Hernani D. Cualing

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.

Dendritic cell and histiocytic neoplasms: biology, diagnosis, and treatment.

BACKGROUND Dendritic and histiocytic cell neoplasms are rare malignancies that make up less than 1% of all neoplasms arising in lymph nodes or soft tissues. These disorders have distinctive disease biology, clinical presentations, pathology, and unique treatment options. Morphology and immunohistochemistry evaluation by a hematopathologist remains key for differentiating between these neoplasms. In this review, we describe tumor biology, clinical features, pathology, and treatment of follicular dendritic cell sarcoma, interdigitating dendritic cell sarcoma, indeterminate dendritic cell sarcoma, histiocytic sarcoma, fibroblastic reticular cell tumors, and disseminated juvenile xanthogranuloma. METHODS A literature search for articles published between 1990 and 2013 was undertaken. Articles are reviewed and salient findings are systematically described. RESULTS Patients with dendritic cell and histiocytic neoplasms have distinct but variable clinical presentations; however, because many tumors have recently been recognized, their true incidence is uncertain. Although the clinical features can present in many organs, most occur in the lymph nodes or skin. Most cases are unifocal and solitary presentations have good prognoses with surgical resection. The role of adjuvant therapy in these disorders remains unclear. In cases with disseminated disease, prognosis is poor and data on treatment options are limited, although chemotherapy and referral to a tertiary care center should be considered. Excisional biopsy is the preferred method of specimen collection for tissue diagnosis, and immunohistochemistry is the most important diagnostic method for differentiating these disorders from other entities. CONCLUSIONS Dendritic cell and histiocytic cell neoplasms are rare hematological disorders with variable clinical presentations and prognoses. Immunohistochemistry remains important for diagnosis. Larger pooled analyses or clinical trials are needed to better understand optimal treatment options in these rare disorders. Whenever possible, patients should be referred to a tertiary care center for disease management.

Pathogenesis, Diagnosis, and Management of Kikuchi-Fujimoto Disease

BACKGROUND Kikuchi-Fujimoto disease (KFD) is a rare lymphohistiocytic disorder with an unknown etiopathogenesis. This disease is misdiagnosed as malignant lymphoma in up to one-third of cases and is associated with the development of systemic lupus erythematosus (SLE). METHODS The medical literature between the years 1972 and 2014 was searched for KFD, and the data were collected and analyzed regarding the epidemiology, clinical presentations, diagnosis, management, and suggested diagnostic and treatment algorithms. RESULTS Although KFD has been reported in other ethnic groups and geographical areas, it is more frequently diagnosed in young women of Asian descent. Patients with the disease typically present with rapidly evolving tender cervical lymphadenopathy, night sweats, fevers, and headache. Diagnosis is based on histopathological examination. Excisional lymph node biopsy is essential for a correct diagnosis. Apoptotic coagulation necrosis with karyorrhectic debris and the proliferation of histiocytes, plasmacytoid dendritic cells, and CD8(+) T cells in the absence of neutrophils are characteristic cytomorphology features. Interface dermatitis at the onset of KFD may be a marker for the subsequent evolution of SLE. The natural course of the disease is typically benign. Short courses of steroids, nonsteroidal anti-inflammatory drugs, or hydroxychloroquine can be administered to patients with more severe symptoms. CONCLUSIONS Although KFD was described more than 40 years ago, the etiology of this disease remains unsolved. Infectious or autoimmune processes were proposed but have not been definitively confirmed. Clinical presentation with systemic B symptoms and adenopathy may lead to an erroneous diagnosis of malignant lymphoma. The introduction of modern methods into hematopathology, including immunohistochemistry, flow cytometry, and molecular clonality studies, has decreased the probability of misdiagnosis. Until reliable prognostic markers are available, patients with KFD should have continued long-term follow-up care due to their increased risk of SLE.

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.

Immunohistochemical expression of survivin in cutaneous sebaceous lesions.

Background:Survivin is a member of the inhibitor of apoptosis family of proteins implicated in the inhibition of apoptosis and cell cycle control, both crucial in the progression to malignancy. Survivin overexpression has been demonstrated in numerous malignancies including cutaneous squamous cell carcinoma and melanoma. To date, there are no studies evaluating the expression of survivin in sebaceous neoplasms. Methods:Immunohistochemical expression of survivin was evaluated in a total of 20 extraocular sebaceous neoplasms: sebaceous hyperplasia (SH, 8), sebaceous adenoma (SA, 8), and sebaceous carcinoma (SC, 4). All the results were independently evaluated by a single dermatopathologist. Results:Nuclear expression of survivin was present in 1.4% of lesional SH cells, 8.2% of SA cells, and 12.5% of SC cells. A significant difference in survivin expression with the Student t test was noted between SH and SA (P = 0.01), SA and SC (P = 0.05), and SH and SC (P = 0.001). Conclusions:There is a statistically significant difference in survivin expression among SH, SA, and SC. These findings demonstrate the potential diagnostic utility of survivin, further assisting in the microscopic differentiation of benign and malignant sebaceous neoplasms. However, larger studies are needed to determine the significance of survivin expression as it relates to recurrence, metastatic potential, and outcome.

“Virtual flow cytometry” of immunostained lymphocytes on microscopic tissue slides: iHCFlow™ tissue cytometry

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.

PRIMARY CUTANEOUS B-CELL LYMPHOMA IN A CHILD

Primary cutaneous B-cell lymphoma is a B-cell lymphoma of the skin with no evidence of extracutaneous involvement at the time of diagnosis. In this report, we describe an 8-year-old boy who presented with a firm, alopecic, skin-colored, smooth nodule over the right frontal scalp. Histological examination revealed a mid-to deep-dermal mononuclear lesion. Immunohistochemical staining revealed a B-cell population that was CD10(+), CD5(−), CD21(+), and bcl2(−). This pattern of reactivity is characteristic of primary cutaneous B-cell lymphoma of follicle-center subtype. To the best of our knowledge, this is the first report of this type of cutaneous lymphoma in a child.

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.

Granulocytic sarcoma and chronic lymphocytic leukemia of the gastrointestinal tract after allogeneic hematopoietic cell transplantation mimicking graft-versus-host disease

Division of Blood and Marrow Transplantation, Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute and University of South Florida, Tampa, FL, USA, Division of Pathology (Hematopathology), Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute and University of South Florida, Tampa, FL, USA, and Center for Cancer Care and Research, Lakeland, FL, USA

Patterns of Lymphohistiocytic Reaction in Skin: An Approach to Cutaneous Lymphohematopoietic Infiltrate Using Histologic Patterns and Immunostains

We propose an approach to the diagnosis of atypical lymphoid infiltrates and malignant lymphomas based on histomorphologic and immunologic patterns. Our approach rests on the evidence that lymphoma patterns often are superimposed on physiologic patterns of lymphoid proliferations/hyperplasias in response to injury, infection, and antigenic stimulation. Hence, we discuss dermotropic considerations based on epidermotropic, dermatotropic, and panniculitic infiltrative lymphohistiocytic patterns. For each histologic pattern, we present histologic and immunophenotypic examples to facilitate the development of a differential diagnosis and arrival at a final diagnosis. The epidemiology and definitions of cutaneous lymphoid hyperplasia, atypical lymphoid hyperplasia, and lymphoma are also presented. Finally, we recommend a specific approach for obtaining and processing of skin specimens, particularly when lymphoma is suspected.