Congenital melanocytic nevus with features of hybrid schwannoma/perineurioma

Neural differentiation by melanocytic nevi represents a well‐recognized phenomenon, and melanocytic nevi with perineurial differentiation have been reported recently. We reported a case of a congenital melanocytic nevus with histopathologic features of hybrid schwannoma/perineurioma. The patient was a 36‐year‐old male who presented with a black tumor on his arm since birth. Histopathology showed a congenital melanocytic nevus in the superficial dermis, but more strikingly, in continuity with the melanocytic nevus, there was a well‐circumscribed but unencapsulated nodule in the deep dermis. The nodule was composed of cellular and myxoid areas with storiform, laminated or whorled growth patterns. The cellular area was mainly composed of proliferation of plump spindle, oval or epithelioid cells. The myxoid area was mainly composed of proliferation of slender spindle cells with mucin deposition. Immunohistochemical stains showed that the cellular area was positive for S100 and CD34, weakly positive for EMA, negative for Glut‐1 and collagen IV, the myxoid area was positive for S100, negative for CD34, strongly positive for EMA and focally positive for Glut‐1 and collagen IV. Our results show that congenital melanocytic nevi may show neural differentiation with histopathologic features of hybrid schwannoma/perineurioma.     

Pigmented neurofibroma

A 24-year-old male patient suffering from a large-coconut-sized neurofibroma is described. In the tumor, sharply demarcated areas of melanin containing cells were seen. These cells were identified as melanin producers by the premelanosomes seen by electron microscope. Although the coexistence of neurofibroma with another melanin-producing tumor, such as cellular blue nevus, could not be ruled out, this tumor shows the close relationship between tumors of the peripheral nervous system and melanocytic malformations or pigmented nevi. These observations are relevant to the controversy over the histiogenesis of these pigmented lesions and support Masson's view that nerve sheath cells are capable of melanogenesis.     

Pigmented plexiform neurofibroma: Distinction from a large congenital melanocytic nevus

The substantial clinical and histologic overlap between neurotized congenital melanocytic nevi and the subset of plexiform neurofibromas with hyperpigmentation and hypertrichosis of the overlying skin (pigmented neurofibroma) has led to considerable confusion in the literature. A dark-brown, hypertrichotic plaque covered much of the right lower aspect of the trunk of a 1-year-old girl with a diffuse and plexiform neurofibroma in the same area, numerous café-au-lait macules, and intertriginous freckling. The latter findings were diagnostic of neurofibromatosis-1, which was further supported by the presence of unidentified bright objects on magnetic resonance imaging of the brain. Histologic examination of the hyperpigmented plaque revealed melanocytic hyperplasia at the dermoepidermal junction and a proliferation of rounded, pigmented melanocytes dispersed individually and in occasional small nests in the papillary dermis and scattered within underlying neurofibromatous tissue. Immunohistochemical staining with A103 (Melan-A/MART-1) and PNL2 confirmed the melanocytic differentiation of the pigmented cells, whereas glial fibrillary acidic protein and Leu-7 were detected only within plexiform areas and slender neuroid spindle cells. This case draws attention to the pigmented neurofibroma as a distinct clinicopathologic entity resulting from proliferation of melanocytes and neurosustentacular cells in the setting of neurofibromatosis-1.     

Melanocytic nevi are associated with neurofibromas in neurofibromatosis, type I, but not sporadic neurofibromas: a study of 226 cases

