Primary cutaneous angioimmunoblastic T-cell lymphoma histologically mimicking an inflammatory dermatosis.

Angioimmunoblastic T-cell lymphoma (AITL) is a systemic lymphoproliferative disease characterized by a polymorphous neoplastic infiltrate involving lymph nodes as well as extranodal locations, including the skin. Cutaneous involvement is seen in approximately 50 percent of cases and is usually secondary to systemic disease. Patients with cutaneous involvement classically present with a transient morbilliform eruption of the trunk; however, papules, nodules, urticarial plaques and erythroderma have also been reported. In contrast, primary cutaneous AITL is exceedingly rare. The authors report a case of a 79-year-old woman with AITL who presented with primary cutaneous tumors and ulcerated nodules, with no evidence of systemic involvement, hypergammaglobinemia, or B symptoms. Histologically, a subtle lymphoid infiltrate was present, dominated by marked fibrosis and a diffuse infiltrate of neutrophils, eosinophils and plasma cells, mimicking an inflammatory or infectious etiology. This presentation presents a unique diagnostic challenge; careful investigation and strong clinical suspicion must be utilized in order to correctly identify AITL in this setting.

Hyaline-vascular castleman disease: a rare cause of solitary subcutaneous soft tissue mass.

Castleman disease (CD) is a rare lymphoproliferative disorder that primarily affects mediastinal, retroperitoneal, and cervical lymph nodes. Clinically, these lesions occur as a localized (unicentric) or less frequently as a systemic (multicentric) disease. Two main distinct histologic variants are recognized, the more common hyaline-vascular (HV) type and the plasma cell (PC) type. Extranodal Castleman disease, HV type (HVCD) is even less common. We describe a case of subcutaneous HVCD in a 57-year-old woman with a palpable chest mass and without systemic symptoms. Although the histologic findings are similar to those of HVCD in lymph nodes and other sites, a plethora of differential diagnosis is raised particularly with the more commonly occurring lymphoproliferative lesions in this location. This is one of the few bona fide cases of HVCD in subcutaneous location published to date. A review of the literature with an emphasis on pathogenesis of the disease subtypes is presented.

A case of acute basophilic leukemia arising from chronic myelogenous leukemia with development of t(7;8)(q32;q13).

Acute basophilic leukemia (ABL) is an uncommon form of acute myelogenous leukemia recently recognized as a distinct entity in the World Health Organization classification of myeloid malignancies. A case is presented of ABL arising from chronic myelogenous leukemia with development of t(7;8)(q32;q13). Discussion includes a literature review.

Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis.

Autophagy is an evolutionarily conserved 'self-eating' process. Although the genes essential for autophagy (named Atg) have been identified in yeast, the molecular mechanism of how Atg proteins control autophagosome formation in mammalian cells remains to be elucidated. Here, we demonstrate that Bif-1 (also known as Endophilin B1) interacts with Beclin 1 through ultraviolet irradiation resistance-associated gene (UVRAG) and functions as a positive mediator of the class III PI(3) kinase (PI(3)KC3). In response to nutrient deprivation, Bif-1 localizes to autophagosomes where it colocalizes with Atg5, as well as microtubule-associated protein light chain 3 (LC3). Furthermore, loss of Bif-1 suppresses autophagosome formation. Although the SH3 domain of Bif-1 is sufficient for binding to UVRAG, both the BAR and SH3 domains are required for Bif-1 to activate PI(3)KC3 and induce autophagosome formation. We also observed that Bif-1 ablation prolongs cell survival under starvation conditions. Moreover, knockout of Bif-1 significantly enhances the development of spontaneous tumours in mice. These findings suggest that Bif-1 joins the UVRAG-Beclin 1 complex as a potential activator of autophagy and tumour suppressor.

Classification and treatment of rare and aggressive types of peripheral T-cell/natural killer-cell lymphomas of the skin.

