Consumption of the epidermis: a diagnostic criterion for the differential diagnosis of melanoma and Spitz nevus

The distinction between melanoma and its most important simulant, Spitz nevus, is usually made on microscopically. We point out "consumption of the epidermis" (COE) as an additional diagnostic criterion. We defined COE as thinning of the epidermis with attenuation of the basal and suprabasal layers and loss of rete ridges in areas of direct contact with neoplastic melanocytes. We analyzed 102 unequivocal melanomas and 125 unequivocal Spitz nevi for the presence of COE. COE had not been used in arriving at the diagnosis of these cases because we were unaware of the criterion at the time that the cases were first evaluated. COE was found in 88 of 102 (86%) of melanomas but only 12 of 125 (9.6%) of Spitz nevi (P < 0.001). We then looked for COE in an independent set of 61 ambiguous melanocytic lesions with overlapping histopathologic features that could not be classified unequivocally as Spitz nevus or melanoma. The cases were analyzed by comparative genomic hybridization (CGH) for aberration patterns suggesting a benign or a malignant process, based on previous studies. COE was found in only 6 of 42 (14%) of the ambiguous cases in which CGH suggested a benign process and 14 of 19 (74%) of the ambiguous cases in which CGH suggested melanoma (P < 0.001). Our data suggest that COE is a useful criterion in the evaluation of melanocytic neoplasms. Because COE was frequently found at the edges of ulcers in the majority of ulcerated melanomas, the thinning of the epidermis in COE may represent an early phase of ulceration. This may prove to be important in distinguishing ulceration due to an effect of the tumor from ulceration due to trauma, which would be expected not to have the same prognostic import. Future studies are required to analyze the prognostic value of COE itself.     

Congenital Spitz Nevus

BACKGROUND: Congenital Spitz nevus has been reported previously in the literature, but the histopathologic features have not been examined in detail. OBJECTIVE: To histologically examine and report on congenital Spitz nevus. METHOD: We examined 10 clinically submitted congenital melanocytic nevi that were histopathologically identified as congenital Spitz nevi and compared them to the characteristics seen in acquired Spitz nevus and superficial congenital melanocytic nevus. RESULTS: Of the 10 congenital Spitz nevi, 9 were compound and 1 was dermal. Two showed features of combined Spitz nevus (Spitz and blue). Six cases showed all 16 listed characteristics of acquired Spitz nevus, with two cases having 15 and two cases having 14 characteristics. Of the superficial congenital melanocytic nevus characteristics, all except three cases had all 12 attributes. The one dermal lesion had all the characteristics of the acquired Spitz nevus and all but one of the characteristics of the superficial congenital melanocytic nevus in regards to intradermal findings. CONCLUSIONS: Congenital Spitz nevi are true congenital lesions, with histopathologic features of both acquired Spitz nevus and superficial congenital melanocytic nevus.     

Comparative genomic hybridization for the diagnosis of melanoma

Despite advancements in protocols, a subset of melanocytic lesions continues to pose diagnostic challenges. This is particularly true in the pediatric population where certain congenital nevi mimic melanoma. Recently, comparative genomic hybridization (CGH) has been utilized to support diagnoses of melanocytic lesions based on DNA copy number changes. Because distinct differences in copy number changes have been shown to occur in malignant melanoma and benign nevi, CGH can be a useful adjunct when diagnosis based on histology alone is indeterminate. The authors discuss the benefits of using CGH to aid in the diagnosis of melanocytic lesions that are difficult to characterize as malignant or benign based on clinical and histologic features alone. This paper presents a brief clinical report and review of the literature. A 13-year-old Caucasian male presented to an academic tertiary care medical center after a shave biopsy unexpectedly revealed malignant melanoma with positive deep margins. Following complete excisional biopsy, the diagnosis of malignant melanoma with depth of 0.92 mm was confirmed, both by the home institution's pathologist and by consultant dermatopathologists at two separate academic tertiary medical centers. Sentinel lymph node biopsy revealed a small focus of metastatic melanoma, this lead to a left-sided modified radical neck dissection. All nodes removed were negative for disease, and surgical and postsurgical care was uncomplicated. Before proceeding with interferon therapy, CGH was performed on the tissue from the primary lesion. Other than a slight amplification of chromosome 16p, no other aberrations were detected favoring a benign lesion. Ultimately, the diagnosis was amended to compound melanocytic nevus of the nose with benign nevus cell rest in the sentinel node. While histopathologic evaluation is the current gold standard for the diagnosis of melanoma, there are many cases where it is inaccurate. The use of CGH in the evaluation of histologically equivocal lesions may allow certain patients to avoid invasive procedures and associated morbidities. The authors propose that, in these select diagnostically challenging cases, tissue analyses by CGH may be beneficial before proceeding to more invasive procedures such as sentinel node biopsy and complete lymphadenectomy.     

