Frequency of clonal intraepithelial T lymphocyte proliferations in enteropathy-type intestinal T cell lymphoma, coeliac disease, and refractory sprue

BACKGROUND: Clonal T cell receptor (TCR) gene rearrangements and loss of T cell antigens such as CD8 and TCR-beta in intraepithelial lymphocytes (IELs) may indicate the development of an enteropathy-type intestinal T cell lymphoma (EITCL) in patients with refractory sprue. AIMS: To define the diagnostic value of these markers in duodenal biopsies from patients with villous atrophy as a result of various underlying disorders. PATIENTS AND METHODS: Duodenal biopsies from eight patients with coeliac disease and five patients with villous atrophy caused by defined disorders were compared with three patients with refractory sprue evolving into overt EITCL, two patients with ulcerative jejunitis, and with eight patients with overt EITCL, for expression of CD3, CD4, CD8, and TCR-beta in IELs using immunohistochemistry and for clonal TCR-gamma gene rearrangements using polymerase chain reaction. In addition, biopsies from six consecutive patients with refractory sprue of uncertain cause were examined. RESULTS: Clonal TCR-gamma gene rearrangements were found in all resected tumours of patients with EITCL, in 3/8 duodenal biopsies of patients with EITCL, in 2/2 patients with ulcerative jejunitis, in 2/3 patients with refractory sprue evolving into overt EITCL, and in 1/6 patients with refractory sprue. No rearrangements were found in biopsies from patients with refractory sprue caused by defined disorders or those with coeliac disease. Clonality in duodenal biopsies was associated with an abnormal phenotype of IELs in all cases and in all but one case in patients with evidence of underlying coeliac disease. Specificity for detection of an EITCL using immunohistology was 77% for CD8 and for TCR-beta staining, and 100% for detection of a clonal TCR-gamma gene rearrangement. Sensitivity was 62% for staining with CD8 and clonality investigation, while sensitivity reached 100% for TCR-beta staining in all investigated patients with EITCL. CONCLUSIONS: Clonal proliferations of phenotypically abnormal IELs in refractory sprue represent an early manifestation of EITCL, for which the term "sprue-like intestinal T cell lymphoma" is proposed. This constellation is also found in duodenal biopsies from patients with an overt EITCL and is not related to other sprue syndromes, resulting in a high specificity for detection of an EITCL or refractory sprue evolving into EITCL. Overt EITCL may develop directly from coeliac disease without a precursor lesion (refractory sprue with clonal IELs) being demonstrable in duodenal biopsies or via a "sprue-like intestinal T cell lymphoma". This latter entity is a complication of coeliac disease.     

Malignant lymphomas in coeliac disease: evidence of increased risks for lymphoma types other than enteropathy-type T cell lymphoma

BACKGROUND: Numerous studies have reported on the association between coeliac disease and the otherwise uncommon enteropathy-type T cell lymphoma (ETTL). A systematic risk assessment of more prevalent lymphoma entities, such as B cell and non-intestinal lymphomas, in coeliac disease has not been performed. AIMS: In light of the increasing number of patients diagnosed with coeliac disease and the unknown aetiology of malignant lymphomas, we aimed to estimate the distribution and risk of lymphoma subtypes in coeliac disease. METHODS: We reviewed and reclassified 56 cases of incident malignant lymphomas occurring in a Swedish population based cohort of 11,650 patients hospitalised with coeliac disease. The observed numbers of lymphoma subtypes were compared with those expected in the Swedish population. RESULTS: The majority (n=32, 57%) of lymphomas in the cohort were not intestinal T cell lymphomas. Significantly increased risks were observed for B cell non-Hodgkin lymphoma (NHL) (standardised incidence ratio (SIR) 2.2 (95% confidence interval (CI) 1.2-3.6); 11 non-intestinal and five intestinal) and for lymphomas of non-intestinal origin (SIR 3.6 (95% CI 2.3-5.2), 11 B and 14 T cell). Furthermore, 44% of patients with B cell NHL had a history of other autoimmune/inflammatory diseases. The relative risks for T cell NHL (SIR 51 (95% CI 35-68); n=37) and for primary gastrointestinal lymphomas (SIR 24 (95% CI 16-34); five B and 25 T cell) were markedly increased, as anticipated. CONCLUSION: Most lymphomas complicating coeliac disease are indeed related to the disease and are not of the ETTL-type. There was a remarkable aggregation of autoimmune/inflammatory disorders, female sex, coeliac disease, and B cell lymphoma.     

