Dennis H. Wright

Enteropathy-Type Intestinal T-Cell Lymphoma: Clinical Features and Treatment of 31 Patients in a Single Center

PURPOSE We report the clinical features and treatment of 31 patients with a diagnosis of enteropathy-type intestinal T-cell lymphoma treated at the Wessex Regional Medical Oncology Unit in Southampton between 1979 and 1996 (23 men, eight women). PATIENTS AND METHODS Patients were identified from our lymphoma database. Details of history, physical examination, staging investigations, treatment, and outcome were taken from patient records. RESULTS Twelve patients (35%) had a documented clinical history of adult-onset celiac disease, and a further three had histologic features consistent with celiac disease in resected areas of the small bowel not infiltrated with lymphoma. After diagnosis, 24 (77%) of the 31 patients were treated with chemotherapy; the remaining seven had surgical treatment alone. More than half were unable to complete their planned chemotherapy courses, often because of poor nutritional status; 12 patients required enteral or parenteral feeding. A response to initial chemotherapy was observed in 14 patients (complete response, n = 10; partial response, n = 4). Observed complications of treatment were gastrointestinal bleeding, small-bowel perforation, and the development of enterocolic fistulae. Relapses occurred 1 to 60 months from diagnosis in 79% of those who responded to initial therapy. Of the total 31 patients, 26 (84%) have died, all from progressive disease or from complications of the disease and/or its treatment. The actuarial 1- and 5-year survival rates are 38.7% and 19.7%, respectively, with 1- and 5-year failure-free survival rates of 19.4% and 3.2%, respectively. CONCLUSION The prognosis for these patients is poor. This, in part, reflects late diagnosis and poor performance status at the time of presentation. The role of salvage treatments and high-dose chemotherapy at relapse is not clear. However, it is encouraging that there are five long-term survivors in our patient population.

EPSTEIN–BARR VIRUS (EBV) INFECTION IN INFECTIOUS MONONUCLEOSIS: VIRUS LATENCY, REPLICATION AND PHENOTYPE OF EBV-INFECTED CELLS

Primary Epstein–Barr virus (EBV) infection may manifest itself as a benign lymphoproliferative disorder, infectious mononucleosis (IM). EBV infection has been characterized in lymphoreticular tissues from nine patients with IM using the abundantly expressed EBV‐encoded nuclear RNAs (EBERs) as a marker of latent infection. Expression of the virus‐encoded nuclear antigen (EBNA) 2 and of the latent membrane protein (LMP) 1 was seen in variable proportions of cells in all cases. Double labelling revealed heterogeneous expression patterns of these proteins. Thus, in addition to cells revealing phenotypes consistent with latencies I (EBNA2−/LMP1−) and III (EBNA2+/LMP1+), cells displaying a latency II pattern (EBNA2−/LMP1+) were observed. Cells expressing EBNA2 but not LMP1 were also detected; whilst this may represent a transitory phenomenon, the exact significance of this observation is at present uncertain. EBER‐specific in situ hybridization in conjunction with immunohistochemistry revealed expression of the EBERs mainly in B‐lymphocytes, many of which showed features of plasma cell differentiation. By contrast, convincing evidence of latent EBV infection was not found in T‐cells, epithelial or endothelial cells. Double‐labelling immunohistochemistry revealed expression of the replication‐associated BZLF1 protein in small lymphoid cells, often showing plasmacytoid differentiation. There was no unambiguous expression of this protein in other cell types. These results suggest that B‐cells are the primary target of EBV infection and that plasma cells may be a source of infectious virus found in the saliva of IM patients.

