Nectin-4 expression in a subset of cutaneous adnexal carcinomas: A potential target for therapy with enfortumab vedotin.

BACKGROUND: Enfortumab vedotin (EV) is an antibody-drug conjugate directed against Nectin-4 that is used to treat urothelial carcinoma. Nectin-4 is inherently expressed in the skin and adnexal structures. Since therapeutic options for cutaneous adnexal carcinomas are limited, we sought to evaluate Nectin-4 expression in adnexal carcinomas and benign adnexal neoplasms to identify tumors that are potentially targetable with EV. METHODS: Eight sebaceous carcinomas (seven periocular and one lymph node metastasis), eight digital papillary adenocarcinomas, seven squamoid eccrine ductal carcinomas, eight poromas, eight trichilemmomas, and seven sebaceous adenomas were subjected to immunohistochemical staining for anti-Nectin-4 antibody. H-scores for Nectin-4 expression were calculated. RESULTS: Benign adnexal neoplasms had a significantly lower mean (±SD) Nectin-4 H-score (142.6 ± 39.1) than did the adnexal carcinomas (198 ± 90.8; p = 0.006). Nectin-4 was expressed in 91% (21/23) of adnexal carcinomas. Sebaceous carcinomas frequently exhibited high expression of Nectin-4 (88% [7/8]), with a mean (±SD) H-score (258.1 ± 58.4) significantly higher than those for digital papillary adenocarcinomas (197.5 ± 52.5; p = 0.035) and squamoid eccrine ductal carcinomas (131.4 ± 114.1; p = 0.031). Sebaceous carcinomas also had significantly higher H-scores than did sebaceous adenomas (186.4 ± 25.0; p = 0.013). CONCLUSIONS: Increased Nectin-4 expression in a subset of cutaneous adnexal carcinomas, particularly sebaceous carcinomas, reveals that EV is a potential therapeutic option for these tumors.

Chordoma metastatic to skin: A report of two cases and a brief review of the literature.

Chordomas are rare, locally aggressive tumors of notochordal origin usually arising in the spine or base of the skull. Skin involvement is rare and typically occurs via direct extension of the primary tumor to the skin. Although there are increasing reports of the skin being involved as a distant metastatic site in patients with chordoma, this remains an exceedingly rare occurrence. We present two cases of patients diagnosed with metastasis of chordoma to the skin that represented distant metastasis. In the first case, a patient with a primary thoracic/lumbar chordoma presented with isolated metastasis to the skin of the left lower jaw 9 years after initial diagnosis of the chordoma. To our knowledge, this is the first reported case of a chordoma of this site to develop distant skin metastasis. In the second case, a patient with a primary sacral chordoma presented with metastasis to the skin of the right side of his chin 6 years after initial diagnosis of the chordoma, following previous metastatic spread to the liver and lung. Finally, we briefly review the literature on chordoma metastasis to the skin and highlight salient features to raise awareness of this uncommon occurrence.

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.

Immunohistochemical expression of TRPS1 in mammary Paget disease, extramammary Paget disease, and their close histopathologic mimics.

BACKGROUND: Trichorhinophalangeal syndrome type 1 (TPRS1) expression has been found to be highly sensitive and specific for breast carcinomas. The frequency of TRPS1 expression in cutaneous neoplasms such as mammary Paget disease (MPD) and extramammary PD (EMPD) is currently unknown. We assessed the utility of TRPS1 immunohistochemistry (IHC) in the evaluation of MPD, EMPD, and their histopathologic mimics, squamous cell carcinoma in situ (SCCIS) and melanoma in situ (MIS). METHODS: Twenty-four MPDs, 19 EMPDs, 13 SCCISs, and 9 MISs were subjected to immunohistochemical analysis using anti-TRPS1 antibody. The intensity (none, 0; weak, 1+ ; moderate, 2+ ; strong, 3+ ) and proportion (<1%, absent; 1%-25%, focal; 26%-75%, patchy; >75%, diffuse) of TRPS1 expression were recorded. Relevant clinical data were documented. RESULTS: TPRS1 expression was present in 100% (24/24) of MPDs, with 88% (21/24) of MPDs exhibiting strong, diffuse immunoreactivity. Sixty-eight percent (13/19) of EMPDs showed TRPS1 expression. Intriguingly, EMPDs lacking TRPS1 expression were consistently of perianal origin. TRPS1 expression was seen in 92% (12/13) of SCCISs but was absent in all MISs. CONCLUSIONS: TRPS1 may be useful to distinguish MPDs/EMPDs from MISs, but its utility is limited in distinguishing them from other pagetoid intraepidermal neoplasms such as SCCISs.