Multiple myeloma superimposed on adult T cell lymphoma

A 77 year-old male was admitted to the hospital because of lumbago and M-proteinemia. IgA (kappa) monoclonal protein (8,100 mg/dl) was demonstrated in serum, and Bence Jones protein (kappa) in urine samples. The bone marrow examination showed an increased number of pathological plasma cells (34. 5%). Multiple osteolytic lesions were evident on X-ray films. A diagnosis of multiple myeloma (MM) was made. He had exudative erythematous skin lesions on his back. His serum was positive for antibody to ATLA. A biopsy specimen from the skin lesions showed Pautrier's micro-abscess which were filled with Leu 3a positive T lymphocytes. 159 base pairs of human T cell leukemia virus I (HTLV-I)/pX position was identified from a cutaneous sample utilizing the polymerase chain reaction method. Thus, a diagnosis of MM superimposed on adult T cell lymphoma was made. An extensive search failed to find any cases complicated with these two diseases except a report by Tagawa et al. concerning a patient with ATL who developed IgA (kappa) MM during a five year follow up. Therefore, this is the first reported case of MM superimposed on ATL.     

Very late central nervous system relapse in a patient with B cell lymphoblastic lymphoma

Very late relapse of lymphoblastic lymphoma (LBL) is very rare. We report a case of a patient who developed central nervous system (CNS) relapse of LBL 16 years after the onset of the primary disease. An 8-year-old girl was hospitalized with a skin tumor in the occipital region on November 27, 1984. Examination of a biopsy of the skin tumor showed typical features of non-Hodgkin's lymphoma (diffuse medium-sized cell type). She received multiagent chemotherapy and went into remission. On July 4, 2000, she was hospitalized with persistent headache. Cranial magnetic resonance imaging showed a cerebellar lesion, which was hypointense on T1-weighted images and of heterogeneous intensity on T2-weighted images. A midline suboccipital craniotomy was performed and pathological examination revealed a diffuse proliferation of lymphoid cells, which were positive for terminal deoxynucleotidyl transferase, but negative for CD45RO, CD3 and CD20. Tumor cells stained positively for CD10, CD22, CD38 and HLA-DR. Revised immunohistochemistry of the primary specimens of skin tumor obtained 16 years earlier revealed a phenotype similar to that of the CNS disease. Polymerase chain reaction products for the immunoglobulin gene from both the skin and cerebellar specimens were an identical size. Thus, the original diagnosis of diffuse medium-sized lymphoma was revised to B cell LBL. An isolated CNS relapse of LBL was apparent in the present case. After salvage chemotherapy, the patient underwent high-dose chemotherapy with autologous peripheral blood stem cell support and subsequent craniospinal irradiation. She went into a lasting complete remission.     

Early sequential development of infective dermatitis, human T cell lymphotropic virus type 1-associated myelopathy, and adult T cell leukemia/lymphoma.

We describe a patient with human T cell lymphotropic virus type 1 (HTLV-1)-associated infective dermatitis who developed HTLV-1-associated myelopathy/tropical spastic paraparesis and adult T cell leukemia/lymphoma at 16 years of age. Long inverse polymerase chain reaction was used to demonstrate monoclonal integration of proviral DNA in the lymphomatous skin lesion.     

Detection of Epstein-Barr virus in posttransplantation T cell lymphoma in a kidney transplant recipient: case report and review.

Posttransplantation T cell lymphomas (PTTLs) are rather unusual, and their etiology remains unclear. We describe a case of Epstein-Barr virus (EBV)-associated small bowel T cell lymphoma in a patient 5 years after kidney transplantation. EBV was detected in a biopsy sample by in situ hybridization, immunohistochemical staining, and polymerase chain reaction analysis. Eight previously reported cases of EBV-associated PTTL are reviewed, in which special attention is paid to the methods used for assessing EBV. This case of EBV-associated PTTL is believed to be the most completely studied from the point of view of the methods used for detection of EBV. The prognosis of PTTL is poor, but it has been reported that therapeutic approaches can be successful if they are given early in the course of the illness. Therefore, it is necessary to improve the diagnosis PTTL and to assess the precise involvement of EBV in posttransplantation lymphoproliferative disorders.     

