Dermal Melanocytic Tumors Research Articles

Report and Review of an Uncommon Entity: Dermal Melanocytic Tumor Resembling Paraganglioma

Report and Review of an Uncommon Entity: Dermal Melanocytic Tumor Resembling Paraganglioma

Pigmented Epithelioid Melanocytoma

Blue nevi are a group of congenital or acquired benign dermal melanocytic tumors. Various clinical and histological variants have been described. Epithelioid blue nevus (EBN), an uncommon variant may present as blue gray nodule over trunk, extremities which might occur either sporadically or in association with Carney complex. Due to clinical and histological overlap with other pigmented melanocytic lesions clinicopathological correlation is essential. We report a case of epithelioid blue nevus on dorsum of right foot in a 22-year-old man.

Dermal melanocytic tumor with CRTC1‐TRIM11 fusion: Report of two additional cases with review of the literature of an emerging entity

"Cutaneous melanocytic tumor with CRTC1-TRIM11 fusion" (CMTCT) is a newly described, potentially novel entity that typically presents as a dermal nodule on the head and neck, extremities, and trunk of adults. Histopathologically, it is reported as a nodular or multinodular tumor composed of epithelioid and spindle cells that are variably immunoreactive for S100-protein, SOX10, and MITF along with more specific melanocytic markers such as MelanA and HMB45. With only 11 cases reported in the English literature so far, the neoplasm appears to behave in a relatively indolent fashion. Nevertheless, in one case, local recurrence and synchronous distant metastasis were evident after 13 years. Additional cases with longer follow-up are essential to determine the neoplasm's biologic behavior with more accuracy. Herein, two cases of CMTCT, one arising on the lower back of a 65-year-old female and the other on the arm of a 33-year-old female in addition to a comprehensive literature review are reported.

A Case of Adjacent, Clonally Distinct Borderline Melanocytic Tumors on the Arm

Atypical Spitz tumor (AST) is a melanocytic proliferation that shares histopathologic features of Spitz nevus and spitzoid melanoma. Distinction of AST from spitzoid melanoma is critical because the majority of ASTs will follow an indolent course. Array-based comparative genomic hybridization (aCGH) has been suggested as a potential tool for evaluating malignant potential in spitzoid tumors. We present a case of a 52-year-old woman with an AST in which aCGH was crucial in guiding correct diagnosis and management. The patient first presented with a flesh-colored papule on her arm that was changing color. Biopsy revealed a dermal nevoid melanocytic tumor of indeterminate histopathology, favored to be a severely atypical nevus. The tumor was excised. One year later, another flesh-colored papule proximal to the excision site of the first tumor was biopsied and showed a predominantly dermal atypical spitzoid melanocytic proliferation with a differential diagnosis of AST versus spitzoid melanoma. Recurrent or metastatic melanoma was also a concern given proximity to the previous excision site. Molecular analysis of both lesions by aCGH revealed distinct molecular signatures, supporting the 2 tumors to be clonally unrelated. Furthermore, the new tumor displayed limited evidence of genomic instability, supporting classification as an AST with predicted indolent behavior. This case highlights the utility of aCGH in evaluating borderline melanocytic lesions, including assessment of malignant potential in ASTs, and clonality analysis to assist in exclusion of metastatic disease.

β-Catenin nuclear expression discriminates deep penetrating nevi from other cutaneous melanocytic tumors.

Recent advances in genomics have improved the molecular classification of cutaneous melanocytic tumors. Among them, deep penetrating nevi (DPN) and plexiform nevi have been linked to joint activation of the MAP kinase and dysregulation of the β-catenin pathways. Immunohistochemical studies have confirmed cytoplasmic and nuclear expression of β-catenin and its downstream effector cyclin D1 in these tumors. We assessed nuclear β-catenin immunohistochemical expression in a large group of DPN as well as in the four most frequent differential diagnoses of DPN: "blue" melanocytic tumors, Spitz tumors, nevoid and SSM melanomas, and pigmented epithelioid melanocytomas (PEM). Nuclear β-catenin expression was positive in 98/100 DPN and 2/16 of melanomas (one SSM and one nevoid melanoma with a plexiform clone) and was negative in all 30 Spitz, 26 blue, and 6 PEM lesions. In 41% DPN, β-catenin expression was positive in more than 30% nuclei. No differences were observed in cytoplasmic and nuclear cyclin D1 expression between these tumor groups, suggesting alternate, β-catenin-independent, activation pathways. We have subsequently studied nuclear β-catenin expression in a set of 13 tumors with an ambiguous diagnosis, for which DPN was part of the differential diagnosis. The three out of four patients showing canonical DPN mutation profiles were the only β-catenin-positive cases. We conclude that nuclear β-catenin expression, independently from CCND1 expression, in a dermal melanocytic tumor is an argument for its classification as DPN. In ambiguous cases and in early combined DPN lesions, this antibody can be helpful as a screening tool. β-Catenin is also potentially expressed in a subset of malignant melanomas with CTNNB1 mutations.

