Nneka I. Comfere

B7-H1 (PD-L1, CD274) suppresses host immunity in T-cell lymphoproliferative disorders

Stromal elements present within the tumor microenvironment may suppress host immunity and promote the growth of malignant lymphocytes in B cell-derived non-Hodgkin lymphoma (NHL). In contrast, little is known about the microenvironments role in T cell-derived NHL. B7-H1 (PD-L1, CD274), a member of the B7 family of costimulatory/co-inhibitory ligands expressed by both malignant cells and stromal cells within the tumor microenvironment, has emerged as an important immune modulator capable of suppressing host immunity. Therefore, B7-H1 expression and function were analyzed in cutaneous and peripheral T-cell NHL. B7-H1 was expressed by tumor cells, monocytes, and monocyte-derived cells within the tumor microenvironment in T-cell NHL and was found to inhibit T-cell proliferation and promote the induction of FoxP3(+) regulatory T cells. Collectively, the data presented provide the first evidence implicating B7-H1 in the suppression of host immunity in T-cell lymphoproliferative disorders and suggest that the targeting of B7-H1 may represent a novel therapeutic approach.

Specificity of IRF4 translocations for primary cutaneous anaplastic large cell lymphoma: a multicenter study of 204 skin biopsies.

Current pathologic criteria cannot reliably distinguish cutaneous anaplastic large cell lymphoma from other CD30-positive T-cell lymphoproliferative disorders (lymphomatoid papulosis, systemic anaplastic large cell lymphoma with skin involvement, and transformed mycosis fungoides). We previously reported IRF4 (interferon regulatory factor-4) translocations in cutaneous anaplastic large cell lymphomas. Here, we investigated the clinical utility of detecting IRF4 translocations in skin biopsies. We performed fluorescence in situ hybridization (FISH) for IRF4 in 204 biopsies involved by T-cell lymphoproliferative disorders from 182 patients at three institutions. In all, 9 of 45 (20%) cutaneous anaplastic large cell lymphomas and 1 of 32 (3%) cases of lymphomatoid papulosis with informative results demonstrated an IRF4 translocation. Remaining informative cases were negative for a translocation (7 systemic anaplastic large cell lymphomas; 44 cases of mycosis fungoides/Sézary syndrome (13 transformed); 24 peripheral T-cell lymphomas, not otherwise specified; 12 CD4-positive small/medium-sized pleomorphic T-cell lymphomas; 5 extranodal NK/T-cell lymphomas, nasal type; 4 gamma-delta T-cell lymphomas; and 5 other uncommon T-cell lymphoproliferative disorders). Among all cutaneous T-cell lymphoproliferative disorders, FISH for IRF4 had a specificity and positive predictive value for cutaneous anaplastic large cell lymphoma of 99 and 90%, respectively (P=0.00002, Fishers exact test). Among anaplastic large cell lymphomas, lymphomatoid papulosis, and transformed mycosis fungoides, specificity and positive predictive value were 98 and 90%, respectively (P=0.005). FISH abnormalities other than translocations and IRF4 protein expression were seen in 13 and 65% of cases, respectively, but were nonspecific with regard to T-cell lymphoproliferative disorder subtype. Our findings support the clinical utility of FISH for IRF4 in the differential diagnosis of T-cell lymphoproliferative disorders in skin biopsies, with detection of a translocation favoring cutaneous anaplastic large cell lymphoma. Like all FISH studies, IRF4 testing must be interpreted in the context of morphology, phenotype, and clinical features.

Monocytes promote tumor cell survival in T-cell lymphoproliferative disorders and are impaired in their ability to differentiate into mature dendritic cells

A variety of nonmalignant cells present in the tumor microenvironment promotes tumorigenesis by stimulating tumor cell growth and metastasis or suppressing host immunity. The role of such stromal cells in T-cell lymphoproliferative disorders is incompletely understood. Monocyte-derived cells (MDCs), including professional antigen-presenting cells such as dendritic cells (DCs), play a central role in T-cell biology. Here, we provide evidence that monocytes promote the survival of malignant T cells and demonstrate that MDCs are abundant within the tumor microenvironment of T cell-derived lymphomas. Malignant T cells were observed to remain viable during in vitro culture with autologous monocytes, but cell death was significantly increased after monocyte depletion. Furthermore, monocytes prevent the induction of cell death in T-cell lymphoma lines in response to either serum starvation or doxorubicin, and promote the engraftment of these cells in nonobese diabetic/severe combined immunodeficient mice. Monocytes are actively recruited to the tumor microenvironment by CCL5 (RANTES), where their differentiation into mature DCs is impaired by tumor-derived interleukin-10. Collectively, the data presented demonstrate a previously undescribed role for monocytes in T-cell lymphoproliferative disorders.

