Rituximab for Non‐Hodgkin's Lymphoma: A Story of Rapid Success in Translation

Translational stories range from straightforward to complex. In this commentary, the story of the rapid and successful translation of rituximab therapy for the treatment of non‐Hodgkin''s lymphoma (NHL) is examined. Development of this monoclonal antibody therapy began in the late 1980s. In 1994, rituximab received its first approval for the treatment of NHL by the United States Food and Drug Administration (FDA). Rituximab has since been approved for additional indications and has transformed medical practice. However, the social and political implications of these rapid successes are only beginning to become clear. In this commentary, key events in the rapid translation of rituximab from the bench to bedside are highlighted and placed into this historical framework. To accomplish this, the story of rituximab is divided into the following six topics, which we believe to be widely applicable to case studies of translation: (1) underlying disease, (2) key basic science, (3) key clinical studies in translation, (4) FDA approval process, (5) changes to medical practice, and (6) the social and political influences on translation.     

Atypical cutaneous γδ T cell proliferation with morphologic features of lymphoma but with clinical features and course of PLEVA or lymphomatoid papulosis

Reactive lymphoid infiltrates of the skin composed predominantly of gamma‐delta (γδ) T cells are not well described in the literature. Herein we report a case of an otherwise healthy 4‐year‐old male who presented with a waxing and waning papular rash characterized by small, discrete crusted papules spread across his trunk, face and extremities. Clinical evaluation revealed no evidence of systemic disease. Microscopic examination revealed a dermal, perivascular infiltrate of highly atypical lymphocytes with a γδ T cell phenotype, worrisome for primary cutaneous γδ T cell lymphoma. The clinical course, however, was that of a reactive condition and prompted consideration of a diagnosis of pityriasis lichenoides et varioliformis acuta (PLEVA) and lymphomatoid papulosis (LyP). In many ways, this case defies current classification schemes and seems to expand the spectrum of reactive γδ T cell infiltrates of the skin.     

Distribution of lymphomas in Poland according to World Health Organization classification: analysis of 11718 cases from National Histopathological Lymphoma Register project - the Polish Lymphoma Research Group study

Most national lymphoma registers rely on broad classifications which include Hodgkin and non-Hodgkin lymphomas (NHL), multiple myeloma and leukaemia. In Poland the National Histopathological Lymphoma Register project (NHLR) was implemented by hematopathologists in accordance with the 2008 WHO classification into haematopoietic and lymphoid tissues. We present the NHLR data and compare lymphoma distribution in Poland, Europe, as well as in North Central and South America. Records of 11718 patients diagnosed in 24 pathology departments from all over the country were retrieved and reclassified into indolent and aggressive lymphomas according to the 2008 revised WHO classification system. DLBCL (32.9%; 2587), CLL/SLL (31.84%; 2504) and MCL (9.04%; 711) were the three most frequent NHL. The ratio of indolent to aggressive NHL was 1.72; 63.25% (4809) to 36.25% (2794) of cases respectively. Multiple myeloma was less frequent as compared to the data from population-based national cancer register (13.32% vs. 28.94%). Major differences between NHLR and European and American data on NHL subtypes concered: higher incidence of aggressive B-cell lymphomas including DLBCL, lower FL and MALT incidence rate. The percentage of unclassified lymphomas in the study was minimal due to participation of hematopathologists.     

Concomitant MDS with isolated 5q deletion and MGUS: case report and review of molecular aspects

Patients with monoclonal gammopathy of undetermined significance (MGUS) have a higher risk for the development of concomitant primary cancers such as multiple myeloma (MM) and myelodysplastic syndrome (MDS). We report the case of patient initially suffering from MGUS of the IgG lambda subtype for more than 10 yr, which evolved to MM and MDS with deletion (5q) with severe pancytopenia. Due to pancytopenia, he received dose‐reduced treatment with lenalidomide and dexamethasone. He achieved an ongoing transfusion independency after about 1 month of treatment. Bone marrow taken 14 months after start of treatment showed a complete cytogenetic response of the del(5q) clone and a plasma cell infiltration below 5%. In contrast to the development of MM in MGUS patients, the subsequent occurrence of MDS after diagnosis of MGUS is infrequent. Moreover, the biological association of MDS with MGUS is not sufficiently understood, but the non‐treatment‐related occurrence supports the pathogenetic role of pre‐existing alterations of stem cells. Here, we summarize data on concomitant MDS and MGUS/MM with particular emphasis on molecular aspects.     

Pathology updates and diagnostic approaches to hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a complex, often under-recognized hyperinflammatory immune dysregulation syndrome arising in a diverse range of clinical scenarios and conditions. The accurate and timely diagnosis of HLH is crucial for patient survival, and usually requires a high level of clinical suspicion. The histologic corollary to clinical HLH – hemophagocytosis – is neither necessary or sufficient for the diagnosis of HLH, as it may be seen in a variety of reactive conditions, or may be absent in true HLH. Nevertheless, the finding of hemophagocytosis in specific clinical situations should prompt the consideration of HLH and further testing to exclude the condition. While traditionally described in bone marrow, identification of hemophagocytosis in other tissues, including lymphoid, splenic, liver, or neural tissue, can be an important asset to the overall recognition of HLH. In this review, we discuss the underlying pathophysiology and etiologies of, morphologic aspects hemophagocytosis and its associated histologic findings in different tissues and give a brief overview of diagnostic criteria and clinical evaluation.     

