histiocytic sarcoma ( hs ) , a rare hematopoietic neoplasm with aggressive characteristics and poor outcomes , can present as localized disease confined to the skin , lymph nodes , and intestinal tract , or as disseminated disease ( 1 , 2 ) . these histiocytic and dendritic cell neoplasms arise from antigen - processing phagocytes and antigen - presenting dendritic cells , cells derived from hematopoietic or mesenchymal stem cells ( 1 ) . hs has often been mistaken for some types of lymphomas , due to their overlapping features and inadequate phenotypic evaluation , particularly immunohistochemical and cytogenetic data ( 2 , 3 ) . current hs diagnosis is based on histological and immunohistochemical evidence of histiocytic differentiation and the exclusion of epithelial , melanocytic , and lymphoid phenotypes ( 4 ) . using both immunohistochemistry and cytogenetics , it is now generally accepted that most neoplasms diagnosed as hs were actually b- or t - cell , non - hodgkin lymphomas ( 1 , 4 ) . hs is a malignancy characterized by the proliferation of histiocytes with positive expression of the macrophage associated antigen cd68 ; negative expression of the t - cell associated and langerhans cell antigen cd1a , s-100 protein , and the dendritic cell - associated antigens cd21 and cd35 ; and also the absence of birbeck granules , junctions , desmosomes and cytoplasmic projections on electron microscopy ( 1 - 6 ) . although several cases of hs have been described ( 4 - 12 ) , primary bone marrow ( bm ) involvement is rare . a 63-yr - old male complaining of weight loss ( 10 kg in 6 months ) , fever of unknown origin and general weakness was referred to our hospital for evaluation . previous medical history , family history and physical examination showed nothing remarkable . at presentation , white blood cell ( wbc ) count was 13.210/l , hemoglobin was 9.4 g / dl and platelet count was 46610/l . his serum protein concentration was 7.5 mg / dl , albumin was 1.4 mg / dl , aspartate aminotransferase was 53 iu / l , alanine aminotransferase was 53 iu / l , total bilirubin was 0.7 mg / dl , lactate dehydrogenase was 231 l , potassium was 4.4 mm / l , chloride was 93 mm / l and total co2 was 29.0 mm / l . his ferritin concentration was 2,339.3 ng / ml and fibrinogen concentration was 552 mg / dl . review of abdominal and chest computed tomography ( ct ) performed at the referring hospital showed nothing unusual , except for a few 1-cm - sized small lymph nodes and mild hepatosplenomegaly . head and neck ct revealed slight enlargement of a neck lymph node , which may have been benign or metastatic , but two target biopsies and an excisional biopsy of the lesion provided no diagnostic information . abdominal and pelvic ct performed at our hospital showed the same results as the ct scans performed at the referring hospital , except for suspicion of bony changes at the lumbar and sacral bones . although fusion whole body positron emission tomography ( pet ) showed lesions indicative of multiple bone metastases ( fig . because there was no evidence of malignancy on chest , abdominal and pelvic ct and prostate ultrasonography , we performed lumbar spine magnetic resonance imaging ( mri ) ( fig . the mri findings suggested that the pet lesions were reactive changes of the bm caused by malignant cell infiltration , such as leukemia , lymphoma or multiple myeloma ( mm ) rather than multiple bone metastases . a bm biopsy showed an increase in plasma cells ( 15% ) , eosinophils and histiocytes , but no malignant cells . due to suspected mm , we tested the monoclonality of the plasmacytosis and fluorescence in situ hybridization myeloma panel . although 2-microglobulin was 3.6 mcg / ml , there was no evidence of monoclonality in plasmacytosis , igh / fgfr3 rearrangement , or rb1 or tp53 deletion . serum protein electrophoresis and immunoelectrophoresis showed increases in -1 , 2 and -globulin fractions , findings consistent with a chronic inflammatory response . ct guided bone biopsies of the lumbar spine and another bm biopsy showed no evidence of malignant cells . the patient chose supportive care , but was readmitted one month later for aggravation of his general condition . the patient still wanted supportive care and died soon afterward . at necropsy , we performed another bm biopsy and a liver biopsy . the liver biopsy showed no evidence of malignancy , except for severe cholestasis with non - specific hepatitis . the bm biopsy , however , revealed a diffuse non - cohesive proliferation of pleomorphic neoplastic cells with large round to oval nuclei , vesicular chromatin and abundant foamy eosinophilic cytoplasm ( fig . 