Folliculocentric lymphocytic hypersensitivity reactions in CLL/SLL patients: A unique clinicopathologic entity amongst non-specific hypersensitivity reactions.

Background: Cutaneous hypersensitivity eruptions in chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) are a clinically and histologically heterogeneous group that can either precede, occur with, or follow the development of a hematologic malignancy. Therefore, establishing the diagnosis requires careful clinical and pathologic correlation and an understanding of the broad spectrum of presentations. Data is lacking on the correlation of skin disease with molecular/cytogenetic risk profiling of the tumor. Objectives: The aims of this study were to characterize the clinical, histological, and genetic aberrations in recurrent cutaneous hypersensitivity reactions in patients with CLL/SLL. Methods: A single site academic retrospective chart review of medical records, histopathology, molecular and cytogenetic data in CLL/SLL patients who developed biopsy-proven cutaneous hypersensitivity reactions. Results: Five hundred one new diagnoses of CLL/SLL with 73 patients requiring cutaneous biopsies for skin lesions or rashes were identified. With exclusion criteria, 20 biopsies were identified from 17 patients (mean age, 69.6 years, females = 9) with unexplained cutaneous eruptions. These were commonly pruritic, erythematous papules above the waist. Most biopsies had a prominent superficial, deep dermal eosinophilic infiltrate (85%), with a robust T-cell predominant dermal infiltrate in 40%. Five out of 17 patients (29%) had a predominately folliculocentric CD4+ T-cell infiltrate; all occurring on the head and neck. Overall, the prevalence of cutaneous hypersensitivity eruptions requiring biopsy was 3.4% (n = 17), and the prevalence of folliculocentric CD4+ T-cell infiltrate was 1% (n = 5). Conclusion: Cutaneous hypersensitivity reactions in CLL/SLL are heterogeneous; however, folliculotropic CD4+ T-cell infiltrates may be seen in a small but distinct clinical subset of patients. Commonly tested cytogenetic aberrations in CLL/SLL do not appear to be correlated with the presence of cutaneous hypersensitivity reactions.

Feasibility of personalized circulating tumor DNA detection in stage II and III melanoma.

The objective of this study was to evaluate the feasibility of developing personalized, tumor-informed assays for patients with high-risk resectable melanoma and examine circulating tumor DNA (ctDNA) levels in relation to clinical status. Pilot prospective study of clinical stage IIB/C and resectable stage III melanoma patients. Tumor tissue was used to design bespoke somatic assays for interrogating ctDNA in patients' plasma using a multiplex PCR (mPCR) next-generation sequencing (NGS)-based approach. Plasma samples for ctDNA analysis were collected pre-/post-surgery and during surveillance. Out of 28 patients (mean 65 years, 50% male), 13 (46%) had detectable ctDNA prior to definitive surgery and 96% (27/28) tested ctDNA-negative within 4 weeks post-surgery. Pre-surgical detection of ctDNA was significantly associated with the later-stage ( P  = 0.02) and clinically evident stage III disease ( P  = 0.007). Twenty patients continue in surveillance with serial ctDNA testing every 3-6 months. With a median follow-up of 443 days, six out of 20 (30%) patients developed detectable ctDNA levels during surveillance. All six of these patients recurred with a mean time to recurrence of 280 days. Detection of ctDNA in surveillance preceded the diagnosis of clinical recurrence in three patients, was detected concurrent with clinical recurrence in two patients and followed clinical recurrence in one patient. One additional patient developed brain metastases without detection of ctDNA during surveillance but had positive pre-surgical ctDNA. Our results demonstrate the feasibility of obtaining a personalized, tumor-informed mPCR NGS-based ctDNA assay for patients with melanoma, particularly in resectable stage III disease.

A Single-Institution Cohort Study With Nevi of Special Site: Recurrence, Progression to Melanoma, and Patterns of Management.

