Marked Hepatosplenomegaly Research Articles

Acute Liver Failure With Malignant Ascites: An Unusual Presentation Of Hepatosplenic T Cell Lymphoma.

Hepatosplenic T cell lymphoma is a rare neoplasm accounting for less than 1 percent of non-Hodgkin lymphomas. It most commonly presents in young men with a median age at diagnosis of 35 years. Ten to 20 percent of patients have a history of chronic immune suppression related to treatment for solid organ transplantation, lymphoma, or inflammatory bowel disease. Most patients with HSTCL present with marked hepatosplenomegaly and thrombocytopenia without lymphadenopathy. Liver involvement is usually characterized by infiltration of dilated sinusoids by atypical lymphoid cells, with portal tracts and hepatocytes generally remaining uninvolved. Our patient presented with severe obstructive jaundice, impending hepatic failure and malignant ascites. He was refractory to steroid and radiation and biliary stenting had to be performed for severe hyperbilirubinemia.

Plasma cell leukemia of IgG secreting type: A rare case

Plasma cell leukemia is very rare comprising 2% plasma cell dyscrasias. We report a case of a 49-year-old male with complaints of chest pain, breathlessness, and acute attacks of gastroenteritis. On examination, there was marked pallor and hepatosplenomegaly. X-ray and computed tomography (CT) scan revealed multiple paratracheal lymph node enlargements. However, there was no diffuse osteopenia or multiple osteolytic lesions. Laboratory analysis revealed high serum calcium 11.5 mg/dL, low hemoglobin 5 g/dL, normal WBC count, thrombocytopenia 22000/mm³ and elevated erythrocyte sedimentation rate (ESR). Peripheral smear showed many atypical cells (41%) with blastoid morphology, giving a blood picture of acute leukemia. However, on closer inspection many of them appeared plasmacytoid. There was marked rouleaux formation of red cells in the background. Bone marrow aspirate and biopsy also revealed near total replacement by such atypical cells with plasmacytoid morphology. Serum electrophoresis revealed a prominent M spike and immunofixation revealed IgG heavy chain and kappa light chain immunostaining ruling out the possibility of Waldenström’s macroglobulinemia. Plasma cell leukemias are predominantly IgD and IgE secreting type. This case is rare in that it is IgG secreting type. Plasma cell leukemias are very aggressive and with higher incidence of organomegaly, lymphadenopathy, thrombocytopenia, hypercalcemia, renal impairment and surprisingly lesser occurrence of lytic bony lesions as in our case.

Blackwater fever like in murine malaria

Blackwater fever (BWF) is the term used to designate the occurrence of hemoglobin pigments in the urine of patients infected with malaria parasites. BWF is more often associated with Plasmodium falciparum infection in man. The pathogenesis of BWF has not been explained satisfactorily. In the present study, the clinical and pathological observations made upon CD1 mice infected with Plasmodium yoelii yoelii lethal strain with clinical signs of hemoglobinuria and acute renal failure were evaluated. From the 40 P. yoelii yoelii-infected mice, 14 presented hemoglobinuria. In the observations, it was emphasized that hemoglobinuria occurred in the animals 1-2days before they die. At 6days post-infection, infected hemoglobinuric mice (HM) exhibited clinical signs such as dark red urine, apnea, and evident oliguria and hematuria; urine microscopical examination showed very few red blood cells. The entire non hemoglobinuric infected mice had a high parasitemia preceding the time of death, while the HM parasitemia was just detectable. In HM, marked hepatosplenomegaly, anemia, and renal and hepatic dysfunction were observed with the blood chemistry analysis at 6days post-infection. Severe renal lesions were demonstrated in histopathological and scanning electron microscopy samples. Occlusion and necrosis of convoluted tubules were the main lesions found. The conditions required for the experimental production of hemoglobinuria in CD1 mouse infected by P. yoelii yoelii is still unknown. The clinical picture of a BWF, like in our rodents, was produced exclusively by the interaction between the parasite and its host. Results showed that hemoglobinuria in CD1 mice infected with P. yoelii yoelii and BWF in man infected with P. falciparum are similar in their pathogenesis.

