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Background Although trichorhinophalangeal syndrome type 1 (TRPS1) was initially thought to be highly sensitive and specific for carcinomas and mesenchymal tumors of mammary origin, more recent data suggest its expression is not limited to breast neoplasms but also can be seen in other cutaneous neoplasms, such as extramammary Paget disease and squamous cell carcinoma (SCC) in situ. Methods Two-hundred cases of non-melanocytic cutaneous neoplasm, including basal cell carcinomas (BCCs) (n = 41), SCCs (n = 35), Merkel cell carcinomas (MCCs) (n = 25), and adnexal neoplasms (n = 99), were tested for TRPS1 expression using a monoclonal anti- TRPS1 rabbit anti-human antibody. Results TRPS1 expression was present in almost all cases of SCC (94%), with a median H-score of 200, while it was either absent or only focally present in most BCCs (90%), with a median H-score of 5. The difference between BCCs and SCCs in H-score was significant (p < .001). All MCCs (100%) lacked TRPS1 expression. TRPS1 expression was frequently seen in most adnexal neoplasms, benign and malignant, in variable intensity and proportion but was consistently absent in apocrine carcinomas. All endocrine mucin-producing sweat gland carcinomas (EMPSGCs) (100%, 6/6) showed diffuse and strong TRPS1 immunoreactivity, with a median H-score of 300, which was significantly different (p < .001) than that of BCCs. Conclusions Our study shows that TRPS1 may be an effective discriminatory marker for BCCs and SCCs. It also has a role in distinguishing BCCs from EMPSGCs.

Dermatofibrosarcoma protuberans (DFSP) is a dermal malignant mesenchymal tumor. Most variants are associated with a high risk of local recurrence and a low risk of metastasis. The classic histomorphology of this tumor is made up of uniform, spindle-shaped cells, arranged in a storiform pattern. Tumor cells characteristically infiltrate the underlying subcutis in a honeycomb pattern. Less common variants of DFSP have been identified: myxoid, pigmented, myoid, granular cell, sclerosing, atrophic, and fibrosarcomatous. Only the fibrosarcomatous variant has been shown to differ significantly from classic DFSP in terms of clinical outcome; fibrosarcomatous DFSP has been shown to be associated with a greater risk of local recurrence and metastatic potential than classic DFSP. However, the other variants may pose diagnostic difficulty as they resemble other types of spindle cell neoplasms, especially in small biopsy specimens. This article reviews the clinical, histologic, and molecular features of DFSP variants, as well as possible pitfalls in their diagnosis and how to resolve them.

Through humoral and cell-mediated mechanisms, the immune system plays a vital role in protecting every organ system. Disorders of the immune system may result in various cutaneous manifestations, including cutaneous malignancies. In patients with immunodeficiency, the risk of development of malignant cutaneous neoplasms is substantially increased. This increased risk may be due to oncogenic viruses that find a suitable microenvironment for tumorigenesis and cancer development. A subset of cutaneous malignancies that develop in patients with immunodeficiency may show aggressive clinical and biological behavior. Here, we report six cases of highly aggressive and deadly cutaneous neoplasms that arose in patients with a known history of immunodeficiency: two cases of Kaposi sarcoma in patients with immunosuppression due to human immunodeficiency virus infection; a case of Merkel cell carcinoma and a case of squamous cell carcinoma (SCC) in patients receiving immunosuppressive drugs after organ transplant; a case of multiple cutaneous tumors, including invasive melanoma, SCC, and sebaceous carcinoma, in a patient with hypogammaglobulinemia and a history of organ transplant; and a case of basal cell carcinoma and melanoma in situ in a patient with primary immunodeficiency.

The SARS-CoV-2 pandemic has highlighted the crucial role of pathologists in the health care system at a time of significant decline in the number of US medical students matching to pathology residency positions. To understand this decline, a national survey of fourth-year US allopathic medical students was conducted to assess experiences, knowledge, and attitudes of pathology and factors that impact specialty choice. Participating in a separate pathology course did not increase the probability of choosing pathology. Experiences significantly associated with choosing pathology included clinical or research opportunities in pathology during the last 2 years of medical school, autopsy observation/participation, and participation in pathology interest groups. Many respondents felt they were not sufficiently exposed to pathology to consider it as a specialty. Those who considered pathology but did not choose it were less likely to report understanding the activities of pathologists and being recruited by pathology faculty and more likely to express a preference for more direct patient contact as compared to those entering pathology. In general, respondents agreed that pathology has a good work–life balance and a satisfying degree of intellectual challenge. On the other hand, respondents generally agreed that information on social media and perception of the pathology job market do not seem to be positive and few agreed that pathology is a highly regarded specialty. We identify steps to address these issues and increase the number of US medical students choosing pathology as a specialty crucial to the future of medicine and public health.