Molecular alterations in malignant blue nevi and related blue lesions

Malignant blue nevi (MBN) are extremely rare dermal melanocytic tumors that arise in association with atypical cellular blue nevi (ACBN), cellular blue nevi (CBN), common blue nevi (BN), or de novo. The frequency of BRAF, NRAS, and KIT mutations in malignant melanoma varies according to histological subtype and localization. These mutations are rarely observed in blue nevi, which have recently been shown to carry activating mutations in GNAQ/GNA11 genes. Only few small molecular studies of MBN have been published. The aim of the present study was to analyze in MBN and related blue lesions such as ACBN, CBN, and BN the prevalence of BRAF, NRAS, KIT, GNAQ, and GNA11 gene mutations and their association with clinicopathological features. We included in our study 12 MBN, 6 ACBN, 29 CBN, and 35 common BN diagnosed between 1996 and 2014. Sanger sequencing method was used for mutation analysis. Overall, GNAQ exon 5 mutation was the most frequent alteration (46%), in 2 of 12 (17%) MBN, 1 of 6 (17%) ACBN, 22 of 29 (76%) CBN, and 13 of 35 (37%) common BN. BRAF V600E and GNA11 exon 5 mutations were respectively detected in 3 of 12 (25%) and in 2 of 12 (17%) MBN while none in ACBN, CBN, and common BN. None of the cases harbored NRAS exon 2/3, KIT exon 9/11/13/17/18, or GNAQ/GNA11 exon 4 mutations. GNAQ gene exon 5 mutations are rare in MBN and ACBN but frequent in CBN and common BN. Remarkably, BRAF V600E and GNA11 exon 5 mutations were only detected in MBN, whereas none were found in ACBN, CBN, or common BN. Our data contribute new elements to the limited data on molecular alterations in MBN.

PARAGANGLIOMA-LIKE DERMAL MELANOCYTIC TUMOR: A RARE SKIN LESION

Paraganglioma-like dermal melanocytic tumor (PDMT) is a very rare dermal nodule, which resembles clear cell sarcoma and skin melanoma in its morphology. Nowadays about 10 cases of the tumor are described in world literature [1–3].

Atypia and differential diagnosis in cellular blue nevi: clinicopathological study of 21 cases.

Cellular blue nevus differs from the classic blue nevus with characteristics such as large size, cellularity, intense pigmentation, and growing pattern with subcutaneous infiltration. It is a dermal melanocytic tumor that can be confused with melanoma due to the atypia it may contain. Hematoxylin-eosin and MIB-1 stained slides of 21 cases diagnosed between 2000-2014 were re-evaluated. In order to attract attention to this rare lesion, 21 cases are presented with the clinical and above-mentioned histopathological findings. Thirteen (61.9%) cases were females and eight (38.1%) were male. The mean age was 25.4 (2-73). The most frequent localization was the sacral and gluteal region (11 cases). The mean diameter was 14.4 mm (4-60 mm). From the parameters defined to assess the atypia, ulceration was identified in four cases. Prominent cellularity and subcutaneous infiltration were seen in three and 16 cases, respectively. Mitosis was seen in six tumors. Immunohistochemically, MIB-1 was present in two cases as 3% and 2% respectively, while in others it was 1% or less. Although there is no precise definition for the "atypical cellular blue nevus", five patients were assessed as atypical cellular blue nevus (a case with infiltrative development of six cm tumor diameter, two cases with two mitosis and a MIB-1 index 3% and 2%, a case with one mitosis and confluent development and a case with one mitosis in addition to focal necrosis areas). No lymph node and/or distant metastasis was observed during follow-up. We think it is more important to rule out the possibility of conventional melanoma in cellular blue nevus with exaggerated morphological findings alongside low proliferative activity rather than to determine the atypia.

Paraganglioma-like dermal melanocytic tumor.