Desmoplastic (sclerotic) nevus: an underrecognized entity that resembles dermatofibroma and desmoplastic melanoma.

Desmoplastic (sclerotic) nevus, a benign melanocytic neoplasm characterized by predominantly spindle-shaped nevus cells within a fibrotic stroma, can be confused with fibrous lesions and other melanocytic proliferations, including desmoplastic melanoma. We compared the histologic and immunohistochemical features of 16 desmoplastic nevi, nine desmoplastic melanomas, four hypopigmented blue nevi, and six dermatofibromas. The similarities between desmoplastic nevi and dermatofibromas included epidermal hyperplasia (12 of 16), presence of keloidal collagen (15 of 16), hypercellularity (16 of 16), and increased numbers of factor XIIIa-positive dendritic cells (12 of 12). The absence of adnexal induction (0 of 16), the rarity of lesions with multinucleated cells (3 of 16) or epidermal hyperpigmentation (2 of 16), and the presence of S-100 immunoreactivity (16 of 16) and melanocytic proliferation (9 of 16) helped differentiate desmoplastic nevi from dermatofibromas. The similarities between desmoplastic nevi and desmoplastic melanomas included the presence of atypical cells (16 of 16) and HMB-45 expression in the superficial portion of the lesions (11 of 16). The infrequent location on the head or neck (1 of 16), the absence of mitotic figures (0 of 16), a significantly lower number of Ki-67-reactive cells, and a decrease in HMB-45 expression in the deep area of the lesions (8 of 11) helped distinguish desmoplastic nevi from desmoplastic melanoma. Desmoplastic nevi had overlapping features with hypopigmented blue nevi, but features tending to favor the latter included a predominance of ovoid nuclei, higher numbers of atypical cells, and homogeneous staining with HMB-45. We conclude that a combination of histologic and immunohistochemical criteria facilitates the reliable diagnosis of desmoplastic nevus from its simulators.     

Histologic classification of the combined nevus. Analysis of the variable expression of melanocytic nevi.

The designation combined nevus gives recognition to mixed cytologic patterns. In the common variant, plump, pigmented spindle cells form fascicles among nests of ordinary nevus cells. In other variants, one or several cellular components that share cytologic features with either a blue nevus or a Spitz nevus are represented. Ninety-five cases, 49% of which were of the common type, were studied. Grossly, most of the lesions were darkly pigmented papules or nodules. The clinical diagnosis in three-fourths of the cases was nevus, blue nevus, or melanoma. Fifteen percent had concomitant histologic features of melanocytic dysplasia, and most of these lesions were of the common type. For the common variant, the cytologic features, pattern of apparent infiltration, and variable representation of the features of a premalignant melanocytic dysplasia often mislead a pathologist in interpreting and predicting biologic potential. In combined nevi, the phenotypic diversity and genetic lability of melanocytic nevus cells is manifested.     

Analysis of mutations in B-RAF, N-RAS, and H-RAS genes in the differential diagnosis of Spitz nevus and spitzoid melanoma

A definite diagnosis cannot be established based on histologic features alone in a large number of Spitz nevi and spitzoid melanomas. In a vast majority of common benign and malignant melanocytic lesions, B-RAF and N-RAS mutations were described, but these were not detected in Spitz nevi. In contrast, H-RAS mutations were frequently encountered in Spitz nevi, but only rarely in melanomas. To date, B-RAF mutation analysis has not been reported in atypical Spitz nevi, and there are only a few reports of it in spitzoid melanomas. We analyzed 96 formalin-fixed, paraffin-embedded spitzoid melanocytic lesions for hotspot mutations in B-RAF, N-RAS, and H-RAS genes to test the assumption whether mutation analysis would assist a more accurate diagnosis of spitzoid melanocytic lesions, which are notoriously difficult to classify. B-RAF or N-RAS mutations were observed in 31 of 36 (86%) spitzoid melanomas, and in 6 of 7 (86%) spitzoid melanoma metastases. In contrast, none of the 14 Spitz nevi and none of the 16 atypical Spitz nevi had mutations in any of the three genes. A B-RAF or N-RAS mutation was found in 8 of 23 (35%) spitzoid lesions suspected for melanoma. H-RAS mutations were detected in 4 of 14 (29%) Spitz nevi, in 3 of 22 (14%) atypical Spitz nevi, in 1 of 15 (7%) spitzoid tumors suspected for melanoma, but in none of the spitzoid melanomas. These results strongly indicate that Spitz nevi and spitzoid melanomas are genetically unrelated entities. Furthermore, we can conclude that mutation analysis may be useful as an additional diagnostic tool to distinguish between benign and malignant spitzoid lesions.     