BACKGROUND: The classification of cutaneous lymphomas has been contentious. Two major competing classifications were the World Health Organization (WHO) and the European Organization for Research and Treatment of Cancer (EORTC). The principal authors met for a consensus meeting resulted in a combined classification called WHO-EORTC Classification of Cutaneous Lymphoma. METHODS: We review the classification of "mature" or peripheral T-cell lymphoma (PTCL) with high predilection to the skin as published by the WHO-EORTC. We also highlight new information and changes from the previous classifications of cutaneous PTCL according to the WHO classification or the EORTC classification. Finally, the salient findings are compared with similar-looking nodal PTCLs with a high frequency of skin involvement. RESULTS: This review focuses on a rare group of cutaneous PTCLs other than mycosis fungoides or its variants. Changes from the previous classifications are discussed, and the rare group of nodal PTCLs with high predilection to the skin are presented. The salient findings, diagnostic features, and treatments are included, along with summary tables and clinical-histopathologic images. CONCLUSIONS: This review may serve as a guide for hematologists, oncologists and dermatologists in the diagnosis and management of these rare, aggressive, and often difficult to diagnose lymphomas. Although cutaneous lymphomas are morphologically identical to systemic lymphomas, the former behave differently, require divergent management, and should be recognized as separate entities. The consensus WHO-EORTC classification presents unified terminology and definitions to promote conformity in diagnosing and treating these cases, to foster a multidisciplinary approach to these often-obscure diseases, and to lead to more advances in identifying molecular targets specific to these entities.

Need for an improved molecular/genetic classification for CD30+ lymphomas involving the skin.

BACKGROUND: The spectrum of diseases that constitute the CD30+ lymphomas, with lymphomatoid papulosis (LyP) at one end, and anaplastic large-cell lymphoma (ALCL) at the other end, shows variable morphology, immunophenotype, and clinical behavior. The border between these diseases is sometimes difficult to establish and there are many grey zones in their classification. METHODS: We reviewed the clinical and research literature and guided by our experiences attempted to discern molecular and phenotypic criteria to improve the classification and identify molecular targets for therapy of CD30-positive cutaneous lymphomas. RESULTS: Functional studies of ALCL cell lines clonally derived from LyP have revealed loss of growth inhibition by transforming growth factor beta (TGF-beta), due to TGF-beta receptor mutations. Studies of genetic variants of the CD30 promoter showed distinct microsatellite alleles associated with development of LyP and lymphoma progression. Studies of LyP and cutaneous ALCL tissues and cell lines suggest a dual role for CD30/CD30 ligand interactions in regression of LyP and progression to lymphoma. CD30 signaling activates NF-kappaB in cell lines derived from cutaneous ALCL but not anaplastic lymphoma kinase (ALK)-positive systemic ALCL in which growth arrest occurs through cell cycle inhibitor p21WAF1/Cip1. Other likely biomarkers of disease progression include differential expression of Bcl-2, fascin, cutaneous lymphocyte antigen, and T-cell receptor clonality. These may lead to improved classification, diagnoses, and therapeutic targets. CONCLUSIONS: The current clinicopathologic classification of CD30+ cutaneous lymphoproliferative disorders is insufficient. Incorporating genetic and molecular criteria would better define the borders between benign/ malignant and aggressive/nonaggressive disorders.

The diagnosis, management, and role of hematopoietic stem cell transplantation in aggressive peripheral T-cell neoplasms.

BACKGROUND: Peripheral T-cell neoplasms (PTCNs) comprise a group of uncommon and heterogeneous lymphoid malignancies. They are more difficult to diagnose and treat and have a worse prognosis than B-cell lymphomas. Although PTCNs initially show a significant degree of chemosensitivity, the outcome of treatment with conventional dose chemotherapy remains poor. METHODS: We reviewed the literature on the diagnosis, treatment, and collective transplant reports regarding PTCNs. RESULTS: The correct diagnosis of peripheral T-cell lymphoma requires a combination of clinical presentation, morphology, immunophenotype, and molecular study. While no specific treatment other than conventional dose chemotherapy is currently available for aggressive PTCN, histone acetylase inhibitors and monoclonal antibodies such as anti-CD7 and anti-CD52 are being studied in T-cell malignancies. The role of autologous and allogeneic transplantation is being investigated for high-risk, relapsed, and refractory PTCNs with some promising results. CONCLUSIONS: Access to hematopathology expertise in a tertiary care setting may lead to earlier and more accurate diagnoses of these diseases. PTCNs comprise a heterogeneous group of diseases with no widely accepted standard of care, and accurate determination of their histologic subtypes correlates with prognosis. Patients in first complete remission with poor risk features and patients with relapsed and refractory disease should be considered for bone marrow transplant due to the poor outcomes obtained with conventional chemotherapy.