Herpes simplex encephalitis and subsequent cytomegalovirus encephalitis after chemoradiotherapy for central nervous system lymphoma: a case report and literature review

Neurological complications during the treatment of hematological malignancies have a wide range of causes. Treatment-related leukoencephalopathy has been recognized as a major complication of combined chemotherapy and radiotherapy for central nervous system (CNS) lymphoma, and can complicate the diagnosis of CNS infection. Herein, we present a patient with diffuse large B-cell lymphoma who developed herpes simplex encephalitis (HSE) and subsequent cytomegalovirus encephalitis after chemoradiotherapy for CNS relapse. Although cerebrospinal fluid examination (CSF) showed no significant pleocytosis, brain magnetic resonance imaging and polymerase chain reaction analysis of the CSF were useful in the diagnosis. With a review of the literature on the association between HSE and radiotherapy for CNS malignancies, our case suggests that an awareness of viral encephalitis is important in the differential diagnosis of acute neurologic disturbance during chemoradiotherapy for CNS lymphoma.     

Type 1 diabetes mellitus, coeliac disease, and lymphoma: a report of four cases.

INTRODUCTION: Patients with Type 1 diabetes mellitus have a high prevalence of coeliac disease, symptoms of which are often mild, atypical, or absent. Untreated coeliac disease is associated with an increased risk of malignancy, particularly of lymphoma. We describe four patients with Type 1 diabetes mellitus and coeliac disease who developed lymphoma. CASE REPORTS: Two patients were male and two female. In three patients, coeliac disease and lymphoma were diagnosed simultaneously. Enteropathy-associated T cell lymphoma occurred in two patients, Hodgkin's disease in one, and B cell lymphoma in one. Response to treatment was in general poor, and three patients died soon after the diagnosis of lymphoma was made. CONCLUSION: As the relative risk of lymphoma is reduced by a gluten-free diet, a high index of suspicion for coeliac disease should exist in all Type 1 diabetic patients with unexplained constitutional or gastrointestinal symptoms.     

Molecular remission in adult T cell leukemia after autologous CD34+ peripheral blood stem cell transplantation.

This report describes a patient with acute-type adult T cell leukemia/lymphoma (ATLL) successfully treated by autologous CD34+ peripheral blood stem cell transplantation after fractionated total body irradiation and high-dose cytarabine and cyclophosphamide. A newly established inverse polymerase chain reaction method was used to demonstrate the disappearance of ATLL clonal cells. The patient achieved a sustained molecular remission after transplantation, but died from opportunistic infection 4 months after transplantation. Thus, autologous CD34+ peripheral blood stem cell transplantation is promising for this type of malignancy. However, a prudent clinical attitude toward immunological fragility after transplantation is needed for better outcome.     

Hepatitis B virus reactivation after a resolutive acute hepatitis leading to a diagnosis of T cell lymphoma

A case of hepatitis B virus reactivation leading to the diagnosis of a T cell lymphoma is reported. A 66-year-old woman with a past history (10 years before) of spontaneously recovered acute hepatitis B (with disappearance of serum hepatitis B surface antigen and appearance of anti-HBs), has been referred for hepatologic consultation for acute hepatitis. The patient was found positive again for hepatitis B surface antigen as well HBeAg and hepatitis B virus DNA. No other cause of liver disease was identified and a diagnosis of spontaneous hepatitis B virus reactivation was made. Five months later a peripheral T cell lymphoma was diagnosed. This unusual case confirms that natural immunity is not protective against hepatitis B virus reactivation and shows that such hepatitis B virus reactivation may precede the usual clinical manifestations of a peripheral T cell lymphoma.     

Pulmonary manifestations of peripheral T‐cell lymphoma: case report and review of the literature

Introduction: Peripheral T‐cell lymphomas (PTCL) represent approximately 10% of non‐Hodgkin's lymphomas. Pulmonary involvement is an uncommon manifestation of this heterogeneous group of malignancies. Methods: Report of a case. Results: This case report describes a 75‐year‐old man with fever, weight loss, anemia, enlargement of spleen and liver, atypical lymphocytes and pulmonary nodules. Lung biopsy showed lymphocytic infiltration of the lung parenchyma. T‐cell receptor gamma gene rearrangement by polymerase chain reaction confirmed the diagnosis of peripheral T‐cell lymphoma. Unfortunately, the patient died because of refractory and aggressive disease. Conclusion: Pulmonary and pleural involvement are seen in patients with PTCL and usually carry a poor prognosis. The subject of pulmonary involvement in peripheral T‐cell lymphoma is discussed. Please cite this paper as: Vahid B, Machare‐Delgado E and Marik PB. Pulmonary manifestations of peripheral T‐cell lymphoma: case report and review of the literature. The Clinical Respiratory Journal 2007; 1:114–117.     