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.

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.

Eosinophilic homogeneous intracytoplasmic inclusion bodies: Unique viral cytopathic changes associated with epidermodysplasia verruciformis and human papillomavirus type 49.

Epidermodysplasia verruciformis (EDV) is a rare genodermatosis that predisposes affected individuals to persistent infection with certain types of human papillomavirus (HPV), particularly those that belong to the genus beta-HPV, including HPV-5 and HPV-8, which carry high oncogenic potential. There are three main HPV-related viral cytopathic changes in cutaneous verrucae in terms of intracytoplasmic inclusion bodies (ICBs), namely, granular, filamentous, and homogeneous type ICBs. To date, only HPV-4, HPV-60, and HPV-65 have been found in association with homogeneous ICBs. We report a unique case of HPV-49-associated EDV in a 41-year-old woman with common variable immunodeficiency, mycosis fungoides, and multiple cutaneous malignancies, including squamous cell carcinoma and Merkel cell carcinoma who presented with multiple pink papules and hyperpigmented macules on the left upper extremity. One of the skin lesions histopathologically revealed keratinocytic nuclear enlargement with abundant blue-gray cytoplasm, accompanied by hypergranulosis, characteristic of EDV, along with peculiar bright eosinophilic and homogeneous ICBs. To the best of our knowledge, this is the first reported case of EDV with detection of HPV-49 by genotyping, which features eosinophilic homogeneous ICBs, like those seen in the setting of HPV-4, HPV-60, or HPV-65 infection.

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.

Cutaneous Lymphoid Hyperplasia With T-Cell Clonality and Monotypic Plasma Cells Secondary to a Tick Bite: A Hidden Critter and the Power of Deeper Levels.

ABSTRACT: Cutaneous lymphoid hyperplasia (CLH) is a benign reactive process with T-cell or B-cell lymphocytic infiltration in the skin, which can simulate cutaneous lymphomas both clinically and histologically. Various antigenic stimuli have been implicated in the development of CLH, including tick bites. Finding histologic evidence of such triggering factors, however, is often difficult. Moreover, the presence of clonality in CLH can potentially be interpreted as a neoplastic process, posing a further diagnostic challenge to dermatopathologists, if one is not aware of such peculiar phenomena. Herein, we describe a case of CLH secondary to a tick bite, featuring both T-cell clonality and monotypic plasma cells with lambda light chain restriction; the diagnostic clue being tick parts, which became evident on assessment of deeper levels. To the best of our knowledge, this is the first reported case of a tick-associated clonal CLH with simultaneous detection of monoclonal T cells and monotypic lambda light chain restriction, mimicking primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder and Borrelia-associated primary cutaneous marginal zone B-cell lymphoma, respectively.

Prognostic significance of acral lentiginous histologic type in T1 melanoma.

Acral lentiginous melanoma (ALM) is a rare type of cutaneous melanoma with a poor prognosis. It is unclear whether the poor outcome of ALM is due to its inherent disease characteristics or advanced stage at initial diagnosis. To address this question, we retrospectively analyzed the clinicopathologic factors of 828 thin (T1; Breslow thickness ≤1.0 mm) melanomas [129 (15.6%) ALMs and 699 (84.4%) non-ALMs] and their nodal and distance metastases and local recurrence rates and determined their relationship with the disease-specific (DSS), overall (OS), and recurrence-free survivals (RFS) at the pathologic stages T1, T1a, and T1b with a median follow-up time of 84.5 months. With the exception of OS at T1b stage, ALM patients showed significantly lower 5- and 10-year DSS, OS, and RFS rates at every pathologic stage when compared with non-ALM. In multivariable analysis, ALM histologic type, SLN positivity, age, and the use of systemic therapy were detected as independent poor prognostic factors associated with significantly lower survival rates. ALM histologic type was associated with lower DSS and OS rates at T1 and T1a stages and lower RFS rates at T1b stage. SLN positivity was associated with lower DSS, OS, and RFS rates at T1, T1a, and T1b stages. Age was associated with lower OS rates at T1 and T1b stages. Whereas the use of systemic therapy was associated with lower DSS rates at T1a stage and RFS rates at T1b stage. In addition, the ALM group showed significantly older median age patients and higher rates of female sex, Hispanic ethnicity, nevoid cytology, non-brisk tumor-infiltrating lymphocytes, nodal metastasis, and local recurrence at every pathologic stage of thin melanoma. Our findings suggest that ALM is inherently more aggressive than other types of cutaneous melanoma. This information may be useful for prognostic stratification of patients with thin melanomas, especially to help guide the clinical decision-making for SLN biopsy and patients entering clinical trials.

