LAIR1 prevents excess inflammatory tissue damage in S. aureus skin infection and Cutaneous T-cell Lymphoma.

Patients with cutaneous T cell lymphoma (CTCL) experience high morbidity and mortality due to S. aureus skin infections and sepsis, but the causative immune defect is unclear. We previously identified high levels of LAIR2, a decoy protein for the inhibitory receptor LAIR1, in advanced CTCL. Mice do not have a LAIR2 homolog, so we used Lair1 knock-out (KO) mice to model LAIR2 overexpression. In a model of subcutaneous S. aureus skin infection, Lair1 KO mice had significantly larger abscesses and areas of dermonecrosis compared to WT. Lair1 KO exhibited a pattern of increased inflammatory responses in infection and sterile immune stimulation, including increased production of proinflammatory cytokines and myeloid chemokines, neutrophil ROS, and collagen/ECM remodeling pathways. Notably, Lair1 KO infected skin had a similar bacterial burden and neutrophils and monocytes had equivalent S. aureus phagocytosis compared to WT. These findings support a model in which lack of LAIR1 signaling causes an excessive inflammatory response that does not improve infection control. CTCL skin lesions harbored similar patterns of increased expression in cytokine and collagen/ECM remodeling pathways, suggesting that high levels of LAIR2 in CTCL recapitulates Lair1 KO, causing inflammatory tissue damage and compromising host defense against S. aureus infection.

CD30+ lymphoproliferative disorder masquerading as an atypical melanocytic proliferation.

Heuristics are cognitive strategies used to facilitate decision-making. They can be helpful tools for expediting pathologic diagnoses, however, they can also affect judgment and lead to biases that guide the pathologist astray. We report the case of a 52-year-old female who presented with two unusual pigmented lesions on the wrist and thigh that clinically and histopathologically resembled an atypical melanocytic proliferation. A biopsy of the thigh revealed a broad proliferation of large, atypical cells forming nests within a heavily pigmented epidermis. The lesion was initially misdiagnosed as melanoma in situ, despite equivocal staining for melanocytic markers, likely due to anchoring and adjustment as well as availability biases, which restricted the differential diagnosis and limited the selection of immunohistochemical stains. It was later discovered through chart review that the patient had a prior history of a cutaneous CD30+ lymphoproliferative disorder, which eventually led to the appropriate diagnosis in this case. Herein, we highlight a rare and unusual presentation of a pigmented epidermotropic CD30+ lymphoproliferative disorder, along with the biases leading to its misdiagnosis and the steps leading to the revelation of the actual diagnosis.

Dermatologic Events Associated with the Anti-CCR4 Antibody Mogamulizumab: Characterization and Management.

The CCR4-directed monoclonal antibody mogamulizumab has been shown to significantly improve progression-free survival and overall response rate compared with vorinostat in adults with relapsed/refractory mycosis fungoides (MF) and Sézary syndrome (SS). One of the most common adverse events seen with mogamulizumab in MF/SS patients is rash. Because of the protean nature of MF/SS and the variable clinical and histopathological features of mogamulizumab-associated rash, healthcare providers may have difficulty distinguishing rash from disease, and may not be aware of appropriate treatment strategies for this generally manageable adverse event. The objective of this report was to combine results from published literature with experiences and recommendations from multiple investigators and institutions into clinical best practice recommendations to assist healthcare providers in identifying and managing mogamulizumab-associated rash. Optimal management, which includes biopsy confirmation and steroid treatment, requires a multidisciplinary approach among oncology, dermatology, and pathology practitioners. INFOGRAPHIC.

Histopathologic and immunophenotypic features of cutaneous solid organ transplant-associated graft-vs-host disease: Comparison with acute hematopoietic cell transplant-associated graft-vs-host disease and cutaneous drug eruption.

BACKGROUND: Although it is relatively common after hematopoietic cell transplant (HCT), graft-vs-host disease (GVHD) is a rare complication following solid organ transplantation (SOT). METHODS: This study evaluated skin biopsy specimens from five cases of SOT GVHD, 15 cases of HCT GVHD, and 15 cases of cutaneous drug eruption. Immunohistochemical staining for CD3, CD4, CD8, T-bet, and GATA-3 was performed to examine the density and immune phenotype of skin-infiltrating lymphocytes. RESULTS: Similar to HCT GVHD, the predominant histopathologic findings in skin biopsy specimens of SOT GVHD were widespread vacuolar interface dermatitis with scattered necrotic keratinocytes. However, the density of dermal inflammation was considerably higher in SOT GVHD. Features that were more predictive of a cutaneous drug eruption over GVHD included spongiosis, confluent parakeratosis, and many eosinophils. Involvement of the hair follicle epithelium was seen in all three disorders. Both forms of cutaneous GVHD showed a predominance of Th1 (CD3+/T-bet+) lymphocytes within the inflammatory infiltrates. This shift was more pronounced in SOT GVHD, particularly among intraepidermal T-cells. CONCLUSIONS: SOT GVHD shares many histopathologic features with HCT GVHD. However, SOT GVHD has a greater tendency to develop brisk lichenoid inflammation.

Diagnostic concordance of clinical diagnosis, tissue culture, and histopathology testing for skin and soft tissue infections: A single-center retrospective study.

