Intravascular T-cell lymphoma with bowel involvement Case report and literature review.код для вставкиСкачать
American Journal of Hematology 78:207–211 (2005) Intravascular T-Cell Lymphoma With Bowel Involvement: Case Report and Literature Review Geoffrey Williams,1 Ann Foyle,2 Darrell White,1 Wenda Greer,2 Steven Burrell,3 and Stephen Couban1* 1 Department of Medicine, Queen Elizabeth II Health Sciences Centre and Dalhousie University, Halifax, Nova Scotia, Canada Department of Pathology, Queen Elizabeth II Health Sciences Centre and Dalhousie University, Halifax, Nova Scotia, Canada 3 Department of Radiology, Queen Elizabeth II Health Sciences Centre and Dalhousie University, Halifax, Nova Scotia, Canada 2 Intravascular lymphoma (IVL) is a rare form of non-Hodgkin lymphoma characterized by massive proliferation of large, neoplastic cells in small- and medium-sized blood vessels. Most cases of IVL are of B-cell immunophenotype; fewer than 15 cases of T-cell IVL have been reported. A 23-year-old male presented with acute abdominal pain, fever, and tender lower abdomen. Pathology at laparotomy revealed infiltration of colonic vessels with large lymphoid cells compatible with IVL. We reviewed all cases of IVL diagnosed at the Queen Elizabeth II Health Sciences Centre in Halifax, Nova Scotia, from August 1992 to August 2002. A literature review was also performed. Five additional cases of IVL were identified at this institution during a 10-year period. Three patients presented with neurological symptoms, and two with abdominal pain. In 4 of 5 cases, patients died of lymphoma within 3 months of presentation; one patient experienced a 10-month remission. While visceral involvement with IVL is common at autopsy, IVL presenting as an acute abdomen in an immunocompetent patient has not previously been described. Among the 15 cases of T-cell IVL reported in the literature, only two occurred in people under age 30. Given the rarity of T-cell IVL, it is remarkable that three cases of T-cell IVL have been diagnosed at our institution during a 10-year period. Am. J. Hematol. 78:207–211, 2005. ª 2005 Wiley-Liss, Inc. Key words: intravascular lymphoma; bowel; angiotropic lymphoma INTRODUCTION Intravascular lymphoma (IVL), also referred to as intravascular lymphomatosis or angiotrophic lymphoma, is a rare form of non-Hodgkin lymphoma characterized by massive proliferation of large, neoplastic mononuclear cells within small- and medium-sized blood vessels. First described as an endothelial neoplasm by Pfleger and Tappeiner in 1959, they suggested the term ‘‘angioendotheliomatosis proliferans systemisata’’ . Subsequently, various terms have been used to describe this entity, including ‘‘proliferating endotheliosis’’ , ‘‘angioendotheliomatois proliferans’’ , and ‘‘neoplastic endotheliosis’’ . The origin of the malignant cell in intravascular lymphoma was debated until recent immunohistochemical studies confirmed a lymphoid origin . Most IVL cases are B-cell tumors, with fifteen reports of T-cell IVL described in the literature [6–9]. The reason for the intravascular predilection of these cells is not known, but lack of specific adhesion ª 2005 Wiley-Liss, Inc. molecules, such as lymphocyte function-associated antigen 1, on the neoplastic cells may be important . IVL is a systemic condition that commonly affects the nervous system, presenting as multifocal cerebrovascular events, paraparesis, encephalopathy, and peripheral neuropathies due to occlusion of blood vessels  and direct neuronal infiltration . Cutaneous involvement is also common . Unlike in other lymphomas, lymph nodes and bone marrow are rarely affected . Systemic symptoms including fever and weight loss are common. Patients are typically middle-aged to elderly, *Correspondence to: Stephen Couban, Department of Medicine, Dalhousie University and Queen Elizabeth II Health Sciences Centre, Room 417, Bethune Building, 1278 Tower Road, Halifax, Nova Scotia, Canada B3H 2Y9. E-mail: firstname.lastname@example.org Received for publication 9 December 2003; Accepted 21 July 2004 Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ajh.20253 208 Case Report: Williams et al. although IVL has been described in a stillborn  and a teenager . The variable and nonspecific presentation may delay diagnosis, which is often made at autopsy. Combination chemotherapy has resulted in long-term remissions in some patients [15,16]. We report a 23-year-old man with T-cell IVL who presented with acute abdominal pain due to ischemic bowel. To our knowledge, this is the first case of IVL presenting as an acute abdomen in an immunocompetent individual. We have also reviewed five additional cases of IVL from our institution from the past 10 years. METHODS We reviewed all cases of IVL diagnosed at the Queen Elizabeth II Health Sciences Centre in Halifax, Nova Scotia, between August 1992 and August 2002. A literature review and bibliographic search of references was also undertaken with standard internet search engines using key words: ‘‘intravascular lymphoma,’’ ‘‘angiotropic lymphoma,’’ and ‘‘T-cell.’’ T-cell clonality was assessed using a PCR-based method described by Diss et al. . Two reactions with primers VgI and VgIII/IV and Jg1/2 are reported to detect 80% of T-cell gamma gene rearrangements. B-cell clonality was similarly assessed using nested PCR with consensus primers for the variable and joining regions as described by Reed et al. . This approach is reported to detect 83% of immunoglobulin heavy chain rearrangements. RESULTS Case Report A 23-year-old previously healthy man presented with a 4-day history of lower abdominal and lumbosacral back pain. The patient was febrile and had a markedly tender lower abdomen. There was no lymphadenopathy or hepatosplenomegaly. Complete blood count and lactate dehydrogenase were normal. The initial clinical diagnosis was acute diverticulitis, and the patient was admitted for intravenous antibiotics. He did not improve, and a CT of the abdomen and pelvis revealed changes suggestive of inflammation with mucosal thickening of the right and transverse colon (Fig. 1). Peritoneal signs developed, and the patient was taken to laparotomy. At laparotomy, a small amount of clear fluid was found in the abdomen. The bowel wall was inflamed with small bowel distension and atony. There was no evidence of Crohn disease. Colotomy of the transverse colon showed a granular appearance with no definite ischemia. The bowel was abnormal from the caecum to the splenic flexure, suspicious for a toxic process such as ulcerative colitis. A subtotal colectomy with ileostomy was performed. The patient did Fig. 1. CT scan demonstrates marked mucosal thickening involving the hepatic flexure of the colon (arrows) as well as abnormal enhancement throughout the transverse colon (arrowheads). The abnormal wall thickening extends from the cecum to just proximal to the splenic flexure. well post-operatively and was discharged, returning 2 weeks later with recurrent abdominal and back pain and watery discharge from his ileostomy. Abdominal films did not suggest new pathology, and these symptoms improved with chemotherapy. Pathology revealed infiltration of colonic vessels by large lymphoid cells (Fig. 2A,B) with immunohistochemical features of T-cell (CD3+, CD5+) non-Hodgkin lymphoma (Fig. 2C). The pathology is typical of intravascular lymphoma. Although hepatosplenic T-cell lymphoma can also be sinusoidal, the clinical presentation is different, with splenic involvement and medium-sized cells rather than large-sized cells in that disorder. Bowel wall ischemia with necrosis was present. Mesenteric lymph nodes were negative for lymphoma. Interestingly, DNA extracted from the paraffin-embedded colon demonstrated evidence of an immunoglobulin heavy chain gene rearrangement, but no T-cell receptor gene rearrangement was found. Peripheral smear showed only normocytic anemia, and a bone marrow aspirate and biopsy were negative for lymphoma. CT thorax, abdomen, and pelvis did not reveal any nodal involvement. MRI head was normal. The patient was diagnosed with a T-cell intravascular non-Hodgkin lymphoma and received 8 cycles of CHOP chemotherapy followed by 8 treatments of prophylactic intrathecal methotrexate. He remains well with no clinical or radiologic evidence of disease 16 months following completion of therapy. Case Series We identified five additional cases of IVL in a systematic review of 1192 cases of lymphoma at our Case Report: Intravascular Lymphoma 209 institution over a 10-year period (1992–2002) (Table I): 2 males and 3 females with a median age at presentation of 64 years (range 38–73 years). Three patients presented with neurological symptoms. Two patients had leg weakness, one of which progressed to paraparesis, while the other developed tremor and migraine-like headaches. Two patients presented with abdominal pain, one due to mesenteric ischemia and the second due to multiorgan visceral involvement. Two patients were diagnosed postmortem. Two cases were of T-cell immunophenotype and three were of B-cell immunophenotype, as assessed using immunohistochemistry (CD3+ and CD5+ for T cells and CD20+ for B-cells). The median survival from presentation of the 3 patients who were diagnosed prior to death was 8 months (range 2–10 months). Both patients with T-cell IVL died within 4 months of presentation. Bone marrow involvement was found in one patient, and no patient had clinical, radiologic, or pathologic evidence of lymph node involvement. Lactate dehydrogenase was elevated in all but one case. Three patients in whom autopsy was performed showed multiorgan involvement with sparing of bone marrow, spleen, and lymph nodes. DISCUSSION Fig. 2. (A) Mucosal ulcer overlying the fatty submucosa of the ileocecal valve. Note the granulation tissue at the base with exudate on the surface. Vessels in the lower right are distended and occluded by neoplastic cells (hematoxylineosin stain, original magnification 2·). (B) Distended, thinwalled vessel filled with