ABSTRACT: Nevi of specialized sites (NOSS) occur on the scalp, ears, flexural, acral, and genital areas and display atypical clinical and histologic features. We assessed NOSS recurrence and progression to melanoma, management patterns, and associations between histologic features and treatment recommendations. We queried all histologic diagnoses of NOSS (n = 275) from 2012 to 2017 from a large U.S. academic medical center with reference dermatopathology laboratory and matched these to clinical records. A blinded panel of dermatopathologists re-evaluated lesions, catalogued histologic findings, and gave management recommendation. Associations with dermatopathologist decision and concordance between new and original recommendations were assessed. Of 117 cases with follow-up, 2 locally recurred (1.46%) and none eventuated in melanoma. Clinical features were not associated with original treatment recommendations. After histopathologic review, large melanocytes [odds ratio ratio (ORR) = 8.00, 95% CI, 1.35-47.4] and junctional mitotic figures (ORR = 65.0, 6.5-650) predicted excision recommendation. Likewise, accumulation of many (>9) high-risk features was associated with excision recommendation. Panel review changed treatment recommendation in 27% of cases. Fair concordance existed between original and panel recommendations (κ = 0.29, 0.15-0.44). The low rate of recurrence and lack of melanoma occurrence suggest that despite an atypical clinical and histopathologic appearance, these nevi have limited potential for malignant transformation. Histopathologic findings seem to be principal drivers behind the recommendation for excision in this analysis. Variability existed in treatment recommendations; the panel's consensus recommendation tended to downgrade treatment. This highlights the importance of further outcomes-based studies to identify true high-risk features and refine management guidelines.

Improved overall survival over time in advanced stage mycosis fungoides: a cross-sectional study.

Mycosis Fungoides (MF) is a rare T-cell lymphoma and evidence on treatment practices, and outcomes are limited. We evaluated changes in practice patterns and corresponding effects on overall survival (OS) in MF using a cross-sectional study of patients diagnosed with MF from 2004 to 2016 in the National Cancer Database. Outcomes evaluated included patterns of care and OS across treatment eras. We found factors associated with chemotherapy use included male gender, treatment from 2004 to 2010 and stage III-IV disease. Factors associated with radiotherapy receipt included stage I-II disease, nonacademic treatment centers, male gender, non-black race, and Medicare status. Immunotherapy use was associated with treatment from 2004 to 2010 and stage III-IV disease. After propensity score matching, there was no OS difference among patients with stage I-II disease between 2004-2010 and 2011-2016. However, amongst patients with stage III-IV disease, OS was significantly improved in those treated from 2011 to 2016.

Pretibial Pruritic Papular Dermatitis: A Comprehensive Clinical and Pathologic Review of Cases at a Single Institution.

BACKGROUND: Studies characterizing clinical and pathologic details of pretibial pruritic papular dermatitis (PPPD) are scarce. Several cases of PPPD at our institution have displayed lymphocyte atypia and CD30 positivity, resembling lymphomatoid papulosis (LyP). We explore the clinical and histological spectrum of PPPD, with emphasis on lymphocyte atypia. METHODS: Retrospective observational study of 40 archived pathological specimens (hematoxylin/eosin, CD3, CD20, and CD30 immunohistochemistry) from 38 PPPD patients in an academic center. Clinical photographs were available in 22 cases. RESULTS: Microscopic epidermal changes were focal, but common (spongiosis 75%, parakeratosis 90%, interface changes 43%, Langerhans cell microgranulomas 25%, multinucleated keratinocytes 55%, Civatte bodies 55%, erosion 20%, and more than focal irregular psoriasiform hyperplasia 37%) and certain dermal changes were universal (papillary dermal fibrosis 100%, stellate fibroblasts 100%, and multinucleated fibroblasts 93%). At least focal lymphocyte atypia was present in all cases. Lymphocytes were almost exclusively CD3 T cells with rare CD20 B cells. Up to 30% of lymphocytes exhibited weak CD30 staining. Clinically, all cases exhibited discrete papules, but plaques and erosions were not uncommon. LIMITATIONS: As a retrospective series, clinical images were not available for all cases. CONCLUSION: This study suggests a broader histological and clinical spectrum of PPPD than previously described. Epidermal changes are common in PPPD, as are atypical lymphocytes and focal CD30 positivity. Although the papular clinical appearance, lymphocyte atypia, and focal CD30 positivity may resemble LyP, the relatively low number of atypical lymphocytes, low intensity of CD30 staining, and absence of spontaneous resolution help to distinguish PPPD from LyP.