An unusual cause of fever

A 5-month old infant presented with a short history of fever of unknown origin. He initially appeared well although there was a resting tachycardia during periods of normal temperature, and pancytopenia. He remained febrile in spite of antibiotic therapy and by 48 h he had developed marked hepatosplenomegaly and coagulopathy. At 72 h a bone marrow aspirate and trephine biopsy showed haemophagocytosis. By this time the infant was encephalopathic and haemodynamically unstable with multi-organ dysfunction. Treatment with high-dose methylprednisolone and cyclosporin was commenced with an initial good response. Unfortunately the patient ultimately died of infective complications of treatment and reactivation of the underlying disease process. Haemophagocytic lymphohistiocytosis (HLH) is a rare disorder of the mononuclear phagocyte system characterised by proliferation of morphologically benign histiocytes resulting in hypercytokinaemia and uncontrolled activation of immune cells. The diagnosis of familial HLH should be considered in any infant with fever, splenomegaly and cytopenia of at least two cell lines. HLH may be cured by immunosuppressive therapy and eventual stem cell transplantation but rapid disease progression to multi-organ failure results in a high mortality.

Multiple esophageal variceal ruptures with massive ascites due to myelofibrosis-induced portal hypertension

A 75-year old man had been diagnosed at 42 years of age as having polycythemia vera and had been monitored at another hospital. Progression of anemia had been recognized at about age 70, and the patient was thus referred to our center in 2008 where secondary myelofibrosis was diagnosed based on bone marrow biopsy findings. Hematemesis due to rupture of esophageal varices occurred in January and February of 2011. The bleeding was stopped by endoscopic variceal ligation. Furthermore, in March of the same year, hematemesis recurred and the patient was transported to our center. He was in irreversible hemorrhagic shock and died. The autopsy showed severe bone marrow fibrosis with mainly argyrophilic fibers, an observation consistent with myelofibrosis. The liver weighed 1856 g the spleen 1572 g, indicating marked hepatosplenomegaly. The liver and spleen both showed extramedullary hemopoiesis. Myelofibrosis is often complicated by portal hypertension and is occasionally associated with gastrointestinal hemorrhage due to esophageal varices. A patient diagnosed as having myelofibrosis needs to be screened for esophageal/gastric varices. Myelofibrosis has a poor prognosis. Therefore, it is necessary to carefully decide the therapeutic strategy in consideration of the patient's concomitant conditions, treatment invasiveness and quality of life.

Hepatobiliary and Pancreatic: Niemann–Pick disease

Niemann-Pick disease, types A and B, are lipid storage disorders caused by complete or partial deficiency of a lysosomal enzyme, acid sphingomyelinase. The disorders are inherited in an autosomal recessive pattern and result in the accumulation of sphingomyelin in various organs including the spleen, liver, lungs, bone marrow and brain. The infantile variant (type A) usually presents within the first year of life with failure to thrive, hepatomegaly and neurological symptoms, sometimes resulting in liver failure with ascites and jaundice. Most babies die at 2–3 years of age. In Niemann-Pick type B disease, the diagnosis is usually made early in childhood because of failure to thrive and the development of hepatosplenomegaly. Patients then develop progressive neurological symptoms and may have deteriorating pulmonary function because of foam cell infiltrates. Most patients die in childhood. An important clue to the diagnosis of Niemann-Pick disease, types A and B, is the presence of large foamy macrophages in the bone marrow or liver. In most patients, the diagnosis is confirmed by genetic tests for mutations in the SMPD1 gene or by the demonstration of low acid sphingomyelinase activity in peripheral blood white cells or in cultured fibroblasts. At present, there is no specific treatment for Niemann-Pick disease. The patient illustrated below was 15-month-old female who presented with a 4-month history of hepatosplenomegaly and failure to thrive. She was the product of a full-term normal pregnancy but her parents were consanguineous and a previous baby had died in the neonatal period. The parents described anorexia and recurrent pneumonia but no vomiting or diarrhea. The baby had a weight and height below the 5 percentile for age. Physical examination revealed marked hepatosplenomegaly but no ascites. Liver enzymes were abnormal with elevation of aspartate aminotransferase (311 u/l), alanine aminotransferase (251 u/l), gamma-glutamyltransferase (77 u/l) and alkaline phosphatase (724 u/l). She had a normal complete blood count, coagulation studies and serum albumin. A computed tomography scan of the chest revealed typical reticulonodular infiltrates in the upper lobes of both lungs (Figure 1). A percutaneous liver biopsy showed lipid-laden foam cells (Figure 2). The diagnosis of Niemann-Pick disease was confirmed by the demonstration of low acid sphingomyelinase activity in peripheral blood white cells. She is receiving symptomatic treatment only.

