68 and CD117 and was negative for CD3, CD20, CD34, CD56, CD79a, CD99, myeloperoxidase, desmin, chromogranin and synaptophysin, supporting a diagnosis of myeloid sarcoma. No leukemic involvement was found on evaluation of peripheral blood or bone marrow aspiration. Chromosomal abnormalities were found at chromosomes 7, 10 and 11. The skin lesions resolved following multiple chemotherapy courses, then recurred requiring additional treatment. De novo myeloid sarcoma involving skin without evidence of leukemia can occur in an infant and may present a diagnostic challenge.     

Origin of cutaneous melanoma in a congenital dysplastic nevus spilus

Cutaneous melanoma developed in contiguity with a congenital nevus spilus on the leg of a 79-year-old white woman. The unique features of the nevus spilus in this case were its relatively large size (diameter, 8 cm), irregular gross appearance, lifelong stability until the recent appearance of a tumor nodule, and the presence of intraepidermal melanocytic dysplasia appearing as multifocal elements within darkly pigmented speckles distributed throughout a lightly pigmented background of lentigo simplex. Based on this observation, we suggest that the presence of intraepidermal melanocytic dysplasia in nevus spilus may be a predisposing factor for the development of melanoma. The malignant potential of "dysplastic" nevus spilus requires further study.     

Histological analysis of intraepidermal proliferations of atypical melanocytes

Fifty cutaneous pigmented lesions characterized by an intraepidermal proliferation of atypical melanocytes were reviewed. Several histological parameters (position of melanocytes in the epidermis, nuclear melanocytic atypia, presence or absence of pagetoid melanocytes, nucleoli, and others) were evaluated. On the basis of the results, the investigated cases were classified into three groups. In group 1, pagetoid melanocytes were present, melanocytic atypia was severe and continuous, all epidermal layers were involved by melanocytic proliferation, and a pattern of epidermal infiltration was recognized. In group 2, pagetoid melanocytes were absent, melanocytic atypia was mild-moderate and discontinuous, the lower epidermis only was involved by melanocytic proliferation, and a pattern of epidermal pseudoinfiltration was recognized. Group 3 cases were in an intermediate area between the two major groups. The results showed that intraepidermal proliferations of atypical melanocytes lie on one line, in which groups 1 and 2 account for the extremes.     

Pseudogranulomatous Spitz nevus: a variant of Spitz nevus with heavy inflammatory infiltrate mimicking a granulomatous dermatitis

Spitz nevus is a benign melanocytic proliferation that shows relatively characteristic clinicopathologic features. Despite this, Spitz nevus is clinically confused with many other lesions, and histopathologically it is sometimes difficult to distinguish it from melanoma. However, Spitz nevus rarely causes differential diagnostic problems with granulomatous dermatitis. This article describes an 8‐year‐old girl who presented with a nodule on her right arm, a clinical appearance of a pyogenic granuloma. Histopathologically, there was a dermal lesion composed of aggregates of large epithelioid cells surrounded by a heavy inflammatory infiltrate, mimicking a sarcoid‐like granulomatous dermatitis. Immunohistochemistry showed epithelioid cells with strong nuclear and cytoplasmic staining with S‐100 protein, thus establishing the diagnosis of a melanocytic tumor. The heavy T‐cell lymphocytic infiltrate that accompanies the large epithelioid cells caused its granulomatous appearance. Molecular assessment showed H27H mutation in the HRAS gene. We suggest the term ‘pseudogranulomatous’ for this variant of Spitz nevus because it indicates that the lesion is not authentically granulomatous and simply mimics a granulomatous dermatitis.     