The use of social media at academic conferences is expanding, and platforms such as Twitter are used to share meeting content with the world. Pathology conferences are no exception, and recently, pathology organizations have promoted social media as a way to enhance meeting exposure. A social media committee was formed ad hoc to implement strategies to enhance social media involvement and coverage at the 2018 and 2019 annual meetings of the Association of Pathology Chairs. This organized approach resulted in an 11-fold increase in social media engagement compared to the year prior to committee formation (2017). In this article, the social media committee reviews the strategies that were employed and the resultant outcome data. In addition, we categorize tweets by topic to identify the topics of greatest interest to meeting participants, and we discuss the differences between Twitter and other social media platforms. Lastly, we review the existing literature on this topic from 23 medical specialties and health care fields.

The pathologist workforce in the United States is a topic of interest to the health-care community as a whole and to institutions responsible for the training of new pathologists in particular. Although a pathologist shortage has been projected, there has been a pervasive belief by medical students and their advisors that there are “no jobs in pathology.” In 2013 and again in 2017, the Program Directors Section of the Association of Pathology Chairs conducted surveys asking pathology residency directors to report the employment status of each of their residents graduating in the previous 5 years. The 2013 Program Directors Section survey indicated that 92% of those graduating in 2010 had obtained employment within 3 years, and 94% of residents graduating in 2008 obtained employment within 5 years. The 2017 survey indicated that 96% of those graduating in 2014 had obtained employment in 3 years, and 97% of residents graduating in 2012 obtained positions within 5 years. These findings are consistent with residents doing 1 or 2 years of fellowship before obtaining employment. Stratification of the data by regions of the country or by the size of the residency programs does not show large differences. The data also indicate a high percentage of employment for graduates of pathology residency programs and a stable job market over the years covered by the surveys.

Abstract The prognostic significance of the width of the ulceration in primary melanomas remains unclear, and there is a relative paucity of data for lymphovascular invasion (LVI), microscopic satellitosis (MS), perineural invasion (PNI), and mitotic rate when compared with other pathological elements currently required for reporting. To evaluate the prognostic importance of the ulceration width and other important pathologic measurements, a single‐institutional retrospective study was conducted using records of cutaneous melanoma patients who underwent sentinel lymph node (SLN) biopsy at The University of Texas, MD Anderson Cancer Center between 2003 and 2008. We identified 1898 eligible patients with median tumor thickness of 1.25 mm and median follow‐up of 6.7 years. By multivariable analyses, the strongest risk factor for SLN positivity was high tumor thickness followed by the presence of LVI. The pathologic measures with the strongest influence on recurrence‐free survival (RFS) were tumor thickness and positive SLN status. Ulceration width and presence of MS were also significantly associated with RFS while PNI was not. Factors with the strongest influence on melanoma‐specific survival (MSS) were positive SLN status and mitotic rate. In conclusion, SLN biopsy should probably be offered if the primary tumor has LVI. MS is an adverse prognostic factor for RFS, but its influence on outcome is modest. Ulceration width predicts RFS but loses its independent prognostic significance for MSS when adjusting for currently used clinicopathological factors. In view of its impact on MSS, mitotic rate should be recorded for cutaneous invasive melanomas across all T categories.