Lethal Myelofibrosis Induced by Bmi1-Deficient Hematopoietic Cells Unveils a Tumor Suppressor Function of the Polycomb Group Genes

Abstract 390Polycomb-group (PcG) proteins form polycomb repressive complex (PRC) 1 and PRC2, and function as transcriptional repressors through histone modifications. They maintain proliferative capacity of hematopoietic stem and progenitor cells by repressing transcription of tumor suppressor genes, thus have been characterized as oncogenes. However, identification of inactivating mutations of a PcG gene, EZH2, unveiled its tumor suppressor function in myeloid malignancies including primary myelofibrosis (PMF). Here, we show that loss of another PcG gene, Bmi1, causes pathological hematopoiesis reminiscent of PMF in mice. We previously reported that deletion of both Ink4a and Arf in Bmi1-deficient mice substantially restores the defective self-renewal capacity of HSCs. To evaluate the repopulating capacity of Bmi1−/−Ink4a-Arf−/− BM cells precisely, we transplanted wild-type, Ink4a-Arf−/−, and Bmi1−/−Ink4a-Arf−/− BM cells into lethally irradiated mice without competitor cells. The recipients repopulated with Bmi1−/−Ink4a-Arf−/− donor cells had 2-fold more megakaryocyte/erythroid progenitors (MEPs) and extramedullary hematopoiesis as evident from a significant increase in the number of LSK HSCs/MPPs in spleen. All the control recipient mice repopulated with Ink4a-Arf−/− BM cells eventually developed sarcoma or lymphoma and succumbed to die by 11 months post-transplant as previously reported with the Ink4a-Arf−/− mice. On the other hand, the recipient mice repopulated with Bmi1−/−Ink4a-Arf−/− BM cells died much earlier than the Ink4a-Arf−/− controls, displayed more progressive pancytopenia, and showed marked hepatosplenomegaly and hypoplastic BM with massive fibrosis at their terminal stage. Although abnormal megakaryocytosis was not obvious in BM and spleen because of severe fibrosis at the terminal stage of the disease, the mice at earlier time point after transplantation showed marked megakaryocytosis in both BM and spleen, implicating pathological megakaryocytosis in the development of lethal myelofibrosis. Together, lethal myelofibrosis induced by Bmi1−/−Ink4a-Arf−/− hematopoietic cells follows the natural course of human PMF.To identify the responsible genes for PMF-like disease in the absence of Bmi1, we compared gene expression profiles of LSK HSCs/MPPs and common myeloid progenitors (CMPs) from wild-type, Ink4a-Arf −/−, and Bmi1−/−Ink4a-Arf −/− BM cells. Absence of Bmi1 caused de-repression of a cohort of genes. We then compared the list of de-repressed genes with that of PMF-associated genes identified by a gene expression profiling of CD34+ cells from human PMF patients (Guglielmelli et al., Stem Cells 25:165–173, 2007). Hmga2, a well-known oncogene, appeared to be commonly upregulated in Bmi1−/−Ink4a-Arf −/− CMPs and PMF CD34+ cells. Chromatin immunoprecipitation assays demonstrated that Bmi1 directly represses the expression of Hmga2 by marking its promoter with a repressive histone mark. To test contribution of Hmga2 to the development of PMF-like disease in mice, we examined the effects of Hmga2 overexpression on hematopoiesis. Forced expression of Hmga2 in HSCs promoted expansion of progenitor cells and significantly facilitated megakaryocytopoiesis in vitro. Hmga2-overexpressing HSCs also induced a mild myeloproliferative state with enhanced megakaryocytopoiesis in recipient mice, although fibrosis was not obviously induced. These results implicated Hmga2 in the development of pathological hematopoiesis in the absence of Bmi1.Collectively, our findings unveiled the tumor suppressor function of Bmi1. Corresponding to our findings, mice with hypomorphic mutations of Eed and Suz12 reportedly showed enhanced hematopoiesis. All these findings might be in line with tumor suppressor function of EZH2 observed in MDS and MPN patients, and suggestive of a broad range of target genes of the PcG proteins, which include both oncogenes and tumor suppressor genes. Although the tumor suppressor genes have been stresses as PcG targets, our findings shed a light on the role of PcG proteins in gene silencing of oncogenes. Thus, the PcG proteins fine-tune the growth of hematopoietic cells in both a positive and a negative manner to maintain hematopoietic homeostasis. Disclosures:No relevant conflicts of interest to declare.

