Spitz melanocytic neoplasms with MLPH::ALK fusions: Report of two cases with previously unreported features and literature review.

ALK-fused Spitz melanocytic neoplasms are a distinct subgroup of melanocytic lesions exhibiting unique histopathologic characteristics. These lesions often manifest as exophytic or polypoid tumors, characterized by fusiform-to-epithelioid melanocytes arranged in a nested, fascicular, or plexiform growth pattern. Several fusion partners of the ALK gene have been identified in spitzoid melanocytic neoplasms, with TPM3 and DCTN1 being the most prevalent. Less common fusion partners include NPM1, TPR, CLIP1, GTF3C2, EEF2, MYO5A, KANK1, and EHBP1. The MLPH gene, which encodes melanophilin (MLPH), playing a crucial role in regulating skin pigmentation by acting as a linker between RAB27A and myosin Va during melanosome transport, has also recently been recognized as a rare fusion partner of ALK in Spitz melanocytic neoplasms. Currently, there exists a sparse documentation within English literature, illustrating a limited number of cases featuring MLPH::ALK fusion in Spitz melanocytic neoplasms. In this report, we present two additional cases, including a previously unreported instance of Spitz melanoma, contributing to the expanding knowledge on ALK-fused Spitz melanocytic neoplasms. In addition, we provide a comprehensive review of the clinical, histopathologic, and molecular features observed in documented cases with this novel fusion.

Multinucleated tumor cells in clear cell renal cell carcinoma.

OBJECTIVES: Multinucleated tumor cells (MTCs) in clear cell renal cell carcinoma (ccRCC) are not well understood. METHODS: Our study included ccRCC cases in a single institution between 2010 and 2019. We classified MTC as MTC with degenerative atypia (MTCD), MTC with no anaplasia (MTCNA), and MTC with anaplasia (MTCA). Clinicopathologic characteristics and outcomes were compared between MTC groups. RESULTS: In all, 92 of 256 people (36%) with ccRCC had MTC. People with ccRCC with MTCD and those with ccRCC but no MTC had similar clinicopathologic characteristics and outcomes. Also, MTCNA and MTCA were associated with larger tumor size, advanced pathologic tumor stage, higher World Health Organization/International Society of Urologic Pathologists nuclear grade, and higher metastatic potential (P < .001 for each parameter). Overall, MTCA was associated with an increased rate of recurrence (P = .004), higher metastatic potential (P < .001), and shorter time to metastasis (P = .033), regardless of tumor stage. Univariate Cox regression revealed MTCNA as a significant predictor of metastasis at 5 years (hazard ratio [HR], 4.171; 95% CI, 1.934-8.998); moreover, MTCA was a significant predictor of recurrence (HR, 5.723; 95% CI, 2.495-13.124), metastasis (HR, 12.024; 5.966-24.232), and death (HR, 5.661; 95% CI, 2.688-11.924) at 5 years. CONCLUSIONS: Although MTCD may not be relevant in tumor grading, MTCNA and MTCA are associated with adverse outcomes.

PRAME and LEF1 in Combined Deep Penetrating Nevus and Combined Blue Nevus: Utility and Pitfalls.

ABSTRACT: Deep penetrating nevi (DPN), particularly those showing combined features, or combined deep penetrating nevi (CDPN), may show histopathological resemblance to blue nevus (BN) and melanoma. Preferentially Expressed Antigen in MElanoma (PRAME) is a marker that helps distinguish melanoma from benign melanocytic lesions. Lymphoid enhancer-binding factor 1 (LEF1) has been proposed to be used in conjunction with ß-catenin for diagnosis of DPN. The immunohistochemical expression of PRAME and LEF1 was evaluated in 10 DPN (including 6 CDPN and 2 DPN-like proliferations with atypical features), 16 BN (including combined and cellular BN), and 2 melanomas with features of DPN or BN. PRAME was negative in most DPN (n = 10/10, n = 9/10, one case with discrepancy between readers) and all BN (n = 16/16), while the 2 melanomas included were positive (n = 2/2). All DPN were positive for LEF1 (n = 9/9) while only a subset of BN were positive (n = 6/16, P = 0.0028; n = 5/16, P = 0.001, per both readers). LEF1 seemed to be easier to interpret than ß-catenin because of its nuclear pattern of expression. The expression of LEF1 in the regular nevus component of combined BN presents a potential pitfall in practice because it may lead to misinterpretation of LEF1 as positive in the BN component of the lesion. However, a subset (approximately one-third) of combined BN seemed to show true LEF1 expression. Taking into account pitfalls in interpretation, the combinatorial panel of PRAME and LEF1, in addition to conventional histopathological features, may be useful to distinguish CDPN from combined BN and other benign and malignant mimics.

BRAF V600E immunohistochemistry as a useful tool in the diagnosis of melanomas with ambiguous morphologies and immunophenotypes.

