James Linder

Mantle zone lymphoma a clinicopathologic study of 22 cases

A clinicopathologic analysis of 22 cases of mantle zone lymphoma (MZL) was performed. In lymph node sections, MZL was characterized by the proliferation of neoplastic small lymphoid cells in wide mantles around benign germinal centers. Eighteen cases were of the intermediate lymphocytic type and four cases were of the small lymphocytic type. Immunohistologic analysis of paraffin sections revealed the following characteristic immunophenotype of MZL: L26, LN2, NUB1 and T2/48 positive, and LN5, LN1, AF6 and UCHL1 negative. The immunophenotype of MZL was identical to that of normal primary lymphoid follicles and the mantle zones of secondary follicles, except for the absence of staining with LN5 in MZL. The median age of the patients was 63 years, and the male‐to‐female ratio was 1.2:1. B symptoms were present in 55% of the patients, and 81% had splenomegaly. An absolute lymphocytosis was present at the time of initial diagnosis in 13% of the patients, and 67% had bone marrow involvement by lymphoma. Thirteen percent of the patients had Stage II disease, 23% had Stage III disease, and 64% had Stage IV disease. All 22 patients received some form of therapy, with 73% receiving multiagent chemotherapy. Eleven patients achieved a complete remission at some time during their course. The overall median survival of the entire group was 88 months. Clinical features which appeared to influence survival adversely included an absolute lymphocyte count above 4000/μl, a platelet count less than 100,000/μl, and male sex. Achievement of a complete remission at any time favorably influenced survival. Pathologic features which appeared to influence survival adversely were a mitotic rate of 10 or more per 10 high‐power fields (HPF) and the presence of 40 or more large lymphoid cells per 10 HPF. These findings lead the authors to conclude that MZL is a distinctive form of low‐grade non‐Hodgkins lymphoma.

Chromosomal abnormalities in indolent lymphoma

Cytogenetic studies were performed on lymph node biopsies from 60 patients with indolent (low grade) non-Hodgkins lymphoma. Thirty-two of the 39 successfully cultured biopsies had abnormal clones. The 32 abnormal clones represented the following histologies: seven small lymphocytic lymphoma (SL), eight follicular small cleaved cell lymphoma (FSC), 14 follicular mixed, small cleaved, and large cell lymphoma (FM), and three composite lymphomas. One of the composite lymphomas had FSC/DSC (diffuse small cleaved cell) and the other two FM/DM (diffuse mixed, small cleaved and large cell). Twenty-seven of the 32 biopsies were immunologically typed, and all were B cell. The clones all exhibited more structural than numerical abnormalities, and there was no difference in the modal chromosome number of the abnormal clones found in each histology. Biopsies with no normal cells were more frequently found in the SL histology (71%) than in the two follicular lymphoma groups (54%-55%). A translocation of the 14q32 segment was the most common abnormality found in all three histologies. In the follicular lymphomas a t(14;18)(q32;q21) was seen in 52% (13 of 25) of these patients, this translocation was not observed in the SL patients. Overall 84% (21 of 25) of the follicular lymphoma patients had abnormalities of 14q32 and/or 18q21. Other specific abnormalities included anomalies of chromosome #3 in FM, an abnormal 10q in FSC and FM lymphoma, and a high incidence of +18 and chromosome #1 abnormalities in patients with t(14;18). The presence of specific chromosome abnormalities in the indolent lymphoma patients suggests a relationship between certain karyotypic features and histology.

Oncological Consequences of Impaired Immune Surveillance Against Ubiquitous Viruses

The immune system is constantly challenged by ubiquitous viruses. Multiple immune defenses have evolved to meet these challenges, and thus immunocompetent individuals successfully respond to infection without sequela. X-linked lymphoproliferative syndrome patients, renal allograft recipients, and acquired immunodeficiency syndrome patients share impaired immune surveillance as a common feature. Such individuals are variously susceptible to numerous untoward complications following infection with Epstein-Barr virus, cytomegalovirus, herpes simplex virus, human papillomavirus, and hepatitis B virus. We hypothesize that failure of the immune system to control these viruses is instrumental in the occurrence of some B-cell lymphomas, Kaposis sarcoma, and squamous-cell and hepatocellular carcinomas, Herein we review some mechanisms responsible for the breakdown of immune surveillance and the permissive role immunodeficiency plays in viral oncogenesis.

