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.     

Pigmented epithelioid melanocytoma: report of first Japanese cases previously diagnosed as cellular blue nevus

Background:  The term 'pigmented epithelioid melanocytoma (PEM)' was recently used for borderline melanocytic tumor/low-grade melanoma including cases previously diagnosed as human animal-type melanoma and epithelioid blue nevus. No Japanese cases have been reported.
Methods:  We reviewed 219 cases previously diagnosed as blue nevus in Japan. Common blue nevus was identified in 154 cases and cellular blue nevus in 65 cases.
Results:  We have found two Japanese cases of PEM previously diagnosed as cellular blue nevus. Two patients were female. The age at presentation was 32 and 28 years. Two lesions were on the buttock. Two cases fulfilled histological criteria proposed for PEM. There is no evidence of recurrence or metastases.
Conclusions:  PEM is a distinct melanocytic tumor and the unifying diagnostic term. PEM is present in Japanese, but these cases may be previously diagnosed as cellular blue nevus. Japanese pathologists should recognize a new concept of PEM, and when they make a diagnosis of PEM, they should be recommended sentinel lymph node sampling.     

Metastatic myxoid melanoma with partial regression of the primary lesion

Myxoid melanoma is a rare variant of malignant melanoma. The diagnostic problems are obviously increased when it presents as amelanotic metastasis in a lymph node. An 82-year-old woman presented a subcutaneous mass in the right axilla. A thorough clinical investigation disclosed a pigmented black lesion on the right forearm. The right axillary lymph nodes and the pigmented lesion were resected. In the lymph nodes, proliferation of tumor cells with an abundant mucous substrate was noted. The cells proliferated in a variable pattern, and there were no melanin granules detected on hematoxylin-eosin-stained sections. However, we found melanin granules in the tumor cells observed under electron microscopy. In the pigmented lesion of the right forearm, there were small clusters of tumor cells with melanin granules, suggesting malignant melanoma. In the present case, myxoid metastasis occurred with the partial spontaneous disappearance of the primary nonmyxoid malignant melanoma.     

Nodal blue nevus: a pitfall in lymph node biopsies

The sentinel lymph node from a 72-year-old female with melanoma revealed a pigmented and spindled melanocytic proliferation in the capsule that extended into the trabeculae. Benign nodal nevi are uncommon but have been reported in lymph nodes of melanoma patients and less often in lymph nodes removed for other reasons. Nodal blue nevi are particularly rare. These melanocytic proliferations can be distinguished from metastatic melanoma by evaluation of the distribution in the node, morphologic characteristics and the assistance of immunohistochemistry.     

Oral mucosal melanoma with unusual clinicopathologic features

Oral mucosal melanoma (OMM) is an extremely rare malignancy, accounting for < 0.5% of all melanomas and all oral malignancies. The rarity of OMM, the heterogeneity in clinical and histopathologic appearances, and the paucity of molecular and genetic studies to date have limited our knowledge of the etiopathogenesis of these cancers. A 39-year-old Hispanic male presented for evaluation of a large, pigmented, plaque-like and nodular growth of the maxillary gingival and palatal mucosa. On presentation, a presumptive clinical diagnosis of mucosal melanoma was made, which was confirmed by incisional biopsy with subsequent histopathologic evaluation. Macroscopically, the morphology and highly pigmented nature of the tumor was suggestive of a rarer subtype of melanoma known as animal-type melanoma, also referred to as pigmented epithelioid melanocytoma. However, microscopically, the tumor showed histopathologic features consistent with a high-grade acral (mucosal) lentiginous melanoma with overt cytomorphologic features of malignancy in addition to showing prominent pigment synthesis resembling animal-type melanoma. A detailed search of the literature did not identify a previous report of OMM with prominent pigment synthesis resembling animal-type melanoma. Identification of melanoma subtypes has specific implications for therapeutic approach, and thus their recognition is important to successful patient management.     

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).     