"Virtual flow cytometry" of immunostained lymphocytes on microscopic tissue slides: iHCFlow tissue cytometry.

BACKGROUND: A method and approach is developed for fully automated measurements of immunostained lymphocytes in tissue sections by means of digital color microscopy and patent pending advanced cell analysis. The validation data for population statistic measurements of immunostained lymphocytes in tissue sections using tissue cytometry (TC) is presented. The report is the first to describe the conversion of immunohistochemistry (IHC) data to a flow cytometry-like two parameter dot-plot display, hence the technique is also a virtual flow cytometry. We believe this approach is a paradigm shift, as well as novel, and called the system iHCFlow TC. Seven issues related to technical obstacles to virtual flow cytometry (FC) are identified. DESIGN: Segmentation of a 512 x 474 RGB image and tabular display of statistical results table took 12-15 s using proprietary developed algorithms. We used a panel of seven antibodies for validation on 14 cases of mantle cell lymphoma giving percentage positive, total lymphocytes, and staining density. A total of 2,027 image frames with 810,800 cell objects (COBs) were evaluated. Antibodies to CD3, CD4, CD8, Bcl-1, Ki-67, CD20, CD5 were subjected to virtual FC on tissue. The results of TC were compared with manual counts of expert observers and with the results of flow cytometric immunophenotyping of the same specimen. RESULTS: The correlation coefficient and 95% confidence interval by linear regression analysis yielded a high concordance between manual human results (M), FC results, and TC results per antibody, (r = 0.9365 M vs. TC, r= 0.9537 FC vs. TC). The technical issues were resolved and the solutions and results were evaluated and presented. CONCLUSION: These results suggest the new technology of TC by iHCFlow could be a clinically valid surrogate for both M and FC analysis when only tissue IHC is available for diagnosis and prognosis. The application for cancer diagnosis, monitoring, and prognosis is for objective, rapid, automated counting of immunostained cells in tissues with percentage results. We report a new paradigm in TC that converts IHC staining of lymphocytes to automated results and a flow cytometry-like report. The dot plot histogram display is familiar, intuitive, informative, and provides the pathologists with an automated tool to rapidly characterize the staining and size distribution of the immunoreactive as well as the negative cell population in the tissue. This systems tool is a major improvement over existing ones and satisfies fully the criteria to perform Cytomics (Ecker and Tarnok, Cytometry A 2005;65:1; Ecker and Steiner, Cytometry A 2004;59:182-190; Ecker et al., Cytometry A 2004;59:172-181).

Lymph node grading for staging of mycosis fungoides may benefit from examination of multiple excised lymph nodes.

BACKGROUND: Lymph node (LN) histopathologic class has been shown to be a significant determinant of survival in patients with mycosis fungoides. Often, histopathologic evaluation of just 1 node is used in staging patients with cutaneous T-cell lymphoma. OBJECTIVE: We examined whether sampling multiple nodes alters the staging and prognostic group placement of patients with mycosis fungoides as compared with sampling just 1 node. METHODS: Multiple LNs were obtained from a single, local region for histopathologic evaluation and grading in 8 patients with mycosis fungoides. RESULTS: Differences in histopathologic grading using multiple nodes were found in 5 of 8 patients. There was a potential upstaging of the assigned disease stage, compared with the stage that might have been assigned had just 1 node been sampled, in 3 patients. The differences in LN grading also potentially led to differences in prognostic group placement in 4 patients. CONCLUSION: Determining histopathologic grades from multiple LNs may allow a more accurate stage and prognosis to be assigned to patients.