large malignant cells (hematoxylineosin, original magnification 40·). (C) Vessels containing neoplastic cells with an immunostain against CD3 (original magnification 25·). Intravascular lymphoma is a rare type of non-Hodgkin lymphoma, which may be of either B- or T-cell immunophenotype. First described in 1959 as an unusual cutaneous small vessel neoplasm , it has since been reported in various extranodal sites. Several reports using standard immunohistochemical techniques have confirmed the lymphoid origin of the malignant cells , and while the etiology is unclear, associations with Epstein-Barr virus  and human T-cell lymphotropic virus  have been suggested in individual cases. Intravascular lymphoma cells are usually not found extravascularly, and bone marrow and lymph node involvement is rare . The reason for the intravascular predilection of these cells is not known. It may result from an abnormal interaction between homing receptors of lymphocytes and cell adhesion molecules of endothelial cells within high endothelial venules . Lack of expression of a lymphocyte adhesion molecule may impair these cells’ ability to exit from blood vessels and reach interstitial tissues. LFA-1 (lymphocyte function-associated antigen-1), a lymphocyte adhesion molecule, was not detectable in intravascular lymphoma cells . However, this antigen is also decreased or absent in other B-cell lymphomas, suggesting that additional abnormalities must account for the unique intravascular predilection of the malignant cells. T-cell IVL has usually been described in patients between 50 and 70 years of age. One case has been reported in a young adult  and one in a stillbirth 210 Case Report: Williams et al. TABLE I. Summary of Index Case and Case Series Patient Age (years) Presentation Immunophenotype K.C. (index case) 23 Abdominal pain T-cell B.V. O.G. R.S. C.K. H.B. 62 73 64 38 67 Right upper quadrant pain Progressive leg weakness Paraplegia Migraine headache and tremor Fatigue and epigastric pain T-cell T-cell B-cell B-cell B-cell . Prognosis is poor, and only two reported cases of survival beyond 1 year have been described [9,11]. There have been two reports of autologous bone marrow transplantation in patients with IVL, and both patients remained in remission at the time of publication of the reports [22,23]. Most cases of T-cell IVL have presented with neurologic or cutaneous involvement or fever of unknown origin . Other presentations include interstitial lung disease  and infiltration of a testis . Postmortem studies have shown that most cases have multiorgan involvement. Renal involvement is particularly common, suggesting that renal biopsy may be both a means of diagnosis and to follow response to treatment . Random skin biopsies were used as a means for diagnosing IVL in two patients . The case of T-cell IVL we have described is unique since the presentation with an acute abdomen has not previously been described in an immunocompetent individual. Interestingly, a review of cases at our institution revealed another patient with T-cell IVL who also presented with abdominal pain. A case of T-cell IVL of the appendix has also been reported in a teenager with HIV . This raises the question of whether T-cell IVL may have a particular predilection for the vascular system of the gastrointestinal tract and suggests that it should be considered as a very rare cause of acute abdominal pain. The young age of our patient at presentation and his response to therapy are also notable features of this case. Molecular analysis revealed a monoclonal immunoglobulin heavy-chain gene rearrangement, and polyclonality of the T-cell receptor gamma gene appears to be inconsistent with the positive immunohistology staining for T cells. This PCR analysis, however, does not detect approximately 20% of T-cell clones. Furthermore, it is well documented that a small proportion of T-cell lymphomas have rearranged immunoglobulin and T-cell receptor genes . A systematic review of consecutive cases of lymphoma at our institution revealed five additional cases with IVL over a 10-year period. These cases are comparable with those reported in the literature, except for the relatively high (3/6) proportion of T-cell IVL. The proportion of patients with T-cell IVL in our series is unusual because Interval from diagnosis to death (weeks) N/A (in remission for >100 weeks) Postmortem diagnosis 8 40 32 Postmortem diagnosis Treatment CHOP None CHOP CHOP + cranial radiation CHOP None only 15 cases of T-cell IVL have been published. The immunophenotype of most cases of IVL is usually established using immunohistochemical studies, and several studies have identified more than one population of lymphoid cells, with the predominant cell type reported as the IVL cell of origin. Few studies have confirmed clonality with PCR technique . This may indicate that the T-cell phenotype is either under-reported or not distinguished from B-cell phenotype on pathology. 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