Cutaneous adnexal carcinosarcoma: Immunohistochemical and molecular evidence of epithelial mesenchymal transition.

Cutaneous carcinosarcomas are rare biphenotypic tumors that simultaneously show epithelial and mesenchymal differentiation. The most common carcinomatous components in skin carcinosarcomas are basal cell carcinoma and squamous cell carcinoma; adnexal carcinomas are rarely encountered. We report a case of an adnexal carcinoma with ductal and squamous differentiation and spindle cell component, which is interpreted as carcinosarcoma. Loss of immunohistochemical expression of E-cadherin and ß-catenin detected in the sarcomatous component suggested epithelial mesenchymal transition (EMT). RNA sequencing analysis identified several gene mutations and alterations such as translocations and upregulations/downregulations, either shared by the two components of the tumor or differentially present in the carcinoma or the sarcoma parts. Thus, mutations in genes, such as TP53, were found in both components of the tumor while mutations in PDGFRA and RB1 (a pathogenic missense mutation) were exclusively present in the sarcomatous areas, further supporting EMT. EMT is a dynamic process by which tumors acquire mesenchymal phenotype while simultaneously losing epithelial properties. Although the pathways involved in EMT have been extensively studied, this phenomenon still needs to be investigated in cutaneous tumors of adnexal origin for a better understanding of their pathogenesis. These molecular changes may represent promising targets for personalized therapies.

Langerhans cell sarcoma involving skin and showing epidermotropism: A comprehensive review.

Langerhans cell sarcoma (LCS) is rare and aggressive; patients have an overall survival rate of less than 50%. We present a 62-year-old man with a history of superficial spreading melanoma of the upper back with sentinel lymph node metastasis, Langerhans cell histiocytosis, and LCS. The patient presented with erythematous papules and scaly areas on his face, neck, arms, chest, abdomen, and legs. A skin biopsy revealed a proliferation of large neoplastic cells involving the dermis and with epidermotropism. These cells had atypical bean-shaped nuclei, with ample cytoplasm and abundant mitotic figures including atypical forms. Immunohistochemical studies showed the tumor to be diffusely positive for CD1a, S100 protein, and langerin (CD207) and negative for melanocytic markers. Some tumor cells were positive for cyclin D1. A diagnosis of LCS involving the skin was established. The present study is a very unusual case of LCS showing epidermotropism. The patient's history of metastatic melanoma posed additional challenges for diagnosis, underlying the need of immunophenotyping in these cases. Consensus for optimal standard therapy has not been established in LCS, and thus, early recognition is important since these neoplasms tend to recur and metastasize. LCS in skin is discussed and published cases are comprehensively reviewed.

Histologic Patterns of Cutaneous Metastases of Breast Carcinoma: A Clinicopathologic Study of 232 Cases.