Combined melanocytic nevi: histologic variants and melanoma mimics

Combined melanocytic nevi are composed of 2 or more distinct populations of nevomelanocytes. Most commonly used to describe the combination of blue nevi with common nevi, it may also be applied to other combinations of benign melanocytic proliferations, including Spitz nevi and nevi with deep dermal pigmented nevomelanocytes. We report the incidence and distribution of these tumors at the Massachusetts General Hospital over the past decade and review guidelines for diagnostic criteria and nomenclature. Between 2000 and 2010 we identified 511 cases of combined nevi, represented by 4 histologically distinct diagnostic categories: (1) blue nevus, (2) nevi with deep dermal pigmented nevomelanocytes (plexiform/deep penetrating, inverted type A/clonal), (3) Spitz or pigmented spindled cell nevus, combined with another type of nevus (usually common or dysplastic), and (4) other combinations including 2 or more nevus types. Nearly one fifth of these tumors displayed atypical features; atypia was observed more often in combined nevi with Spitz or deep pigmented elements (26 of 55, 47%, and 25 of 98, 26%, respectively) than in combined common and blue nevi (37 of 336, 11%). Clinical follow-up data were available for 83% of the patients with atypical combined nevi; none developed recurrence or metastasis with a mean follow-up of over 4 years.     

Spitz nevus of the tongue with pseudoepitheliomatous hyperplasia: report of three cases of a pseudomalignant condition

Three cases of Spitz nevus of the tongue associated with pseudoepitheliomatous hyperplasia are reported: two occurring in children and one in an adult. The location at an unusual site and the complex pattern resulting from the intimate admixture of the neoplastic melanocytic component and the hyperplastic keratinocytic component led in each case to consider diagnoses such as malignant melanoma and invasive squamous cell carcinoma. Staining for S-100 protein and keratin was useful to identify and separate the two components. Spitz nevus of the tongue carries some intriguing similarities with granular cell tumor, suggesting a possible histogenetic and pathogenetic relationship.     

The Surgical Management of Spitz Nevi

BACKGROUND: The biologic behavior of Spitz nevi and atypical Spitz nevi ranges from completely benign to the rare malignant melanoma. Various recommendations for the surgical approach to these lesions have been proposed. OBJECTIVE: To determine any trend in the surgical management of Spitz nevi and atypical Spitz nevi among a community of dermatologists. METHODS: Retrospective review of the clinical features, surgical management and outcome of 89 patients with the diagnosis of Spitz nevus or atypical Spitz nevus. RESULTS: All biopsy techniques had a high incidence of involved margins: shave (67%), excision (28%), and punch (21%). Of the atypical Spitz nevi with positive margins on biopsy, there was a trend (7/9) toward reexcision with narrow margins (average 2.2 mm). CONCLUSION: The majority of atypical Spitz nevi incompletely removed by biopsy were excised with narrow uncontrolled margins. A stratified surgical approach depending on the clinical and histopathologic features of the Spitz lesion is proposed. More aggressive surgical management of Spitz lesions with atypical features may be warranted. Further studies to determine the biologic potential of these lesions are needed.     

Copy number variations and clinical outcome in atypical spitz tumors

Atypical Spitz tumors (ASTs) are rare spitzoid neoplasms of uncertain biological behavior. Our study was designed to characterize genetic abnormalities that may help to differentiate ASTs from melanoma or Spitz nevi. We examined copy number variation in formalin-fixed, paraffin-embedded samples using an Agilent 44k array comparative genomic hybridization platform. Sixteen patients with AST (8 with positive sentinel lymph node biopsy, 1 with distant metastasis), 8 patients with Spitz nevi, and 3 patients with melanoma (2 spitzoid, 1 superficial spreading) were evaluated. Chromosomal aberrations were found in 7 of 16 ASTs, 1 with fatal outcome, 2 spitzoid melanomas, and 1 conventional melanoma. We found no difference in chromosomal instability between AST patients with positive and negative sentinel lymph node biopsies. Our patient with widely metastatic AST lacked the most frequent aberrations in melanoma involving chromosomes 6 and 11q that are loci targeted by fluorescence in situ hybridization (FISH) probes developed to distinguish malignant melanoma from benign melanocytic lesions. The vast majority of chromosomal abnormalities observed in ASTs are not commonly found in melanomas, suggesting that AST may be a distinct clinical entity and raising additional questions regarding their malignant potential, prognosis, and clinical management. The current FISH probes failed to detect 1 spitzoid melanoma, 1 fatal metastatic AST case, and the other chromosomally aberrant ASTs in our series, but detected 1 spitzoid melanoma and 1 conventional melanoma. Thus, a comprehensive, genome-wide approach to chromosomal abnormalities offered greater sensitivity and specificity than current FISH probes in identifying spitzoid lesions of uncertain malignant potential in this series.     