BACKGROUND: Tissue culture and histopathology are the conventional diagnostic modalities for skin and soft tissue infections (SSTIs), but few studies have investigated their concordance. OBJECTIVE: Determine concordance between histopathology and tissue culture in the diagnosis of suspected SSTIs. METHODS: Single-center retrospective study of 355 cases with suspected SSTIs identified from the dermatology inpatient consultation log January 2014-July 2017. RESULTS: Overall concordance between histopathology testing and tissue culture results was high (76.1%). Concordance was high for cases defined as no evidence of infection, fungal infection and mycobacterial infection by histopathology (77.8%, 74.2%, and 80.0%) and tissue culture (92.1%, 67.7%, and 83.3%). Concordance was lower for suspected SSTIs with bacterial infection by histopathology (61.9%) and tissue culture (28.4%). Concordance rates were not significantly affected by age, sex, race, antimicrobial agent use, immunologic status, or biopsy size. LIMITATIONS: Retrospective and single-institution nature of the study. CONCLUSION: This study demonstrated a high concordance between histopathology and tissue culture in SSTIs with no clinical evidence of infection and suspected fungal and mycobacterial SSTIs, though concordance was lower for suspected SSTIs with evidence of bacterial infection. Clinicians should not be deterred from relying on initial histopathological results based on patients' immunosuppressed status, antimicrobial agent use, age, or biopsy tissue size.

Novel cell adhesion/migration pathways are predictive markers of HDAC inhibitor resistance in cutaneous T cell lymphoma.

BACKGROUND: Treatment for Cutaneous T Cell Lymphoma (CTCL) is generally not curative. Therefore, selecting therapy that is effective and tolerable is critical to clinical decision-making. Histone deacetylase inhibitors (HDACi), epigenetic modifier drugs, are commonly used but effective in only ~30% of patients. There are no predictive markers of HDACi response and the CTCL histone acetylation landscape remains unmapped. We sought to identify pre-treatment molecular markers of resistance in CTCL that progressed on HDACi therapy. METHODS: Purified T cells from 39 pre/post-treatment peripheral blood samples and skin biopsies from 20 patients were subjected to RNA-seq and ChIP-seq for histone acetylation marks (H3K14/9 ac, H3K27ac). We correlated significant differences in histone acetylation with gene expression in HDACi-resistant/sensitive CTCL. We extended these findings in additional CTCL patient cohorts (RNA-seq, microarray) and using ELISA in matched CTCL patient plasma. FINDINGS: Resistant CTCL exhibited high levels of histone acetylation, which correlated with increased expression of 338 genes (FDR < 0·05), including some novel to CTCL: BIRC5 (anti-apoptotic); RRM2 (cell cycle); TXNDC5, GSTM1 (redox); and CXCR4, LAIR2 (cell adhesion/migration). Several of these, including LAIR2, were elevated pre-treatment in HDACi-resistant CTCL. In CTCL patient plasma (n = 6), LAIR2 protein was also elevated (p < 0·01) compared to controls. INTERPRETATION: This study is the first to connect genome-wide differences in chromatin acetylation and gene expression to HDACi-resistance in primary CTCL. Our results identify novel markers with high pre-treatment expression, such as LAIR2, as potential prognostic and/or predictors of HDACi-resistance in CTCL. FUNDING: NIH:CA156690, CA188286; NCATS: WU-ICTS UL1 TR000448; Siteman Cancer Center: CA091842.

Dermatologic Conditions of the Early Post-Transplant Period in Hematopoietic Stem Cell Transplant Recipients.

Hematopoietic stem cell transplants (HSCTs) are used to treat a variety of conditions, including hematologic malignancies, bone marrow failure syndromes, and immunodeficiencies. Over 60,000 HSCTs are performed annually worldwide, and the numbers continue to increase. Indeed, as new conditioning regimens develop, more and more individuals, including those of older age, will be eligible for transplants. Nevertheless, although HSCTs are clearly a life-saving and necessary treatment for thousands of patients per year, there is still substantial morbidity and mortality associated with the procedure. Of note, skin eruptions in the post-HSCT period are frequent and often significantly reduce quality of life in recipients. Moreover, these cutaneous findings sometimes herald an underlying systemic condition, presenting possible opportunities for timelier intervention. Dermatologists therefore play a vital role in distinguishing life-threatening conditions from benign issues and prompting recognition of critical complications earlier in their course. This article aims to review the major dermatologic conditions occurring in the early post-HSCT period.

Concurrent metastases of papillary thyroid carcinoma to the scalp and Meckel's cave.

We present the case of a 65-year-old man with severe headaches and unilateral facial weakness, seen in consultation by the dermatology service to rule out primary cutaneous melanoma after brain imaging identified an enlarging mass within the right trigeminal (Meckel's) cave. Examination revealed only a pair of erythematous papules on the scalp, for which biopsy demonstrated metastatic papillary thyroid carcinoma. Further evaluation and subsequent thyroidectomy confirmed the origin of widespread internal disease, followed by definitive excision of scalp lesions and multimodal management of systemic involvement. Whereas presentation of metastasis to the skin is highly variable, a low threshold for biopsy may allow for histological identification of internal disease not otherwise considered in the clinical differential.

Hoarseness as a presentation of mycosis fungoides infiltrating the larynx.

Laryngeal involvement is a rare manifestation of mycosis fungoides (MF), with only nine reported cases of cutaneous T cell lymphoma with laryngeal or vocal cord involvement. Herein, we report the case of a patient with a 7-year history of MF who presented to the emergency department with hoarseness, throat tightness and cough, as well as erythroderma and skin tumours. Laryngoscopy and CT imaging were concerning for lymphomatous involvement of the left false vocal cord. A biopsy was taken of the false vocal cord lesion, which revealed an aberrant immunophenotype consistent with MF. The patient was started on doxorubicin with initial rapid improvement in symptoms. Within 2 months, her respiratory status and skin involvement worsened. Subsequent studies showed bone marrow involvement. The patient expired 4 months after original presentation. This report describes the patient's presentation and clinical course, and reviews the literature on vocal cord and laryngeal involvement of MF.