ABSTRACT: Cutaneous metastasis may be the initial sign of internal malignancy but more often represents a late manifestation of widely disseminated disease. Breast carcinoma is the most common malignancy to metastasize to the skin. Although several studies have detailed the histopathologic patterns of cutaneous metastasis from internal malignancies, very little has been published regarding metastases of breast carcinoma to the skin. Furthermore, the histopathologic and clinical features observed in the cases of breast carcinoma with local skin involvement as opposed to cases exhibiting distant cutaneous metastases have not been adequately investigated. We have reviewed 232 cases of breast carcinoma with cutaneous metastases from 2 large institutions. All cases of carcinoma of the breast with involvement of the skin of the anterior chest wall were compared with those with distant cutaneous metastases. Two hundred thirty-two cases in 199 patients were included, of which 126 had skin involvement exclusively involving the ipsilateral anterior chest, and 106 had biopsy-proven distant cutaneous metastases. Twelve patients had both local and distal spread. Distant cutaneous metastases showed a predilection for the contralateral anterior chest wall area, followed by the head and neck, back, and abdomen. Histologically, most of the tumors presented in this series showed features of infiltrating ductal carcinoma. In both ipsilateral and distant metastases, the tumors demonstrated little change in histologic features from the primary lesion; however, the distant metastases showed a tendency to display more poorly differentiated features. The mean patient survival when cutaneous involvement was localized to the skin of the anterior chest wall was 23 months as compared with 20.6 months when distant sites were affected. A comparison of the clinicopathologic features of the patients presented in this series suggests that alternate biological mechanisms may apply for local and distant skin metastases from breast carcinoma.

Localized cutaneous argyria: Review of a rare clinical mimicker of melanocytic lesions.

Localized cutaneous argyria is a rare cutaneous disorder that has been associated with occupational exposure, dental procedures, topical agents, acupuncture, earrings, and nasal piercings. In this paper, we review the current literature on localized cutaneous argyria, highlight its clinical and histologic diagnostic features, and then discuss the clinical and histological differential diagnoses for blue-gray skin and black dermal pigment, respectively. We also discuss the utility of ancillary techniques, such as deeper histologic levels, special stains, darkfield microscopy, and advanced micro-analytical techniques in helping diagnose localized cutaneous argyria. Furthermore, we emphasize that a thorough clinical history and astute clinico-pathologic correlation can be the most important diagnostic techniques in correctly diagnosing this rare disorder. Our review aims serve as a reminder to clinicians and pathologists of the importance of including localized cutaneous argyria in the clinical and histological differential diagnosis of pigmented lesions.

The utility of digital pathology in improving the diagnostic skills of pathology trainees in commonly encountered pigmented cutaneous lesions during the COVID-19 pandemic: A single academic institution experience.

Digital pathology has become an integral part of pathology education in recent years, particularly during the COVID-19 pandemic, for its potential utility as a teaching tool that augments the traditional 1-to-1 sign-out experience. Herein, we evaluate the utility of whole slide imaging (WSI) in reducing diagnostic errors in pigmented cutaneous lesions by pathology fellows without subspecialty training in dermatopathology. Ten cases of 4 pigmented cutaneous lesions commonly encountered by general pathologists were selected. Corresponding whole slide images were distributed to our fellows, along with two sets of online surveys, each composed of 10 multiple-choice questions with 4 answers. Identical cases were used for both surveys to minimize variability in trainees' scores depending on the perceived level of difficulty, with the second set being distributed after random shuffling. Brief image-based teaching slides as self-assessment tool were provided to trainees between each survey. Pre- and post-self-assessment scores were analyzed. 61% (17/28) and 39% (11/28) of fellows completed the first and second surveys, respectively. The mean score in the first survey was 5.2/10. The mean score in the second survey following self-assessment increased to 7.2/10. 64% (7/11) of trainees showed an improvement in their scores, with 1 trainee improving his/her score by 8 points. No fellow scored less post-self-assessment than on the initial assessment. The difference in individual scores between two surveys was statistically significant (p = 0.003). Our study demonstrates the utility of WSI-based self-assessment learning as a source of improving diagnostic skills of pathology trainees in a short period of time.

TERT amplification but not activation of canonical Wnt/ß-catenin pathway is involved in acral lentiginous melanoma progression to metastasis.

