Diagnosis Of Hepatosplenic T-cell Lymphoma Research Articles

Hepatosplenic T-Cell Lymphoma Mimicking Acute Onset of Cholestatic Hepatitis in a Young Immunocompetent Man: A Case Report

We herein report a case of hepatosplenic T-cell lymphoma (HSTCL) incidentally found in a 30-year-old man who came to the emergency department after an ankle trauma. At admission, laboratory tests revealed abnormal liver enzymes and pancytopenia, and imaging showed mild hepatosplenomegaly. During hospitalization, the patient’s clinical condition worsened rapidly, with a concomitant increase in cholestatic enzymes, severe jaundice, and the worsening of pancytopenia. Causes of liver injury, including many infectious diseases, were explored until the diagnosis of HSTCL was made by liver and bone marrow biopsies. Subsequently, the patient underwent six cycles of chemotherapy with a CHOP (cyclophosphamide, hydroxydaunorubicin, oncovin and prednisone or prednisolone) regimen and one with Hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone) but, despite this aggressive treatment, died due to disease progression 2 months after diagnosis. This rare disease should be considered in the diagnostic workup of acute cholestatic hepatitis presenting with concomitant hepatosplenomegaly and cytopenia.

ADDRESSING THE INFILTRATIVE PATTERN: COMPLEX DIAGNOSIS

Alterations in liver function tests are frequent, so the approach based on the predominant alteration and the patient's medical history is relevant. Carrying out a liver biopsy in cases of diagnostic doubt is imperative. The objective of this work is to describe a clinical case of an infiltrative pattern approach that culminated in the diagnosis of Hepatosplenic T-cell Lymphoma (HSCTL). Clinical case report. Presentation. Woman, 72 years old. History of a sister with cirrhosis. Consumption of alcohol and herbalists; arterial hypertension and Sjögren. He was admitted for persistent fatigue and jaundice. Laboratories with anemia, thrombocytopenia and kidney injury; Hepatic biochemistry with a predominantly cholestatic pattern at the expense of alkaline phosphatase and direct hyperbilirubinemia. Without acute liver failure. By imaging the liver, vessels and normal bile duct; splenomegaly; Negative hepatitis viral panel, positive ANAs and Anti-actin, negative antimitochondrials, normal immunoglobulins. HAI vs. DILI / HILI is suspected. Liver biopsy reports HSTCL-type lymphoproliferative process (Figure 1). It was supplemented with bone marrow aspirate and PET-CT. He started prednisone and cyclophosphamide. The systematic approach to altered liver biochemistry requires integrating personal and family risk factors for liver disease. The infiltrative pattern that resembles the cholestatic one represents a diagnostic challenge as it is little recognized. In this case, we report a rare neoplasm corresponding to 5% of peripheral T lymphomas; they usually develop in young adults and in the absence of lymphadenopathy. It also has an adverse prognosis due to refractoriness to chemotherapy. The HSTCL presented in this clinical case represents a complex and infrequent diagnosis. The symptoms and age group were atypical and the identification was possible through a systematic evaluation of the infiltrative pattern and differential diagnoses. The authors declare that there is no conflict of interest.

2059 A Case of Hepatosplenic T-cell Lymphoma in a Patient on Vedolizumab for Crohn’s Disease

INTRODUCTION: Hepatosplenic T-cell lymphoma (HSTCL) is a rare malignancy, most commonly affecting young males with often fatal prognosis. In patients with inflammatory bowel disease (IBD), HSTCL has been associated with thiopurine analog and tumor necrosis factor (TNF)-α inhibitor therapy; particularly when used in combination, the risk increases up to 4 fold. Development of HSTCL has not been reported in association with vedolizumab. CASE DESCRIPTION/METHODS: A 22-year-old male with severe, stricturing colonic Crohn’s disease of 10 years duration, on vedolizumab monotherapy every 4 weeks for 15 months, was incidentally noted to be pancytopenic in October 2016 and subsequently diagnosed with HSTCL by bone marrow biopsy. Previous IBD therapies included mesalamine, azathioprine, infliximab, adalimumab, intravenous immunoglobulin (IVIG), budesonide, certolizumab pegol and most recently 6 mercaptopurine (6-MP). The 6-MP was discontinued 1 year prior to HSTCL diagnosis. He achieved remission with chemotherapy, followed by autologous stem-cell transplant in September 2017. Unfortunately his disease relapsed only a few months later. He achieved a second remission with salvage chemotherapy, and proceeded to allogeneic bone marrow transplant in April 2018. Since diagnosis of HSTCL, he did not receive any therapy for Crohn’s disease and has been asymptomatic from his IBD. Colonoscopy demonstrated complete endoscopic and histologic remission as well. On last bone marrow biopsy, over 200 days post-transplant, there was no evidence of HSTCL relapse 24 months following HSTCL diagnosis. DISCUSSION: Fortunately, our case had a favorable outcome compared to those reported in the literature with a median overall survival of 10 months, and up to 17 months in patients who receive stem cell transplant. In addition, following stem cell transplant, our patient achieved cure of his Crohn’s disease. A recent review of patients with immunoregulatory disorders who developed HSTCL noted that 56% of patients were treated with TNF-α inhibitors versus 89% with immunomodulators, indicating that the latter pose higher risk. To our knowledge, there have not been reports of HSTCL associated with vedolizumab use nor is there a known mechanism by which vedolizumab could cause HSTCL. In our case, TNF-α inhibitor was stopped 5 years prior and thiopurine analog 1 year prior to diagnosis, raising the question as to how long the risk of HSTCL remains elevated after cessation of such agents.