Cutaneous T-Cell Acute Lymphoblastic Leukemia and the Expression Pattern of Terminal Deoxynucleotidyl Transferase Immunostaining in Mycosis Fungoides and Spongiotic Dermatitis.

BACKGROUND/AIMS: T-cell acute lymphoblastic leukemia (T-ALL) is an uncommon, aggressive malignancy that rarely presents in the skin and is generally not considered as part of the differential diagnosis by dermatologists and dermatopathologists. We describe an unusual case of T-ALL presenting with folliculocentric, erythematous papules on the face, histologically resembling mycosis fungoides (MF). Immunostaining for terminal deoxynucleotidyl transferase (TdT) was positive in tumor cells, supporting the diagnosis of cutaneous involvement by T-ALL. TdT is a nuclear enzyme expressed by immature lymphoid malignancies, but the expression pattern of this marker is not well characterized in the skin. We aimed to assess TdT staining in skin biopsies with similar-appearing lymphocytic infiltrates. METHODS: We evaluated the immunostaining profile of TdT in a cohort of 23 patients, including 13 cases of MF and 10 cases of spongiotic dermatitis. RESULTS: The lymphocytes in the MF and spongiotic dermatitis cases lacked nuclear staining for TdT. Nonspecific, granular, cytoplasmic staining was observed in a small number of background cells. CONCLUSIONS: TdT may assist dermatopathologists in discriminating malignant infiltrates of T-ALL from other conditions.

Cutaneous lesions of angioimmunoblastic T-cell lymphoma: Clinical, pathological, and immunophenotypic features.

BACKGROUND: Angioimmunoblastic T-cell lymphoma (AITL) is a systemic peripheral T-cell lymphoma with a follicular helper T-cell (TFH ) immunophenotype that frequently involves the skin. However, the histopathology of cutaneous involvement by AITL has not been fully established. METHODS: We reviewed the clinicopathological features of 19 patients seen at our institution with AITL involving the skin. Pan-T-cell and TFH marker expression was evaluated by immunohistochemistry. Epstein-Barr virus (EBV) was detected using in situ hybridization (ISH) for Epstein-Barr virus-encoded small RNA (EBER). T-cell receptor (TCR) gene rearrangement was evaluated by PCR. RESULTS: AITL affected both trunk and extremities in 15/19 cases (79%). Perivascular infiltration by small and/or medium-sized lymphocytes was seen in 18/19 (95%). Granulomatous inflammation was identified in 4/19 (21%). Aberrant loss of CD2, CD5, or CD7 was identified in 1/18 (6%), 2/18 (11%), or 7/19 (37%) cases, respectively. Seventeen of eighteen evaluable cases (95%) expressed 2 to 3 TFH markers: PD-1 in 19/19 (100%), BCL6 in 94% (17/18), and CD10 in 37% (7/19). EBV-positive cells were detected in 3/18 (17%) with varying density. Clonal TCR gene rearrangement was identified in 9/11 (82%). CONCLUSIONS: Cutaneous involvement by AITL shows relatively non-specific histopathological features. However, an immunohistochemical panel including TFH markers and EBER ISH is useful in differential diagnosis.

Cutaneous carcinosarcoma: a series of six cases and a review of the literature.

BACKGROUND: Cutaneous carcinosarcoma is a rare tumor with distinct malignant epithelial and mesenchymal cell populations. The histologic subtypes of epithelial and mesenchymal components in cutaneous carcinosarcoma are variable, as an assortment of carcinomatous and sarcomatous patterns have been described in the literature. METHODS: Clinical information was obtained from patient charts and archival slides were retrieved and reviewed. RESULTS: We present a novel series of six distinct cases of cutaneous carcinosarcoma and review the literature. Our cases consisted of basal cell, pilomatrical, squamous cell, and trichoblastic variants. These cases occurred in elderly men on sun exposed skin with treatment and follow up was available for 4 of 6 cases. The four cases were treated with Mohs micrographic surgery with mean follow up of nine months. CONCLUSION: We report six cases of cutaneous carcinosarcoma with distinctive clinical and histologic characterization not previously described in a single series.