Malignant histiocytosis of the intestine: Its relationship to malabsorption and ulcerative jejunitis

The clinical and histopathologic features in seven patients with intestinal lymphoma are reported. Three of these presented with ulcerative jejunitis and four with overt lymphomas. A short history of abdominal pain with weight loss followed by intestinal obstruction, hemorrhage, or perforation characterized all the patients except one in whom a nine year history of malabsorption preceded the acute phase of the disease. Malabsorption was demonstrated in four of the patients, and all showed villous atrophy with crypt hyperplasia of the jejunum remote from areas of ulceration or frank lymphoma. The malignant lymphoma cells showed varying degrees of pleomorphism and exhibited phagocytosis of platelets, red cells, and cell debris. The accompanying infiltrate of inflammatory cells often overshadowed the neoplastic histiocytes, and in those cases showing little pleomorphism these cells could be easily overlooked. In the intestine the tumor cells were usually present as a diffuse infiltrate in the lamina propria or within the bases of ulcers and in five of seven cases did not give rise to macroscopic tumor masses. In all patients dissemination of tumor cells to the lymph nodes, liver, spleen, and bone marrow was evident, the infiltrate in all these organs resembling that seen in malignant histiocytosis. The morphology of the tumor cells, their phagocytic nature, the diffuse character of the tumor infiltrate, and the pattern of dissemination suggest that this lesion should be designated malignant histiocytosis of the intestine rather than histiocytic lymphoma (reticulum cell sarcoma). It is suggested that the tumor may arise from cells of monocyte-histiocyte lineage normally present in the lamina propria of the gut and that a prolonged cryptic phase accompanied, and often overshadowed, by an inflammatory reaction may give rise to malabsorption and ulcerative jejunitis before overt lymphoma is manifest.

Identification of tissue histiocytes on paraffin sections by a new monoclonal antibody.

A mouse monoclonal antibody (MAC 387) with specificity for monocytes and tissue histiocytes was produced by immunization of a BALB/c mouse with peripheral blood monocyte components derived by affinity chromatography of detergent-solubilized monocyte material on Sepharose 4B coupled to rabbit anti-monocyte antibodies. MAC 387 strongly stained the cytoplasm of cells of the monocyte/macrophage series on paraffin sections after controlled trypsinization of sections. The antibody showed broad reactivity for a variety of tissue histiocytes, including infiltrating and reactive histiocytes, alveolar macrophages, Kupffer cells, follicle-center macrophages, splenic red pulp macrophages, tumor-infiltrating macrophages, sinus histiocytes, epithelioid giant cells (variably), and cases of histiocytosis X and dermatopathic lymphadenopathy. Molecular weight data obtained by Western blotting, immunoprecipitation, and immunoaffinity-purification revealed that the antigen was present in different forms in the monocyte and granulocyte. In the granulocyte, free alpha (Mr 12 KD) and beta (Mr 14 KD) chains expressing the MAC 387 epitope were found together with associations of one alpha and one beta chain linked by disulfide bonds to yield a heterodimer of Mr 26 KD. In the monocyte, free alpha and beta chains are not found, but instead the heterodimer and associations of two (Mr 56 KD) and four (Mr 112 KD) heterodimers are disulfide-linked together. This new monoclonal reagent should have particular value for identification of tissue histiocytes in routine paraffin sections and particularly for demonstration of histiocytes in malignant lymphomas.

Primary malignant lymphoma of the thyroid--a tumour of mucosa-associated lymphoid tissue: review of seventy-six cases.

Seventy‐six cases of primary thyroid lymphoma have been reviewed employing the Kiel classification. These lymphomas are almost entirely of follicle centre cell origin, occur predominantly in elderly females, and are frequently associated with lymphocytic thyroiditis or Hashimotos disease. The overall prognosis is variable, with long‐term survival in a substantial number of cases following thyroidectomy and radiotherapy. Results of histological examination including immunoperoxidase studies are described. It is proposed that thyroid lymphoma represents a neoplasm of mucosa‐associated lymphoid tissue (MALT), and the implications of this are discussed.

Primary gastrointestinal lymphomas: a classification of 66 cases.

