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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.

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/β-catenin (Wnt) pathway have been suggested to correlate with prognosis of ALM. Thus, immunohistochemical expression of β-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 β-catenin was variably detected in all cases. Metastatic ALM revealed lower expression of β-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.

Melanomas, like nonmelanoma skin cancers, are known to be causally related to sun exposure. It is therefore not surprising to see benign nevi and melanomas in a background of solar damage, which at times may complicate their distinction. Because of their long-standing nature, nevi often occur before the development of solar elastosis and as such are intimately associated with the solar elastosis. In contrast, visible solar elastosis often occurs before the development of melanoma, in which case the band of solar elastosis is displaced downward from the overlying invasive melanoma and/or its host response. We describe 4 cases in which invasive melanoma cells were intimately admixed with actinically damaged elastin fibers in the absence of a prominent host response. In each case, melanoma cells were admixed with prominent solar elastosis and lacked a significant host response, suggesting that they were either histiocytes or an associated melanocytic nevus. Recognition of this potential pitfall may be helpful in the diagnosis of primary/in-transit/satellite/metastatic melanoma as well as when evaluating marginal status and determining Breslow thickness.

Primary cutaneous Merkel cell carcinoma (MCC) is an aggressive neuroendocrine malignancy in which lymphovascular invasion (LVI) correlates with more aggressive phenotype. The prognostic significance of LVI detected by D2-40 immunohistochemistry (IHC) in MCC remains controversial. We aimed to determine how LVI detected by D2-40 IHC compares with LVI detected by hematoxylin and eosin (HE) staining in predicting MCC metastasis. Clinical and histopathologic features of MCCs diagnosed and treated in 2002 to 2015 were assembled and included 58 MCC tumors from 58 patients. HE-stained tissue sections and D2-40 IHC studies were reviewed. When LVI was present, the location (peritumoral or intratumoral) and the size of the largest invaded vessel were recorded. LVI findings by HE staining and D2-40 IHC were compared with each other and with histologic features and clinical outcomes. HE staining showed LVI in 37 of 58 cases; D2-40 IHC confirmed LVI in 30 of these cases but failed to confirm LVI in 7. D2-40 IHC also detected 14 cases of LVI not identified on HE staining. Histologically, D2-40-detected LVI was associated with infiltrative growth pattern and nonbrisk lymphoid infiltrate (P = .005 and P = .055, respectively). There was a statistically significant difference between the frequency of detection of peritumoral LVI by HE in comparison to D2-40 IHC (P = .0009). MCCs in which D2-40 IHC-detected both intratumoral and peritumoral LVI were typically larger than MCCs without (mean, 24.5 mm versus 17.3 mm; P = .03) and more frequently metastasized (87% versus 51%; P = .03). D2-40 IHC detection of both intratumoral and peritumoral LVI is associated with metastasis.

Background Serum protein acidic and rich in cysteine (SPARC) is a matricellular glycoprotein, which regulates cell proliferation and facilitates intracellular transport of albumin bound particles including chemotherapeutic agents such as Nab-paclitaxel/ABI-007. Therefore the presence of SPARC may achieve higher intra-tumoral drug concentration with lower dosage and thus reduce systemic side-effects. Several trials of ABI-007, in melanoma, show promising clinical activity. Design Fifty-four cases of dermal based neoplasms were retrieved including 24 angiosarcomas (AS), 10 hemangiomas, 9 nodular melanomas, 4 Kaposi sarcomas (KS), 3 leiomyosarcomas (LMS), 3 atypical fibroxanthomas (AFX) and 1 spindle cell squamous cell carcinoma (SSCC). SPARC immunohistochemistry (IHC) was performed with a mouse monoclonal antibody. Results SPARC expression was detected in a majority of AS (17/24), melanomas (8/9), AFX (3/3), LMS (3/3) and KS (4/4) with some expression in hemangiomas (3/10), while being negative in SSCC (0/1); and was significantly associated with tumor group (p = 0.017). Although a significant difference in overall survival was observed between SPARC expression groups (positive vs. negative) for all patients, there was no significant difference noted among angiosarcoma patients. Conclusion We have confirmed the presence of SPARC expression in melanoma, KS, LMS and AS and also detected it for the first time in AFX. Since paclitaxel has shown some effectiveness in AS, melanoma and KS, ABI-007 could also be beneficial in these patients.

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.

Capsular nevi (CN) are clusters of benign melanocytes situated in the capsule of lymph nodes and occur in up to 20% of lympadenectomy specimens. The molecular profile of CN in relation to prognostic parameters in patients with primary cutaneous melanoma (PCM) has not been previously investigated. We assessed BRAF V600E mutation by immunohistochemistry (IHC) in the CN of sentinel lymph nodes (SLN) in PCM patients and correlated the findings with demographic characteristics, PCM histopathologic and molecular features, and clinical outcome parameters. Seventy-eight cases of CN involving SLN of PCM patients were evaluated for BRAF V600E mutation by IHC. The results were correlated with patient demographics, PCM histopathologic and molecular features, and outcome measures. Thirty-six (46%) of 78 CN cases expressed BRAF V600E mutation by IHC. Nineteen (53%) of those BRAF-positive CN cases were from patients with at least American Joint Committee on Cancer stage II melanoma, whereas 62% of BRAF-negative CN cases (26/42) were from patients with stage I melanoma (P = .013). Twelve (33%) of the 36 BRAF-positive CN cases had metastatic melanoma involving lymph nodes, compared with 14% (6/42) of BRAF-negative CN cases (P = .061). CN mutation status was not associated with patient demographics, histopathologic or molecular features of the PCM, or survival outcomes. A high percentage of CN identified in the SLN of patients with PCM harbor BRAF V600E mutation. Positive mutation was associated with adverse clinicopathological parameters, specifically increased tumor stage and lymph node metastasis. These findings suggest that BRAF V600E mutation in CN of SLN may be useful as an adverse predictive biomarker in patients with melanoma.