BACKGROUND: Neurofibromatosis, type 1, is associated with cutaneous melanin pigmentation, but an association with ordinary melanocytic nevi has not been described. METHODs: This retrospective case-control study was designed to see if neurofibromas in patients with neurofibromatosis, type 1 (NF-1) differ from sporadic neurofibromas (SN) in their incidence of associated melanocytic nevi and other histologic features. Slides from 114 NF-1 were compared with 112 SN and 300 intradermal melanocytic nevi (IDN). RESULTS: Small lentiginous melanocytic nevi were identified over 13 NF-1 (11%) but no SN (P=0.0002). Compared with other NF-1, NF-1 with nevi were more frequently associated with melanocytic hyperplasia, giant melanosomes and diffuse neurofibroma (P<0.03). Compared with SN, NF-1 were also more frequently associated with melanocytic hyperplasia, lentigo simplex-like changes, diffuse neurofibroma and plexiform neurofibroma (P<0.001). Sebaceous hyperplasia (14%), dermal elastosis (9%), lipomatous change (8%), epithelial cysts (4%) and keratin granulomas or folliculitis (3%) were not significantly different in prevalence between NF-1, SN and the control group of IDN. CONCLUSIONS: This study suggests that there is a difference in the potential for melanocytic proliferation in NF-1 compared with SN. NF-1, SN and IDN are associated with a similar range of incidental histologic changes. Ball NJ, Kho GT. Melanocytic nevi are associated with neurofibromas in neurofibromatosis, type 1, but not sporadic neurofibromas. A study of 226 cases.     

Histological features and outcome of inverted type‐A melanocytic nevi

The presence of enlarged epithelioid/spindled nests located deep in the reticular dermis of a biphasic melanocytic neoplasm can mimic melanoma arising in a pre‐existing nevus, causing over‐interpretation of malignancy. We aimed to define the clinicopathologic significance of epithelioid/spindled nests in melanocytic nevi. Retrospectively using clinical and histologic information, we characterized 121 patients with a single lesion showing epithelioid/spindled melanocytes in the reticular dermis or subcutaneous fat, surrounded by melanophages, sometimes blending in with the adnexa. The majority of nevi occurred in women in the ages of 10 to 39 years, where the most frequent presentation was a changing mole. While 78% of the lesions displayed an anatomic (Clark’s) level of IV‐V, there was no ulceration, significant regression or inflammation. Up to 2 mitoses were found in only 12% of the cases, not correlating with the severity of cytological atypia. No recurrence or metastasis occurred during 45.5 months (mean) of clinical follow up in 26 patients. Notwithstanding the deep dermal extension, these findings suggest a benign histopathology and clinical outcome. Having compared the overlapping histopathology and clinical features between deep penetrating/clonal nevus and combined nevus, we posit that “inverted type‐A nevus” might be considered a variant of the two.     

A pediatric case of pigmented epithelioid melanocytoma with chromosomal copy number alterations in 15q and 17q and a novel NTRK3-SCAPER gene fusion

Pigmented epithelioid melanocytoma (PEM) represents a group of rare, heavily pigmented melanocytic tumors encompassing lesions previously designated as “animal-type melanomas” and “epithelioid blue nevi.” Despite the association of multiple such tumors in the setting of Carney complex, most cases of PEM occur spontaneously as solitary neoplasms in otherwise healthy patients. PEM may arise in both children and adults, and has a known propensity to spread to the regional lymph nodes. Despite this latter finding, recurrence at the biopsy site or spread beyond the lymph node basin is exceptionally uncommon. Although the molecular basis for PEM continues to be characterized, findings to date suggest that this category of melanocytic neoplasia has genetic alterations distinct from those seen in common nevi, dysplastic nevi, Spitz nevi, and melanoma. Herein, we present an in-depth clinical, histopathologic, and molecular analysis of a case of PEM occurring on the scalp of a young African American girl found to have a novel NTRK3-SCAPER gene fusion.     

Intraneural dendritic cell neurofibroma with pseudorosettes

Dendritic cell neurofibroma with pseudorosettes (DCNWPR) is a recently proposed variant of neurofibroma. However, its peripheral nerve sheath origin has subsequently been questioned, and it has been suggested that the neoplasm could represent a hitherto undescribed variant of melanocytic nevus with neural differentiation. Here we report a case of DCNWPR that arose almost exclusively within the confinement of the perineurium in the skin. This observation gives further evidence that this entity is a peripheral nerve sheath tumor and is unrelated to melanocytic neoplasms.     