Animal type melanoma: a report of a case with balloon-cell change and sentinel lymph node metastasis

Animal type melanoma is a rare histopathologic variant of melanoma characterized by sheets and nodules of heavily pigmented epithelioid melanocytes that involve the entire thickness of the dermis. This human neoplasm mimics melanocytic neoplasms seen in gray horses and laboratory animals; thus, is termed animal type melanoma. It is quite rare and, with only a few reported cases, its biological behavior is not well understood. We report an example of animal type melanoma on the back of a 27-year-old man. The lesion showed areas of melanoma in situ, which ruled out the possibility of metastatic melanoma. Features of regression were also seen at dermo-epidermal junction and papillary dermis. In some areas, neoplastic melanocytes exhibited a balloon-cell appearance; in others the neoplasm was composed of sheets and fascicles of heavily pigmented epithelioid melanocytes that permeated the entire dermis and extended into the dermal-subcutaneous interface, mimicking a cellular blue nevus. Epithelioid melanocytes in deeper areas showed abundant, heavily pigmented cytoplasm and pleomorphic nuclei with prominent eosinophilic nucleoli and some mitotic figures. The neoplastic cells did not show evidence of maturation in deeper areas of the lesion. In some sections, a nodule of heavily pigmented epithelioid melanocytes was seen far from the main bulk of the lesion, at the dermal-subcutaneous interface, raising the possibility of a satellite lesion. A lymphoscintigraphy showed a sentinel lymph node in the right axilla and a subsequent axillary lymphadenectomy demonstrated that the architecture of the sentinel lymph node was effaced by metastatic melanoma. The patient received adjuvant chemotherapy with inteferon alfa-2b and four months after this treatment the patient is alive and well, without evidence of recurrences or additional metastases.     

Distant metastasis due to heavily pigmented epithelioid melanoma with underlying BRAF V600E,NOTCH1, ERBB3, and PTEN mutations

Pigment‐synthesizing melanoma (PSM) describes a morphologically and genetically diverse group of melanomas. In contrast, pigmented epithelioid melanocytoma (PEM) encompasses a spectrum of indolent tumors now classified as borderline/intermediate melanocytic tumors. Herein, we report a case of widely metastatic heavily pigmented epithelioid melanoma with fatal outcome in a 36‐year‐old woman. Next‐generation sequencing identified somatic (tumoral) mutations in BRAF V600E, PTEN, NOTCH1, and ERBB3. By contrast, GNAQ and GNA11 were wild type. Prkar1α and p16 expression were maintained. Identification of mutations in NOTCH1 and ERBB3 may support the diagnosis of heavily pigmented epithelioid melanoma. In contrast, PRKCA fusion genes and PRKAR1A mutations support the diagnosis of PEM. Given the heterogeneity, potential overlap (loss of Prkar1α expression), and evolving genetic profiles of these two distinct groups of tumors, careful appraisal of molecular profiles in the light of histomorphology and clinical history is necessary for distinction between PEM and PSMs including heavily pigmented epithelioid melanomas, with significant potential impact on prognosis and therapy.     

骨桥蛋白及基质金属蛋白酶—9在恶性黑素瘤中的表达

目的 探讨骨桥蛋白及基质金属蛋白酶-9(MMP-9)在人恶性黑素瘤中的表达及意义。方法 采用免疫组化SP法检测23例原发性恶性黑素瘤、17例转移性恶性黑素瘤及20例色素痣中骨桥蛋白和MMP-9的表达。结果 40例恶性黑素瘤中骨桥蛋白及MMP-9表达的阳性率分别为87.5%、75.0%;20例色素痣中的阳性表达率分别为15.0%、10.0%。骨桥蛋白及MMP-9在恶性黑素瘤中阳性表达率明显高于色素痣,差异具有统计学意义(P<0.05)。骨桥蛋白和MMP-9的表达与年龄、性别、发病部位、是否淋巴结转移等因素均无关(P>0.05)。40例恶性黑素瘤中,骨桥蛋白与MMP-9均表达29例,均不表达4例。结论 骨桥蛋白及MMP-9在人恶性黑素瘤中高表达,但与淋巴结转移无相关性。     

Anti‐TNF‐Alpha Antibody Induced Interstitial Granulomatous Dermatitis

Cutaneous melanoma is a common and frequently lethal melanocytic neoplasm that can quickly metastasize to regional lymph nodes. Currently, prognosis is determined by measuring tumor thickness but more reliable markers for metastatic spread are urgently needed. We investigated whether the extent of tumor lymphangiogenesis can predict melanoma metastasis to sentinel lymph nodes (SLN). We quantified the extent of tumor lymphangiogenesis, as well as other factors, in excised primary tumors and in SLN biopsy samples from 45 patients with primary cutaneous melanoma. Primary melanomas from patients whose tumors had metastasized to the SLN, along with their metastastic foci, contained prominent hotspots of increased lymphatic vessel density, compared to non‐metastatic tumors. Multivariate risk analysis revealed that the lymphatic vascular area (LVA) of primary melanomas, an index of tumor lymphangiogenesis, was the most sensitive prognostic marker for SLN metastasis, and was even able to more accurately predict which tumors would become metastatic to SLN than measuring tumor thickness. The extent of tumor lymphangiogenesis is a highly sensitive (83%) and specific (89%) prognostic marker of lymph node metastasis. Assessment of lymphangiogenesis in primary melanomas may be a more effective approach than measuring tumor thickness in selecting patients with early metastatic disease for aggressive therapy.     