Abstract Background Immune checkpoint therapy has dramatically changed the landscape of cancer therapy, providing an efficacious and durable therapeutic option for patients with advanced-stage disease. However, dermatologic toxicities are a well-recognized side effect in patients receiving this therapy. A spectrum of immune related adverse events (irAEs) involving the skin can occur and include immunobullous disorders, lichenoid dermatitis, and vitiligo. Granulomatous/sarcoid-like lesions are now being recognized with the current class of checkpoint inhibitors (CPIs) that involve the dermis, the subcutaneous tissue (panniculitis), and lymph nodes. Case presentation We report 3 patients who developed granulomatous/sarcoid-like lesions while being treated with immune checkpoint therapy for advanced-stage melanoma, and we provide a comprehensive review of the literature in which similar cases are described. To date, 26 patients (including the 3 from this report) have been described with a median age of 57 years who developed granulomatous/sarcoid-like lesions associated with CPIs (median onset 6 months), of which 77% of patients had melanoma as primary tumor. To manage this adverse side effect, therapy was withheld in 38% of patients and 44% of the patients were treated with systemic steroids and 8% patients with localized therapy (one patient with intralesional triamcinolone). 96% of patients demonstrated either resolution or improvement of granulomatous/sarcoid-like lesions associated with CPIs irrespective of medical intervention. Therapeutic response, stable disease, or remission of primary malignancy was observed in 71% of reported patients who developed granulomatous/sarcoid-like lesions associated with CPIs over a median follow-up of 11.5 months since initiation of treatment. Conclusions The development of granulomatous/sarcoid-like lesions associated with CPIs is a recognized manifestation with the current class of immune checkpoint therapy that may clinically and radiographically mimic disease recurrence. Awareness of this type of toxicity is important for appropriate management and possible measurement of therapeutic response in a subset of patients who manifest this type of immune-mediated reaction.

Cutaneous T-Cell Lymphomas (CTCL) are rare, but potentially devastating malignancies, whose pathogenesis remains poorly elucidated. Unfortunately, currently it is not possible to predict based on the available criteria in which patients the cancer will progress and which patients will experience an indolent disease course. Furthermore, at early stages this malignancy often masquerades as psoriasis, chronic eczema or other benign inflammatory dermatoses. As a result, it takes on average 6 y to diagnose this lymphoma since its initial presentation. In this study, we performed transcription expression profiling using TruSeq targeted RNA gene expression on 181 fresh and formalin-fixed and paraffin-embedded (FFPE) skin samples from CTCL patients and patients affected by benign inflammatory dermatoses that often mimic CTCL clinically and on histology (e.g., psoriasis, chronic eczema, etc.) We also analyzed multiple longitudinal biopsies that were obtained from the same patients over time. Our results underscore significant molecular heterogeneity with respect to gene expression between different patients and even within the same patients over time. Our study also confirmed TOX, FYB, LEF1, CCR4, ITK, EED, POU2AF, IL26, STAT5, BLK, GTSF1 and PSORS1C2 genes as being differentially expressed between CTCL and benign skin biopsies. In addition, we found that differential expression for a subset of these markers (e.g., TOX, FYB, GTSF1 and CCR4) may be useful in prognosticating this disease. This research, combined with other molecular analyses, prepares the foundation for the development of personalized molecular approach toward diagnosis and management of CTCL.

We demonstrate that SCF-KIT signaling induces synthesis and secretion of endothelin-3 (ET3) in human umbilical vein endothelial cells and melanoma cells in vitro, gastrointestinal stromal tumors, human sun-exposed skin, and myenteric plexus of human colon post-fasting in vivo. This is the first report of a physiological mechanism of ET3 induction. Integrating our finding with supporting data from literature leads us to discover a previously unreported pathway of nitric oxide (NO) generation derived from physiological endothelial NO synthase (eNOS) or neuronal NOS (nNOS) activation (referred to as the KIT-ET3-NO pathway). It involves: (1) SCF-expressing cells communicate with neighboring KIT-expressing cells directly or indirectly (cleaved soluble SCF). (2) SCF-KIT signaling induces timely local ET3 synthesis and secretion. (3) ET3 binds to ETBR on both sides of intercellular space. (4) ET3-binding-initiated-ETBR activation increases cytosolic Ca2+, activates cell-specific eNOS or nNOS. (5) Temporally- and spatially-precise NO generation. NO diffuses into neighboring cells, thus acts in both SCF- and KIT-expressing cells. (6) NO modulates diverse cell-specific functions by NO/cGMP pathway, controlling transcriptional factors, or other mechanisms. We demonstrate the critical physiological role of the KIT-ET3-NO pathway in fulfilling high demand (exceeding basal level) of endothelium-dependent NO generation for coping with atherosclerosis, pregnancy, and aging. The KIT-ET3-NO pathway most likely also play critical roles in other cell functions that involve dual requirement of SCF-KIT signaling and NO. New strategies (e.g. enhancing the KIT-ET3-NO pathway) to harness the benefit of endogenous eNOS and nNOS activation and precise NO generation for correcting pathophysiology and restoring functions warrant investigation.