Hepatosplenic T-cell lymphoma: Report of two cases

Hepatosplenic T-cell lymphoma (HSTCL) is a rare type of lymphoma. Presenting with hepatosplenomegaly, fever, cytopenia without significant lymphadenopathy, most patients are young men with poor outcomes. Here is the report of two cases of HSTCL from Maharaj Nakorn Chiang-Mai Hospital, Thailand. Both patients were middle-aged men presented with prolonged fever, hepatosplenomegaly and cytopenia. Abnormal lymphoid cells, not demonstrated by flow cytometry, were microscopically revealed in the patients’ bone marrow. The diagnosis of HSTCL was based on the histopathologic section obtained from splenectomy and liver biopsy. Both patients received cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP) regimen initially while one of them was salvaged with etoposide, methylprednisolone, cytarabine, cisplatin (ESHAP) and methotrexate, high-dose cytarabine, methylprednisolone (cycle B of hyperCVAD) regimen. They responded poorly to chemotherapy and succumbed to severe sepsis. The presented cases confirmed that HSTCL is very difficult to diagnose and current treatment modalities appear to be ineffective

Coexistent hairy cell leukaemia and hepatosplenic t-cell lymphoma: a case report

BackgroundHairy cell leukaemia (HCL) is a chronic B-cell leukaemia characterized by expansion of neoplastic cells in the spleen, bone marrow and blood. Symptoms of HCL are related to pancytopenia and immune deficiency. Patients with HCL have an increased risk of second malignancy either in a form of synchronous disease or in a form of an increased incidence of a second neoplasm after the treatment of HCL. Hepatosplenic T-cell lymphoma (HSTCL) is a rare form of aggressive extranodal T-cell lymphoma. Its pathogenesis is connected to a chronic immune deficiency status and its coexistence with other neoplasms is practically non-existent.CaseWe present a case of a 53-year-old female patient suffering from hepatosplenomegaly, peripheral lymphadenopathy and related B symptoms. An excisional biopsy of the enlarged axillary lymph node revealed partial infiltration with CD3+/CD56+/TIA + T cell lymphoma. Bone marrow trephine biopsy and flow cytometric immunophenotypization of bone marrow cells and peripheral blood showed presence of two types of neoplastic cells in the peripheral blood and in the bone marrow (composite lymphoma). One of them showed typical morphologic characteristics and immunohistochemical features of HCL, while another one was morphologically and immunophenotypically consistent with the diagnosis of HSTCL, respectively. The patient was treated with multivalent chemotherapy including rituximab but all treatments turned out to be only partially effective. While HCL responded to the treatment, HSTCL was refractory to the chemotherapy and the patient died 7 months after the initial diagnosis because of haematemesis induced by Mallory-Weiss syndrome.ConclusionThis is the first recorded case of coexistent HCL and HSTCL in the same patient. A multidisciplinary approach, encompassing careful morphology interpretation, immunophenotypic, cytogenetic and molecular analyses, is mandatory to obtain an accurate diagnosis of composite lymphoma.Virtual slidesThe virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/9354870531161685.

