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hepatosplenic t - cell lymphoma ( hstcl ) is a rare and aggressive extranodal t - cell lymphoma that comprises < 5% of peripheral t - cell lymphomas.1 it is characterized by extranodal infiltration of malignant mature post - thymic t - lymphocytes in the sinusoids of the liver , spleen , and bone marrow.1 the majority of cases harbor the  t - cell receptor ( tcr ) , but recently , a few cases have been shown to express the  tcr .
since the first report of an  hepatosplenic t - cell lymphoma (  hstcl ) in 2000,2 < 30 cases have been reported in the literature . as the majority of early cases were of the  subtype ,
hepatosplenic gamma - delta t - cell lymphoma  in the revised european american lymphoma ( real ) classification.3 with increasing reports of new cases with the  subtype , the term  hstcl  is preferred in the current world health organization ( who ) classification.4 comparison of the two subtypes5 shows similar clinicopathologic and cytogenetic features ; however , due to the paucity of reported cases , it is not clear whether they are prognostically distinct entities .
diagnosis proved challenging due to an unusual blastoid morphology with the absence of typical intrasinusoidal distribution of tumor cells in the bone marrow .
this unique case adds to the growing list of this rare subtype of t - cell lymphomas , which warrant urgent attention due to the lack of effective treatment options and dismal prognosis .
a male in his 20s from nepal with no chronic illness presented at our hospital with a one - month history of high - grade fever , skin rash , weight loss , symptoms of anemia , and abdominal pain .
he was in fair general condition with normal vital signs except for fever ( 39 c ) .
physical examination revealed a purpuric rash over his trunk and extremities , hepatomegaly ( 4 cm ) , and splenomegaly ( 10 cm ) below the costal margin .
initial investigations showed bicytopenia with a platelet count of 36  10/l and hemoglobin 7.0 g / dl with normal mean corpuscular volume of 90 fl ( elevated reticulocytes at 233  10/l ; reticulocyte index 4.5% , suggesting adequate marrow response ) .
a peripheral blood smear showed a leukoerythroblastic picture with several blast - like cells with fine chromatin and one or more prominent nucleoli ( fig .
1 ) . there were also features of hemolysis , including spherocytosis , significant polychromasia , and nucleated red blood cells .
iu / l ; normal up to 225 ) and haptoglobin was low ( <3 mg / dl ) .
serologies and polymerase chain reaction ( pcr ) tests for hepatitis b and c virus , human immunodeficiency virus , cytomegalovirus , epstein 
barr virus , leishmania , and human t - lymphotropic virus type 1 were negative .
scan showed marked splenomegaly with a span of 21.8 cm associated with arterial hypoperfusion ( perhaps explaining the abdominal pain ) .
enlarged axillary , porta hepatis , mesenteric , and para - aortic lymph nodes were also noted ( the largest lymph node was 19  13 mm in the abdomen ) . a whole - body fdg pet / ct scan showed moderate uptake in the left axillary and upper retroperitoneal lymph nodes , suggesting lymphoma activity with spleen and bone marrow involvement .
the aspirate showed hypercellular marrow with erythroid hyperplasia ( mixed normoblastic and megaloblastoid ) , hypoplastic granulopoiesis , and reduced megakaryocytes .
there was marrow infiltration with 18% abnormal pleomorphic cells with patchy distribution , mostly showing blast morphology with primitive chromatin , prominent nucleoli , and irregular nuclear contour .
2 ) . flow cytometric analysis ( navios , beckman coulter ) of the bone marrow aspirate ( fig .
3 ) revealed a population of abnormal t - cells ( 18% ) of high side scatter expressing cd2 , cd3 , cd8 , and tcr  with brighter cd45 and dimmer cd7 than the normal t - lymphocytes with partial loss of cd5 .
these cells were negative for cd4 , cd56 , cd16 , cd57 , cd34 , cd1a , and tdt .
flow cytometry analysis of the tcr v  ( vb ) repertoire revealed that the abnormal cells failed to express any of the tcr vb regions , suggesting monoclonality .
the immunostains confirmed that the remarkably increased t - cells were positive for cd2 , cd3 , cd5 , and cd8 with loss of cd7 expression ( fig .