Combination chemotherapy followed by autologous stem cell transplant for enteropathy-associated T cell lymphoma

Enteropathy-associated T cell lymphoma (EATL) is a rare entity associated with coeliac disease, with a poor prognosis due to perforation and gastro-intestinal bleeding during treatment, and a high relapse risk. Six patients were treated with two cycles of IVE (ifosphamide, etoposide, epirubicin), followed by two cycles of high-dose methotrexate (3 g/m(2)) with folinic acid rescue and a BEAM (carmustine, etoposide, cytarabine, melphalan) autograft. Enteral feeding was given throughout treatment. Four patients remain alive in complete remission at 1.83-4.32 years; two have relapsed. Given the historically poor outcome in these patients, this regimen appears very promising in the treatment of EATL.     

Changes in intraepithelial lymphocyte subpopulations in coeliac disease and enteropathy associated T cell lymphoma (malignant histiocytosis of the intestine).

Studies of the morphologic and phenotypic diversity of intraepithelial T cells in human small intestine have shown them to be heterogeneous, yet distinct from most extra intestinal T cells. In this study sequential immunoenzymatic staining was used to define new intraepithelial lymphocyte subpopulations in man. In normal human jejunum approximately 6% of the intraepithelial T cells expressing CD3 (an antigen associated with the T cell receptor) do not express the T cell subset antigens CD4 or CD8. Approximately 20% of CD7+ cells (T cells and null cells) do not express CD4 or CD8 and 14% of the CD7+ cells do not express CD3 and are therefore not T cells. The CD7+, CD3+/-, CD4-, CD8- population is concentrated in the tips of the villi. In coeliac disease, the ratios of the subsets change significantly. The percentage of CD3+, 4-, 8- cells increases to 28%, the proportion of CD7+, 4-, 8- cells remains unchanged and the CD7+, CD3- (non-T cell) population is reduced to 1.4% of the CD7+ cells. In contrast, in patients with villous atrophy of uncertain aetiology, all CD4-, CD8- lymphocyte subsets are decreased compared with normal biopsies. Finally, in enteropathy associated T cell lymphoma (malignant histiocytosis of the intestine) in which the 'uninvolved mucosa' is histologically similar to untreated coeliac disease, the changes in the intraepithelial T cell sub-sets are indistinguishable from those in coeliac disease, suggesting that the lymphoma is a complication of coeliac disease.     

Quiescent nasal T/NK cell lymphoma manifested as primary central nervous system lymphoma

A 57-year-old man was diagnosed as primary T/NK-cell central nervous system lymphoma (CNSL) with intraocular involvement. However, review of a surgical specimen taken three years before for chronic paranasal sinusitis revealed an overlooked nasal T/NK cell lymphoma (TNKL), which showed similar histomorphology and immunophenotype with the CNS disease. Another patient, a 43-year-old woman, was initially diagnosed as a rare primary leptomeningeal T-cell lymphoma with ocular manifestation. Three years later, an isolated nasal TNKL emerged. Immunohistochemical and cytogenetic studies confirmed the same nature of the CNSL and the nasal TNKL. The nasal TNKLs of both patients had a strong expression of CD3, CD56, and Epstein-Barr virus antigens, but features of angiodestruction and mucosal ulceration were absent. We propose that: 1. a locally silent “quiescent” form of nasal TNKL may exist; and 2. a thorough examination and even blind biopsy of the nasal cavity is indicated when primary T/NK-cell CNSL is diagnosed. Am. J. Hematol. 60:161–163, 1999. © 1999 Wiley-Liss, Inc.     

T cell depletion in untreated adult coeliac disease.

The proportional and absolute numbers of circulating thymus dependent lymphocytes (T cells) were reduced in untreated patients with coeliac disease but were normal after treatment with a gluten free diet. There was an inverse correlation between circulating T cell numbers and jejunal intraepithelial lymphocytes. This evidence suggests a possible role for T cells in the pathogenesis of coeliac disease and is a further example of disturbed cell mediated immunity in this condition.     