CASH algorithm versus 3‐point checklist and its modified version in evaluation of melanocytic pigmented skin lesions: The 4‐point checklist

Dermoscopy, in expert hands, increases accuracy, sensitivity and specificity in diagnosis of pigmented skin lesions of a single operator, compared with clinical examination. Simplified algorithmic methods have been developed to help less expert dermoscopists in diagnosis of melanocytic lesions. This study included 125 melanocytic skin lesions divided into melanocytic nevi, dysplastic nevi and thin melanomas (<1 mm). We compared the 3‐point checklist and CASH algorithm to analyze different pigmented skin lesions. Based on preliminary results, we proposed a new modified algorithm, called the 4‐point checklist, whose accuracy is similar to the CASH algorithm and whose simplicity is similar to the 3‐point checklist.     

Neurofibromas and neurotized melanocytic nevi are immunohistochemically distinct neoplasms.

Neurofibromas are often clinically, as well as histologically, indistinguishable from completely neurotized melanocytic nevi. We tested the hypothesis that immunologic markers would differentiate the perineural fibroblasts and Schwann cells of neurofibromas from the neurotized cells of melanocytic origin. We examined eight partially neurotized acquired melanocytic nevi, three partially neurotized congenital melanocytic nevi, and five neurofibromas, with antibodies directed against S-100 protein, Leu-7(HNK-1), glial fibrillary acid protein (GFAP), and myelin-basic protein (MBP). A histologic diagnosis of neurofibroma was based on identification of a dermal proliferation of spindle-shaped cells with wavy nuclei, in a background of loose reticulated collagen. Neurotized nevi were diagnosed upon recognition of scattered nests of type A or B nevus cells, surrounded by basement membrane, present in the papillary dermis of lesions otherwise indistinguishable from neurofibromas. The congenital nevi were all large melanocytic nevi known to be present at birth. S-100 stained the majority of neoplastic cells in all neurofibromas, neurotized acquired nevi, and neurotized congenital nevi. Neurofibromas showed focal staining for Leu-7, GFAP, and MBP. In contrast, neurotized acquired and congenital nevi failed to express these markers. We believe that Leu-7, GFAP, and MBP may be helpful in differentiating neurofibromas from completely neurotized melanocytic nevi. The differences in the immunohistochemical profiles of neurofibromas and neurotized nevi support the concept that these neoplasms are histogenically distinct, despite their similar histologic appearance.     

Immunoperoxidase technique modified by counterstain with azure B as a diagnostic aid in evaluating heavily pigmented melanocytic neoplasms

Heavily-pigmented melanocytic neoplasms are difficult to evaluate on routine hematoxylin and eosin stained slides because pigmented melanocytes are difficult to distinguish from the numerous melanophages that are usually seen in the background of these lesions. Immunoperoxidase staining for S100 protein or HMB-45 antibody using diaminobenzidine (DAB) as chromogen, which forms a brown product, does not adequately distinguish melanocytes from melanophages. We modified this technique by replacing hematoxylin as the counterstain with azure B, which stains melanin green-blue. Thus, positive melanocytes appear brown while melanin granules in their cytoplasm are green-blue. However, negative melanophages only stain green-blue. This technique is useful in evaluating heavily pigmented melanocytic lesions such as malignant melanomas, melanosis of regressing malignant melanoma, residual malignant melanoma in areas of granulation tissue with melanophages, blue nevi, pigmented spindle cell variant of Spitz's nevi and combined nevi.     

