Clinical and Histopathologic Spectrum of Toxic Erythema of Chemotherapy: A Series of 56 Cases From a Single Institution.

INTRODUCTION: Although many individual cases and small series of toxic erythema of chemotherapy (TEC) have been described, the full spectrum of findings is not well understood. OBJECTIVE: To provide a comprehensive review of the clinical and histopathologic features of TEC with an emphasis on novel histopathologic findings. METHODS: We searched our electronic medical record for "toxic erythema of chemotherapy" or "neutrophilic eccrine hidradenitis." Fifty-six cases meeting clinical and histopathologic criteria were identified. The electronic medical record and accompanying hematoxylin and eosin-stained slides were retrospectively reviewed. RESULTS: The clinical findings were heterogeneous but included classic presentations such as intertriginous eruptions (34%) and acral erythema (25%). The most common histopathologic features were apoptotic keratinocytes (95%), basal vacuolar change (91%), and epithelial dysmaturation (79%). Eccrine squamous syringometaplasia was seen in over half of the cases (33/56; 59%), whereas neutrophilic eccrine hidradenitis was uncommon (16%). Interestingly, many cases showed prominent interstitial histiocytes (55%). Other novel findings included irregular orthohyperkeratosis (23%), irregular epidermal hyperplasia (14%), and acantholysis (9%). LIMITATIONS: As a retrospective study, it is subject to information bias. CONCLUSION: This is the largest reported series of TEC. In addition to confirming previously reported features, we identify novel histopathologic findings to add to the spectrum of TEC.

Utility of GLI1 RNA Chromogenic in Situ Hybridization in Distinguishing Basal Cell Carcinoma From Histopathologic Mimics.

Basal cell carcinoma (BCC) is the most common human malignancy and is a leading cause of nonmelanoma skin cancer-related morbidity. BCC has several histologic mimics which may have treatment and prognostic implications. Furthermore, BCC may show alternative differentiation toward a variety of cutaneous structures. The vast majority of BCCs harbor mutations in the hedgehog signaling pathway, resulting in increased expression of the GLI family of transcription factors. GLI1 immunohistochemistry has been shown to discriminate between several tumor types but demonstrates high background signal and lack of specificity. In this study, we evaluated the utility of GLI1 RNA chromogenic in situ hybridization (CISH) as a novel method of distinguishing between BCC and other epithelial neoplasms. Expression of GLI1 by RNA CISH was retrospectively evaluated in a total of 220 cases, including 60 BCCs, 37 squamous cell carcinomas (SCCs) including conventional, basaloid, and human papillomavirus infection (HPV)-associated tumors, 16 sebaceous neoplasms, 10 Merkel cell carcinomas, 58 benign follicular tumors, and 39 ductal tumors. The threshold for positivity was determined to be greater than or equal to 3 GLI1 signals in at least 50% of tumor cells. Positive GLI1 expression was identified in 57/60 BCCs, including metastatic BCC, collision lesions with SCC, and BCCs with squamous, ductal, or clear cell differentiation or with other unusual features compared to 1/37 SCCs, 0/11 sebaceous carcinomas, 0/5 sebaceomas, 1/10 Merkel cell carcinomas, 0/39 ductal tumors, and 28/58 follicular tumors. With careful evaluation, GLI1 RNA CISH is highly sensitive (95%) and specific (98%) in distinguishing between BCC and nonfollicular epithelial neoplasms. However, GLI1 CISH is not specific for distinguishing BCC from most benign follicular tumors. Overall, detection of GLI1 RNA by CISH may be a useful tool for precise classification of histologically challenging basaloid tumors, particularly in the setting of small biopsy specimens, metaplastic differentiation, or metastatic disease.

Two cases of challenging cutaneous lymphoid infiltrates presenting in the context of COVID-19 vaccination: A reactive lymphomatoid papulosis-like eruption and a bona fide lymphoma.