T cell gamma chain gene rearrangement without T cell receptor beta chain gene rearrangement in two cases of non-Hodgkin's lymphoma

We report two patients with non-Hodgkin's lymphoma whose neoplastic cells had rearranged T cell gamma chain (T gamma) genes, and had the germ line DNA of T cell receptor beta chain (T beta) and immunoglobulin genes. Surface marker analysis of the neoplastic cells revealed that leukemic cells from one patient were derived from common thymocytes, while in the other patient the clonality and cell lineage could not be identified, probably due to the low percentage of neoplastic cells in the specimen. No phenotypic changes were observed after cultivation with phorbol myristate acetate, except for induction of Tac antigens on cells of one patient. Leukemic cells with only the T gamma gene rearrangement are thought to be precursor T cells that differentiate into mature T cells following T beta gene rearrangement. This suggests that such T cells with only the T gamma gene rearrangement exist among common thymocytes.     

Production of a panel of recombinant gliadins for the characterisation of T cell reactivity in coeliac disease

BACKGROUND/AIMS: Coeliac disease is a chronic intestinal disorder most probably caused by an abnormal immune reaction to wheat gliadin. The identification of the HLA-DQ2 and HLA-DQ8 as the molecules responsible for the HLA association in coeliac disease strongly implicates a role for CD4 T cells in disease pathogenesis. Indeed, CD4 T cells specific for gliadin have been isolated from the small intestine of patients with coeliac disease. However, identification of T cell epitopes within gliadin has been hampered by the heterogeneous nature of the gliadin antigen. To aid the characterisation of gliadin T cell epitopes, multiple recombinant gliadins have been produced from a commercial Nordic wheat cultivar. METHODS: The alpha-gliadin and gamma-gliadin genes were amplified by polymerase chain reaction from cDNA and genomic DNA, cloned into a pET expression vector, and sequenced. Genes encoding mature gliadins were expressed in Escherichia coli and tested for recognition by T cells. RESULTS: In total, 16 alpha-gliadin genes with complete open reading frames were sequenced. These genes encoded 11 distinct gliadin proteins, only one of which was found in the Swiss-Prot database. Expression of these gliadin genes produced a panel of recombinant alpha-gliadin proteins of purity suitable for use as an antigen for T cell stimulation. CONCLUSION: This study provides an insight into the complexity of the gliadin antigen present in a wheat strain and has defined a panel of pure gliadin antigens that should prove invaluable for the future mapping of epitopes recognised by intestinal T cells in coeliac disease.     

A case of T cell lymphoma of the lung

A 70-year-old woman complained of cough, sputum and fever. Chest roentgenogram showed a mass-like lesion with pleural effusion in the left thorax. Bronchoscopy revealed a polypoid lesion at the orifice of left B10 and mucosal swelling of the left lower lobe bronchi. The biopsied material of the polypoid lesion was diagnosed as malignant lymphoma (diffuse small cell type by LSG classification) and the immunohistochemical examination showed monoclonal proliferation of T lymphocytes. The atypical lymphocytes which were positive for T lymphocyte surface marker were detected in the pleural effusion. There was no evidence of metastasis in any part of the body under clinical examinations, and the lung was thought to be a primary site of the lymphoma. The doubling time of tumor was estimated to be 134 days. Four-drug combination chemotherapy resulted in a marked decrease of the tumor size. Immunohistochemical study to determine the subpopulation of lymphoma cells are required for diagnosis of pulmonary lymphoma, because the biological characters of T cell lymphoma might differ from those of B cell lymphoma.     

Gamma/delta T cell lymphoma

A 54-year-old woman complained of fever and hepato-splenomegaly. The pathological findings of a liver biopsy specimen revealed the infiltration of lymphocytes in the sinusoids and that of the laparoscopically resected spleen revealed the infiltration of lymphocytes in the red pulp, which was positive for CD3, CD43, CD45RO and T-cell intracellular antigen-1 (TIA-1) and was negative for betaF1, while the white pulp was spared. Genetic analysis of the spleen cells revealed the rearrangement of T-cell receptor (TCR) Cbeta1, Jdelta1 and Jgamma. Epstein-Barr virus (EBV) genomic DNA was detected in the spleen cells. Atypical lymphocytes appeared in the peripheral blood and bone marrow, chromosomal analysis revealed del (13) (q12 q14), trisomy 8 and breakage of RB gene. Elevated level of serum vascular endothelial growth factor (VEGF) was observed. Hepatosplenic gammadelta T cell lymphoma (GDTL) was diagnosed. The patient was treated with chemotherapy by cyclophosphamide, hydroxydoxorubicin, vincristine and prednisolone (CHOP), however, it was ineffective, and the patient died of hemorrhage from the lymphoma involvement of the intestine 5 months after the onset of disease.