F-18 flourodeoxyglucose positron emission tomography/computed tomography findings in a case of hepatosplenic T-cell lymphoma

T-cell lymphoma (TCL) is a biologically diverse and uncommon group of lymphoid malignant diseases. Compared with its B-cell counterparts, TCL is notably more difficult to diagnose and manage owing to its rarity and biologic heterogeneity. Hepatosplenic TCL is an extremely rare subtype of TCL. A 37-year-old Indian male presented to his physician with swelling and pain in left hypochondrium. Clinical examination revealed pallor, icterus and massive splenomegaly. His blood examination revealed pancytopenia. His bone marrow biopsy was suggestive of lymphoma. Whole body F-18 flourodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) scan revealed diffuse increased metabolic activity in massively enlarged spleen, liver and bone marrow. There was no evidence of metabolically active lymphadenopathy anywhere in the body. Guided by the FDG PET/CT findings, a liver biopsy was advised. Liver histopathology revealed the presence of hepatosplenic TCL. A final diagnosis of hepatosplenic TCL with liver, spleen and bone marrow involvement was made. Even though rare, hepatosplenic TCL should be considered as a possible diagnosis in patients presenting with similar clinical picture and FDG PET/CT scan findings.

Hepatosplenic T-cell lymphoma associated to thiopurine in Ulcerative Colitis patient from Brazil: A case report

Hepatosplenic T-cell lymphoma (HSTCL) is a rare and usually fatal peripheral T-cell lymphoma that primarily affects men younger than 35 years old. Treatment with thiopurines of patients with inflammatory bowel disease (IBD) has been associated with HSTCL, especially when submitted to a combined therapy with antibodies to tumor necrosis factor (anti-TNFs). Herein, we describe the case of an 25-year-old man with diagnosis of Ulcerative Colitis disease since 2003. He was initially treated with sulfasalazine 6g/dia, interspersed with prednisone during episodes of exacerbation. In July 2007 he started treatment with 50mg of azathioprine after a disease exacerbation. The dose was adjusted by the weight through 150mg/day, maintaining remission. Within 3 years and 3 months under azathioprine therapy he started to show changes in blood count and leukopenia. After an hematology evaluation, there was a diagnose of HSTCL. He died 8 months after diagnosis from chemotherapy-refractory lymphoma. Through a literature review, we identified 16 cases of HSTCL in patients with Inflammatory Bowel Disease treated with azathioprine or 6-mercaptopurine alone. Only 06 of these patients had the diagnosis of Ulcerative Colitis. The median age at diagnosis of HSTCL was 24 years (range, 15-35 years). The median duration of thiopurine exposure was 06 years (range, 3-17 years). 11 of these patients died, with only 04 patients achieving remission. Despite the known benefits in the treatment of IBD, additional research is needed to better understand the role of thiopurines and TNF-alpha inhibitors in promoting HSTCL. The absolute risk and the frequency of HSTCL is very low. With respect to safety, however, special caution in prescribing this therapy to male 35 years-old and younger IBD patients should be recommended, mainly during a period of 24 months or more.

Cytogenetic and molecular characterization of a hepatosplenic T-cell lymphoma: report of a novel chromosomal aberration

Hepatosplenic T-cell lymphomas (HSTCL) are rare cancers and comprise 5% of peripheral T-cell lymphomas. These well-characterized extranodal lymphomas have a disguised onset, secondary to intrasinusoidal infiltration of the spleen, liver, and bone marrow, with a rapidly progressive course that is poorly responsive to chemotherapy and often ensues in the setting of immune system suppression. We describe the clinical, immunophenotypic, cytogenetic, fluorescence in situ hybridization, and molecular analyses for T cell receptor gene rearrangement in a 21-year-old man diagnosed with HSTCL. Immunophenotypic analysis revealed negativity for CD5 as well as double negativity for CD4/CD8 mature T-cell immunophenotype, which suggested the diagnosis of hepatosplenic T-cell lymphoma. Molecular analysis confirmed a TCR gene rearrangement, thereby verifying the common T-cell origin of the present HSTCL case. Furthermore, cytogenetic analysis revealed a novel chromosomal rearrangement, t(7;15)(p22;q21). Metaphase fluorescence in situ hybridization analysis confirmed the translocation of a chromosomal segment from 15q21 to 7p22.

Hepatosplenic T-Cell Lymphoma in a Young Man With Crohn's Disease: Case Report and Literature Review

Hepatosplenic T-cell lymphoma (HSTCL) is a rare form of peripheral T-cell lymphoma. It is associated with an aggressive clinical course, a poor response to conventional treatment, and an exceedingly high mortality rate. Recent reports suggest an excessive number of cases of HSTCL in young patients with Crohn's disease who are treated with thiopurines (azathioprine or 6-mercaptopurine [6-MP]) either in conjunction with or without agents that inhibit tumor necrosis factor-alpha (TNF-alpha). Herein, we describe the case of an 18-year-old man with Crohn's disease who developed HSTCL after 5 years of 6-MP treatment. He died 7 months after diagnosis from chemotherapy-refractory lymphoma. Through a literature review, we identified 28 cases of HSTCL in Crohn's patients. All patients were treated with azathioprine or 6-MP; 22 of 28 (79%) received concomitant treatment with infliximab, and 3 of these 22 patients later received treatment with adalimumab. The median age at diagnosis of HSTCL was 22 years (range, 12-40 years). The median survival for all patients was 8 months (range, 5 days-31+ months), with only 1 patient achieving remission. Additional research is needed to better understand the role of thiopurines and TNF-alpha inhibitors in promoting HSTCL and what can be done to prevent and treat this devastating malignancy in young patients with Crohn's disease.