Activated-cytotoxic TCRαβ+CD4+ peripheral T-cell lymphoma with hypodermal localization: Case report of a lymphoproliferative disorder probably evolved from the CD4+ cytotoxic T-cell subpopulation

The World Health Organization (WHO) classification of hematopoietic and lymphoid tumors identifies distinctive subtypes of peripheral T-cell lymphoma (PTCL), and, additionally, some PTCLs involving mostly extranodal sites like the skin. The difficulty of classifying PTCLs according to the normal stages of T-cell differentiation and the lack of definitive diagnostic markers for most of the subtypes make the diagnosis of these diseases challenging. PTCL cases which do not fit into any of the specifically defined entities are categorized as PTCL not otherwise specified (PTCL-NOS). PTCLs-NOS represent less than 2% of the total cases of T-cell lymphoma involving the skin. This article illustrates a case of a PTCL-NOS in which tumor cells have an activated cytotoxic TCRαβ+CD3+CD4+CD56+ T-cell phenotype and histopathologic features of subcutaneous panniculitis-like T-cell lymphoma, leading to a fatal outcome.     

Telehematopathology in a clinical consultative practice

We studied a series of 60 telepathology cases sent in consultation to the Department of Hematopathology from January 1, 1995, through July 31, 2000. Cases from the United States and the world representing academic, private, military, and federal sectors were reviewed. Ninety percent of patients were adults (54 of 60), and male patients outnumbered female patients 2 to 1. Ages were from 1 to 79 years (mean, 42 years). Forty-three cases were lymph nodes (72%), 14 were bone marrow or peripheral blood (23%), and 3 were from other sites (5%). Twenty-seven of the consultant diagnoses were benign (27 of 60). Twenty-nine were malignant (non-Hodgkin lymphoma, Hodgkin disease, and "other malignancy" groups), and 4 were nondiagnostic. Glass slide/paraffin tissue blocks were available in only 35 (58%) of 60 cases. The concordance rate for diagnostic telehematopathology cases with subsequent glass slide/paraffin block follow-up was 91% (29 of 32 cases). The discordance rate was 9% (3 of 32). This finding shows a high degree of diagnostic accuracy for consultative telehematopathology. Of 118 images analyzed, 58 were considered very good/good (49%), 32 were poor/very poor (27%), and 28 were fair (24%). Poor images had suboptimal resolution, color, or technical quality of transmission, and most poor images were low-power images. Additional case problems included insufficient immunoperoxidase stain availability, selection, and labeling; transmitted field selection; specimen preparation and staining; presence or absence of accompanying clinical data; and availability of ancillary studies such as flow cytometric, cytogenetic, and molecular data. From this analysis, the following recommendations are offered. To optimize telehematopathology consultation, include any additional information that have a significant influence on the final consultant diagnosis. Include any pertinent clinical information, laboratory data, special stains, immunoperoxidase stains, and molecular data. Select representative and diagnostically significant low-power and high-power fields for an accurate diagnosis. Label every immunostain or special stain submitted. Always send glass slides and tissue blocks when requested by the consultant. Optimize telemedicine microscopy and computer equipment with appropriate technical expertise, training, and support. In conclusion, the field of telepathology offers an exciting and potentially powerful solution to the problem of national and global subspecialty consultation. Hematopathology is potentially well suited to this technologically advanced marriage of computer and Internet technologies with modern microscopy, molecular diagnostics, immunophenotypic profiling, and the consultant pathologist.     

An Intriguing High Performance Liquid Chromatogram of a Double Heterozygosity for Hb Q-India/Hb D-Punjab

Cation exchange high performance liquid chromatography (HPLC) is commonly utilized as the first method of screening for thalassemias and hemoglobinopathies worldwide. This method of diagnosis requires knowledge of the clinical background and complete blood counts as well as skill and experience in interpreting the sometimes complex results produced. An asymptomatic 27-year-old pregnant North Indian woman was found to have a highly unusual chromatographic pattern with multiple unexpected peaks during routine antenatal screening. Most concerning was a C-window peak as Hb C (HBB: c.19G>A) is rare in ethnic Asian Indian populations. Cellulose acetate electrophoresis at alkaline pH (8.6) and parental screening were performed. These revealed the correct diagnosis to be a double heterozygosity for Hb Q-India (HBA1: c.193G>C) (an uncommon asymptomatic α-globin chain variant) plus Hb D-Punjab (HBB: c.364G>C) (a β-globin chain variant that is common in this region and is asymptomatic in the heterozygous state). The unexpected C-window peak was the hybrid of the abnormal α-Q-India and β-D-Punjab globin chains. Another small peak was explained as a variant Hb A₂ formed by the combination of α-Q-India and δ-globin chains. Hematopathologists should be cognizant of the complex pattern resulting from coinheritance of both α- and β-globin structural variants. Second-line testing and parental testing are invaluable in resolving unknown peaks, especially if rare or unexpected variants are being considered. Although both Hb Q-India and Hb D-Punjab are relatively common in northwestern India, to the best of our knowledge, only two recent reports describe a total of three cases of such diagnostically puzzling coinheritance.