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Although clinicians often put vasculitis and microvascular occlusion in the same differential diagnosis, biopsy findings often are either vasculitis or occlusion. However, both vasculitis and occlusion are present in some cases of levamisole-associated vasculopathy and certain infections. Depth of dermal involvement and vessel size should be reported, because superficial and deep small vessel leukocytoclastic vasculitis and/or involvement of medium-sized vessels may be associated with systemic disease. Microvascular occlusion of vessels in the fat should prompt consideration of calciphylaxis. Clues to ultimate clinical diagnosis can be garnered from depth of involvement, size of vessels affected, and presence of both vasculitis and occlusion.

Pyoderma gangrenosum (PG) is a sterile neutrophilic dermatosis manifesting as painful inflammatory plaques and ulcers, frequently associated with inflammatory bowel disease, rheumatoid arthritis, myelodysplastic syndrome, and acute myeloid leukemia.1 We present a case of a young woman with a novel mutation in NFkB1 who experienced common variable immunodeficiency (CVID) and severe recurrent PG episodes.

Background Purpura in inpatients commonly leads to dermatologic consultation. The differential diagnosis is broad and algorithms are intricate. Objective We evaluated inpatient consultations for complex purpura to document the most common diagnoses and to validate the true diagnostic utility of histopathology, clinical morphology, and distribution. Methods We reviewed a case series of 68 inpatients during a 4-year period with a dermatologic consultation for purpura and biopsy findings of vasculitis or microvascular occlusion. Results Key features of complex purpura are nonbranching (round) versus branching (retiform) morphology, dependent versus acral or generalized distribution, and leukocytoclastic vasculitis versus microvascular occlusion (with emphasis on depth of involvement). Dependent nonbranching purpura with only superficial vessels involved by leukocytoclastic vasculitis was most often due to IgA vasculitis or cutaneous single-organ small-vessel vasculitis. In contrast, deeper involvement by leukocytoclastic vasculitis was suggestive of systemic disease (eg, antineutrophil cytoplasmic antibody–associated vasculitis). Branching purpura was concerning, with greater than 90% sensitivity and specificity for microvascular occlusion and associated high mortality (≈50%). The majority of patients who died had acral branching lesions. Limitations Small sample size, inpatients at a tertiary care center, and retrospective nature are some limitations. Conclusion Nonbranching dependent purpura corresponded to leukocytoclastic vasculitis, with the most common diagnoses being IgA vasculitis or skin-limited small-vessel vasculitis; patients with deep involvement often had systemic diseases. In this series, branching purpura was due to microvascular occlusion rather than medium-vessel vasculitis, and had associated high mortality.

BACKGROUND: Acral inflammatory lesions that have some resemblance to idiopathic or autoimmune-associated perniosis (chilblains) have been described in multiple countries during the COVID-19 pandemic. METHODS: We examined histopathologic findings in six consecutive such cases from five patients received in mid-May to mid-June of 2020, evaluating immunohistochemical staining for the SARS-CoV-2 nucleocapsid protein. We compared these six cases to eight cases diagnosed as perniosis between January and June of 2019. RESULTS: Five of six lesions with perniosis-like histopathology during the COVID-19 pandemic had distinctive tight cuffing of lymphocytes; intravascular material was present in one case. SARS-CoV-2 immunohistochemical staining using an antibody directed at the nucleocapsid protein was negative in all six cases. Only one of eight specimens with microscopic findings of perniosis received prior to the COVID-19 pandemic had tightly cuffed perivascular lymphocytes, and none had obvious intravascular occlusion. CONCLUSIONS: A tightly cuffed pattern of perivascular lymphocytes is a feature of perniosis during the COVID-19 pandemic. The absence of SARS-CoV-2 nucleocapsid protein in these cases suggests against the virus being directly present in these lesions. This article is protected by copyright. All rights reserved.

Cutaneous leishmaniasis (CL) is a common disease affecting millions in endemic areas worldwide. We present a case of lupoid leishmaniasis, a rare variant of CL, which clinically mimicked sarcoidosis and/or granulomatous rosacea for 10 years until ultimate diagnosis. An 82-year-old U.S. citizen with an extensive travel history presented with a 10-year history of facial plaques on the cheeks and was previously diagnosed and treated as sarcoidosis. Multiple biopsies (previously and at presentation) revealed tuberculoid granulomas with negative special stains for microorganisms and negative sterile tissue cultures for acid-fast bacilli, bacteria, and fungal organisms. A diagnosis of granulomatous rosacea was rendered and multiple medical therapies were attempted, none with sustained improvement. Repeat biopsy of a new lesion revealed intracellular organisms consistent with leishmaniasis, which was confirmed by polymerase chain reaction (PCR). Lupoid leishmaniasis is a rare presentation of CL including facial plaques that can mimic granulomatous diseases affecting the face including sarcoidosis and granulomatous rosacea. CL can sometimes be challenging to diagnose through standard histopathologic examination; immunohistochemistry for CD1a can be used to augment tissue-based examination and PCR should be sent early in cases with sufficient concern.