COVID-19 infection and vaccination may be associated with a wide variety of cutaneous and immune manifestations. Here, we describe two patients who presented with monoclonal cutaneous T-cell infiltrates that showed cytologic and immunophenotypic features concerning for lymphoma shortly following COVID-19 vaccination. In one case, the eruption completely resolved. The second patient showed initial resolution, but her disease recurred and progressed following a breakthrough SARS-CoV-2 infection. These cases suggest that immune stimulation following exposure to SARS-Cov-2 protein(s) in vaccine or infection may facilitate the development of a lymphoma or lymphoproliferative disorder in susceptible individuals. Moreover, they show that separating these cases from pseudolymphomatous reactive conditions is often challenging and requires close clinical correlation.

PRAME Expression in Challenging Dermal Melanocytic Neoplasms and Soft Tissue Tumors With Melanocytic Differentiation.

ABSTRACT: Preferentially expressed antigen in melanoma (PRAME) is an immunohistochemical biomarker that is diffusely expressed in most cutaneous melanomas and is negative in most benign nevi. Histologically challenging dermal melanocytic neoplasms, such as cellular blue nevi (CBN) and deep penetrating nevi (DPN), and soft tissue tumors with melanocytic differentiation, such as clear cell sarcoma and perivascular epithelioid cell tumor, may resemble primary or metastatic melanoma. PRAME immunohistochemistry (IHC) was applied to archived formalin-fixed, paraffin-embedded specimens of various dermal melanocytic neoplasms and soft tissue neoplasms with melanocytic differentiation. Staining was graded based on the percentage of melanocytes labeled (0-4+ as previously reported). The gold standard was final pathologic diagnosis using histologic, immunophenotypic, and in some cases molecular findings. Fifty-four cases were evaluated. 62.5% (5/8) of blue nevus-like melanomas and 50% (1/2) of DPN-like melanomas were PRAME positive (4+). Of the other tumors, 100% (20/20) of CBN (including 1 atypical CBN with borderline features); 100% (12/12) of DPN, combined DPN, or borderline DPN; 88.9% (8/9) of perivascular epithelioid cell tumors; and 100% (3/3) of clear cell sarcoma were PRAME negative (0-2+). Within the borderline categories specifically, all 8 tumors (1 borderline CBN and 7 borderline DPN) showed low (0-2+) PRAME expression. Overall, the sensitivity for melanoma in this context was 60%, with a specificity of 97.7%. Although our sample size is limited, the results suggest that IHC staining for PRAME may be useful in supporting a diagnosis of melanoma in the setting of challenging dermal melanocytic neoplasms and other epithelioid neoplasms with melanocytic differentiation. However, PRAME IHC lacks sensitivity in this context.

Cutaneous manifestations of lupus erythematosus: a practical clinicopathological review for pathologists.

Accurate diagnosis of connective tissue diseases is often challenging, and relies upon careful correlation between clinical and histopathological features, direct immunofluorescence studies and laboratory work-up. Lupus erythematosus (LE) is a prototype of connective tissue disease with a variety of cutaneous and systemic manifestations. Microscopically, cutaneous LE is classically characterised by an interface dermatitis although other histopathological patterns also exist, depending upon the clinical presentation, location and chronicity of the skin lesions. In this article, we review the clinical, serological, histopathological and direct immunofluorescence findings in LE-specific and LE non-specific skin lesions, with an emphasis upon lesser-known variants, newly described features and helpful ancillary studies. This review will guide general pathologists and dermatopathologists in accurately diagnosing and subclassifying cutaneous LE.

Primary cutaneous malignant perivascular epithelioid cell tumor: Case of a rare tumor with review of the literature.

Perivascular epithelioid cell tumors (PEComas) are mesenchymal neoplasms with characteristic epithelioid or spindled cytomorphology that typically grow around blood vessels. These tumors are phenotypically and immunohistochemically distinct, expressing markers of both melanocytic and smooth muscle differentiation. Herein, we describe a case of histopathologically malignant cutaneous PEComa without metastatic spread, with review of the pertinent literature. Telescoping punch biopsy demonstrated an epithelioid neoplasm with marked atypia, hypercellularity, and increased mitotic activity. Immunohistochemical stains for HMB-45, NK1-C3, PGP9.5, MiTF, CD10, and CD68 were positive within tumor cells. In addition, there was diffuse expression of caldesmon and focal cytoplasmic staining for smooth muscle actin on the excision specimen. The patient underwent treatment with surgical excision with adjuvant radiation and surveillance computed tomography (CT). The patient remains free of recurrence or metastatic disease after 10 months of follow-up. To our knowledge, this is only the third reported case of a malignant cutaneous PEComa reported in the literature to date.