Paraganglioma-like dermal melanocytic tumor (PDMT) is a rare subtype of benign dermal melanocytic tumor, first described in 2004. Its histopathologic features resemble those of paraganglioma, showing presence of a distinctive partitioning of the tumor into small and large packets, nests, or short cords by delicate fibrous septa (zellballen pattern). But the immunostaining characteristics are those of melanocytic lesions, as PDMT express S-100, melan A, HMB 45 and lack pancytokeratin markers. It has a benign course, although a lesion of low malignant potential cannot be excluded. We describe a case of 60-year-old female who presented with three PDMT lesions on her right leg. To the best of our knowledge this is the first case reported from India.

Proliferative Activity, Chromosomal Aberrations, and Tumor-Specific Mutations in the Differential Diagnosis between Blue Nevi and Melanoma

Blue nevi are a clinically and pathologically heterogeneous group of benign pigmented dermal melanocytic tumors that may exhibit histologic overlap with malignant melanoma. This study evaluates the role of immunohistochemical and molecular analyses in the classification and differential diagnosis between blue nevi and melanoma. Twenty-three dermal melanocytic tumors, initially diagnosed as benign or ambiguous, were subjected to immunohistochemical staining for phosphohistone H3 and MIB-1 to evaluate mitotic activity, comparative genomic hybridization to detect chromosomal aberrations, and GNAQ, GNA11, BRAF, NRAS, and KRAS sequencing. Of 19 patients with follow-up information (median, 1.6 years), 3 developed recurrent or metastatic disease. Nevertheless, 11 of the 19 patients with follow-up had <2 years of follow-up. Nine of 23 patients showed chromosomal aberrations, including all 3 patients with tumor recurrence or progression. There was no significant correlation between mutation status (P = 0.6) or mitotic rate (P = 0.3) and outcome. In conclusion, three of nine patients with chromosomal aberrations developed tumor recurrence or progression. Patients with histologically ambiguous dermal melanocytic proliferations that exhibit copy number aberrations should undergo careful clinical follow-up.

GNAQ and GNA11 mutations in melanocytomas of the central nervous system

Melanocytic tumors in the central nervous system (CNS) include metastatic melanoma and less commonly primary melanocytic tumors, which usually arise from melanocytes of the leptomeninges. The latter include, in order of increasing biologic potential, melanocytomas, melanocytic neoplasms of intermediate grade/differentiation and primary melanomas.(2) Primary leptomeningeal melanocytic neoplasms belong to a larger taxonomic group of benign and malignant tumors arising from melanocytes that are not associated with epithelia. The group also includes blue nevi, melanomas arising in association with blue nevi (so-called “malignant blue nevi”), uveal nevi and uveal melanomas (4, 5, 7). Neoplasms in this group share morphologic features such as predominance of spindled and epithelioid cells, conspicuous pigmentation and absence of epithelial involvement, along with frequent mutations of GNAQ or GNA11, two closely related G-proteins of the Gq family that encode critical amino acids required for the GTPase function of the proteins. GNAQ or GNA11 mutations occur in a mutually exclusive pattern and affect codon 183 in exon 4 or codon 209 in exon 5 of either gene.(7) Mutations at these sites cripple enzymatic function and lead to a constitutively activated GTP-bound state. When in this state, GNAQ and GNA11 act as dominant-acting oncogenes that activate several critical signalling pathways including the MAP-kinase pathway (5, 7). A recent study reported mutations in exon 5 of GNAQ in 6/12 (50%) melanocytomas, 5 of which were in paraspinal locations.(3) We extended this analysis to include exons 4 and 5 of both GNAQ and GNA11. Five cases of CNS melanocytoma were identified from the consultation files of one of the authors (M.K.R.). Sections were cut from formalin-fixed, paraffin-embedded tumor tissue, and stained with hematoxylin-eosin; immunohistochemistry was performed. Tumor DNA was extracted from tissue carefully microdissected from deparaffinized, unstained sections. Direct (Sanger) sequencing for exons 4 and 5 of each of GNAQ and GNA11 was performed using methods described previously.(7) The clinical and pathologic features of the tumors are summarized in Table 1. The tumors occurred in 3 males and 2 females, with a median age of 42 years (range 29-61 years). They were composed of spindle-shaped, oval or epithelioid cells arranged in nests and vague whorls. Tumor cells ranged from amelanotic (Fig. 1a) to conspicuously pigmented (Fig. 1c). Immunohistochemically, all tumors were diffusely positive for S-100 and HMB-45, and negative for epithelial membrane antigen. Mutations were identified in exon 4 of GNAQ (1 case, Fig. 1b) and exon 5 of GNA11 (1 case, Fig. 1d). The mutations [GNAQ:(c.548G>A, p.(Arg183Gln) and GNA11:c.626A>C, p.(Gln209Pro)] are identical to those seen in uveal melanoma and intradermal melanocytic proliferations (6, 7). Our results expand the spectrum of GNAQ and GNA11 mutations that may occur in melanocytomas. To our knowledge, this is the first description of mutations in GNA11 and in exon 4 of GNAQ in melanocytomas. Figure 1 a) Case 1 – A monomorphous population of slightly spindled, amelanotic cells in vaguely whorling array is present (hematoxylin-eosin, x100). Inset - Diffuse cytoplasmic immunolabeling for HMB-45 confirms the melanocytic nature of the tumor cells ... TABLE Clinical and pathologic features of melanocytomas The occurrence of GNAQ and GNA11 mutations in melanocytomas,(3) dermal melanocytic tumors(6, 7) and uveal melanomas(6, 7) suggests the possibility of a developmental link between the cells of origin of these tumors. Indeed, this thesis is supported by the recent description of a developmental pathway in which a subgroup of melanocytes derives from Schwann cell precursors.(1) Although we identified a GNAQ exon 4 mutation in 1 of 5 cases of melanocytoma, exon 4 mutations in either GNAQ or GNA11 are rare in uveal melanomas (7/145, 4.8%) and blue nevi (2/96, 2.1%) (7). Mutational analysis of larger numbers of tumors is required to determine the true incidence of the different mutations in GNAQ and GNA11, and to investigate associations of specific mutations with clinical features, pathologic characteristics, and biologic behavior of melanocytomas.