4 ) and negative for cd34 , tdt , cd99 , granzyme b , and alk1 .
cytogenetic analysis of the bone marrow sample revealed normal karyotype , and tcr gene rearrangement performed using peripheral blood showed no evidence of clonality .
based on the peripheral blood and bone marrow findings , a diagnosis of  mature t - cell lymphoma was made .
after further multidisciplinary discussion , a diagnosis of hstcl stage iv (  subtype ) was confirmed .
the hyper - cvad protocol was initiated after discussion at a multidisciplinary conference , and the patient subsequently received the first cycle of treatment , which was complicated by febrile neutropenia and hypotension .
he was managed with intravenous antibiotics but continued to have lymphoma - related fevers with persistent massive splenomegaly and no changes in his complete blood count findings . at this point
magnetic resonance imaging of the brain showed a small lesion ( 7  9  9 mm ) in the right temporal lobe , and the possibility of lymphomatous deposition was considered as a likely etiology .
a lumbar puncture was not pursued because of refractory thrombocytopenia ( < 50,000/l ) . repeated bone marrow examinations after the first cycle of treatment showed increasing abnormal t - cells ( 53% ) with blast morphology scattered in many cohesive clusters .
flow cytometry findings were comparable to those at presentation except for loss of cd5 expression .
a second bone marrow aspirate revealed abnormal karyotype with 47,x ,- y , i(7 ) ( q10),+8,+8,add(13)(p11.1 ) /46,x ,- y , i(7)(q10),+8,add(13 ) ( p11.1 ) /46,xy .
interval fluorescence in situ hybridization analysis revealed additional signals at 7q31 ( d7s486 probe ) on chromosome 7 in 15% of the analyzed cells . at this time
after further discussion , a second cycle of hyper - cvad was initiated , which was complicated by enterobacter cloacae sepsis that was treated with meropenem .
after two cycles of hyper - cvad therapy , bone marrow evaluation showed 17% neoplastic t - cells ( similar to 18% at initial diagnosis ) and flow cytometry showed the same immunophenotype ( as at initial diagnosis ) except for persistent loss of cd5 .
interval pet - ct imaging showed no significant change compared to baseline , suggesting the absence of response to hyper - cvad therapy .
given the poor prognosis of the disease , the patient was offered salvage therapy with regimens containing high - dose cytarabine and platinum analogs ( dhap or esha ) , followed by autologous stem cell transplantation .
the poor prognosis of the disease and its refractoriness to chemotherapy along with the salvage therapy options were discussed with the patient .
this case of  hstcl confirms several of the previous findings of this rare disease5,6 and also illustrates some atypical features that make it a diagnostic challenge , especially given its extremely low incidence .
the peak incidence of hstcl is in adolescents and young adults with a median age at presentation of 20 years and with a gender ratio of 9:1 ( male : female ) .
the largest case series of  hstcl ( 14 cases ) was reported by macon et al.5 who showed no significant clinicopathologic and cytogenetic difference between the  and  subtypes , except for female preponderance , older median age , and variable age distribution in the former .
up to 20% of  hstcl cases arise in the background of chronic immune suppression , particularly solid organ transplantation,79 a finding denied by nagai et al for the  subtype.6 it is worth mentioning that our patient had no significant past medical history . in this context
hstcl usually presents with marked splenomegaly and hepatomegaly , but without lymphadenopathy.1 interestingly , our patient had no palpable lymphadenopathy , but ct and pet imaging unveiled axillary , porta hepatis , and retroperitoneal lymphadenopathy .
patients also commonly have b symptoms , such as fever , fatigue , and weight loss.1 abnormalities in liver function tests may be seen in half of the patients.1 thrombocytopenia is also a common feature of this disease with associated leukopenia and anemia .
autoimmune hemolytic anemia (  warm  type and cold agglutinin disease)10,11 and immune thrombocytopenic purpura12 have been reported as initial manifestations of the disease in rare cases .
cytopenias may result from hypersplenism , bone marrow failure , cytokine - mediated hemophagocytic histiocytosis,13 or a combination of these mechanisms .
the pathogenesis of autoimmune hemolytic anemia in hstcl is unknown , although neoplastic t - cells as mediators of autoimmune disease have been proposed as a potential explanation.14 our patient initially presented with a picture of coombs-negative hemolytic anemia .
it is also worth noting that 5%10% of autoimmune hemolytic anemias are coombs negative,15 and several causes for this phenomenon have been identified , which include hemolysis by natural killer ( nk ) cells independent of antibody , small number of subthreshold immunoglobulin ( ig ) g attached to red blood cells , low - affinity autoantibodies , iga autoantibodies , and igm autoantibodies.14 coombs-negative hemolytic anemia was previously reported in one case of  hstcl.16 to the best of our knowledge , this is the first reported case of  hstcl with such a presentation .