The morphologic spectrum of germline‐mutated BAP1‐inactivated melanocytic tumors includes lesions with conventional nevic melanocytes: A case report and review of literature

Germline mutations in BRCA1‐associated protein 1 (BAP1) are associated with several neoplasms, including BAP1‐inactivated melanocytic tumors (BIMTs). BIMTs are classically described as biphenotypic melanocytic proliferations with BAP1‐deficient large epithelioid and rhabdoid melanocytes showing various degrees of cytologic atypia. This morphology has been traditionally classified as “spitzoid” despite the various differences between these lesions and the more classic Spitz nevi. Herein, we report a case of an otherwise healthy 11‐year‐old female patient with a family history of several malignancies who presented with multiple pink to brown papules. Histologic and immunohistochemical evaluation identified three lesions with loss of nuclear BAP1 staining. The histologic spectrum of these lesions included junctional spitzoid cells within a triphenotypic proliferation and a separate lesion composed entirely of dermal small to medium‐sized epithelioid melanocytes with maturation. BAP1 gene sequencing revealed a germline frameshift pathogenic BAP1 mutation, denoted c.1717delC. This case provides further evidence that not all BIMTs conform to classic morphological criteria and that the morphologic spectrum includes lesions resembling conventional nevi. As BIMTs can serve as an early marker of the BAP1 hereditary tumor predisposition syndrome, we believe a need exists for a more comprehensive combined clinical and pathological approach for BIMT identification.     

The clinical appearance of clonal nevi (inverted type A nevi)

BACKGROUND: The term "clonal nevus" is used to describe a variant of melanocytic nevus that histologically exhibits a localized proliferation of pigmented epithelioid dermal melanocytes within an otherwise ordinary nevus (Ball NJ, Golitz LE. Melanocytic nevi with focal atypical epithelioid cell components: a review of seventy-three cases. J Am Acad Dermatol 1994; 30: 724-729). Reports to date have focused on the histologic appearance of these lesions. AIM: To characterize the clinical appearance of clonal nevi. METHODS: Clinical and histologic examinations were performed of a single clonal nevus from each of five patients (two men and three women; age range, 37-80 years). RESULTS: All nevi were round to oval in shape with smooth, well-defined borders. They were uniformly tan to light brown in color, except for a single blue-gray to blue-black focus of hyperpigmentation. The diameters of the nevi ranged from 2.5 to 10 mm. In individual nevi, the hyperpigmented focus was either centrally or eccentrically located and measured 1-2 mm in diameter. Histologically, these lesions showed banal melanocytes associated with a localized proliferation of melanocytes with abundant pigmented cytoplasm in the dermis, admixed with melanophages. CONCLUSIONS: The appearance of clonal nevi--tan with a focus of blue-gray to blue-black pigmentation--allows one to recognize the lesion clinically.     

Intradermal melanocytic nevus with prominent schwannian differentiation.

Features of peripheral nerve sheath differentiation such as neuroid cords, nerve corpuscles, fascicle-like structures, and, exceptionally, palisading have been reported in melanocytic nevi. We report an intradermal melanocytic nevus with prominent Verocay-like bodies. The upper portion of the neoplasm was composed of typical round intradermal nevus cells, many of which were pigmented. Within the deeper portion, there was a nonpigmented spindle cell proliferation with prominent Verocay bodies, simulating a neurilemmoma. Typical nevus nests merged with neurilemmoma-like areas. The entire lesion stained positively for S-100 and Mart-1 proteins and negatively for HMB-45 stain. Diffuse Mart-1 positivity excluded a collision of a melanocytic lesion with a neurilemmoma. The histopathologic features of this nevus further support a close relation between nevus cells and Schwann cells.     