3 ) . immunohistochemistry showed positive expression of cd68 ( macrophage / histiocytic marker ) , s100 protein , cd31 , cd99 and vimentin . neoplastic cells were weakly positive for cd21 ( mature b - cell and follicular dendritic cell marker ) , cd4 ( t - cell marker ) and lysozyme and negative for cd3 ( t - cell marker ) , cd20/cd79a ( b - cell markers ) , cd56 ( nk cell marker ) , cytokeratin , smooth muscle actin ( sma , a myeloid cell marker ) , smmhc and hmb45 . together , these morphologic and immunohistochemical features are consistent with the bm involvement of hs . hs is a rare and aggressive malignant disorder commonly presenting at extranodal sites and showing a poor response to therapy , with most patients dying from the disease ( 1 ) . hs may also be associated with other hematological disorders , such as acute leukemia , lymphoma and myelodysplasia ( 1 , 7 ) . genetic or epigenetic inactivation of pten , p16ink4a , and p14arf has been observed in hs , indicating that these proteins are involved in the development of hs and providing insights into the pathogenesis of these tumors ( 13 ) . differential diagnosis of hs includes langerhans cell sarcoma ( lcs ) , diffuse large b - cell lymphoma , peripheral t - cell lymphoma , anaplastic large cell lymphoma ( alcl ) , metastatic carcinoma , and melanoma . the diagnosis of hs is based on histological and immunohistochemical evidence of histiocytic differentiation and exclusion of other malignancies with epithelial , melanocytic and lymphoid phenotypes ( 4 ) . malignant hs cells strongly express the hemoglobin scavenger marker cd163 , which is regarded as a specific marker for hs ( 4 ) . tumor cells in our patient showed expression of histiocytic markers ( cd68 ) and lysozyme with weak expression of cd21 . the cells , however , did not express b - cell , t - cell , and myeloid markers , including cd3 , cd20 , cd56 , and cd79a , or sma and smmhc . the expression of histiocytic markers was unusual for alcl , and no rearrangement of the t - cell receptor -chain gene was identified . although these cells showed expression of s100 protein , the latter may have been derived from activated normal macrophages ( 1 , 9 ) . metastatic carcinoma and melanoma were ruled out by the absence of expression of cytokeratins and hmb45 ( 9 ) . morphologically , tumor cells in lcs have nuclei that are grooved , indented , folded , or lobulated , with fine chromatin and a thin nuclear membrane , features that are absent in hs ( 2 , 9 ) . the tumor cells in our patient had abundant clear cytoplasm , without spindle or fusiform cells , showing a whorled , fascicular or storiform pattern . these morphologic differences could distinguish the disease in our patient from lcs , and from follicular and interdigitating dendritic cell tumors ( 1 ) . . in one study , 6 of 11 patients died of disease within 0.5 to 36 months ( 10 ) . in a study of 18 patients who underwent chemotherapy , 3 achieved complete remission , 6 had no response , and 7 died of disease ( 1 ) . in another study of four adult patients with widespread disease , all failed chemotherapy and died from disease within 0.5 to 14 months after diagnosis ( 14 ) . in other studies , 6 of 8 adult patients died of disease 5 to 48 months after diagnosis despite aggressive chemotherapy ( 15 ) . the patient described here died of disease 2 months after his first visit to our hospital . due to the rarity of this malignancy , chemotherapy regimens have not been standardized , with most studies being retrospective reviews ( 8) . nonetheless , chemotherapy used to treat large cell lymphomas is a reasonable approach for patients with hs ( 12 ) , although thalidomide may also benefit these patients ( 3 , 11 ) . in summary , immunohistochemical features suggesting hs include the strong expression of histiocytic markers such as cd68 , lysozyme and cd163 . proper recognition of hs is important , because the clinical presentation and morphologic appearance of this neoplasm may lead to a misdiagnosis as other hematologic malignancies .
histiocytic sarcoma ( hs ) is a very rare neoplasm that often shows an aggressive clinical course and systemic symptoms , such as fever , weight loss , adenopathy , hepatosplenomegaly and pancytopenia . 
 it may present as localized or disseminated disease . 
 we describe here a 63-yr - old male who manifested systemic symptoms , including fever , weight loss and generalized weakness . 
 abdominal and chest computed tomography failed to show specific findings , but there was suspicion of multiple bony changes at the lumbar spine . 
 fusion whole body positron emission tomography , bone scan and lumbar spine magnetic resonance imaging showed multiple bone lesions , suggesting a malignancy involving the bone marrow ( bm ) . 
 several bm and bone biopsies were inconclusive for diagnosis . 
 necropsy showed replacement of the bm by a diffuse proliferation of neoplastic cells with markedly increased cellularity ( 95% ) . 
 the neoplastic cells were positive for lysozyme and cd68 , but negative for t- and b - cell lineage markers , and megakaryocytic , epithelial , muscular and melanocytic markers . 
 morphologic findings also distinguished it from other dendritic cell neoplasms .