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Abstract: Cutaneous sebaceous neoplasia comprises a spectrum of disease ranging from benign adenomas to malignant carcinomas. The hallmark of these lesions is sebaceous differentiation. However, poorly-differentiated sebaceous carcinoma (SC), which lacks significant overt sebaceous differentiation, can show morphologic overlap with a variety of other basaloid cutaneous neoplasms. The accurate classification of SC is essential not only for diagnosis, but also because of the potential association with Muir-Torre syndrome. Androgen receptor (AR) is a sensitive, but not entirely specific immunohistochemical marker that has been used for the diagnosis of SC. PReferentially expressed Antigen in MElanoma (PRAME) demonstrates strong cytoplasmic labeling of mature sebocytes and has been reported to be expressed in a variety of sebaceous neoplasms, including in the basaloid cell component. Therefore, we sought to compare the diagnostic use of cytoplasmic PRAME expression with that of AR for the distinction of SC from a cohort of basaloid cutaneous mimics; namely basal cell carcinoma, basaloid squamous cell carcinoma, pilomatricoma, cutaneous lymphadenoma, and extra-mammary Paget disease. We report that cytoplasmic PRAME expression is uncommon in poorly differentiated SC, and although specific, it shows very low sensitivity (22%). In contrast, AR was moderately sensitive (66%) and highly specific (92%) for the distinction of SC from basaloid mimics. These attributes, in addition to the nuclear expression of AR in the sebocytic and basaloid components of SC, suggest that AR is superior to PRAME for the diagnosis of SC., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) is a cutaneous drug eruption with a characteristic distribution of erythema on the gluteal/inguinal region and intertriginous areas with unclear pathogenesis. In this study, we aimed to characterize the T-helper immune phenotype in SDRIFE in comparison with psoriasis and eczema to further the understanding of the pathophysiology and immune response of this rare disorder. Immunohistochemical staining was performed on 9 skin biopsies each from SDRIFE, psoriasis, and eczema using immunohistochemistry for CD3 and dual CD4/T-bet, CD4/GATA3, and CD4/RORC to quantify the percentage of Th1, Th2, and Th17 cells, respectively. A significant difference was detected in the average percentage of Th1 between all 3 groups with the highest percentage of Th1 cells seen in psoriasis, followed by SDRIFE and eczema. SDRIFE showed significantly lower Th2 expression as compared to both psoriasis and eczema. There was a trend towards a higher average percentage of Th17 in psoriasis and SDRIFE, and the ratio of Th17:Th2 was significantly higher in samples of SDRIFE compared with both eczema and psoriasis. The findings characterize SDRIFE as a Th1 and possibly Th17-driven process, which could inform future therapeutic options and substantiate the model of SDRIFE as a delayed-type hypersensitivity reaction., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Classic Hodgkin lymphoma (CHL) is a B-cell-derived lymphoma that classically displays a bimodal age distribution. CHL typically involves the mediastinum, lymph nodes, and other visceral organs. CHL is characterized histologically by the presence of a relatively paucicellular neoplastic cell population composed of large atypical cells (including Hodgkin and Reed-Sternberg forms) in a reactive mixed inflammatory background, often with prominent necrosis. CHL rarely occurs in the skin, and the associated mixed inflammatory infiltrate or necrotic appearance can create diagnostic uncertainty. Herein, we report the case of a 31-year-old man presenting with a painful dendritic rash of the anterior chest wall with axillary lymphadenopathy. After multiple nondiagnostic biopsies that revealed largely necrotic material, a chest wall skin biopsy was obtained. The skin biopsy was diagnostic of CHL, based on the presence of large atypical dermal cells, including Hodgkin and Reed-Sternberg forms, which expressed CD15, CD30 and Fascin, in a typical mixed inflammatory and necrotic background. Through the lens of this case, we discuss the characteristics and mechanisms of skin involvement of CHL, and the histopathologic and immunohistochemical pitfalls when considering the rare diagnosis of CHL in the skin., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Epithelioid fibrous histiocytoma (EFH) is a distinctive benign cutaneous neoplasm composed of uniform epithelioid cells, often with binucleated cells. EFH are characterized by the presence of anaplastic lymphoma kinase ( ALK ) gene rearrangements with a variety of binding partners. These rearrangements result in the overexpression of ALK , which can be detected using immunohistochemistry. Cytoplasmic ALK