Sentinel lymph node biopsy in patients with diagnostically controversial spitzoid melanocytic tumors.

Melanomas can be difficult to diagnose histologically if they deviate in their growth pattern or cytology only minimally from a nevus. On occasion, even experts on melanocytic lesions may not reach a consensus on whether a lesion is a benign but unusual nevus or a malignant melanoma mimicking a nevus. This diagnostic dilemma is particularly well known for the distinction of Spitz nevus from melanoma. Diagnostic uncertainty and disagreement among consultant pathologists lead to confusion about the prognosis and clinical management of patients. In this study we present the clinical and pathologic findings of 10 patients with diagnostically controversial melanocytic tumors, who underwent sentinel lymph node biopsy. In all of these cases, the diagnostic controversy among experts was between Spitz nevus and melanoma. Seven patients were female, and three were male, ranging in age from 7 to 46 years (mean 21 years). Histologic examination of the sentinel lymph nodes revealed tumor deposits in the lymph node parenchyma in 5 of 10 patients. Among patients with positive sentinel lymph nodes, two had satellite nodules and one showed additional tumor deposits in three nonsentinel regional lymph nodes. All patients are alive and free of disease with a follow-up of 10-54 months (mean 34 months). Our study illustrates the role of a sentinel lymph node biopsy in the evaluation of patients with diagnostically controversial melanocytic tumors. Although the presence of metastatic tumor deposits in the sentinel lymph node supports the diagnosis of malignant melanoma, further studies are needed to determine the prognostic significance of the sentinel lymph node findings in such patients.     

HMB-45 staining of dysplastic nevi. Support for a spectrum of progression toward melanoma

Dysplastic nevi are melanocytic tumors that occupy intermediate positions in the spectrum of melanocytic proliferations. Although they are invariably cured if completely excised, their biologic potential if left untreated is unknown. We examined a series of such lesions with HMB-45, a melanocyte-specific antibody, in order to explore protein expression within these borderline lesions. HMB-45 has previously been shown to label intraepidermal melanocytes within melanomas and within all nevi. Intradermal melanoma cells also label with HMB-45, but dermal nevus cells within common melanocytic nevi do not normally stain. In contrast, we found mild to moderate staining of nevus cells within the papillary dermis of dysplastic nevi and within residual nevus cells adjacent to malignant melanomas. In the same lesions, we demonstrated strong staining of intraepidermal melanocytes. Thus, dermal nevus cells within dysplastic nevi and within residual nevus cells adjacent to malignant melanomas are expressing low-level amounts of a protein expressed by melanoma cells, but not by dermal nevus cells within wholly benign melanocytic tumors. This lends support to the concept of these lesions as precursor lesions with undetermined biologic potential.     

Junctional Spitz Tumor (Nevus) of the Upper Lip

Spitz tumor (nevus) is a rare, melanocytic lesion that primarily affects children and adolescents. The lesion may share many clinical and histological similarities with malignant melanoma and careful microscopic examination is required to render the proper diagnosis. Complete excision with close follow-up is considered the appropriate treatment. Despite the common presentation of Spitz nevi on the facial skin, lip involvement has only rarely been described in the English language literature. In the present study, a case of Spitz tumor located on the vermilion border of the upper lip in a 16-year old female patient is reported.     

Lymphatic invasion in Spitz nevi

Forty-nine Spitz nevi occurring in children were reviewed and sampled extensively in order to assess the incidence of vascular invasion. Evidence of vascular invasion was found in seven (14.3%) cases. The endothelium of such vessels was negative on immunoperoxidase staining for Factor VIII-related antigen suggesting the nevus cells to be in lymphatic channels and not blood vessels. No unusual histological or clinical features characterized the group. All patients are alive and well some years after local excision therapy. It is concluded that lymphatic invasion by nevus cells in Spitz nevi is not uncommon and its presence should not tempt the pathologist into a diagnosis of melanoma.     