Melanomas arising in association with blue nevi or mimicking cellular blue nevi comprise a relatively rare and heterogeneous group of melanomas. It remains controversial which prognostic indicators predictive of outcome in conventional cutaneous melanomas are applicable to this type of melanoma. Here, we describe the clinical and histopathologic features of 24 melanomas arising in association with blue nevi and correlate these with clinical outcome. The mean patient age was 49 years (range: 23-85) with a slight female predominance (15 females:9 males). The most common anatomic locations included the head and neck region (50%), the trunk (21%), and the buttock/sacrococcygeum (17%). Histologically, the tumors were typically situated in the mid to deep dermis with variable involvement of the subcutis, but uniformly lacked a prominent intraepithelial component. The mean tumor thickness (defined as either the standard Breslow thickness or, if not available due to the lack of orientation or lack of epidermis, the largest tumor dimension) was 20.9 mm (range: 0.6-130 mm). The mean mitotic figure count was 6.5/mm(2) (range: 1-30/mm(2)). Perineural invasion was common (38%). Follow-up was available for 21 cases (median 2.1 years). The median overall survival, recurrence-free survival, time to local recurrence, and time to distant recurrence were 5.2, 0.7, 2.6, and 1.6 years, respectively. Logistic regression analyses demonstrated a significant association between tumor thickness and recurrence-free survival (hazard ratio=1.02 per mm; P=0.04) and reduced time to distant metastasis (hazard ratio=1.03 per mm; P=0.02) with a similar trend toward reduced time to local recurrence (hazard ratio=1.02 per mm; P=0.07). No other parameters (age, anatomic location, mitotic figures, lymphovascular or perineural invasion, or type of associated blue nevus) emerged as significant. In addition, we provide a comprehensive review of 109 cases of melanoma blue nevus type described in the English literature and summarize our findings in this context.

Pathology laboratories routinely encounter cutaneous neoplasms in which the differential diagnosis includes primary tumors as well as metastatic carcinomas. This distinction is important since metastatic lesions portend a poor prognosis and, in rare cases, they can be the first sign of internal malignancy. In most cases analysis of histologic features and correlation with clinical information allow one to establish the correct diagnosis. However, occasionally, and especially in the case of adenocarcinomas, the morphologic features may be very similar in both primary cutaneous tumors (especially those of sweat gland origin) and metastatic lesions. This article reviews the use of immunohistochemistry as an adjunctive tool in the analysis of primary and metastatic carcinomas involving the skin. It also provides an algorithm including selected markers that can be used in this context.

Panniculitis is broadly defined as inflammation of the subcutaneous tissue. Although a number of diseases involve the panniculus, the spectrum of morphological patterns is limited, namely lobular and septal. Therefore, despite the perceived complexity of this topic, careful analysis of the pattern and the inflammatory infiltrate allows a histological diagnosis in a majority of cases. In this review we will cover the most important types of panniculitis, and will offer a diagnostic algorithm to help analyse this type of biopsy.

The spectrum of cutaneous lesions in oncological patients includes entities encountered in the general population, lesions associated with underlying malignant processes (such as paraneoplastic syndromes) and conditions related to the immunosuppressed status of these patients or their antineoplastic treatment. The paraneoplastic syndromes represent a group of skin conditions that may precede or coexist with the diagnosis of malignancy and may also signal tumour recurrences. In general, there is a high prevalence of immunosuppression in oncological patients, related to the alteration of humoral and cellular immunity or their immunosuppressive therapy. Thus, these patients are especially susceptible to certain infections associated with high morbidity and mortality. Correct and early recognition of the cutaneous manifestations in oncological patients provides an important insight into underlying malignant process, possible complications (iatrogenic or not) and prognosis. In this review we offer a practical overview of inflammatory or neoplastic conditions associated with internal malignancies and cutaneous infectious in oncological patients.

Basal cell carcinoma is the most common malignancy in Caucasian individuals. Metastatic basal cell carcinoma is extremely rare (with a rate estimated as 0.03%). Actin has been detected in aggressive forms of basal cell carcinoma, but their expression in metastatic lesions is not known. We compared the expression of actin and actin-related cytoskeletal proteins in relatively less aggressive basal cell carcinoma (nodular), aggressive basal cell carcinoma (infiltrative/morpheaform), and metastatic basal cell carcinoma. We studied 12 cases of nodular basal cell carcinoma, 10 cases of infiltrative basal cell carcinoma, and 10 cases of metastatic basal cell carcinoma with immunohistochemistry for alpha-smooth muscle actin, calponin, myosin, and E-cadherin. Expression was interpreted as positive when at least 5% of the tumor exhibited at least weak expression. Five of the ten patients with metastatic basal cell carcinoma had an antecedent history of radiotherapy. Actin was present in 3 of 12 (25%) of the nodular, all 10 of the infiltrative, and 3 of 10 of the metastatic basal cell carcinomas (P

Non-compaction of the ventricular myocardium is an anomaly of myocardial morphogenesis that leads to persistence of the embryonic myocardium with an excessively prominent trabecular meshwork and deep intertrabecular recesses. This report describes 3 cases of isolated left ventricular non-compaction in adults leading to terminal heart failure. We describe their distinctive myocardial histopathology and prospective diagnosis by cardiac magnetic resonance imaging (CMR). Heart transplantation was the only treatment option for all 3 of these severely ill patients. Isolated ventricular non-compaction should be considered in patients with severe idiopathic cardiomyopathy whose symptoms appear in early adulthood, and consideration given for early transplantation. Non-invasive imaging with CMR can confirm the diagnosis.