Anti–Bullous Pemphigoid 180 and 230 Antibodies in a Sample of Unaffected Subjects

OBJECTIVE To evaluate the prevalence of autoantibodies against 2 hemidesmosomal proteins typically found in patients with bullous pemphigoid (BP), BP antigen II (BP180) and BP antigen I (BP230), in persons without BP. DESIGN Cross-sectional study. SETTING Academic medical center. Patients An age- and sex-stratified, random, population-based sample of local county patients seen during 2007: 20 men and 20 women per decade of age (from age 20 to 89 years) and 57 patients (33 women and 24 men) aged 90 to 99 years. Intervention Stored serum samples were retrieved for analysis by enzyme-linked immunosorbent assay and indirect immunofluorescence. MAIN OUTCOME MEASURE Presence of circulating autoantibodies to BP180 and BP230. RESULTS Of the 337 study patients, 25 (7.4%) were positive for 1 or both autoantibodies; these 25 samples all tested negative with indirect immunofluorescence. Autoantibody levels did not vary by age or sex. CONCLUSIONS Bullous pemphigoid has a higher incidence in the elderly population, but the prevalence of antibodies to BP180 and BP230 did not increase significantly with age or vary by sex in this population-based sample. Other exogenous factors may affect the development of these autoantibodies in a population without clinically evident immunobullous disease, including limitations inherent to the test (false-positive rate).

Cutaneous manifestations of Wegener's granulomatosis : a clinicopathologic study of 17 patients and correlation to antineutrophil cytoplasmic antibody status

Background:  Wegener’s granulomatosis (WG), a systemic vasculitis, can be associated with cutaneous signs and symptoms before, during or after the diagnosis of systemic disease.

Favorable long-term outcomes in patients with histologically dysplastic nevi that approach a specimen border

BACKGROUND Patients with multiple clinically dysplastic nevi are at increased risk for development of melanoma. However, the risk of melanoma arising in a histologically dysplastic nevus (HDN) is unknown. OBJECTIVE We sought to determine the rate of melanoma development in patients with HDNs that approached a microscopic border but were not re-excised. METHODS We performed a retrospective study of patients evaluated in our dermatology department from January 1, 1980, to December 31, 1989, who had a HDN that extended to within 0.2 mm of a microscopic punch, shave, or excision border and was not re-excised. RESULTS The average follow-up in our cohort of 115 patients was 17.4 years (range: 0.0-29.9): 82 patients (71.3%) were followed up for longer than 10 years, 78 (67.8%) longer than 15 years, and 73 (63.4%) had more than 20 years of follow-up; 66 of 115 nevi were mildly dysplastic, 42 moderately dysplastic, and 7 had severe dysplasia. No patient developed metastatic melanoma or melanoma at the site of removal of a HDN. LIMITATIONS This was a retrospective study performed at 1 large academic medical center. CONCLUSION During a long-term follow-up period, no patient developed melanoma at the site of an incompletely or narrowly removed HDN, providing evidence that routine re-excision of mildly or moderately dysplastic nevi may not be necessary.

The role of CD10 in distinguishing atypical fibroxanthoma from sarcomatoid (spindle cell) squamous cell carcinoma

Background: The role of CD10 needs clarification in a broader immunohistochemical battery for distinguishing atypical fibroxanthoma (AFX) from spindle cell squamous cell carcinoma (sSCC).