Pigmented epithelioid melanocytoma: two case reports

Because of indolent course without mortality, the term "pigmented epithelioid melanocytoma" has been suggested as a replacement for "equine" or "animal-type" melanoma and for the epithelioid blue nevus of the Carney type, from which they are histologically indistinguishable. This report reviews this concept and recounts in detail two of eighteen cases occurring in residents of the Central Coast of California. This paper also contains clinical photographs of pigmented epithelioid melanocytoma, unlike prior reports.     

恶性黑素瘤血管内皮细胞生长因子和nm23抑癌基因蛋白表达及微血管密度的研究

目的 探讨血管内皮细胞生长因子(VEGF)、nm23抑癌基因和微血管密度(MVD)与恶性黑素瘤发病的关系。方法 采用免疫组化法检测47例恶性黑素瘤和10例黑素细胞痣组织中VEGF、nm23和CD34的表达并计算其MVD。结果 恶性黑素瘤VEGF阳性表达率和MVD值均明显高于黑素细胞痣(P均<0.01),有淋巴结转移者明显高于无淋巴结转移者(P值分别<0.05和<0.01);随着浸润深度增加,Ⅰ级与Ⅳ、Ⅴ级恶性黑素瘤比较,VEGF阳性表达率和MVD值差异均有统计学意义(P值分别<0.05和<0.01)。恶性黑素瘤中nm23阳性表达率明显低于黑素细胞痣(P<0.01),有淋巴结转移者明显低于无淋巴结转移者(P<0.01),与临床分型和浸润深度无明显关系。结论 VEGF和nm23表达在恶性黑素瘤的发展和转移中起重要作用。     

Sentinel lymph nodes study in 30 cases of melanoma

In 30 cases of melanoma, we attempted to detect sentinel lymph nodes using 1-2% patent blue dye and were able to detect them in 27 cases (90%): 19 cases out of 21 cases in the groin area (90%), 5 out of 5 cases in the axilla area (100%), and 3 out of 4 cases in the neck area (75%). The numbers of sentinel lymph nodes were one in 16 cases, two in 7 cases, three in 2 cases, and four in 2 cases. The cases with three and four nodes were all in the groin area. In 22 cases, tumor metastasis was negative in sentinel lymph nodes. Sentinel lymph nodes were detected in 36 out of 174 samples, and tumor metastasis was negative except in these sentinel lymph nodes (false negative 0%). In the groin area, sentinel lymph nodes were located around the femoral and great saphenous vein junction. In the axilla area, sentinel lymph nodes were located in the central, lateral and subscapular lymph nodes. In the head and neck area, sentinel lymph nodes were found in the submandibular and occipital lymph nodes. The positions of sentinel lymph nodes differed a little with tumor location. By accumulating cases, it should become possible to predict the positions of sentinel lymph nodes before operations. Sentinel lymph node biopsy is easy and requires only a small incision.     

Congenital pauci-melanotic cellular blue nevus

Unusual or atypical melanocytic nevi can be confused with malignant melanoma. Two patients are presented here with a rare variant of melanocytic nevus. Both were men. One was 39 years old and sought medical attention after trauma of a "congenital mole". The other was 24 years old and presented with a history of a slowly growing lesion, which had been known since childhood. In both patients, the lesion occurred on the buttock. They were dermal and superficial subcutaneous nodules measuring 1.5 and 2.3 cm in greatest dimension, respectively. The tumors were composed of densely cellular fascicles of melanocytes arranged in a lobulated growth pattern. Rare nests of small epithelioid melanocytes were also seen. No melanin pigment was seen on hematoxylin and eosin-stained sections. Focal minimal pigment was noted by Fontana-Masson stain in one case. Involvement of numerous peripheral nerve trunks by fusiform melanocytes was a prominent feature. Rare mitotic figures were seen in melanocytes [1-2 mitoses per 50 high-power fields (HPF)]. The MIB-1 labeling index was low (less than 5% of the lesional cell population was immunopositive). Both tumors were excised with negative surgical margins. One patient underwent sentinel lymph node biopsy because there was controversy regarding the biologic potential of the lesion. No melanocytic tumor deposits were found in the lymph nodes. On clinical follow up of 11 years and 18 months after complete excision, both patients are alive and well with no evidence of recurrence. We regard these lesions as congenital monophasic and pauci-melanotic variants of cellular blue nevus. The nevi are presented here to enhance our knowledge of the morphologic spectrum of melanocytic tumors and to help avoid confusion with malignant melanoma.     