Progression from atypical/dysplastic intraepidermal proliferations and carcinoma in situ to invasive tumors: a pathway based on current knowledge

Oncology research efforts in recent years have begun to elucidate the role of the peritumoral stroma in the development of dysplasia and subsequent invasive malignancy. In the skin, the stroma surrounding keratinocytic and melanocytic tumors reacts to the dysplastic epidermis in a similar fashion to the wound healing response. Once epidermal genetic mutations and aberrant molecular signaling have occurred, the stroma responds through a 3-phase process-extracellular matrix degradation is produced by matrix metalloproteinases; angiogenesis is induced by vascular endothelial growth factor and mast cell mediators; and the inflammatory response is elicited by cytokines and cyclin D1 overexpression balanced by the immunosuppression of mast cell mediators such as tumor necrosis factor alpha, histamine, and transforming growth factor beta. By reacting like injured dermis, the actions of various stromal mediators directly allow for, and even encourage, the progression of in situ atypia/dysplasia to invasive malignancy. The intent of this article is to review the multistep biological and chemical stromal processes, which are involved in the progression of atypical/dysplastic intraepidermal proliferations to invasive malignancy.     

Unusual and unknown aspect of cutaneous malignant melanoma: minimal deviation malignant melanoma. Retrospective study of 45 cases

Minimal deviation malignant melanoma (MDMM) is a rare melanocytic tumor of the skin that shares both malignant and benign histologic features: 1) a vertical growth phase similar to that of malignant melanomas with expansile nodules invading throughout the reticular dermis (Clark's level IV), and even the subcutaneous fat (Clark's level V); 2) but a monotonous and uniform proliferation of melanocytic cells that are only moderately atypical. A very slight cellular maturation from the top to bottom of the lesions may be observed, but usually there is no maturation at all. By themselves, the cells do not appear as malignant. A borderline variant of MDMM shows identical cytological and growth pattern features, but remains confined to a Clark's level III of invasion. Over the past 14 years, 45 cases (female to male ratio: 1.5:1.0) of MDMM, 8 of which were of the borderline variant, were observed. The lesions appeared as acquired pigmented tumors, 0.5 to 1.0 cm in size which predominated on the trunk. Young adults (mean age: 34 years) were most frequently involved. Based on the cytological characteristics of the cellular proliferation, they could be subdivided in 4 groups: 1) epithelioid and spindle cell type (15 cases); 2) epithelioid type (14 cases); 3) spindle cell type (7 cases); and 4) pigmented spindle cell type (9 cases). The mean thickness of the 45 cases was 3.06 mm (1.24 mm for the borderline lesions; 3.40 mm for the MDMM). Tumors with a spindle cell component appeared thicker than those without. Mitoses were numerous (mean: 3.2/10 high power fields). Each tumor but one showed a junctional component. This appeared as melanocytic hyperplasia or melanocytic nests at the dermoepidermal interface. Moreover, 10 cases (7 MDMM and 3 borderline tumors) disclosed intraepidermal spread of melanocytes. However, as observed with the dermal component of the lesions, these intraepidermal melanocytes never appeared cytologically malignant, although moderate atypism could be observed. At last, an association with a compound or dermal nevus was seen in 8 cases. MDMM appears as a particular subgroup of cutaneous malignant melanomas with distinct and characteristic histologic features. Its differential diagnosis includes blue nevus, especially the cellular variant, combined nevus, spindle and epithelioid cell nevus (Spitz-Allen's nevus) and cutaneous metastasis of malignant melanoma. The most important features for the differential diagnosis are the growth pattern, the absence of cellular maturation, the absence of real malignant cells and moderate cellular atypism.(ABSTRACT TRUNCATED AT 400 WORDS)     

Histogenetic categorization of atypical melanocytic tumor of uncertain biological malignant potential

Several reports have demonstrated difficulties and lack of agreement in the histopathological diagnosis of particular melanocytic lesions, with problems in their management. A histogenetic approach to the study of these lesions originated the following classification: 1. superficial atypical proliferation significance; 2. melanocytic tumor of uncertain potential; 3. pigmented epithelioid melanocitoma of uncertain potential; 4. microinvasive radial growth phase of uncertain potential. The terminology remains controversial, reflecting the uncertainty of the diagnosis and the biological potential of these atypical melanocytic lesions.     