Neurofibromatosis Type 1 (NF1) is one of the most common genetic tumor predisposition syndromes in humans. Mutant NF1 results in dysregulated RAS allowing neoplasms throughout the neuroaxis. Plexiform neurofibromas (pNF) afflict up to 50% of patients with NF1. They are complex tumors of the peripheral nerve that cause major morbidity via nerve dysregulation and mortality via conversion to malignant sarcoma. Genetically engineered mouse models (GEMM) of NF1 provide valuable insights for the identification of therapies that have utility in people with pNF. Preclinical studies in GEMMs implicate mast cells and the c-Kit/Kit ligand pathway in pNF tumorigenesis. Kit ligand is a potent chemokine secreted by tumorigenic, Nf1-deficient Schwann cells. Ketotifen is an FDA-approved drug for the treatment of allergic conjunctivitis and asthma that promotes mast cell stabilization and has been used in prior case studies to treat or prevent pNFs. This study investigated the effect of ketotifen on mast cell infiltration and degranulation in the presence and absence of Kit ligand provocation and the effect of ketotifen on shrinking or preventing pNF formation in the Nf1flox/flox;PostnCre+ GEMM. Ketotifen decreased mast cell infiltration in response to exogenous Kit ligand administration, but did not affect mast cell degranulation. Importantly, ketotifen did not reduce mast cells numbers or activity in pNF and did not prevent pNF formation or decrease the volume of established pNF despite administration of pharmacologically active doses. These findings suggest that ketotifen has limited use as monotherapy to prevent or reduce pNF burden in the setting of Nf1 mutations.

Toxoplasma gondii is a common parasite that infects warm-blooded animals, including humans, and is a foodborne pathogen. We report a case of acute toxoplasmosis in a 76-year-old man after ingestion of the undercooked heart of a white-tailed deer (Odocoileus virginianus) in Tennessee. The patient’s adult grandson, who also consumed part of the heart, became ill with nearly identical symptoms, though he did not seek medical care. This case highlights important public health concerns about deer-to-human transmission of Toxoplasma.

In this report, the authors present a case of diffuse dermal angiomatosis (DDA) with an underlying mass lesion of the breast, which proved to be a large calcified, thrombosed artery with adjacent fat necrosis. Histologically, DDA consists of hyperplastic vessels, which diffusely infiltrate the papillary and reticular dermis forming small vascular lumina. The condition is associated with various underlying conditions, many of which result in local tissue ischemia. In the past, DDA was most commonly reported on the lower extremities; however, it seems that this entity is more common on the breast than previously recognized. Various treatments have proven beneficial, including revascularization, oral corticosteroids, smoking cessation, and isotretinoin. In this case, our patient benefited from primary excision of the affected area.

// Benjamin M. Wahle 1, 2 , Eric T. Hawley 1 , Yongzheng He 1 , Abbi E. Smith 1 , Jin Yuan 1 , Andi R. Masters 3 , David R. Jones 3 , Jeffrey R. Gehlhausen 1 , Su-Jung Park 1 , Simon J. Conway 1 , D. Wade Clapp 1 and Charles W. Yates 1, 2 1 Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA 2 Department of Otolaryngology/Head and Neck Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA 3 Clinical Pharmacology Analytical Core, Indiana University Simon Cancer Center, Indianapolis, Indiana, USA Correspondence to: D. Wade Clapp, email: dclapp@iu.edu Charles W. Yates, email: cwyates@iupui.edu Keywords: neurofibromatosis type 2; vestibular schwannoma; cyclooxygenase 2; non-steroidal anti-inflammatory agents; transgenic mice Abbreviations: COX-2 (cyclooxygenase-2), NSAID (nonsteroidal antiinflamatory drug) Received: March 31, 2017 Accepted: October 02, 2017 Published: October 24, 2017 ABSTRACT Mutations in the tumor suppressor gene NF2 lead to Neurofibromatosis type 2 (NF2), a tumor predisposition syndrome characterized by the development of schwannomas, including bilateral vestibular schwannomas with complete penetrance. Recent work has implicated the importance of COX-2 in schwannoma growth. Using a genetically engineered murine model of NF2, we demonstrate that selective inhibition of COX-2 with celecoxib fails to prevent the spontaneous development of schwannomas or sensorineural hearing loss in vivo , despite elevated expression levels of COX-2 in Nf2 -deficient tumor tissue. These results suggest that COX-2 is nonessential to schwannomagenesis and that the proposed tumor suppressive effects of NSAIDs on schwannomas may occur through COX-2 independent mechanisms.