We report three melanoma cases in which BRAF V600E immunohistochemistry (IHC) was valuable for diagnosis. Patient 1: In a patient with a history of primary melanoma on the chest and metastatic melanoma to right breast after undergoing multiple local and systemic therapies, a lung metastasis exhibited chondroid differentiation, aberrant myofibroblastic marker expression, and rare pancytokeratin positivity, without melanocytic marker expression. Patient 2: After targeted and immunotherapy for primary melanoma on the scalp as well as regional and distant metastatic melanoma, an omental metastasis showed CDX2-positive glandular structures that were negative for melanocytic markers. It was initially misdiagnosed as primary gastrointestinal adenocarcinoma. Patient 3: A patient with history of melanoma showing epithelioid morphology on the right thigh presented with multiple soft tissue nodules on skin, lymph nodes and internal organs after being lost to follow-up for 4 years. A biopsy specimen from the right thigh showed spindled cells with scattered pancytokeratin cocktail positivity and ambiguous staining for melanocytic markers. For melanomas with ambiguous morphologies and/or immunophenotypes in each of the three patients, BRAF V600E expression by IHC was maintained in both primary and metastatic melanoma specimens examined. These cases highlight the utility of BRAF V600E IHC in the diagnosis of melanoma.

Ductal differentiation: A rare phenomenon in Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma that may occasionally present divergent histopathologic features. We present two cases of MCC demonstrating ductal differentiation, one on the lower lip of an 81-year-old man and another on the right forearm of a 67-year-old man. The histopathologic features included TTF1-negative, infiltrative, high-grade basaloid tumor with paranuclear punctate positivity for cytokeratin (CK) 20 and synaptophysin. Rare luminal structures lined by atypical epithelioid cells positive for CEA and CK19 were noted, confirming the presence of ductal differentiation. Although the ductal differentiation is unusual, other histopathologic features and the immunohistochemical profile supported the diagnosis of MCC. Like most divergent features, ductal differentiation is rare in MCC and typically constitutes a very small proportion of the tumor, and is therefore under-recognized. Although the clinical significance of this feature is unclear, recognition and documentation of ductal differentiation and distinguishing it from other mimics such as acantholysis within squamous nests and entrapped eccrine ducts is essential to determine its clinical significance. We also discuss the differential diagnoses of cutaneous basaloid neoplasms with ductal differentiation.

Diagnostic utility of PRAME expression by immunohistochemistry in subungual and non-subungual acral melanocytic lesions.

BACKGROUND: The immunohistochemical (IHC) marker PReferentially expressed Antigen in MElanoma (PRAME) has shown promise in the diagnosis of melanocytic lesions. A few studies have investigated PRAME IHC expression in acral melanomas, but PRAME expression in subungual melanomas is largely unknown. We evaluated the utility of PRAME IHC expression in distinguishing subungual melanomas (SUM) and non-subungual acral melanomas (AM) from acral nevi (AN). METHODS: Twenty-two SUM, 20 AM, and 14 AN were identified. IHC studies were performed using an anti-PRAME antibody. The percentage of lesional cells with PRAME expression was recorded and categorized as follows: 0%, 0; 1%-25%, 1+; 26%-50%, 2+; 51%-75%, 3+; and >75%, 4+. Patient demographics and other relevant clinicopathologic parameters were recorded. RESULTS: Diffuse (4+) PRAME IHC expression was identified in 55% (12/22) SUM and 70% (14/20) AM, respectively. Any PRAME expression (1+ to 4+) was identified in 73% (16/22) SUMs and 95% (19/20) AM, respectively. One of 14 (7%) AN exhibited PRAME expression; interestingly, the pattern of expression was diffuse. CONCLUSIONS: In our study, PRAME IHC expression was useful in identifying AM, including SUM. However, there are exceptions of PRAME-negative melanomas and PRAME-positive nevi.

Amyloid deposition with a granulomatous reaction in a resection specimen: A clue for a pre-existing Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is an aggressive, highly metastatic, cutaneous neuroendocrine malignancy with poor prognosis. Here, we describe a MCC excision specimen with a rare case of tumor-associated amyloid deposition in the absence of residual tumor cells. A 72-year-old man presented with a lesion of 5-6 months' duration on his left elbow, clinically thought to be a ganglion cyst. The biopsy specimen revealed a Stage IIA MCC with classic histomorphologic and immunophenotypic findings, with tumor extending to the tissue edges. The patient underwent wide local excision with negative margins and a negative sentinel lymph node biopsy. Although the patient did not receive any presurgical chemotherapy, immunotherapy, or targeted therapy, the re-excision specimen showed only amphophilic, feathery deposits that were salmon-pink with Congo red stain and further confirmed as amyloid by electron microscopy; there were no residual carcinoma cells. Amyloid deposition in MCC has been described in rare case reports. Our case was extraordinary in that there was only amyloid deposition and an associated granulomatous reaction, without identifiable MCC cells. This case demonstrates that amyloid deposition may be evidence of a prior MCC at the site of a prior procedure and may warrant careful evaluation for residual MCC.