We report a case of cutaneous Stenotrophomonas maltophilia infection which presented with clinical and histopathological findings that mimicked a gamma/delta (γδ) T-cell lymphoma. In this case, tissue culture of the biopsy specimen was key to determining the diagnosis and allowing appropriate treatment with oral trimethoprim–sulfamethoxazole and topical silvadene. A prompt complete resolution of lesions was observed following antibiotic treatment, with no recurrence of disease over the last 5 years, supporting an infectious rather than malignant etiology. In our patient, radiation therapy was indicated based on the misdiagnosis of γδ T-cell lymphoma, which was supported both clinically and histopathologically. However, tissue culture in this case avoided unnecessary radiation exposure and highlights the role of tissue culture in the evaluation of the biopsy of an undiagnosed cutaneous lesion.

We describe a 40-year-old man who was found to have a cystic mass in the pancreatic tail during workup for weight loss and abdominal discomfort. Although computed tomography scan showed a single cyst associated with dilatation of the main pancreatic duct, gross and histologic examination of the distal pancreatectomy specimen actually revealed a central cyst that was surrounded by multiple smaller cystic spaces. This distinctive appearance was formed from extensive cystic dilatation and squamous metaplasia of the native pancreatic duct system. Further, a traumatic neuroma was discovered near the junction between normal and abnormal parenchyma. We believe that this case represents a variant of the newly-described squamoid cyst of panreatic ducts which we term squamoid cystosis of pancreatic ducts. The presence of chronic pancreatitis and a traumatic neuroma supports the hypothesis that squamoid cysts are non-neoplastic lesions arising from prior duct obstruction.

Vemurafenib and dabrafenib selectively inhibit the v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) kinase, resulting in high response rates and increased survival in melanoma. Approximately 22% of individuals treated with vemurafenib develop cutaneous squamous cell carcinoma (cSCC) during therapy. The prevailing explanation for this is drug-induced paradoxical ERK activation, resulting in hyperproliferation. Here we show an unexpected and novel effect of vemurafenib/PLX4720 in suppressing apoptosis through the inhibition of multiple off-target kinases upstream of c-Jun N-terminal kinase (JNK), principally ZAK. JNK signaling is suppressed in multiple contexts, including in cSCC of vemurafenib-treated patients, as well as in mice. Expression of a mutant ZAK that cannot be inhibited reverses the suppression of JNK activation and apoptosis. Our results implicate suppression of JNK-dependent apoptosis as a significant, independent mechanism that cooperates with paradoxical ERK activation to induce cSCC, suggesting broad implications for understanding toxicities associated with BRAF inhibitors and for their use in combination therapies.

The current study characterizes the mitosis-associated histone dual modification on the core of histone H3: trimethylation of histone H3 lysine 79 and simultaneous phosphorylation of H3 threonine 80 (H3K79me3T80ph). Through the use of protein and microscopy-based techniques, we find that H3K79me3T80ph shares a similar spatial and temporal regulation as H3S10ph but additionally requires methyltransferase activity. In addition, we find that Aurora kinase activity is necessary for the catalysis of H3K79me3T80ph in vivo. Finally, our analysis of H3K79me3T80ph using a tissue microarray indicates that H3K79me3T80ph marks a subset of primary cutaneous melanomas with metastatic potential indicating that H3K79me3T80ph may identify a subset of invasive melanomas with a more aggressive clinical behaviour.

Clusterin expression is common in systemic and cutaneous anaplastic large cell lymphoma (ALCL). Mycosis fungoides (MF) in large cell transformation can resemble ALCL. In this study, we immunohistochemically assessed for clusterin in 97 skin biopsy specimens, including 70 MF cases and 27 other cutaneous neoplasms including ALCL, peripheral T-cell lymphoma unspecified (PTCL), and lymphomatoid papulosis (LyP). Clusterin was positive in 36 (51%) of 70 cases of MF and correlated with clinical stage in 68 cases: 3 of 21 stage I, 11 of 20 stage II, and 23 of 27 stage III/IV. Clusterin expression also correlated with type of skin lesion (3/19 patch, 13/28 plaque, and 20/23 tumor/erythroderma) and number of large cells (6/30 small cell, 12/18 with increased large cells, and 18/22 with large cell transformation). Clusterin expression was not specific for MF as it also was positive in 3 of 3 cases of LyP, 2 of 2 systemic ALCL cases involving skin, 7 of 16 cutaneous ALCLs, and 1 of 6 PTCLs. [ABSTRACT FROM AUTHOR]