expression is by far the most common pattern encountered. Here, we describe a case of EFH with a distinctive intranuclear dot-like ALK expression pattern. Subsequent next-generation DNA sequencing revealed a novel SP100::ALK gene fusion. Speckled protein-100 (SP100) is a constituent of nuclear dots, also known as promyelocytic leukemia bodies, which are still poorly understood membraneless subnuclear structures. Thus, this novel ALK fusion partner seems to explain this distinctive pattern of ALK localization. We examined ALK expression patterns in 11 other cases of EFH, but all showed typical cytoplasmic localization. This study expands the morphologic and molecular spectrum of EFH, provides a dramatic illustration of the ability of fusion partners to control protein localization, and implies that tumorigenic ALK signaling may occur at a variety of subcellular locations., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Proliferating pilar tumors (PPTs) are rare neoplasms of external root sheath derivation, which most commonly occur on the scalp of elderly women. Although typically showing classic histologic features such as trichilemmal type keratinization, a lobular architecture and peripheral palisading, squamous cell carcinoma (SCC) remains a common diagnostic pitfall. Therefore, we sought to explore the molecular pathogenesis of PPTs and compare it with that of cutaneous squamous cell carcinoma (cSCC). Herein, we describe the use of a next-generation DNA sequencing platform to provide the most comprehensive molecular genetic analysis to date of a cohort of 5 PPTs and compare them to 5 head and neck cutaneous SCCs. Recurrent broad arm-level gains of 15q and concurrent single-copy losses of 6q and 6p22.2 were observed in 4 of 5 (80%) PPT cases. Other recurrent mutations or alterations of significance were not found in PPTs. Notably, these chromosomal changes were not identified in any of the 5 cutaneous SCCs, which instead showed recurrent alterations in the known SCC driver genes TP53 , CDKN2A , and NOTCH1 . Here, we show for the first time that PPTs are molecularly distinct from cutaneous SCC and provide evidence that recurrent alterations in chromosome 15 and chromosome 6 are central to the pathogenesis of PPTs., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Hidradenoma is a benign cutaneous adnexal neoplasm that occurs across a wide age range and at a variety of anatomic sites. Its most characteristic morphologic feature is the presence of diverse cell types including squamoid, clear, plasmacytoid, and mucinous cells. Hidradenoma is morphologically and molecularly similar to mucoepidermoid carcinoma, and both tumors are characterized by recurrent CRTC1-MAML2 cytogenetic translocations. Previous studies have suggested that approximately half of hidradenomas possess this translocation. This finding raised the question of whether translocation-negative hidradenomas might have an alternate molecular basis. Here, we sought to reevaluate the frequency of MAML2 translocation in hidradenoma in a series of 20 cases. We find that 90% show evidence of MAML2 translocation, suggesting that this genetic event is a nearly invariant feature of hidradenoma. These results inform our molecular understanding of this tumor and may be useful in challenging cases to distinguish hidradenoma from its histologic mimics., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Trichilemmoma is a benign cutaneous neoplasm that recapitulates the outer root sheath of the hair follicle. Trichilemmomas may occur sporadically or in association with Cowden syndrome, which is characterized by germline mutations in the lipid phosphatase PTEN (phosphatase and tensin homolog on chromosome 10). Interestingly, most sporadic trichilemmomas do not show PTEN aberrations, but rather activating mutations in HRAS. Despite these important advances, a comprehensive genetic analysis of trichilemmoma has not been reported. Here, we used a next-generation DNA sequencing platform to study 9 sporadic trichilemmoma cases. Seven cases (7/9; 78%) harbored activating mutations in HRAS, consistent with previous findings. Unexpectedly, we identified recurrent mutations in the tyrosine phosphatase PTPN14 (protein tyrosine phosphatase nonreceptor type 14) in 4 cases (4/9; 44%). Three of these cases also harbored HRAS mutations, whereas one case occurred in the absence of a HRAS mutation and showed evidence of biallelic inactivation of PTPN14. Finally, one case (1/9; 11%) showed biallelic inactivation of PTEN in the absence of a HRAS (or PTPN14) mutation. These data suggest at least 3 distinct pathways of molecular pathogenesis in sporadic trichilemmoma and identify PTPN14 as a potentially important contributor to trichilemmoma biology., Competing Interests: J. Hanna has disclosed that he is a recipient of research funding from the