Atypical Compound Nevus Arising in Mature Cystic Ovarian Teratoma (Dermoid Cyst)

Mature cystic ovarian teratomas (MCOT) are the most common ovarian neoplasm and contain components of one or more embryonic germ cell layers. Ectodermal components are most common. Rarely (1–3%), malignant transformation can occur in MCOT and are usually epidermoid, although multiple case reports of melanomas have been described. Four compound nevi and three blue nevi have also been reported; however, atypical (dysplastic) nevi have not been reported to our knowledge. A 28‐year‐old woman presented with a right ovarian mass. A 5 × 4 × 2.5 cm cystic ovarian mass was filled with hair and grumous keratinaceous debris. The lining was smooth with a 1 cm dark macule. Histologically, the mass was predominantly lined by epidermis and appendages. The pigmented lesion consisted predominantly of melanocytic nests irregularly disposed on sides and tips of distorted rete ridges, some with bridging between adjacent rete ridges, and junctional extension lateral to the small dermal component of nevus. Slight fibrosis invested some rete ridges. Moderate atypia was present. Although melanomas and melanocytic nevi have rarely been described previously in MCOT, we present the first atypical (dysplastic) compound nevus, to our knowledge. This case expands the spectrum of melanocytic lesions arising in MCOT.     

Expression of Activated Mapk, AKT and C‐Kit in Melanocytic Lesions

Neurofibromatosis is associated with cutaneous melanin pigmentation, but an association with ordinary melanocytic nevi has not been described. This retrospective case‐control study was designed to see if neurofibromas in patients with Neurofibromatosis, Type I (NF‐1) differ from sporadic neurofibromas (SN) in their incidence of associated melanocytic nevi and other histologic features. Slides from 114 NF‐1 were compared with 112 SN. Lentiginous melanocytic nevi were identified over 13 NF‐1 (11%) but no SN (p = 0.00019, Fisher's test). Compared with other NF‐1, NF‐1 with nevi were more frequently associated with melanocytic hyperplasia, honeycomb infiltration of the subcutis (p < 0.03, Fisher's test), and a greater number of biopsies (p = 0.04, t‐test). Compared with SN, NF‐1 were more frequently associated with melanocytic hyperplasia, lentigo simplex‐like changes, honeycomb infiltration of the subcutis (p < 0.001, Chi squared test), plexiform neurofibroma and epidermolytic hyperkeratosis (p < 0.03, Fisher's test). SN more frequently presented as a polyp or papule (p < 0.009). Sebaceous hyperplasia (present in 14% of cases), dermal elastosis (9%), lipomatous neurofibroma (8%), epithelial cysts (4%), and keratin granulomas or folliculitis (3%) were equally common in NF‐1 and SN. This study suggests that there may be a fundamental difference in the potential for melanocytic proliferation in NF‐1 compared with SN.     

Cutaneous granular cell tumor with epidermal involvement: a potential mimic of melanocytic neoplasia

BACKGROUND: Cutaneous granular cell tumor (GCT) may present with extension into the junctional region of the epidermis and thus may mimic melanocytic neoplasms. METHODS: We reviewed three cases of cutaneous GCT where a melanocytic neoplasm was either initially diagnosed or considered in the differential diagnosis. Histopathology was evaluated in regards to features associated with melanocytic neoplasms. Immunohistochemistry was performed to delineate a panel useful in the distinction of these and other entities. RESULTS: All cases consisted of spindle and epithelioid cells with granular cytoplasm and bland nuclei and were centered in the superficial dermis with extension into the epidermis. Two cases resembled Spitz nevi and one case demonstrated lentiginous growth. All cases stained positively with calretinin and inhibin. Two of the three cases stained diffusely with S100 and 2/2 cases with CD56. HAM56 and CD68 were positive in one case and another showed positivity for NSE and PGP9.5. HMB-45, tyrosinase, and Melan-A were non-reactive in all cases tested. CONCLUSIONS: GCT may involve the epidermis and has a growth pattern similar to melanocytic neoplasms. An immunohistochemical (IHC) panel including S100, Melan-A, tyrosinase, HMB-45, CD56, CD68, calretinin, inhibin, and PGP9.5 may aid in the distinction and may spare the patient from unnecessary morbidity.     