Radiation-induced pemphigus or pemphigoid disease in 3 patients with distinct underlying malignancies.

The cutaneous lesions of radiation-induced pemphigus or pemphigoid disease may resemble other skin diseases, including recurrent underlying cancer. We performed a computerized search of Mayo Clinic (Rochester, Minnesota) archives and identified 3 cases of pemphigus or pemphigoid disease that occurred after radiation therapy for breast, cervical, and metastatic malignancies, respectively. In 2 of these patients, the disease was initially confined to the irradiated field but subsequently disseminated to other parts of the patients' bodies, including mucosal surfaces. In all 3 patients, the blistering disease occurred 5 to 14 months after the onset of radiation therapy. All 3 were treated with corticosteroids and demonstrated complete recovery of the skin eruption after radiotherapy was discontinued. Although the precise mechanism of this cutaneous eruption is unknown, clinicians should be alert for this potentially serious complication and evaluate all cutaneous eruptions developing during and after radiotherapy.

Histiocytoid Sweet syndrome may indicate leukemia cutis: a novel application of fluorescence in situ hybridization.

BACKGROUND: In patients with malignancy-associated Sweet syndrome, a thorough evaluation for leukemia cutis should be considered. OBJECTIVE: We sought to describe the clinicopathologic characteristics of histiocytoid Sweet syndrome. METHODS: We retrospectively identified patients with histiocytoid Sweet syndrome at our institution from January 1992 through December 2010. We evaluated the underlying cutaneous infiltrate using immunohistochemistry and fluorescence in situ hybridization. RESULTS: We re-evaluated all 22 patients with hematologic malignancy-associated Sweet syndrome. Six patients had a monocytoid infiltrate that was consistent with histiocytoid Sweet syndrome; subsequent evaluation of these patients demonstrated cytogenetic abnormalities on prior bone-marrow biopsy specimens. Fluorescence in situ hybridization analysis was feasible in cutaneous specimens from 5 of the 6 patients and demonstrated the same cytogenetic abnormalities that were identified on prior bone-marrow biopsy specimens in 4 patients. Therefore, these 4 patients may have had a form of leukemia cutis. LIMITATIONS: This was a retrospective study. CONCLUSION: For patients with histiocytoid Sweet syndrome, an underlying hematologic malignancy, and a monocytoid infiltrate on biopsy specimen, fluorescence in situ hybridization of the cutaneous infiltrate may be beneficial to identify cytogenetic abnormalities that may indicate leukemia cutis.

GATA-3 expression identifies a high-risk subset of PTCL, NOS with distinct molecular and clinical features.

The cell of origin and the tumor microenvironment's role remain elusive for the most common peripheral T-cell lymphomas (PTCLs). As macrophages promote the growth and survival of malignant T cells and are abundant constituents of the tumor microenvironment, their functional polarization was examined in T-cell lymphoproliferative disorders. Cytokines that are abundant within the tumor microenvironment, particularly interleukin (IL)-10, were observed to promote alternative macrophage polarization. Macrophage polarization was signal transducer and activator of transcription 3 dependent and was impaired by the Janus kinase inhibitor ruxolitinib. In conventional T cells, the production of T helper (Th)2-associated cytokines and IL-10, both of which promote alternative macrophage polarization, is regulated by the T-cell transcription factor GATA-binding protein 3 (GATA-3). Therefore, its role in the T-cell lymphomas was examined. GATA-3 expression was observed in 45% of PTCLs, not otherwise specified (PTCL, NOS) and was associated with distinct molecular features, including the production of Th2-associated cytokines. In addition, GATA-3 expression identified a subset of PTCL, NOS with distinct clinical features, including inferior progression-free and overall survival. Collectively, these data suggest that further understanding the cell of origin and lymphocyte ontogeny among the T-cell lymphomas may improve our understanding of the tumor microenvironment's pathogenic role in these aggressive lymphomas.