Hodgkin lymphoma in 2 children with chronic granulomatous disease

Hodgkin lymphoma in 2 children with chronic granulomatous disease

An unusual case of IgE-multiple myeloma presenting with systemic amyloidosis 2 years after cervical plasmacytoma resection

A 69-year-old man suffered from a fractured cervical vertebra, and magnetic resonance imaging revealed a solitary mass occupying the injured lesion. Surgical resection of the mass was conducted, and the infiltration of plasma cells expressing IgE-lambda monoclonal protein was shown on pathological investigation. Concurrently, a monoclonal band of IgE-lambda was shown in the sera on immunoelectrophoresis, and the proliferation of plasma cells (more than 10%) was also detected in bone marrow aspirates. A rare IgE-multiple myeloma (MM) was diagnosed, and careful monthly follow-up was started. During this observation period, the level of IgE gradually increased and, at 2 years after the initial diagnosis, bilateral leg edema and ascites with marked hepatosplenomegaly appeared. Combination chemotherapy of melphalan and prednisolone (MP) was started, which resulted in the partial, transient resolution of symptoms. Additional treatment with bortezomib and dexamethasone could neither resolve these clinical symptoms nor decrease the serum IgE concentration. At 5 months after the start of chemotherapy, amyloid deposition was suggested based on typical echocardiographic findings, and the diagnosis of amyloidosis was confirmed based on the histopathology of a liver biopsy. In spite of MP plus thalidomide treatment, cardiac failure due to amyloidosis aggravated, and the patient died of multiple organ failure. This is the second reported case in which IgE-MM was complicated by systemic amyloidosis.

Clinical and hematological study for Parvovirus b19 infection in children with acute leukemia

The role of Parvovirus B19 in acute leukemia is under debate. This study aimed to detect parvovirus B19 DNA together with its antibodies in the sera of children with recent acute leukemia and those with acute leukemia receiving chemotherapy to clarify the contribution of this infection to changes observed in hematological and clinical presentations in these populations. Two groups were included: Group I comprised 45 children with acute leukemia receiving chemotherapy and Group II comprised 40 children with recently diagnosed acute leukemia. Serum parvovirus B19 IgG and IgM were investigated by enzyme-linked immunosorbant assay and the virus DNA was sought by polymerase chain reaction assay. Viral DNA was found in 22.2% of Group I patients and in 45% of Group II patients. Hemoglobin levels were significantly reduced in patients with recent infection, accompanied by statistically significant lymphocytosis in Group I patients. Group II patients with recent infection had marked neutropenia with lymphocytosis and thrombocytopenia. There was statistically significant lymphadenopathy and hepatosplenomegaly in patients with recent infection in both groups. Parvovirus B19 infection is an important cause of cytopenia in children with acute leukemia both when recently diagnosed and receiving chemotherapy. This can affect the schedule of chemotherapy. Moreover, the presence of Parvovirus B19 is associated with marked lymphadenopathy and hepatosplenomegaly.