Animal‐type melanoma – tumor cell invasion of dermal lymphatics and molecular identification of lymph node metastasis

Animal-type melanoma (ATM) represents a rare subtype within the wide spectrum of melanocytic tumors. Clinically, ATM lesions appear as sharply demarcated, brown, black and dark blue pigmented nodules, which show grey-white surface elements on dermatoscopy. The tumor is restricted to the dermis and arranged in irregular fascicles, which are composed of spindle-shaped and epithelioid melanocytes. Moderate tumor cell pleomorphism, mitoses and apoptotic cells all suggest a malignant process. Abundant, finely dispersed melanin pigment within tumor cells as well as numerous melanophages are strongly suggestive of ATM. Even though locoregional lymph node metastases are frequently found at diagnosis, the course of ATM is generally benign. Specific molecular changes may be detected in melanocytes from lesions and lymph nodes on fluorescence in situ hybridization (FISH). Such findings strongly indicate the malignant potential of ATM. The peculiar biology of ATM, as a moderately malignant tumor, is reflected in a new histopathological classification within the spectrum of dermal borderline melanocytic tumors (BMT).

Paraganglioma-like dermal melanocytic tumor: a case report

Paraganglioma-like dermal melanocytic tumor is a rare subtype of benign dermal melanocytic tumors. Its histopathologic features resemble those of paraganglioma, but the immunostaining characteristics are those of melanocytic lesions.We report a case of a 60-year-old male with a paraganglioma-like dermal melanocytic tumor of his left cheek and briefly review the English literature.

Paraganglioma-like Dermal Melanocytic Tumor

We are reporting a previously undescribed primary dermal melanocytic tumor identified by reviewing all dermal melanocytic tumors referred in consultation that did not qualify histologically as a previously described entity. From these cases, 8 were remarkably similar. We termed them "paraganglioma-like dermal melanocytic tumor" (PDMT) based on their nested growth pattern. This term is used descriptively and does not imply any histogenetic or biologic similarity to true paraganglioma. PDMT is primarily a tumor of the extremities of adult females (18-53 years, mean 35 years; males 2; females 6) which present as a dermal nodule (range, 0.5-4.2 cm; mean, 1.4 cm) composed of nests of clear to amphophilic oval cells separated by delicate fibrous strands. Nuclear atypia was mild and mitotic activity low (1-4 mitoses/10 HPF). Melanin was not obvious on light microscopy. Tumors expressed S-100 protein (8 of 8), Melan-A (4 of 8), HMB-45 (8 of 8), and microphthalmia transcription factor (8 of 8) and lacked pancytokeratin (8 of 8) and smooth muscle actin (8 of 8). FISH analysis of 5 cases revealed an intact EWS gene locus, supporting absence of the clear cell sarcoma 12;22 translocation. Follow-up information in 8 patients (range, 35-92 months; mean, 54 months) indicated that all were alive without disease. PDMT comprises a clinically and pathologically unique subtype of dermal melanocytic tumors. Our study suggests a benign course, although a lesion of low malignant potential cannot be excluded.