Thymic lesions in fatal infectious mononucleosis

Thymic lesions were studied in 35 patients with fatal infectious mononucleosis (FIM) including 21 males with the X-linked lymphoproliferative syndrome (XLP) and 14 non-XLP patients. Six patterns based on the lymphocyte content and status of Hassalls bodies were observed: massive lymphoproliferation effaced the architecture and Hassalls bodies (HB) in 6 cases. Epstein-Barr virus (EBV)-laden B cells surrounded by cytotoxic T cells and natural killer cells were found in one of these cases. Only 5 of the 35 thymuses contained normal-appearing HB. Seven showed a moderate reduction in HB. Rarely, multinucleated giant cells and hyaline globules were seen where one might expect HB to reside. Plasma cells and macrophages were generally abundant. Eight displayed a marked depletion of HB. In 7, no HB were recognized. Massive necrosis was seen in one of these cases. Stress involution was encountered in only two patients, both of whom had sporadic fatal IM. Thymic lesions and alterations were similar but less extensive in sporadic FIM. These morphological studies, taken in context with clinical and experimental reports, suggest that destruction of thymic epithelium may contribute to the progression of immune defects seen in XLP following EBV infection. The destruction of HB that we observed was similar in appearance to lesions in several other immune deficiency disorders.

The Promise and Perils of CNS Drug Delivery: A Video Debate

Neurodegenerative and infectious disorders related to host genetics, aging, and environment are rapidly increasing. Drugs, vaccines, or regenerative proteins offer “real” possibilities for positively affecting disease outcomes but are limited by access across the blood-brain barrier. New developments in nanomedicine and cell based drug delivery are becoming available. These discoveries can lead to improved neurological disease outcomes. Such obstacles include the toxicities inherent in the delivery systems de novo such as immuno- and neurological dysfunctions and perturbations of blood-brain barrier function. This debate by leading experts in the field highlights the promise and perils of CNS drug delivery. Click on Supplemental HTML to watch the streaming video.

Cutaneous necrotizing granulomatous vasculitis with evolution to T-cell lymphoma

The evolution of unusual cutaneous vasculitis to a systemic T cell lymphoma was observed over a 12-year period. Precise classification of the skin biopsy specimens during the course of this patients illness was difficult. Different observers suggested malignant hemangioendothelioma, malignant lymphoma, regressing atypical histiocytosis, and granulomatous vasculitis. In retrospect, the biopsy specimens likely represented the spectrum of cutaneous lymphomatoid granulomatosis. This condition is yet another example of a reactive lymphoid proliferation proceeding to a malignant lymphoma.