Adherence to the National Comprehensive Cancer Network Criteria of Complete Circumferential Peripheral and Deep Margin Assessment in Treatment of High-Risk Basal and Squamous Cell Carcinoma.

BACKGROUND: The National Comprehensive Cancer Network (NCCN) has established guidelines for the treatment of keratinocyte carcinomas (KCs). Complete circumferential peripheral and deep margin assessment (CCPDMA) is recommended for "high-risk" tumors that cannot be closed primarily. If flap or grafts are needed and CCPDMA was not used, it is recommended that reconstruction be delayed until achieving clear margins. OBJECTIVE: To measure provider utilization rates of the NCCN guidelines for high-risk KCs and assess barriers that are limiting adherence. MATERIALS AND METHODS: A ten-item questionnaire was distributed to NCCN nonmelanoma skin cancer panel members and physicians participating in KC treatment at academic institutions. RESULTS: Response rate was 49% (57/116). Responses were categorized by practice area: Mohs surgery, pathology, and other specialties: General Dermatology, Otolaryngology, Plastic Surgery, Surgical Oncology, Radiation Oncology, and Oral and Maxillofacial Surgery. Mohs surgeons were most likely to use CCPDMA for tumors meeting NCCN criteria with 14/15 using this technique in a majority of their cases, versus 2/6 pathologists and 10/16 specialists from other fields. Reasons cited for not using CCPDMA included deference to pathologists to determine the appropriate method for margin assessment and logistical difficulty. CONCLUSION: Further efforts are needed to increase adherence to NCCN's guidelines regarding CCPDMA in KCs.

A Newborn Female with a Diffuse Rash.

Langerhans cell histiocytosis is a rare and clinically heterogeneous group of dendritic histiocytic disorders with typical onset in the neonatal period or infancy, although it can present at any age. Histiocytes accumulate in one or more organs, leading to a variable clinical presentation of disease. We report a case of biopsy-proven Langerhans cell histiocytosis in a newborn and discuss the workup and management of this disease, along with reviewing its clinical variants.

Advances in noninvasive imaging of melanoma.

Melanoma is the most dangerous type of skin cancer and its incidence has risen sharply in recent decades. Early detection of disease is critical for improving patient outcomes. Any pigmented lesion that is clinically concerning must be removed by biopsy for morphologic investigation on histology. However, biopsies are invasive and can cause significant morbidity, and their accuracy in detecting melanoma may be limited by sampling error. The advent of noninvasive imaging devices has allowed for assessment of intact skin, thereby minimizing the need for biopsy; and these technologies are increasingly being used in the diagnosis and management of melanoma. Reflectance confocal microscopy, optical coherence tomography, ultrasonography, and multispectral imaging are noninvasive imaging techniques that have emerged as diagnostic aids to physical exam and/or conventional dermoscopy. This review summarizes the current knowledge about these techniques and discusses their practical applications and limitations.

Concordance of handheld reflectance confocal microscopy (RCM) with histopathology in the diagnosis of lentigo maligna (LM): A prospective study.

BACKGROUND: Reflectance confocal microscopy (RCM) provides real-time noninvasive imaging of cell structure and may be useful in diagnosing lentigo maligna (LM). Few studies have compared performance of RCM with histopathology in diagnosing LM, and specific features influencing RCM interpretation are not well described. OBJECTIVE: We sought to determine concordance rate between RCM and histopathology in the evaluation of suspected LM and to identify factors that may obscure diagnosis. METHODS: We designed a prospective study involving 17 participants seen for evaluation at a large tertiary referral center. Cases included primary lesions and possible recurrent and/or previously treated lesions. A total of 63 clinically equivocal sites were assessed by RCM and histopathology. RESULTS: RCM and histopathology interpretations were concordant in 56 of 63 sites (89%). There were no false-negative and 7 false-positive results using RCM (sensitivity 100%, specificity 71%, positive predictive value 85%, negative predictive value 100%). Features suggestive of LM in the false-positive group included the presence of numerous hyperreflectile large cells at the dermoepidermal junction and follicular localization of these cells. LIMITATIONS: A larger test set is needed to more reliably distinguish LM from benign lesions using RCM and to improve specificity. CONCLUSION: RCM shows excellent sensitivity for detecting LM although features of benign macules on a background of actinically damaged skin can obscure diagnosis and limit its specificity.