Bertarelli Rare Cancers Fund. Lippincott CME Institute has identified and resolved all conflicts of interest concerning this educational activity., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Endocrine mucin-producing sweat gland carcinoma (EMPSGC) is a rare low-grade adnexal malignancy with a predilection for the eyelids of elderly White women, which is associated with invasive mucinous carcinoma with endocrine features in one-third of cases. EMPSGC is characterized by the presence of neuroendocrine differentiation and mucin production. However, EMPSGC displays a variety of architectural patterns including solid, cribriform, papillary, and cystic growth. In addition, EMPSGC may also display nonendocrine cytologic features, such as apocrine change. Because of their variable appearance, EMPSGC can show significant morphologic overlap with certain histologic mimics, namely basal cell carcinoma, hidrocystoma, apocrine hidradenoma, and tubular adenoma. In addition, the often limited sampling of this anatomically delicate area can make the diagnosis of EMPSGC challenging. EMPSGC expresses neuroendocrine markers, including synaptophysin and chromogranin, often in a focal distribution. However, insulinoma-associated protein 1 (INSM1) has been found to be a more sensitive marker for EMPSGC. Recent studies have also demonstrated the expression of the gel-forming mucin 2 (MUC2) in EMPSGC, possibly signifying a lacrimal or conjunctival origin of these neoplasms. In this article, we discuss EMPSGC in the context of its histologic mimics (BCC, hidrocystoma, apocrine hidradenoma, and tubular adenoma) and we investigate the utility of the immunohistochemical expression of INSM1 and MUC2 in the distinction of EMPSGC from them. We demonstrate that INSM1 and MUC2 can reliably distinguish EMPSGC from these histologic mimics., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Objectives: Cardiovascular diseases, such as coronary heart disease (CHD), are the main cause of mortality and morbidity worldwide. Although CHD cannot be entirely predicted by classic risk factors, it is preventable. Therefore, predicting CHD risk is crucial to clinical cardiology research, and the development of innovative methods for predicting CHD risk is of great practical interest. The Framingham risk score (FRS) is one of the most frequently implemented risk models. However, recent advances in the field of analytics may enhance the prediction of CHD risk beyond the FRS. Here, we propose a model based on an artificial neural network (ANN) for predicting CHD risk with respect to the Framingham Heart Study (FHS) dataset. The performance of this model was compared to that of the FRS., Methods: A sample of 3066 subjects from the FHS offspring cohort was subjected to an ANN. A multilayer perceptron ANN architecture was used and the lift, gains, receiver operating characteristic (ROC), and precision-recall predicted by the ANN were compared with those of the FRS., Results: The lift and gain curves of the ANN model outperformed those of the FRS model in terms of top percentiles. The ROC curve showed that, for higher risk scores, the ANN model had higher sensitivity and higher specificity than those of the FRS model, although its area under the curve (AUC) was lower. For the precision-recall measures, the ANN generated significantly better results than the FRS with a higher AUC., Conclusions: The findings suggest that the ANN model is a promising approach for predicting CHD risk and a good screening procedure to identify high-risk subjects., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: The infundibulocystic variant of basal cell carcinoma (BCC) is characterized histologically by anastamosing strands of basaloid epithelium with associated small infundibular-type cysts. Since its first description in 1987, this rare entity has generated considerable controversy with some authors classifying it as a benign follicular neoplasm rather than a BCC subtype. Prior studies aiming to settle this issue using immunohistochemical analysis reached opposite conclusions. The defining feature of BCC is activation of the Hedgehog signaling pathway, and mutations in Patched-1 (PTCH1) are the most common molecular finding in both sporadic and inherited forms of BCC. Mutations in other downstream components including Smoothened (SMO) and Suppressor of Fused (SUFU) also occur, but are much less common. Here, we report a molecular genetic analysis of a small series of infundibulocystic BCC using a next-generation DNA sequencing platform. All 4 cases harbored mutations or other genetic alterations in components of the Hedgehog pathway, supporting the classification of this entity as a BCC variant. Interestingly, these tumors were enriched for genetic alterations downstream of PTCH1, involving SUFU, SMO, GLI1, and GLI2. This observation