Nevo de Spitz y otros tumores spitzoides en la infancia. Parte 1: aspectos clínicos,histológicos e inmunohistoquímicos

A Spitz nevus is a melanocytic neoplasm of epithelioid and/or spindle cells that usually appears in childhood. These lesions are by nature benign, but their features can sometimes make them difficult to distinguish from melanomas. Spitzoid melanocytic lesions have been grouped into 3 types in recent decades: Spitz nevi, atypical Spitz tumors, and spitzoid melanomas. Atypical Spitz tumors are spitzoid melanocytic proliferations that have atypical histopathologic features that are insufficient to support a diagnosis of melanoma. The malignant potential of these lesions is at present uncertain. This review examines the clinical, dermoscopic, and histopathologic features of this group of lesions.     

CDKN2A and MC1R variants influence dermoscopic and confocal features of benign melanocytic lesions in multiple melanoma patients

Non‐invasive diagnostic tools are effective in the histomorphological study of melanocytic lesions. The role of melanoma susceptibility genes on melanocytic nevi histopathological features is not clear. The current study aimed to correlate genetic alterations and histomorphological features of melanocytic nevi. Clinical, dermoscopic and confocal features of 34 multiple melanoma patients and 34 controls were compared. Among patients with melanoma, carriers of CDKN2A mutations and/or MC1R variants, and wild‐type genes were also compared. In patients with melanoma, a lighter phototype (P = 0.051), a higher number of nevi (P < 0.01) and clinically atypical nevi (P < 0.01) were observed. At dermoscopy, these nevi showed a complex pattern (P = 0.011), atypical network (P = 0.018) and irregular pigmentation (P = 0.037); at confocal, an irregular meshwork pattern (P = 0.026) with atypical nests (P = 0.016) and an inflammatory infiltrate (P = 0.048) were observed. Among patients with melanoma genetically tested, CDKN2A G101W mutation carriers were more frequently younger (P = 0.023), with clinically atypical nevi (P = 0.050), with cytological atypia (P = 0.033) at confocal. G101W mutation and MC1R variants carriers showed hypopigmented nevi (P = 0.002) and, at confocal, roundish cells infiltrating the junction (P = 0.019). These data suggest an influence of CDKN2A mutation and MC1R variants in the development of dysplastic melanocytic lesions. Non‐invasive histomorphological evaluation, together with genetic studies, improves melanoma risk identification and early diagnosis, for a patient‐tailored management.     

Malignant TFE3‐rearranged perivascular epithelioid cell neoplasm (PEComa) presenting as a subcutaneous mass

Perivascular epithelioid cell neoplasms (PEComas) are a group of mesenchymal tumours with concurrent melanocytic and myogenic differentiation. Although many cases are sporadic, PEComas can be associated with tuberous sclerosis. A distinct subset of deep‐seated PEComas has been shown to carry TFE3 fusions. To our knowledge, this is the first reported case of primary subcutaneous malignant PEComa with molecular confirmation of TFE3 gene rearrangement.     

Cutaneous syncytial myoepithelioma: A recently described neoplasm which may mimic nevoid melanoma and epithelioid sarcoma

Cutaneous syncytial myoepithelioma is a recently described rare tumor of the dermis. It is derived and composed purely of myoepithelial cells and shows a characteristic syncytial growth pattern of neoplastic cells with little intervening stroma and no recognizable ductal structures. It represents a diagnostic challenge to dermatopathologists given its rarity and unusual immunophenotype. Molecular testing for rearrangement of the EWSR1 gene plays a significant role in confirming the diagnosis in most cases. Herein, we present 2 cases with mundane clinical presentations and challenging histopathological findings. In both cases, the lesion was composed of relatively well‐circumscribed proliferation of epithelioid and spindle cells in the superficial dermis growing in a syncytial fashion and showing focal adipocytic metaplasia. The 2 cases had slightly different immunohistochemical profiles, but shared focal positivity for S100, EMA and pan‐keratin or p63. Break‐apart FISH demonstrated the presence of an EWSR1 gene rearrangement confirming the diagnosis in both cases. We discuss the most important differential diagnoses, particularly melanocytic lesions and epithelioid sarcoma and the original diagnostic considerations that the cases were referred to us with. We also review the molecular features and spectrum of immunohistochemical findings in these lesions and their role in excluding entities in the differential diagnosis.