Histiocytic Sarcoma of Bone Marrow With Partial Cohesive Neoplastic Cells and Hemophagocytosis: a Case Report

Background: Histiocytic sarcoma (HS) is a rare hematolymphoid neoplasms whose cells show morphologic and immunophenotypic features of mature tissue histiocytes. We herein report a HS case without nodules or lymphadenectasis conrmed with the help of immunohistochemistry (IHC) on bone marrow (BM) biopsy and smear. Case presentation: A 63-year-old female patient with a history of cerebral infarction presented with fever, retching and hypodynamic sign for three weeks. The peripheral blood examination showed aggressive pancytopenia accompanying with the positivity for Epstein-Barr virus (EBV) antibody. The computed tomography and abdomen ultrasound scan didn’t reveal any nodules or lymphadenectasis other than hypersplenotrophy. Signicantly, the BM aspirate shows vast pleomorphic tumor cells atypically distributed in both forms of single diffuse and cohesive. The hemophagocyte phagocytized granulocytes on BM smear exhibited the lymphoma related hemophagocytic syndrome. Immunohistochemically, neoplastic cells were immunopositively for macrophage-associated antigen cluster of CD4, CD68, CD163, but negative for the T-cell, B-cell and myeloid lineage markers of CD15, CD20, PAX-5, CD5, CD30, CD3, CD56, CD38, CD138, ALK and MPO, conrming the hypothesis of HS in BM. Conclusion: The rare HS case of bone marrow with atypically partial cohesive pleomorphic tumor cells had the hemophagocytic syndrome, presented highly aggressive clinical course and challenged to the diagnoses.

Conclusion: The rare HS case of bone marrow with atypically partial cohesive pleomorphic tumor cells had the hemophagocytic syndrome, presented highly aggressive clinical course and challenged to the diagnoses.

Background
Histiocytic sarcoma (HS) is a rare hematopoietic neoplasm derived from the monocyte/macrophage system [1]. HS has a wide patient age range from infancy to old age with median age of 52 years and a slight male predominance [2]. Clinically, HS could affect solitary organs such as lymph nodes, gastrointestinal tract, soft tissue, skin, bone marrow, spleen and even central nervous system, usually associated with other analogical hematologic malignancies of follicular lymphoma, mantle cell lymphoma and acute/chronic lymphocytic leukemia [3,4]. Given its rarity, complicated organs symptoms and histologic overlap with diverse mimics, the diagnosis of histiocytic sarcoma had been extremely challenged.
According to the 2016 World Health Organization (WHO) classi cations, cytomorphology and immunohistochemistry generally help to strictly distinguish HS from B-cell, T-cell or anaplastic cell lymphoma, even other associated lymphocytic leukemia. HS cells are usually single diffuse variety in morphology and immunohistochemically positive for one or more histiocytic markers of CD68, CD163, lysozyme and CD4 [5]. We herein report a rapid invasiveness HS case without nodules and lymphadenectasis, involving a 63-year-old female patient diagnosed as bone marrow HS with atypically cohesive clusters neoplastic cell accompanying with EBV infection.  1). Moreover, the BM aspirate showed that BM karyocytes were active proliferation with abundant cohesive clusters or singly diffuse scattered malignancy cells in the scanning view ( Fig. 2A-2C). These cells varied in morphology of irregular round, oval, spindle-shaped and tadpole shape with abundant basophilic cytoplasm, grooved, strip-like pleomorphic nuclei and faintly visible nucleoli. Furthermore, a frequent phenomenon that hemophagocyte phagocytized granulocytes, erythrocyte and pigment granules appeared in BM smear, which commonly hinted malignant histiocytosis, hemophagocytic syndrome, lymphoma and lymphocytic leukemia (Fig. 2D). Immunohistochemical staining of neoplastic cells (antibody dilution, 1:100; MaiXin, Technologies, Inc., FuJian, China) was negative for CD20, paired box PAX-5, CD5, CD30, CD3, CD56, CD15, CD38, CD138, ALK, MPO while it was positive for CD4, CD68, CD163 (Fig. 3), ruling out B-cell lymphoma, T-cell lymphoma, and myeloid origin. In view of the iconic immunohistochemical marker, abundant hemophagocytes and the positive EBV infection, this HS case was con rmed.