Acral lentiginous melanoma (ALM) is a rare tumor that occurs on non-sun exposed skin areas of the hands and feet. Reports suggest that ALM exhibits poor prognosis, although mechanisms driving this remain poorly understood. Alterations in TERT and the Wnt/ß-catenin (Wnt) pathway have been suggested to correlate with prognosis of ALM. Thus, immunohistochemical expression of ß-catenin and LEF1 along with TERT amplification by FISH was investigated in 34 primary ALMs, 20 metastatic ALMs, 10 primary non-ALMs, and 15 acral nevi. Foot/toe was the most common primary tumor location (85%) for ALM. TERT amplification was detected in 6 of 28 (21.4%) primary ALM, 2 of 8 (25%) primary non-ALM, and 8 of 18 (44.4%) metastatic ALM, the latter showing significantly higher frequency compared with primary melanomas (P = 0.043). Most metastatic ALMs positive for TERT amplification lacked BRAF V600E (87.5%). Cytoplasmic and nonnuclear expression of ß-catenin was variably detected in all cases. Metastatic ALM revealed lower expression of ß-catenin compared with primary ALM (P = 0.017). No differences in LEF1 expression were detected among the groups; however, acral nevi showed decreased labeling with dermal descent, in contrast to melanoma. No molecular-genetic alteration correlated with prognosis. TERT amplification by FISH is a frequent finding in primary ALM and appears to increase in metastatic tumors, suggesting a role in tumor progression to metastasis. Although TERT amplification has been reported to be infrequent in primary non-ALM, it showed comparable frequency with ALM in our series. Our immunohistochemical findings are not fully supportive of activation of either canonical or noncanonical Wnt cascades in ALM. TERT amplification by FISH and LEF1 immunohistochemistry may help in the differential diagnosis between primary ALM and acral nevus. TERT amplification appears to be a promising target for therapy in patients with metastatic ALM.

Prognostic model for patient survival in primary anorectal mucosal melanoma: stage at presentation determines relevance of histopathologic features.

Pathological staging of primary anorectal mucosal melanoma is often performed according to the American Joint Commission on Cancer (AJCC) guidelines for cutaneous melanoma, as an anorectal melanoma-specific staging system does not exist. However, it remains unknown whether prognostic factors derived for cutaneous melanoma also stratify risk in anorectal melanoma. We retrospectively determined correlations between clinicopathological parameters and disease-specific survival in 160 patients. Patients were grouped by clinical stage at presentation (localized disease, regional or distant metastases). Cox proportional hazards regression models determined associations with disease-specific survival. We also summarized the somatic mutations identified in a subset of tumors analyzed for hotspot mutations in cancer-associated gene panels. Most of the patients were white (82%) and female (61%). The median age was 62 years. With a median follow-up of 1.63 years, median disease-specific survival was 1.75 years, and 121 patients (76%) died of anorectal melanoma. Patients presenting with regional (34%) or distant metastases (24%) had significantly shorter disease-specific survival compared to those with disease localized to the anorectum (42%). Of the 71 anorectal melanoma tumors analyzed for hotspot genetic alterations, somatic mutations involving the KIT gene (24%) were most common followed by NRAS (19%). Increasing primary tumor thickness, lymphovascular invasion, and absence of regression also correlated with shorter disease-specific survival. Primary tumor parameters correlated with shorter disease-specific survival in patients presenting with localized disease (tumor thickness) or regional metastases (tumor thickness, absence of regression, and lymphovascular invasion), but not in patients presenting with distant metastases. Grouping of patients according to a schema based on modifications of the 8th edition AJCC cutaneous melanoma staging system stratified survival in anorectal melanoma. Our findings support stage-specific associations between primary tumor parameters and disease-specific survival in anorectal melanoma. Moreover, the AJCC cutaneous melanoma staging system and minor modifications of it predicted survival among anorectal melanoma patients.

Cutaneous neoplasms composed of melanoma and carcinoma: A rare but important diagnostic pitfall and review of the literature.

We report two cases of combined cutaneous tumors composed of melanoma and carcinoma. The first tumor presented as a 5-mm pink-blue macule over the right zygomatic arch in an 85-year-old man. Shave biopsy and immunohistochemical studies revealed that the tumor was composed of melanoma (highlighted by SOX10 and MART-1, with high Ki-67 proliferative index) intermixed with nodular basal cell carcinoma (highlighted by pan-cytokeratin and Ber-EP4). The neoplastic melanocytes were confined to the basal cell carcinoma nodules, and a diagnosis of combined melanoma in situ and basal cell carcinoma was rendered. After therapeutic excision, the patient was disease-free at 9 months after the initial diagnosis. The second tumor presented as a 6-mm pink-brown crusted papule on the right forehead in an 89-year-old man. Shave biopsy and immunohistochemical studies revealed that the tumor was composed of malignant melanoma (MM) (highlighted by S100 and MART-1) intermixed with squamous cell carcinoma (SCC) (highlighted by cytokeratin and p63), and a diagnosis of combined MM-SCC was rendered. These two cases highlight the importance of recognizing these rare types of melanocytic-epithelial cutaneous neoplasms to arrive at an accurate diagnosis that may inform appropriate disease stage and therapy.