Lung Cancer Cytology Something Old, Something New

The diagnosis of lung cancer by cytologic methods is of historic interest because it was an early demonstration that malignancy could be diagnosed by examining exfoliated cells. As reviewed by Johnston and Frable,1 Donne and Walsh separately noted that exfoliated respiratory cells occurred in sputum in 1845. The first major series of patients in which the examination of sputum led to a diagnosis of lung cancer was by Hamplen in 1919; 13 of 25 cases were successfully diagnosed. After several years of quiescence, pulmonary cytology enjoyed a period of rapid development in the 1970s and 1980s, particularly as fine-needle aspiration (FNA) was validated as an alternative to open lung biopsy or transbronchial biopsy for the diagnosis of pulmonary malignant neoplasm and infectious and inflammatory lung diseases. During this time, technical advances in radiologic technique permitted the imaging of small lesions and guidance of aspiration biopsy, as well as improvements in the design of bronchoscopes. Despite the important advances we are observing in body imaging (eg, spiral computed tomography [CT] scanning of the chest) and molecular diagnostics, it is encouraging that the morphologic examination of respiratory material still contributes substantially to diagnosis and patient management. This is illustrated in the work by Sturgis and colleagues2 in this issue of the Journal. Their statistical analysis of the cytomorphologic features of small cell carcinoma (SCCa) of the lung provides insight into the morphologic subclassification of lung cancer. Before commenting on their observations, it is useful to summarize the 5 major techniques to obtain cellular material for the diagnosis of lung cancer. The oldest and most fundamental method is sputum collection, which depends on the spontaneous exfoliation of cells. There are 3 bronchoscopic techniques: bronchial washing, bronchial brushing, and bronchoalveolar lavage. Finally, FNA techniques can be performed through the chest wall under radiographic guidance or transbronchoscopically. No collection method is necessarily superior to the others. The choice of cell collection technique is shaped by factors such as the personal preference of the physician, the status of the patient, the location of the lesion, and the differential diagnosis. However, the cytologist should understand that while cells obtained by different techniques have substantially similar morphologic characteristics, important differences are caused by differences in cell preservation and specimen processing. An example is the different sensitivity for lung cancer detection between freshly smeared and fixed, blended sputum specimens. Artifacts caused by the mechanical blending of the specimen lower the sensitivity of disease detection for small cell undifferentiated carcinoma and adenocarcinoma. The mechanical blending disrupts cell fragments and shears mucin-containing vacuoles from cells, thus complicating the diagnosis of adenocarcinoma. Fixation affects the nuclear diameter and the staining quality of the nuclear chromatin. For example, nuclei of SCCa are larger and more vesicular in samples collected by brushing or needle aspiration compared with sputum samples. In recent years, liquid-based thin-layer methods have been adopted for specimen collection and processing. These methods create unique artifacts that also must be understood by the diagnostic cytologist. The key question addressed by Sturgis et al2 is the relative value of different morphologic features in discriminating SCCa from non-SCCa (NSCCa). Of course, SCCa is not a homogeneous diagnosis. The International Association for the Study of Lung Cancer has proposed 3 categories of

Nerve growth factor receptor expression on dendritic reticulum cells in follicular lymphoid proliferations

Using an antibody to the nerve growth factor receptor (NGFR), we examined dendritic reticulum cells (DRCs) immunohistochemically in 62 formalin-fixed, paraffin-embedded lymph nodes from patients with reactive follicular hyperplasia or with various types of lymphoma. A dendritic staining pattern within germinal centers was present in 25 of 26 routinely processed lymph nodes with reactive follicular hyperplasia. In contrast, dendritic staining with anti-NGFR was present within neoplastic follicles in only three of 28 follicular lymphomas. Staining of benign, residual germinal centers with anti-NGFR was present in mantle zone lymphoma and Hodgkins disease. These findings suggest a possible role for the NGFR in the maturation and/or activation of normal DRCs. The loss of NGFR expression in most follicular lymphomas indicates that DRCs are altered as part of the neoplastic process. The possibility that DRCs may play a role in the pathogenesis of follicular lymphoma is suggested.

Infectious Mononucleosis and Complications

Infectious mononucleosis (IM) is a febrile illness of older children and young adults caused by the Epstein-Barr virus (EBV). The diagnosis is based on the triad of physical, hematologic and serologic findings. In this chapter we review the discovery of IM, the typical and atypical cases. We emphasize immunologic determination of the outcome of the infection by EBV. Several monographs discuss the historical and clinical aspects of IM (12,39,54).

Genetic Diseases, Hamartomas, and Familial Occurrence of Neoplasms

Most malignant neoplasms likely arise from the deleterious effects of environmental carcinogens. In addition, it appears that genetic predisposition or resistance governs responses of individuals to these agents. This interaction between environmental carcinogens and genetic factors has been termed ecogenetics. Ultimately, the final step in the genesis of malignant neoplasms involves molecular and/or cytogenetic alterations that free the cell from internal or external host regulatory control.