Hepatosplenic T Cell Lymphoma Associated with Infliximab Use in Young Patients Treated for Inflammatory Bowel Disease: Update

In February 2007, the Food and Drug Administration (FDA) reported eight cases of hepatosplenic T cell lymphoma (HSTCL) associated with infliximab use in young patients treated for inflammatory bowel disease (IBD) that were received by our Adverse Event Reporting System (AERS) database (1). Although our initial report described cases of HSTCL associated with infliximab use, cases have since been reported with another member of the TNF blocker class as well. This publication serves as an update of cumulative HSTCL cases associated with immunosuppressant use since our previous publication (1). As a class, the FDA-approved TNF blockers currently include the biological agents infliximab, adalimumab, etanercept, and certolizumab. These agents block the biological effects of TNF-α including induction of proinflammatory cytokines as well as leukocyte chemotaxis and activation. From time of marketing in 1998 through June 30, 2008, FDA's AERS database has received a total of 15 cases of HSTCL in patients with IBD treated with TNF blocker therapy: 13 cases were associated with infliximab use and 2 cases were associated with infliximab use followed by adalimumab use; all patients were receiving concomitant immunosuppressants (Table 1). These numbers are cumulative and include the cases reported in our previous publication (the first eight cases in Table 1 [note that cases 4 and 11 also were reported in the literature]) (2,3).TABLE 1: Select clinical and demographic data of AERS cases of alpha/beta and gamma/delta T cell lymphoma associated with infliximab use or infliximab/adalimumab use from marketing in 1998 to June 30, 2008† (n = 15)In addition to patients with IBD, AERS has received 1 case of fatal γδ HSTCL in a 61-year-old female who received adalimumab for 1 year, concomitantly with steroids only, to treat rheumatoid arthritis; she had received approximately 1 year of methotrexate therapy 3 years before the diagnosis of HSTCL. There have been no other cases of HSTCL associated with adalimumab use to treat any indication reported to AERS or published in the scientific literature. There have been no cases of HSTCL associated with infiximab use to treat any condition other than IBD reported to AERS or the scientific literature. As for other TNF-blocking agents (ie, etanercept or certolizumab), no cases of HSTCL for any indication have been reported to AERS or the scientific literature (note that etanercept is not indicated for treatment of IBD and certolizumab was approved by the FDA in April 2008). Smaller numbers of HSTCL cases have been reported in association with other immunomodulating agents (without TNF blockers) used to treat IBD: 7 cases are associated with azathioprine use and 3 cases are associated with mercaptopurine use. Seven cases associated with azathioprine use have been published; many of these reports provided little specific clinical and/or demographic data (4–10). Of the 7 cases, all developed HSTCL (5 reported γδ subtype, 2 did not report a subtype) associated with azathioprine use to treat Crohn disease (CD; n = 4), ulcerative colitis (UC; n = 2), or UC/hepatitis (n = 1) for a duration of 4 to 17 years (mean 7.5 years). Two of these patients were receiving steroids concomitantly; no concomitant immunosuppressants were reported for the other 5 patients. Three patients were male, 1 patient was female, and sex was not specified for 3 patients; the mean age was 22 years (n = 5). Five of the 7 cases were fatal. AERS has received 2 fatal cases of γδ HSTCL in male patients (younger than 18 and 33) using mercaptopurine to treat CD for a duration of 3 to 5 years; an additional case in the literature identified a patient of unknown age and sex who developed HSTCL after using mercaptopurine for an unknown duration to treat CD (little information provided) (11). No AERS or literature cases associated with mesalamine or methotrexate therapy when used alone to treat IBD were identified. As discussed in our previous publication, HSTCL is a rarely occurring tumor (2); to date, there have been fewer than 200 cumulative cases of this lymphoma reported in the literature. In turn, the pediatric IBD population is estimated to be 100,000 children (younger than 18 years of age) affected in the United States; the number of patients with severe IBD would be smaller (12). Because 15 of the fewer than 200 known HSTCL cases are associated with infliximab use (and rarely adalimumab use), it appears that young patients using these products may be at greater risk for developing this lymphoma. It has not been established that infliximab or adalamimub had an exclusive or primary role in the pathogenesis of each reported case of HSTCL. These cases could be causally related to a number of factors (eg, underlying disease, exposure to concomitant immunosuppressant medications). Health care practitioners are encouraged to report cases of HSTCL to FDA (http://www.fda.gov/medwatch).