morphologically , hstcl is characterized by a monotonous neoplastic infiltrate consisting of medium - sized lymphocytes with a moderate cytoplasm and irregular cellular borders .
the splenic red pulp is expanded with infiltration of cords and sinuses associated with atrophy of the white pulp .
liver biopsy also shows an intrasinusoidal infiltrative pattern.1 the bone marrow is frequently involved in the disease.1 trephine biopsy typically shows a hypercellular marrow with characteristic selective infiltration and expansion of the sinuses , which is a useful diagnostic criterion.17,18 however , with progression , the pattern of bone marrow involvement becomes increasingly interstitial,16 which was likely the case in our patient , thereby posing a diagnostic challenge .
furthermore , morphology of the tumor cells was predominantly blastoid , another atypical feature of hstcl that is typically associated with disease progression.16,17,19 cohesive clustering of lymphoma cells was another unusual finding .
these atypical findings , along with the possibility of false - negative initial karyotype and tcr rearrangement studies , delayed the definitive diagnosis .
the false - negative result is possibly related to sample dilution , leading to loss of signal below the detection limit . given the blastoid morphology of the cells , acute lymphoblastic leukemia / lymphoma was considered in the differential diagnosis . however , the negativity for precursor markers ( cd34 , tdt , and cd99 ) excluded this possibility . other differential diagnoses considered included splenic marginal zone lymphoma , t - cell large granular lymphocytic leukemia , and aggressive nk / t - cell leukemia , which were excluded because of the inappropriate morphology and immunophenotype .
hstcl typically has the following phenotype : cd2 + , cd3 + , cd4 , cd5 , cd8 , cd16 , cd56+/ , and tcr/+.4,20 frequently , loss of cd3 , cd5 , and/or cd7 ( cd5 lost in this case ) occurs with disease progression .
the lymphoid infiltrate in our case was cd8 + , which is reported in a minority of cases.4,20 interestingly , macon et al.5 showed that the  type was more likely to be cd8 + when compared to the  type .
nk cell markers may also be usually expressed with an inactive cytotoxic profile ( tia+ , granzyme , and perforin ) ; however , our case did not show any .
most  hstcls are associated with the presence of an isochromosome 7q ( i[q10 ] ) with associated abnormalities such as trisomy 8 and loss of chromosome y. the isochromosome 7q has also been demonstrated in  hstcl cases.5,11,21 all the abovementioned karyotypic abnormalities were observed in our patient .
the biological significance of the isochromosome 7q has not been worked out to date and is not entirely specific to this disease .
the prognosis of hstcl ,  or  type , is extremely poor with a median survival of less than one year.5 according to the international peripheral t - cell and natural killer / t - cell lymphoma study,22 the five - year overall survival was only 7% and five - year failure - free survival was 0% , this being the worst among all subtypes of t - cell lymphomas .
the majority of patients respond to chop or chop - like regimens but quickly relapse with very few long - term survivors.19 therapies that are quite effective in curing a substantial number of patients with other aggressive lymphoid malignancies such as diffuse large b - cell lymphoma have been shown to be ineffective for hstcl .
several case reports have studied the efficacy of new treatments , such as bortezomib , alemtuzumab , and allogeneic bone marrow transplantation,2326 but more efforts are still needed to treat this rare but devastating disease .
hepatosplenic t - cell lymphoma ( hstcl ) is a rare and aggressive extranodal t - cell lymphoma that comprises < 5% of peripheral t - cell lymphomas . 
 the majority of cases harbor the  t - cell receptor ( tcr ) , but recently , a few cases have been shown to express the  tcr . 
 comparison of these two subtypes (  and  ) shows similar clinicopathologic and cytogenetic features ; however , due to the paucity of reported cases , it is not clear whether they are prognostically distinct entities . we report a case of  hstcl with a rather unusual presentation of coombs-negative hemolytic anemia . 
 diagnosis proved challenging due to an unusual blastoid morphology with the absence of typical intrasinusoidal distribution of tumor cells in the bone marrow . 
 this unique case adds to the growing list of this rare subtype of t - cell lymphomas , which warrant urgent attention due to the lack of effective treatment options and dismal prognosis .