Giant congenital melanocytic nevus with neurofibroma-like changes and spina bifida occulta

A 12‐year‐old Iranian girl presented with a bathing trunk congenital melanocytic nevus. Multiple other pigmented lesions were present. The nevi were distributed over the entire body including the oral mucosa. There were also bilateral, soft, pendulous tumors and nodules in the area covered by the giant congenital melanocytic nevus. The tumors had been present since birth and showed continuous growth during childhood. She was otherwise healthy. Her parents were not consanguineous. There was no family history of similar lesions. Physical examination revealed a large dark‐brown circumferential plaque extending evenly from the upper back and abdomen down to the lumbar region, buttocks, and thighs ( Fig. 1 ). It had a smooth surface, with excessive growth of hair. There were soft, redundant, exuberant folds of skin overhanging the back and buttock, localized to the area covered by the bathing trunk nevus. On palpation, they appeared as deep, multilobulated masses mimicking giant neurofibromas. There were also several smaller dark‐ or skin‐colored, soft, dermal nodules in this area. On other parts of the integument, there were numerous pigmented nevi of different sizes and colors, including speckled nevi, café‐au‐lait spots, and some clinically dysplastic nevi. There was hypertrichosis over some of the nevi. Mucosal examination revealed dark‐brown macules on the hard palate and conjunctiva. General physical examination was otherwise normal. There was no axillary freckling. Ophthalmologic examination was negative for Lisch nodules, and the fundal appearance was normal. Neurological examination revealed no abnormalities. Spinal X‐ray showed spina bifida occulta in the fifth lumbar vertebra. Brain and spinal magnetic resonance imaging (MRI) with gadolinium contrast was performed to detect neurocutaneous melanosis, which was negative. Two deep incisional biopsies were performed of the proliferative nodules over the hips, with the clinical impression of giant neurofibroma. Histologic examination revealed superficial nests of melanocytes with focal involvement of the dermo‐epidermal junction, extending into the dermis ( Fig. 2 ). The melanocytes became spindle shaped within the reticular dermis ( Fig. 3 ). Immunohistochemical techniques showed strong positive staining for both S100 protein and MART‐1 in both the superficial and deep portions of the proliferation, consistent with a melanocytic nevus.

Figure 1 Open in figure viewer PowerPoint Bathing trunk melanocytic nevus with large, pendulous skin lesions mimicking neurofibromas over the buttocks and lower back and multiple other melanocytic nevi of variable size distributed all over the body     

Comparison of Seborrheic Keratoses, Inflamed Seborrheic Keratoses, and Inverted Follicular Keratoses Using P53, BCL‐1, and BCL‐2

Background: Recurrent nevi may histologically resemble malignant melanoma Design: Recurrent nevi with clinical history, original melanocytic neoplasm and recurrence were included. Proliferation marker Ki‐67 was used when residual and recurrent nevus was present on the same slide. Results: There were 356 biopsies from 328 patients (ages 6 to 93 years (mean = 31), female: male = 255:101, time to recurrence 1–63 months (mean = 7.85)). Sites: back (170), abdomen (46), arm (46), leg (34), head and neck (26), chest (26), and buttock (8). Initial biopsies: 208 nevi, 142 dysplastic nevi, 1 blue, 1 pigmented spindle cell, 2 Spitz nevi, and 2 melanomas in situ. 3 patterns of recurrence were observed: 1) junctional melanocytic hyperplasia with epidermal effacement and scar, 2) compound melanocytic proliferation with epidermal effacement and scar, and 3) junctional melanocytic hyperplasia with retained retiform epidermis. Recurrent and residual nevi had similar proliferation rates. Conclusion: Recurrent nevi occurred more commonly in females and on the trunk. Cytologic atypia, asymmetry, and retention of retiform epidermis were worrisome histologic features. Clinical history, effacement of the epidermis and limitation of changes to the scar, distinguished recurrence from melanoma. Low proliferation rate may be a useful adjunct to distinguish recurrent nevi from melanoma.