BAP-1 Expression Status by Immunohistochemistry in Cellular Blue Nevus and Blue Nevus-like Melanoma.

The family of blue nevi includes the common blue nevus (BN), cellular blue nevus (CBN), and atypical BN, while melanomas with BN-like morphology can either arise in association with a blue nevus (MABN) or in the de novo setting mimicking cellular blue nevus (MMCBN). Recent molecular and immunohistochemical studies have demonstrated loss of BAP-1 in MABN/MMCBN but not in BN/CBN, suggesting that loss of BAP-1 correlates with a malignant phenotype in these lesions. In this study, we applied anti-BAP-1 antibodies to a series of CBN/BN (n = 11) and MABN/MMCBN (n = 4). Nuclear BAP-1 expression was detected in the majority of CBN/BN (n = 10/11) but was lost in 1 case. Most cases of MABN/MMCBN showed loss of nuclear BAP-1 expression (n = 3/4), with one case of MMCBN showing preserved BAP-1 expression. Demonstration of BAP-1 loss in a single case of CBN and preservation of BAP-1 expression in 1 case of MMCBN may indicate that detection of alterations in BAP-1 protein expression by immunohistochemistry may not be a completely reliable biomarker for the distinction of BN/CBN from MABN/MMCBN. Further investigation of the significance of BAP-1 loss/preservation in BN-like tumors is warranted.

Measurement of Tumor Thickness in Cutaneous Squamous Cell Carcinomas: Do the Different Methods Provide Better Prognostic Data?

Cutaneous squamous cell carcinoma (cSCC) is the second most common cause of nonmelanoma skin cancers. Although it has a relatively low mortality rate, it may be locally destructive and potentially metastasize. Tumor thickness of the primary lesion is one important parameter associated with biologic behavior. Such measurement is currently performed in different ways depending on the anatomic location and subspecialty (eg, skin vs. head and neck vs. gynecologic pathology). Furthermore, the new The American Joint Committee on Cancer eighth edition has changed the previously recommended method of measurement of cSCC of head and neck from a modified Breslow thickness to measuring from the granular layer of adjacent, normal-appearing skin to the deepest invasive tumor cell. This study evaluated the clinical significance on patient outcome by measuring tumor thickness using 4 common, currently available methods (measurement from: A. uninvolved dermoepidermal junction; B. top of granular cell layer of the epidermis overlying the tumor, that is, similar to Breslow thickness; C. dermoepidermal junction with in situ cSCC; D. top of granular layer of uninvolved skin) in 85 specimens from nongenital areas of 78 patients with cSCC. Thirty-five percent of them were from the head and neck area. Measurements were performed in millimeters using the digital ruler of image analysis software (Olympus cellSens Standard) on whole-slide scanned images. Associations between recurrence-free survival (RFS) and each method were assessed. When thickness was considered as a continuous measure, there was no statistically significant association between any of the 4 measurement techniques and RFS. When using the currently recommended 6.0-mm cutoff, methods B and C were significantly associated with RFS. Similarly, when optimal cutoff values were selected, all 4 methods were significantly associated with RFS in univariable analysis. However, in a multivariable model that included the techniques and location of lesion, only method B, using the optimal cutoff value of 8.7 mm, was independently associated with RFS. In summary, in our series of cSCC, measurement of thickness using a Breslow method (method B) was significantly associated with RFS using the optimal cutoff and the currently recommended 6.0 mm in univariable analyses and the optimal cutoff in a multivariable assessment. Therefore, our data indicate that measurement of tumor thickness in a manner similar to Breslow thickness may be used to help predict recurrence in patients with cSCC.