A Case of Pure Red Cell Aplasia Associated with Angioimmunoblastic T-cell Lymphoma

Pure red cell aplasia is a bone marrow failure characterized by a progressive normocytic anemia and reticulocytopenia without leucopenia and thrombocytopenia. It is associated with various hematologic diseases. However, pure red cell aplasia with angioimmunoblastic T cell lymphoma has rarely been reported. Here we describe a 43-year-old woman with pure red cell aplasia associated with angioimmunoblastic T-cell lymphoma. She had severe anemia (hemoglobin 6.9 g/dL) and a low reticulocyte count (0.2%). Direct and indirect Coombs' tests were positive. A CT scan of the abdomen revealed marked hepatosplenomegaly and small multiple lymphadenopathies. A bone marrow biopsy revealed focal infiltration of abnormal lymphoid cells and absence of red cell precursors. Splenic biopsy was compatible with angioimmunoblastic T-cell lymphoma. Ultimately, diagnosis of pure red cell aplasia associated with angioimmunoblastic T-cell lymphoma was made. After initiating CHOP therapy, the patient achieved complete remission, which was accompanied, shortly thereafter, by a rise in hemoglobin levels which finally returned to normal.

Use of rituximab for refractory cytopenias associated with autoimmune lymphoproliferative syndrome (ALPS).

ALPS is a disorder of apoptosis resulting in accumulation of autoreactive lymphocytes, leading to marked lymphadenopathy, hepatosplenomegaly, and multilineage cytopenias due to splenic sequestration and/or autoimmune destruction often presenting in childhood. We summarize our experience of rituximab use during the last 8 years in 12 patients, 9 children, and 3 adults, out of 259 individuals with ALPS, belonging to 166 families currently enrolled in studies at the National Institutes of Health. Refractory immune thrombocytopenia (platelet count <20,000) in nine patients and autoimmune hemolytic anemia (AIHA) in three patients led to treatment with rituximab. Among them, seven patients had undergone prior surgical splenectomy; three had significant splenomegaly; and two had no palpable spleen. In seven out of nine patients with ALPS and thrombocytopenia, rituximab therapy led to median response duration of 21 months (range 14-36 months). In contrast, none of the three children treated with rituximab for AIHA responded. Noted toxicities included profound and prolonged hypogammaglobulinemia in three patients requiring replacement IVIG, total absence of antibody response to polysaccharide vaccines lasting up to 4 years after rituximab infusions in one patient and prolonged neutropenia in one patient. Toxicities including hypogammaglobulinemia and neutropenia constitute an additional infection risk burden, especially in asplenic individuals, and may warrant avoidance of rituximab until other immunosuppressive medication options are exhausted. Long-term follow-up of ALPS patients with cytopenias after any treatment is necessary to determine relative risks and benefits.

Anti-E Alloimmunization: A Rare Cause of Severe Fetal Hemolytic Disease Resulting in Pregnancy Loss

We report a case of severe intrauterine hemolysis caused by sole anti-E alloimmunization. A 36-year-old multipara woman presented with hydrops fetalis at 27 weeks of gestation. She had a history of previous neonatal death. In this pregnancy, she was found to have very high titer of anti-E antibody. Ultrasonography detected marked skin edema, cardiomegaly, hepatosplenomegaly, pleural effusion, ascites, placentomegaly, and polyhydramnios. The Doppler peak systolic velocity in the middle cerebral artery was 0.8 m/s, indicating severe fetal anemia. Multiple intrauterine transfusions for the anemic fetus were administered. However, persistent severe fetal anemia and placentomegaly caused poor neonatal death and mirror syndrome in the mother. Uncommon red blood cell alloimmunization has to be watched for early in any population, especially in a woman with a history of unexplained perinatal loss.