Bone marrow derived mesenchymal stem cells inhibit inflammation and preserve vascular endothelial integrity in the lungs after hemorrhagic shock.

Hemorrhagic shock (HS) and trauma is currently the leading cause of death in young adults worldwide. Morbidity and mortality after HS and trauma is often the result of multi-organ failure such as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), conditions with few therapeutic options. Bone marrow derived mesenchymal stem cells (MSCs) are a multipotent stem cell population that has shown therapeutic promise in numerous pre-clinical and clinical models of disease. In this paper, in vitro studies with pulmonary endothelial cells (PECs) reveal that conditioned media (CM) from MSCs and MSC-PEC co-cultures inhibits PEC permeability by preserving adherens junctions (VE-cadherin and ß-catenin). Leukocyte adhesion and adhesion molecule expression (VCAM-1 and ICAM-1) are inhibited in PECs treated with CM from MSC-PEC co-cultures. Further support for the modulatory effects of MSCs on pulmonary endothelial function and inflammation is demonstrated in our in vivo studies on HS in the rat. In a rat "fixed volume" model of mild HS, we show that MSCs administered IV potently inhibit systemic levels of inflammatory cytokines and chemokines in the serum of treated animals. In vivo MSCs also inhibit pulmonary endothelial permeability and lung edema with concurrent preservation of the vascular endothelial barrier proteins: VE-cadherin, Claudin-1, and Occludin-1. Leukocyte infiltrates (CD68 and MPO positive cells) are also decreased in lungs with MSC treatment. Taken together, these data suggest that MSCs, acting directly and through soluble factors, are potent stabilizers of the vascular endothelium and inflammation. These data are the first to demonstrate the therapeutic potential of MSCs in HS and have implications for the potential use of MSCs as a cellular therapy in HS-induced lung injury.

Human Bone Marrow Derived Mesenchymal Stem Cells Regulate Leukocyte-Endothelial Interactions and Activation of Transcription Factor NF-Kappa B.

Bone marrow derived mesenchymal stem cells (MSCs) have been shown to demonstrate benefit in multiple disease models characterized by inflammation such as sepsis and acute lung injury. Mechanistically we hypothesized that MSCs exhibit these properties through inhibition of leukocyte activation and modulation of leukocyte-endothelial interactions; key interlinked processes involved in the deleterious effects of injury and inflammation. In this paper we found that MSCs co-cultured with a monocytoid line, U937, inhibit U937 binding to pulmonary endothelial cells (PECs) stimulated with the inflammatory cytokine TNFα. Furthermore, we show that these effects on functional adhesion are not due to changes in inflammatory adhesion molecule expression on U937s. No changes were found in CD62L, CD29, CD11b and CD18 expression on U937s co-cultured with MSCs. To determine if the effects of MSCs on leukocyte-endothelial interactions are due to the effects of MSCs on leukocyte activation, we investigated whether MSCs affect functional activation of the transcription factor NF-Kappa B. We found that MSCs significantly inhibit transcriptional activation of NF-kappa B in U937s. We also found that MSCs inhibit DNA binding of NF-kappa B subunits p50 and p65 to putative NF-kappa B DNA binding sites. Concomitant with a decrease in NF-kappa B activation was a significant increase in IL-10, an anti-inflammatory cytokine known to inhibit activation of NF-kappa B. Taken together, these findings show that MSCs have potent effects on leukocyte-endothelial interactions which may be due to the direct effects of MSCs on IL-10 and NF-kB. These findings suggest a potential therapeutic role for MSCs in diseases characterized by inflammation such as acute lung injury or multi-organ failure induced by traumatic injury.