was of particular interest given that rare kindreds of the Multiple Hereditary Infundibulocystic BCC syndrome (MHIBCC), which is related, but possibly distinct from the nevoid BCC syndrome, harbored mutations in SUFU. Our results support the classification of the infundibulocystic variant as a subtype of BCC, and suggest that the level at which genetic alterations occur within the Hedgehog pathway may be an important determinant of the morphologic features in BCC., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Fibroepithelioma of Pinkus (FEP) is a rare cutaneous neoplasm with a characteristic fenestrated architecture and a prominent spindle cell stromal component and which invariably pursues an indolent course. The classification of FEP has been much debated since its first description in 1953, with some arguing that it represents a variant of a basal cell carcinoma (BCC) while others view it as a variant of a trichoblastoma. Multiple previous immunohistochemical studies aiming to clarify this issue have yielded conflicting results. To date, there have been no molecular studies of FEP. We identified 16 cases of fenestrated follicular neoplasms and classified them as BCC or FEP based solely on histomorphologic criteria. CK20 immunohistochemistry supported this classification scheme, with FEP showing significantly more CK20-positive Merkel cells than BCC. We then analyzed a subset of these tumors by a targeted next-generation DNA sequencing platform. All the BCC cases harbored pathogenic PTCH1 mutations, confirming the diagnosis. By contrast, none of the FEP cases harbored a PTCH1 mutation or indeed any mutation known to be causally linked to the development of BCC. Our results suggest that FEP can be distinguished from BCC on morphologic, immunohistochemical, and molecular genetic grounds. We argue that FEP is better considered a benign follicular neoplasm and support its classification as a variant of trichoblastoma.

Cutaneous mixed tumors, also known as chondroid syringomas, are benign adnexal neoplasms that share histomorphologic features with pleomorphic adenomas of the salivary gland. Recent work suggests that the similarity between these 2 tumor types extends to the molecular level because both harbor identical chromosomal rearrangements involving the PLAG1 gene. The resulting nuclear PLAG1 overexpression can be detected by immunohistochemistry and has become a useful diagnostic adjunct for both tumor types. In the skin, however, there are 2 morphologically distinct types of mixed tumor, which have been referred to as apocrine-type cutaneous mixed tumor (AMT) and eccrine-type cutaneous mixed tumor (EMT). Previous studies of PLAG1 expression in cutaneous mixed tumor did not distinguish between these types. Here, we evaluated PLAG1 expression by immunohistochemistry in a cohort of 25 cutaneous mixed tumors stratified by type. PLAG1 was overexpressed in the majority of AMT cases (14 of 16) but in none of the EMT cases (0 of 9). A second gene, HMGA2, known to be upregulated in a subset of salivary gland pleomorphic adenomas, was overexpressed in only 1 case of AMT (1 of 16) and in none of the cases of EMT (0 of 9). Our results indicate that apocrine- and eccrine-type mixed tumors are associated with different pathways of molecular pathogenesis and suggest that the emerging relationship between skin and salivary gland mixed tumors is likely limited to those of apocrine type.

Background: It has been shown that progressive neuromuscular blockade (NMB) affects the electromyogram power spectrum and compound muscle action potential duration in skeletal muscle. These measures are linked to the mean muscle action potential conduction velocity (APCV), but no studies have confirmed a relation between the mean APCV and NMB. The aim of this study was to determine whether diaphragm mean APCV is affected by NMB., Methods: The effects of NMB on diaphragm mean APCV were evaluated in five mongrel dogs. Progressive NMB was induced by slow intravenous infusion of atracurium. During spontaneous breathing, the diaphragm mean APCV was determined by electromyogram signals, in the time and frequency domains. The magnitude of NMB was quantified by the amplitude of the compound muscle action potential and by changes in muscle shortening during supramaximal stimulation of the phrenic nerve., Results: Progressive NMB was associated with a decrease in diaphragm mean APCV. At approximately 70% reduction in the compound muscle action potential amplitude, diaphragm mean APCV had decreased more than 20%. Recovery after NMB was characterized by a restoration of the mean APCV to control values., Conclusion: This study shows that progressive NMB paralyzes motor units within the diaphragm in an orderly manner, and the blockade first affects muscle fibers with high APCV before it affects fibers with lower APCV.