Capecitabine is a 5-fluorouracil basedchemotherapeutic drug widely used in the treatmentof solid tumors, especially colorectal and breast. Someof the most common side effects of capecitabine arecutaneous in nature, including hand-foot syndrome(palmar-plantar erythrodysesthesia). Several reports inthe literature link capecitabine use with photosensitivelichenoid eruptions. Herein, we present a case ofcapecitabine-induced lichenoid eruption in an elderlyfemale with metastatic breast cancer and discuss ourfindings in relationship to previously reported cases ofthis and other capecitabine-induced skin pathologies.

Schwannomas are predominantly benign nerve sheath neoplasms caused by Nf2 gene inactivation. Presently, treatment options are mainly limited to surgical tumor resection due to the lack of effective pharmacological drugs. Although the mechanistic understanding of Nf2 gene function has advanced, it has so far been primarily restricted to Schwann cell-intrinsic events. Extracellular cues determining Schwann cell behavior with regard to schwannoma development remain unknown. Here we show pro-tumourigenic microenvironmental effects on Schwann cells where an altered axonal microenvironment in cooperation with injury signals contribute to a persistent regenerative Schwann cell response promoting schwannoma development. Specifically in genetically engineered mice following crush injuries on sciatic nerves, we found macroscopic nerve swellings in mice with homozygous nf2 gene deletion in Schwann cells and in animals with heterozygous nf2 knockout in both Schwann cells and axons. However, patient-mimicking schwannomas could only be provoked in animals with combined heterozygous nf2 knockout in Schwann cells and axons. We identified a severe re-myelination defect and sustained macrophage presence in the tumor tissue as major abnormalities. Strikingly, treatment of tumor-developing mice after nerve crush injury with medium-dose aspirin significantly decreased schwannoma progression in this disease model. Our results suggest a multifactorial concept for schwannoma formation—emphasizing axonal factors and mechanical nerve irritation as predilection site for schwannoma development. Furthermore, we provide evidence supporting the potential efficacy of anti-inflammatory drugs in the treatment of schwannomas. Electronic supplementary material The online version of this article (doi:10.1007/s00401-016-1583-8) contains supplementary material, which is available to authorized users.

Neurofibromatosis type 2 (NF2) is a genetic disease resulting from germline loss of the NF2 tumor suppressor gene. The hallmark of NF2 is hearing and vestibular loss of function in young adults caused by the development of vestibular schwannomas, which occur bilaterally in nearly all patients and are associated with homozygous loss of NF2. Individuals affected with NF2 also acquire schwannomas of other cranial, spinal and peripheral nerves. Importantly, non-familial schwannomas, the most common tumor of the peripheral nervous system, are also caused by bi-allelic loss of NF2 gene function. A major limitation in the identification of genetic and pharmacologic targets for schwannomas has been the lack of a robust preclinical model that accurately recapitulates human NF2 disease. In order to develop a more robust model, we intercrossed a mouse expressing Cre Recombinase under the control of the 3.9PeriCre promoter with an Nf2 conditional knockout mouse previously generated by Dr. Marco Giovannini to conditionally ablate Nf2 in neural crest-derived cell populations. Histological analysis of the dorsal root ganglion (DRG) and proximal spinal nerves of 3.9PeriCre+;Nf2flox/flox mice revealed that intercrossed mice spontaneously develop tumors between 8 and 10 months at every single spinal level. Microscopic analysis implicated these tumors as schwannomas, as they display a dense pattern of cellularity consistent with the established criteria of GEM schwannoma, including S100β1 positivity. Quantitation of the DRG volume indicated that 3.9PeriCre+ mice have a statistically significant increase when compared to 3.9PeriCre- littermates. FDG-PET studies corroborated this finding, as comparative studies showed an increase in the metabolic activity of paraspinal tumors found in 3.9PeriCre+ mice. Auditory Brainstem Response testing has revealed that 3.9PeriCre+ mice acquire an age-dependent increase in hearing threshold by 8 months when compared to age-matched 3.9PeriCre- controls. Histological analysis of Cranial Nerve VIII confirmed that the hearing loss was directly associated with the development of vestibular schwannomas. To test for concomitant vestibular loss of function, three different behavioral studies (contact righting, trunk curl, and swim) were performed to isolate and test the integrity of the vestibular sense in 3.9PeriCre;Nf2flox/flox mice. These studies indicated that 3.9PeriCre+ mice develop vestibular deficits, as all three studies identified highly significant differences between the two genotypes. Collectively, these genetically engineered mice acquire a physiologic phenotype that closely recapitulates important features of human NF2 disease and provides opportunities for testing putative therapeutic targets using genetic intercrosses or novel small molecule inhibitors. Citation Format: Jeff R. Gehlhausen, Su Jung Park, Matthew Shew, Wade Clapp, Charles Yates. Generation of a murine model of Neurofibromatosis Type 2 that accurately recapitulates the spontaneous development of vestibular and spinal schwannomas found in NF2 patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 355. doi:10.1158/1538-7445.AM2013-355