Using Noval Experimental PM 701 in Refractory Hodgkin's Disease Combined with conventional Therapy

Background: To the many profound changes we now face in health care, Complementary and Alternative Medicine (CAM) must be added as a major factor. There is evidence of the increasing use of CAM by patients diagnosed with cancer. Interest in CAM continues to grow at an exponential rate despite the advances made by conventional medicine. Given the increasing desire of cancer patients to use CAM, it is important that clinicians have a good understanding of the evidence available in this field and build a trust with their patients. Many oncologists are not familiar with CAM used by many of their patients.Aims: To report the effectiveness and safety of a natural experimental agent used with conventional therapy in a patient with Stage IV Hodgkin's lymphoma refractory to treatment.Methods: An eight-years-old Saudi girl was diagnosed as Stage IV Hodgkin's lymphoma with lung infiltration. The patient was started on chemotherapy (ABVD), and needed prolonged hospitalization due to weakness, loss of appetite, cachexia, dyspnea, cough, fever, and marked hepatosplenomegaly. She had six cycles of chemotherapy with a slight improvement in her general condition. However, she as considered refractory to conventional therapy. We were planning to refer her for bone marrow transplant. The patient was sent home to be readmitted for the seventh cycle of ABVD. Unfortunately, the patient's general condition deteriorated and she was admitted to the Intensive Care Unit (ICU), with acute Respiratory Distress Syndrome (RDS). She was markedly unstable and required respiratory ventilation support. After discussions involving the parents, it was suggested to use an experimental natural remedy of proven efficacy in inducing apoptosis in tissue cultures and animals in our laboratories. On the fifth day in ICU, the patient was initiated with full dose ABVD combined with the natural remedy, classified as PM 701. Within 2 days, the patient became fully conscious, showed improved general condition and returned to the pediatric ward to continue her treatment.Results: After the seventh cycle of chemotherapy and the use of natural remedy, her general condition improved markedly with significant reduction of the hepatosplenomegaly and pleural effusions. Repeated CT scans of chest and abdomen showed marked regression of her disease. She had one more cycle of chemotherapy combined with PM 701 and assessment after the eighth cycle showed complete remission of her disease including in the lungs. This natural agent has been fully studied with animal models at the King Fahed Medical Research Center's laboratory and showed potent selective apoptosis of cancer cells, effective and safe in animal models.Summary: Most childhood malignancy is curable with combined intensive conventional chemotherapy, however up to 30% may have relapse or be resistant to chemotherapy. We report in this case successful management with the combination of conventional therapy with experimental medicine (PM 701) in the treatment of refractory Hodgkin's lymphoma, which needs further control studies in the future to prove the efficacy and safety to be used on oncology patients. Integration between chemotherapy and natural CAM should be under close supervision to ensure safety and effectiveness. Scientific research needs more effort to support this line of medicine.

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.

Hepatosplenic γδ T-Cell Lymphoma Masquerading as T Cell Acute Lymphoblastic Leukemia