Since the two muscles (costal and crural) that constitute the diaphragm are separate and histologically different, their individual recovery pattern from neuromuscular blockade also may be different. Therefore, we studied the recovery of force and shortening in the in vivo diaphragm from atracurium-induced neuromuscular blockade in seven pentobarbital anesthetized dogs to assess segmental differences. Transdiaphragmatic pressure (Pdi), shortening of costal and crural segments, integrated electromyogram (EMG), and tidal volume (VT) were measured during spontaneous breathing. After atracurium had reduced VT to 30% of control, breathing parameters were followed until recovered to 90% of control values. In addition, force-frequency curves generated by supramaximal tetanic stimuli of the phrenic nerve were measured. Recovery times for tidal Pdi, tidal EMG, tidal shortening, low-frequency shortening, and twitch Pdi were twice as fast as for VT (40 +/- 4 min), reflecting a slower rate of recovery of accessory inspiratory muscles. High-frequency recovery was typically slower than that of VT. During tidal breathing and tetanic stimulation, costal and crural shortening recovered simultaneously. On the other hand, comparison between costal and crural by analysis of pressure-shortening relationships showed a segmental difference (crural shortened 30% more than costal at the same Pdi), which implied reduced afterload on the crural segment. However, since shortening and pressure were linearly related during paralysis and recovery, measurements of Pdi alone can accurately reflect changes in contractile mass when heterogeneity and afterload are controlled.

Another study documented that percutaneous transtracheal ventilation with a special 3.5-mm I.D. cannula was possible in experimental complete upper airway obstruction (CAO) using Ambu-assisted ventilation. The effects of ventilation during CAO by occlusion of the endotracheal tube was evaluated by use of a portable oscillatory pressure device (POPD) attached to a 10-g (I.D. 2.4 mm) angiocath catheter inserted through the tracheal wall. Eight pigs were anesthetized and ventilated with the POPD for 15 minutes after CAO with a mean peak airway pressure of 14 cm H2O and continuous positive airway pressure of 5-7 cm H2O, tidal volume below 100 ml, and a rate below 0.5 Hz. A Venturi delivered an FIO2 of 0.68-0.92. All eight showed markedly stable blood gases and cardiovascular parameters (heart rate and systemic and pulmonary arterial pressures). A similar trend was obtained in a separate group of four pigs ventilated with an Ambu bag for 30 minutes; however, the PO2 was lower. In the control group, asphyxia after CAO produced cardiorespiratory failure in every animal in less than 6 minutes. Low-frequency ventilation with a POPD for CAO ensures adequate gas exchange using a standard transtracheal catheter of only 2.4 mm I.D.

The results of a study on the epidemiology of airborne (aerobic) surgical infections are presented. The first phase of the study was carried out in a surgical suite which contained no environmental or traffic control systems. The second phase of the study took place within a modern "up to date" operating room suite containing multiple air screens as well as an elaborate ventilation system utilizing HEPA type filters which provided the operating room with clinically sterile air. One hundred and fifty-six patients were also studied. All patients underwent major procedures. The ratio of clean, clean-contaminated, and dirty cases was the same in both groups. Preoperatively, a nasal swab, clean voided urine (or vaginal swab) and a rectal swab were obtained on each patient. Daily nasal cultures and cultures of suspected sites of infection were obtained postoperatively. Daily nasal cultures and "glove sweat" cultures were obtained on all personnel attending the patient. Environmental cultures of the operating room, the operating room hallway, recovery room and patients' rooms were also taken. All samples were checked for the presence of staphylococci, streptococci, Escherichia coli, proteus species, enterobacter, klebsiella, and pseudomonas. In all, 15,000 cultures were taken during the study. The rate of infection was essentially the same in both phases of the study. Environmental air only occasionaly served as the source of infecting organisms. The results of the study support the conclusion that the most common source of infecting organisms in surgical infections is thepatient or those around him. The most common time of contamination is during the surgical procedure itself. Surgical infections can best be minimized by meticulous observation of fundamental principles of antisepsis rather than by dependence on elaborate and costly ventilation and air control systems.