Agressive Lymphoma without Lymphadenopathy

Hepatosplenic T cell lymphomas are among a rare breed of aggressive non Hodgkin tumors that usually comprise of immature cytotoxic T cells. They most commonly involve young adults who generally present with constitutional symptoms of fever, weight loss and night sweats. Diagnosis can be challenging in the absence of lymphadenopathy and paucity of bone marrow findings. The discovery of neoplastic cells in peripheral blood is often a finding late in the clinical course. Demonstation of sinusoidal infiltration of T cells on either liver or splenic biopsy is ususally diagnostic. These cells are positive for clonal rearrangement of the γ gene of the T cell receptor which is a hallmark of this disease. Prognosis remains poor and most patients die within two years of diagnosis. We report a case of a patient who presented with unexplained fever and hepatosplenomegaly and after extensive workup was diagnosed with hepatosplenic T cell lymphoma.A 42 year old male with no significant past medical history presented with complains of abdominal pain, fever, malaise and 30lb weight loss over a period of six weeks. Pain was described as intermittent episodes of bilateral flank fullness associated with nausea and vomiting. He had traveled to Mexico 8 weeks earlier and according to him his symptoms began soon after his trip. He denied any headaches, cough, shortness of breath,. No dysuria, and no diarrhea. No smoking alcoholism or illicit drug use was reported. No sick or new sexual contacts. Family history was noncontributory. Vital signs were significant for temperature of 101 F. Physical examination revealed presence of marked hepatosplenomegaly. There was no lympadenopathy as well as no murmurs or rubs. Labs showed pancytopenia with blood counts of 2.7, 9.8 and 101 for WBC, Hb and platelets respectively. Additionally, alkaline phosphatase was elevated while rest of the liver functions was normal. Preliminary diagnosis of infectious versus malignant etiology was made. Peripheral smear did not show any malignant cells. Infectious workup returned negative for HIV, hepatitis, histoplasma, brucella, leptospira, coccidioidomycosis, syphilis, leishmaniasis as well as malaria and dengue fever. A bone marrow biopsy was performed for further evaluation and showed moderately hypercellular bone marrow with erythroid and megakaryocytic hyperplasia but no evidence of malignancy or granulomatous process. Meanwhile patient remained persistently febrile without any growth on blood cultues. An echo was normal with no evidence of endocarditis. Tuberculin test was non reactive. Given the results of the bone marrow biopsy and hepatosplenomegaly without any lymphadenopathy it was thought that a localized infiltrative process of he liver or spleen was likely. Patient thus underwent a liver biopsy disclosing intra sinusoidal collections of atypical CD3, CD7, TIA-1 and CD56 positive lymphocytes also bearing T cell receptor clonal rearrangement consistent with a diagnosis of hepatosplenic T-cell lymphoma which was further classified as gammadelta type.. He was subsequently started on ECHOP regimen and is currently in remission on a three month followup Hepatosplenic lymphoma, though is a rare tumor, should be considered in patients with unexplained hepatosplenomegaly without lymphadenopathy and normal peripheral smear. Liver biopsy is diagnostic most of the time.

Pituitary gland involvement by a gamma delta hepatosplenic lymphoma, a mimicker of pituitary adenoma: report of a rare case

The authors report an unusual case of hepatosplenic T-cell lymphoma in a 41-year-old male patient. He presented initially with low grade fever, hepatosplenomegaly and pancytopenia. Splenectomy was done which showed infiltration of red pulp by monomorphic lymphocytes. Liver was also infiltrated with similar cells. A provisional diagnosis of hairy cell leukemia was made. Subsequently, after 6 months he was found to have a sellar mass, which on microscopy revealed lymphoma cells. These cells were positive for leukocyte common antigen and T-cell markers. Finally, based on overall clinical, histomorphological and immunophenotypic features, a diagnosis of hepatosplenic T-cell lymphoma, possibly gamma delta type, involving pituitary gland was established. On follow up, this patient showed evidence of bone marrow involvement and died after 1.5-year of diagnosis. This case highlights the involvement of rare site by a rare lymphoma and should be kept in mind in the differential diagnoses of pituitary tumors.