Hepatosplenic γδ T-Cell Lymphoma (HSTCL) is an uncommon type of Peripheral T cell lymphomas characterized by hepatosplenomegaly without significant lymphadenopathy, with clinically significant cytopenias, predominance in young adult males and an aggressive clinical course. HSTCL have a characteristic immunophenotype CD2+, CD3+, CD4−, CD5−, CD7+, CD8-, TCRγδ+ and are associated with isochromosome 7q cytogenetic abnormality. The predominant laboratory findings are reduced peripheral blood cells ranging from isolated reduction of one lineage to pancytopenia. Lymphocytosis is usually uncommon at the point of diagnosis; however tumor cells may be commonly seen in blood. Two subpopulations of atypical cells are seen – small sized cells with irregular nuclear margins and the medium to large size cells which often resemble blasts. The blast like cells are known to increase with disease progression and a complete blastic transformation though known has been mostly reported in the terminal phase of the disease.We present three cases of HSTCL, all of which presented with lymphocytosis and increased blast like cells (17%–91%) at diagnosis. These cases included two females and one male in an age group of 13– 17 years. They all presented with generalized systemic complaints, bleeding symptoms and on examination had pedal edema, facial puffiness and moderate to marked hepatosplenomegaly. Immunophenotyping performed on peripheral blood sample using a limited primary panel of antibodies showed a common phenotype: surface CD3+, CD4−, CD8−, CD7+ & CD34−. In addition CD2 and CD5 were positive in two cases, CD56 was positive in one case while CD16 was negative in all three cases. Based on the blast like morphology of tumor cells and an aberrant T cell phenotype, all three cases were initially labeled as T cell Acute Lymphoblastic Leukemia (T-ALL) and treated as per the T-ALL treatment protocol of our institute. However they did not respond to treatment. These cases were reviewed in detail and a repeat Immunophenotypic analysis was done using a more elaborate panel. In addition to the initial Immunophenotypic markers, all three cases were positive for Surface TCR γδ and negative for Tdt. Hence a diagnosis of HSTCL was arrived at. Cytogenetically only one case showed the characteristic finding of isochromosome 7q.The diagnosis of HSTCL was not considered initially because of the blast like morphology of tumor cells and as surface TCR αβ/γδ is not part of our primary antibody panel. In addition in one case, cytoplasmic CD3 was interpreted as positive without taking into account surface CD3 positivity.This case series highlights the importance of using a comprehensive antibody panel for the diagnosis of hematolymphoid neoplasms including cytoplasmic markers and Tdt. It re-establishes the importance of assessing cytoplasmic positivity only after the surface positivity has been looked for. Aberrant surface CD3 expression and cytoplasmic γδ positivity is well known in T-ALL and a few cases of Tdt negative T-ALL are also known. However to the best of our knowledge there are no published reports of T-ALL expressing surface TCR γδ and in comparison HSTCL though surface CD3 positive, are Tdt negative. We suggest that in all such cases which are surface CD3 positive, CD34 negative and Tdt negative, Surface TCR γδ should be looked for and if found to be positive a diagnosis of HSTCL can be arrived at in the correct clinical setting. In conclusion, it is important to be aware of this rare entity of HSTCL presenting with leucocytosis & blast like cells and to differentiate it from T-ALL, as these two entities have different treatment and prognosis.

An Unusual Cause for GI Bleed

Purpose: Agnogenic myeloid metaplasia (AMM) is a rare myeloproliferative disorder characterized by bone marrow fibrosis, marked splenomegaly, and extramedullary hematopoeisis (EMH). EMH can occur in almost any organ, but clinically significant involvement of the gastrointestinal (GI) tract is very rare. Methods: A 62-year-old female with AMM with myelofibrosis was transferred to our institution for evaluation of overt gastrointestinal bleeding of obscure origin. She presented with a six-month history of recurrent hematochezia. Her extensive previous workup had included six negative upper endoscopies and three colonoscopies, which were unremarkable except for the presence of blood throughout the colon. Three nuclear medicine bleeding scans had also been performed, two of which showed active bleeding arising from the right lateral hemipelvis. Subsequent angiograms, however, were negative. The patient had received 17 units of PRBC over the two weeks prior to her transfer to our institution. Results: Physical exam revealed a chronically ill patient with marked hepatosplenomegaly. Laboratory data showed a hemoglobin of 7.9 mg/dL and platelet count of 46,000/uL. CT enterography demonstrated an abnormal focal accumulation of intravenous contrast in the wall or lumen of a loop of mid-to-distal ileum, without mass or abnormal wall thickening. Angiography was again negative, and retrograde double balloon enteroscopy was nondiagnostic. Video capsule endoscopy visualized a small, smooth, dome-like protuberance arising from otherwise normal appearing small bowel mucosa at 4 hours and 40 minutes. At the apex of the lesion, there appeared to be a small umbilication, and possibly an adjacent clot. Due to the severity of her bleeding, she underwent exploratory laparotomy with intraoperative enteroscopy. A lesion was palpated in the jejunum, and endoscopically identified as the same lesion seen on capsule study. This was resected, and on gross pathology was described as a 0.7-cm submucosal nodule with mild erythema and umbilication. Histology and immunoperoxidase studies revealed a cluster of erythroid cells, granulocytic and myeloid precursors, and megakaryocytes, consistent with focal EMH. Postoperatively, the patient had no further bleeding. Conclusion: EMH is common in patients with myelofibrosis, affecting organs containing tissue of mesenchymal origin. However, clinically significant GI tract involvement is very rare. GI bleeding from EMH in the esophagus, small bowel, and colon has been described in a small number of case reports. To our knowledge, this is the first case of GI bleeding arising from a single focus of small bowel EMH visualized on video capsule endoscopy.