Case Presentation
Unfortunately, the rapid invasiveness of HS gave rise to the patient's poor physical condition. The functional gastrointestinal disorders, pleural and abdominal pelvic effusion occurred successively within three days. Soon she had septic shock with electrolyte disturbance and metabolic acidosis on May 23, 2019 and nally died of respiratory failure on May 24, 2019. We were unable to collect more information on the cytogenetic or treatment of this HS case.

Discussion
Histiocytic sarcoma, also formerly known as "true histiocytic lymphoma", is rare because of its prevalence rate less than 1% of all non-Hodgkin's lymphomas [4]. The differential diagnosis of HS involves various lymphomas, histiocytic and dendritic cell neoplasms, melanomas, metastatic carcinoma and pleomorphic sarcomas [5], which is confronted with challenges of misdiagnosis and requires pro cient recognition of clinic features, the atypical-morphology of tumor cell, the expression of histiocyte-associated makers.
Microscopically, HS is characterized by large and pleomorphic cells with ''Pac-Man''-like nuclei and abundant vacuolated cytoplasm [6]. Commonly, a predominant noncohesive proliferation diffused among HS neoplastic cells, no matter in solid nodules with reactive eosinophilic in ltration stroma [7] or in bone marrow with abundant phagocytes [8]. Moreover, although the association of HS with other lymphocytic leukemia/lymphomas had been frequently reported in recent years, most of which still presented as the noncohesive or single diffuse proliferation cells in biopsy [9][10][11]. The atypical cohesive growth pattern of large neoplastic cells only appeared in several cases of B-cell lymphomas of plasma blastic lymphoma (PBL) [12,13], T-cell lymphomas of anaplastic large cell lymphoma (ALCL) [14,15], other metastatic carcinoma to bone marrow [16] and one case of classic Hodgkin lymphoma (CHL) [17]. Interestingly, in this case, a rare sight that neoplastic cell in tightness cohesive clusters with symplasm morphological was distinctly observed on this bone marrow smear, even accompanying with the hemophagocytosis and EBV infection. Thus the mimic cohesive morphology of large neoplastic cells deserves additional attention in terms of differential diagnosis for this case.
The immunohistochemistry (IHC) helps to differentiate HS from other large neoplastic cells lymphomas of B cell type or T cell type. WHO classi ed PBL as an uncommon mature B-cell lymphoma, occurring most frequently in HIV-positive patients, but exceptions do exist, which was characterized by positive expression of the following postgerminal centre B cell associated and plasma cell associated markers: multiple melanoma oncogene (MUM1) epithelial membrane antigen (EMA) and CD138 [13]. The ALCL is de ned as a CD30 + peripheral T-cell neoplasm that is not reproducibly distinguishable on morphological grounds from ALCL-ALK+, but lacks the ALK protein and exists the case of ALCL-ALK- [18,19]. This HS case is strictly pro led by the crucial marker of CD163, CD68 and CD4 [5,20], differentiated with typical absence of CHL maker (CD15), myeloid maker (MPO), T cell of ALCL (CD30, ALK) and B cell (CD20, CD138, PAX-5).
Additionally, most studies have demonstrated that BRAF V600E mutations occur in nearly two-thirds of HS, while the tumor-suppressor gene CDKN2A was the frequently altered gene (46%) [21,22]. A targeted next-generation sequencing (NGS) study recently demonstrated recurrent mutations activating the 57% mitogen-activated protein kinase (MAPK) pathway (MAP2K1, KRAS, NRAS, BRAF, PTPN11, NF1, CBL) and the 21% phosphoinositide 3-kinase (PI3K) pathway (PTEN, MTOR, PIK3R1, PIK3CA) in HS cases, respectively. Unfortunately, the death of our patient in this case terminated the gene-related determination. Anyway, these hadoop ndings of gene mutation or arrangement should contribute to the diagnosis and treatment of HS.