Programmed death 1 is expressed in cutaneous infiltrates of mycosis fungoides and Sézary syndrome

Expression of PD-1 (receptor Programmed Death 1, CD279) in some peripheral T-cell lymphomas has recently been demonstrated. Because antibody-based therapies have improved outcomes in non-Hodgkin lymphoma, and antibodies targeting PD-1 are in clinical development, expression of this molecule in cutaneous T-cell lymphoma may be of therapeutic interest. There are no studies to date specifically addressing the frequency and extent of PD-1 expression in mycosis fungoides or Sezary syndrome. We thus characterized PD-1 expression in mycosis fungoides and Sezary syndrome by immunohistochemistry on lesion skin biopsies and by flow cytometry on peripheral blood tumor cells. Fifteen of 30 cases of mycosis fungoides and 8 of 11 cases of Sezary syndrome were positive for PD-1 by immunohistochemistry. Circulating tumor cells from five of the immunohistochemistry-positive cases of Sezary syndrome were evaluated by flow cytometry and also found to be positive. These data indicate that a substantial proportion of patients with mycosis fungoides and Sezary syndrome are positive for PD-1. This result warrants further investigation of PD-1 as a potential therapeutic target.

Unusual cutaneous manifestations of B-cell chronic lymphocytic leukemia

BACKGROUND B-cell chronic lymphocytic leukemia (B-CLL) is a low-grade lymphoproliferative disorder with characteristic histomorphologic features and an identifiable immunophenotype. The skin can be involved in the context of known disease, but cutaneous signs are rarely the presenting findings. OBJECTIVE Evaluation of unusual clinical cutaneous presentations of B-CLL. METHODS We conducted a retrospective case series analysis of 3 patients with unusual cutaneous clinicopathologic presentations of B-cell chronic lymphocytic leukemia, including erythematous plaques, angiomatosis/telangiectasia, and erosive skin changes, respectively, without a previous clinical history of chronic lymphocytic lymphoma. Main outcome measures were clinical cutaneous presentations and histopathologic results in the diagnosis of underlying disease. RESULTS In the 3 cases, lesion locations were the lower cheek, lower extremity, and penis (groin region). Histomorphologic testing showed mild to dense perivascular and periadnexal lymphoid aggregates throughout the dermis and extending into the panniculus, consistent with B-CLL. The diagnosis was confirmed with immunohistochemical studies that showed coexpression of CD5 and CD20 in the neoplastic lymphocytic infiltrate. LIMITATIONS None. CONCLUSION Cutaneous manifestations are an uncommon presentation of subclinical B-CLL. Cutaneous changes were the presenting features of underlying lymphoma in all 3 cases, highlighting the importance of maintaining a high index of suspicion for a lymphoproliferative process in cases with unusual or atypical clinicopathologic features. Additional investigations into the behavior of B-CLL in the skin may elucidate further the evolution of cutaneous lesions in this disease.

Addressing the Interprofessional Collaboration Competencies of the Association of American Medical Colleges: A Systematic Review of Assessment Instruments in Undergraduate Medical Education.

Purpose To summarize characteristics and validity evidence of tools that assess teamwork in undergraduate medical education (UME), and provide recommendations for addressing the interprofessional collaboration competencies of the Association of American Medical Colleges (AAMC). Method The authors conducted a systematic review, searching MEDLINE, MEDLINE In-process, CINAHL, and PsycINFO from January 1, 1979, through April 1, 2014; they searched reference lists and national meeting abstracts. They included original research reports that described a quantitative tool used to assess teamwork in UME. They abstracted characteristics and validity evidence for the tools, plus study quality, according to established frameworks. Two authors independently abstracted 25% of articles and calculated agreement. Authors then applied predefined criteria to identify tools best suited to address the AAMC’s teamwork competencies. Results Of 13,549 citations, 70 articles describing 64 teamwork assessment tools were included. Of these 64 tools, 27 (42%) assessed teamwork in classroom, 31 (48%) in simulation, and only 7 (11%) in actual clinical settings. The majority (47; 73%) of tools assessed medical students’ teamwork in interprofessional teams. On the basis of content concordance, strength of validity evidence, generalizability of scores, and level of outcomes, four published tools were recommended to assess the AAMC’s teamwork competencies: the Collaborative Healthcare Interdisciplinary Relationship Planning Scale, Readiness for Interprofessional Learning Scale, Communication and Teamwork Skills assessment, and Teamwork Mini-Clinical Evaluation Exercise. Conclusions Substantial validity evidence supports the use of several UME teamwork assessments. Four tools have been appropriately designed and sufficiently studied to constitute appropriate assessments of the AAMC’s teamwork competencies.