Anaplastic Large Cell Lymphoma in Leukemic Presentation

It is extremely rare that a patient with anaplastic large cell lymphoma (ALCL) demonstrates circulating lymphoma cells. A 10-year-old Japanese boy was presented with high-grade fever and cough. The physical examination revealed marked hepatosplenomegaly with ascites and lymphadenopathy in the cervical and periauricular areas. The white cell count was 26.2x10(9)/L with 95% of abnormal lymphoid cells, which were small to medium-sized with a high nucleus/cytoplasm ratio, basophilic cytoplasm, condensed nuclear chromatins, and 1 or 2 distinct nucleoli, hemoglobin 6.4 g/dL, and platelet 0.9x10(9)/L. A flow cytometric analysis of abnormal cells in both the peripheral blood and bone marrow samples was strongly positive for CD30 on their cell membranes. Karyogram and fluorescent in situ hybridization showed abnormal cells to have a characteristic chromosomal translocation, t(2;5)(p23;q35). Reverse transcriptase-polymerase chain reaction of peripheral blood cell-derived mRNA also indicated the fusion gene product of anaplastic lymphoma kinase and nucleophosmin. Subsequently, the patient was diagnosed to have ALCL with a rare clinical feature of a peripheral leukemic presentation, and his disease revealed to be refractory to chemotherapy. On the basis of the 11 childhood cases of ALCL with leukemic presentation so far published and reviewed herein, the prognosis is very poor.

AML1 mutations induced MDS and MDS/AML in a mouse BMT model

AbstractMyelodysplastic syndrome (MDS) is a hematopoietic stem-cell disorder characterized by trilineage dysplasia and susceptibility to acute myelogenous leukemia (AML). Analysis of molecular basis of MDS has been hampered by the heterogeneity of the disease. Recently, mutations of the transcription factor AML1/RUNX1 have been identified in 15% to 40% of MDS–refractory anemia with excess of blasts (RAEB) and MDS/AML. We performed mouse bone marrow transplantation (BMT) using bone marrow cells transduced with the AML1 mutants. Most mice developed MDS and MDS/AML-like symptoms within 4 to 13 months after BMT. Interestingly, among integration sites identified, Evi1 seemed to collaborate with an AML1 mutant harboring a point mutation in the Runt homology domain (D171N) to induce MDS/AML with an identical phenotype characterized by marked hepatosplenomegaly, myeloid dysplasia, leukocytosis, and biphenotypic surface markers. Collaboration between AML1-D171N and Evi1 was confirmed by a BMT model where coexpression of AML1-D171N and Evi1 induced acute leukemia of the same phenotype with much shorter latencies. On the other hand, a C-terminal truncated AML1 mutant (S291fsX300) induced pancytopenia with erythroid dysplasia in transplanted mice, followed by progression to MDS-RAEB or MDS/AML. Thus, we have developed a useful mouse model of MDS/AML that should help in the understanding of the molecular basis of MDS and the progression of MDS to overt leukemia.

Disseminierte Histoplasmose nach Tropenaufenthalt bei bekannter Sarkoidose

A 40-year-old man with grade II sarcoidosis went on a two-week visit to Ecuador. Afterwards he was treated with low-dose corticosteroids because of slight deterioration on the X-ray film. Unilateral hilar enlargement followed by bouts of high fever and a greatly increased erythrocyte sedimentation rate, suggested an acute exacerbation of the sarcoidosis and was, therefore, treated with an increase in steroid dosage plus azathioprine. Bronchoalveolar lavage fluid and tissue samples from lung, bone-marrow and spleen were suggestive of an infection with Histoplasma capsulatum. There was now bilateral hilar enlargement with right upper lobe infiltration, marked hepatosplenomegaly and thrombocytopenia (17,000/microliters), but serological tests remained negative. The fulminant course with dissemination could not be arrested despite administration of fluconazole (400 mg/d) and amphotericin B (total dosage 1.14 g). Histoplasma capsulatum was cultured from lung and spleen tissue post-mortem.