Metastatic melanoma with balloon/histiocytoid cytomorphology after treatment with immunotherapy: A histologic mimic and diagnostic pitfall

Epithelioid cells with foamy cytoplasm (histiocytoid features) are typical histopathologic findings among benign and malignant histiocytic neoplasms such as xanthoma and atypical fibroxanthoma. However, these changes are unusual in melanoma, which is typically composed of nested and variably pigmented atypical epithelioid cells. Here, we report a patient with metastatic melanoma in lymph nodes presenting with prominent balloon cell/histiocytoid features expressing melanocytic markers, after treatment with nivolumab. This report suggests that the spectrum of neoplasms with histiocytoid features should be expanded to include melanoma, a pattern that, to the best of our knowledge, is uncommon, especially in the setting of post‐neoadjuvant therapy.     

Angiosarcomatous transdifferentiation of metastatic melanoma

Melanoma is known to show considerable variation in its histopathological presentation. In exceptional cases, heterologous or divergent differentiation (metaplastic melanoma) can be observed. We report a case of a 69-year-old man who was diagnosed with nodular melanoma on the right upper leg. One year later, the patient presented with an inguinal lymph node metastasis and a lymph node dissection was carried out. In two out of five positive lymph nodes, an angiosarcomatous component was found next to a conventional melanoma component. Shortly after, the patient developed two in-transit metastases in which again an angiosarcomatous component was seen. The vascular component stained positive for ERG and CD31 and negative for melanocytic markers (Mart-1, S100, SOX-10), while the conventional melanoma had an opposite staining pattern. Molecular analysis on both components showed an identical mutation in the NRAS gene, which in our opinion proves the divergent differentiation. To the best of our knowledge, this is the first case report describing angiosarcomatous transdifferentiation of melanoma.     

Focal Regression‐Like Changes in Dysplastic Back Nevi :A Diagnostic Pitfall for Malignant Melanoma

The spectrum of melanocytic proliferations ranges from banal to overtly malignant. Borderline melanocytic lesions which bridge these two extremes pose a challenge, as their biological nature remains undefined. We set out to evaluate the utility of the sentinel lymph node biopsy in such lesions. Our compendium was defined by 11 cases of borderline melanocytic proliferations whereby sentinel node sampling was conducted. There were three severely atypical dermal‐epidermal melanocytic proliferations manifesting borderline features with nevoid melanoma (calf, shoulder, knee), three arising in association with a deep penetrating nevus (chest, shoulder, and arm), three atypical Spitz's tumors (helix, calf, arm, back), and two atypical pigment‐synthesizing melanocytic tumors, resembling equine melanotic disease in one and cellular blue nevus in another (buttock, calf, arm). The patient population comprised seven males and five females ranging in age from age 9–36 (mean: 25 years). At least one positive sentinel lymph node was uncovered in seven of the cases with a positive sentinel lymph observed in all but one case of deep penetrating nevus and atypical Spitz's tumor. The identification of sentinel lymph node positivity in seven of the twelve cases (58%) validates the role of sentinel lymph node biopsy in the setting of borderline melanocytic proliferations.     

Lymphatic Mapping in the Management of Melanoma in Children

Abstract: Lymphatic mapping allows the surgeon to identify and remove the first draining (sentinel) lymph node from a primary melanoma with minimal morbidity. The procedure facilitates accurate staging and identification of patients in need of additional therapy. We used lymphatic mapping and sentinel lymph node biopsy in two children with melanoma. Both patients had evidence of metastatic melanoma in their sentinel lymph nodes and underwent regional lymphadenectomy. Malignant melanoma and atypical pigmented lesions in children remain diagnostically challenging for the pathologist and clinician. Misdiagnoses occur, and the correct interpretation of a melanocytic tumor is too often made only after recurrence or metastasis has occurred. The use of lymphatic mapping facilitates accurate staging and identifies children in whom additional therapy may be indicated. In addition, it can assist in the assessment of the biologic potential of a difficult lesion.