Desmoplastic melanoma

Desmoplastic melanoma is an uncommonly encountered variant of malignant melanoma. Three histological subtypes exist: desmoplastic, neurotropic, and neural transforming. Desmoplastic melanoma commonly presents in conjunction with existing melanocytic lesions or as an amelanotic firm nodule. Local recurrences are common. Thirty patients over a 6-year period were treated at our institution for desmoplastic melanoma. All lesions were treated with local excision. Local recurrence occurred in seven patients (23%) and was treated by aggressive re-excision in each instance. Clinical regional metastasis (lymph nodal basins) were detected in two patients (6%). Distant metastasis (lung) developed in two patients (6%). Twenty-three patients (76%) were found to have desmoplastic subtype, whereas five (17%) had neurotropic subtype. Six patients (20%) had associated pigmented melanotic lesions. Average length of follow-up has been 18 months. Overall survival is 96 per cent. Presentations and histologic diagnosis can sometimes be difficult and misleading. Treatment is aggressive local excision with follow-up necessary to detect resectable recurrent lesions.     

Melanoma associated with blue nevus and melanoma mimicking cellular blue nevus: a clinicopathologic study of 10 cases on the spectrum of so-called 'malignant blue nevus'

The term "malignant blue nevus" refers to a rare and heterogeneous group of melanomas that arise in several clinical settings. This includes melanomas arising in association with a common or cellular blue nevus and those arising de novo and resembling cellular blue nevi. We reviewed the clinicopathologic features of 10 cases of malignant blue nevi. Six cases proved to be de novo melanoma mimicking cellular blue nevus, but lacking a clear-cut benign component. Two melanomas arose in association with a common blue nevus, and two with a cellular blue nevus. The patients' (5 males, 5 females) ages ranged from 11 to 77 years (average age, 48.1 years). The head and neck was the most common location (6 of 10 patients), with five scalp tumors. Four tumors were located on the trunk; none was located on the extremities. Tumor size ranged from 0.5 to 2.2 cm (average size, 1.1cm). Most lesions had been present for many years before surgical removal. Pigmented dendritic cells were observed in 9 of 10 cases. The malignant and benign components were easily distinguished in the four cases that arose in association with a common or cellular blue nevus. Abrupt transition between a benign blue nevus and melanoma was readily recognized at scanning magnification as distinctive nodules of epithelioid to spindled cells with a sheet-like growth pattern. In all cases, malignancy was evidenced by increased mitotic rate, necrosis, nuclear atypia, pleomorphism, hyperchromasia, and prominent nucleoli. All 7 patients with follow-up information experienced recurrence (3 patients) or metastasis (4 patients). Three patients died of disease. Malignant blue nevus is a heterogeneous group of melanomas that are highly aggressive and often lethal, with a propensity for metastasis to the lymph nodes and lungs.     

Desmoplastic Melanocytic Nevus of Oral Mucosa

The desmoplastic melanocytic nevus is an uncommon variant that easily may be confused with a fibrohistiocytic neoplasm or a desmoplastic melanoma. It is believed that the following report describes the first known example of a desmoplastic melanocytic nevus arising in the oral mucosa. The histopathologic and immunohistochemical features that allow separation from other microscopically similar pathoses are stressed.     

Malignant Melanoma Arising in a Pregnant African American Woman with a Congenital Blue Nevus

Background. The incidence of cutaneous melanoma in African-Americans is relatively low. Despite the slightly greater occurrence of congenital melanocytic nevi in black persons compared with white persons, the cumulative risk of melanoma arising in these lesions is very small. In addition, the overwhelming majority of melanomas in black persons occur on nonglaborous skin where congenital melanocytic nevi are rare.
Objective. The objective was to describe and an unusual case of melanoma arising in a congenital nevus with combined features of a blue nevus on the scalp of a pregnant African-American woman.
Results. Histologic examination revealed a polypoid malignant melanoma arising in association with a congenital blue nevus in a young African-American woman. The lesion was located on the right parietal scalp and had been enlarging over the course of her pregnancy. Pathology from parotidectomy and neck dissection confirmed metastatic melanoma involving two intraparotid lymph nodes and 3 of 26 cervical lymph nodes. Despite aggressive chemotherapy, she died in 1 year after the diagnosis.
Methods. A case is reported and the literature is reviewed.
Conclusion. Clinicians must take great care in documenting and following pigmented lesions in all patients including African-American persons. Excision is indicated for lesions that undergo significant change during pregnancy.