Using routine histology, resin embedded sections and immunohistochemical techniques on formalin‐fixed, paraffin processed tissue, 66 cases of primary gastrointestinal lymphoma have been classified. This study necessitated the development of reliable criteria to separate lymphomas of true histiocytic origin from those of lymphocytic origin. Among the morphologic properties of malignant histiocytes were complex pleomorphic nuclei, abundant well delineated cytoplasm and phagocytosis. These cells were shown to contain all major immunoglobulin chains, C3, Iysozyme and in some cases al1 antitrypsin. Malignant lymphomas derived from histiocytes could be divided into two groups: malignant histiocytosis of the intestine (MHI), a recently described diffuse pleomorphic lymphoma associated with villous atrophy of the small intestine, and histiocytic lymphoma (HL) which forms solid tumor masses in a similar manner to lymphocyte derived tumors. Immunohistochemical studies of lymphocyte derived tumors were negative apart from one case with plasmacytoid differentiation. Of the 66 cases, 50% were of histiocytic origin (33% MHI, 17% HL) and 41% of lymphocyte origin, there was one case of Hodgkins disease and five cases were unclassified. The role of the histiocyte in gastrointestinal mucosa deserves further study.

Is adult-onset coeliac disease due to a low-grade lymphoma of intraepithelial T lymphocytes?

Enteropathy-associated T-cell lymphoma commonly presents with malabsorption, and debate continues as to whether adult-onset coeliac disease (CD) is itself a form of low-grade lymphoma. A 59-year-old man with adult-onset CD required resection of a segment of oedematous jejunum. Histological examination of this tissue revealed an intense intraepithelial lymphocytosis. Immunophenotypic (CD3-, CD4-, CD8-, CD34-, and CD45 RO-) and cytogenetic (deletion of the Y chromosome and chromosome 9) abnormalities were found, together with monoclonal T-cell-receptor gene rearrangements. Some patients with adult-onset CD may have low-grade lymphoma from the outset of their illness.

Biopsy pathology of the lymphoreticular system

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The nature of the immunoglobulin-containing cells in malignant lymphoma: an immunoperoxidase study.

Using the immunoperoxidase technique, an attempt has been made to accurately characterize immunoglobulin (Ig)-containing cells in 185 cases of human malignant lymphoma. By applying a variety of antisera Ig synthesizing cells can be distinguished from cells taking up Ig from the environment. The use of thin (1 mu) paraffin sections has permitted detailed comparison to be made between Ig synthesizing cells of follicle center cell lymphomas and those of reactive follicle centers in human tonsils. Using cell pellets, similar comparison has been made with peripheral blood lymphocytes synthesizing Ig following stimulation with pokeweed mitogen. In follicle center cell lymphomas Ig synthesis is a function of cleaved and noncleaved follicle center cells, not plasma cells, and these cells are strikingly similar to Ig synthesizing cells normally present in nonneoplastic reactive follicle centers and the cells that synthesize Ig following pokeweed stimulation of peripheral blood lymphocytes. these results suggest pathways of B-cell maturation different from those commonly proposed and help to clarify certain inconsistencies in the classification of malignant lymphomas.

Lymphocyte predominance Hodgkin's disease—an immunohistochemical study

Lymph node biopsies from 57 local and referred cases, previously diagnosed at Southampton between 1978 and 1987 as lymphocyte predominance Hodgkins disease were examined using the monoclonal antibodies MT1, UCHL1, L26, LN‐1, E29/68 (EMA), Leu‐M1 (CD15) and Ber‐H2 (CD30). Of the 34 cases with a nodular architecture, 21 (19 male, two female) contained polylobated Reed‐Sternberg cell variants with a B‐cell phenotype, which lacked expression of CD15. In all cases, the polylobated cells showed positive staining with L26 and LN‐1. Six cases expressed EMA and three showed positive staining with Ber‐H2. Two cases lacking polylobated cells were reclassified as reactive follicular hyperplasia with progressive transformation of germinal centres. The remaining 11 cases had an atypical immunophenotype and were reclassified, mainly as mixed cellularity Hodgkins disease. In six cases, the lymph node architecture showed a mixture of nodular and diffuse growth patterns. Five of these cases contained polylobated cells with the typical morphology and immunophenotype of those seen in nodular lymphocyte predominance Hodgkins disease. The sixth case contained cells expressing CD15, and was reclassified as nodular sclerosing Hodgkins disease. Of the fifteen biopsies with a diffuse architecture, four contained polylobated B‐cells lacking expression of CD15. These were considered to be diffuse lymphocyte predominance Hodgkins disease. The remaining 11 cases were reclassified as either Hodgkins disease, mixed cellularity or as T‐cell lymphomas.