Histiocytic and dendritic cell sarcomas are among the rarest of tumors affecting lymphoid tissues [1
]. These tumors arise from phagocytes and related accessory cells, which have major roles in the processing and presentation of antigens to lymphocytes. Currently, the WHO includes the following 5 entities under this designation: histiocytic sarcoma (HS), follicular dendritic cell sarcoma (FDCS), interdigitating dendritic cell sarcoma (IDCS), Langerhans cell sarcoma (LCS), and dendritic cell sarcoma, not otherwise specified (DCS, NOS)[1
]. The pathologic diagnosis of HS is often challenging and requires histologic, immunohistochemical, and, occasionally, electron microscopic analysis [1
]. We reached the diagnosis of HS in our case based on the exclusion of other sarcomas and carcinomas including other members of the HS/dendritic cell sarcoma group. A comparison between immunophenotypes and ultrastructural features of the neoplastic cells of present case and reported lymphoid tissue phagocytic and accessory cell neoplasms is shown in Table .
Comparison Between Immunophenotypes and Ultrastructural Features of Neoplastic Cells in Present Case and Lymphoid Tissue Phagocytic and Accessory Cells Neoplasms*
Histologically, the tumor showed diffuse infiltrate of large, round to ovoid pleomorphic cells; large multinucleated forms, mitoses, and necrosis were commonly seen. Interestingly, our case showed an uncommon phenotype, namely a prominent spindle cell component, causing significant diagnostic confusion with other spindle cell neoplasms. The neoplastic cells demonstrated immunohistochemical staining characteristics similar to those of normal monocytes/histiocytes, namely strong immunoreactivity with CD163, CD68, lysozyme, NSE, and vimentin. In addition, there was focal expression of S-100 protein, CD45, and CD4, reflecting the physiologic pattern of expression of this T-helper antigen by histiocytes [1
]. Electron microscopy revealed presence of numerous lysosomes and lack of desmosomes, Birbeck granules and prominent interdigitating cell processes.
Histiocytic sarcoma with a prominent spindle cell component has morphologic similarity with IDCS. The latter consistently expresses S-100 protein, ATPase and HLA-DR, and is variably, weakly positive for CD68, lysozyme, and CD45 [1
]. Unlike HS, IDCS cells do not express non-specific esterases [1
]. In addition, cytologic atypia and mitotic rate are low, and necrosis is usually absent [1
]. On electron microscopy, IDDCS cells show long cytoplasmic finger-like projections and lack the abundance of lysosomes – a characteristic ultrastructural feature of histiocytes.
In the case presented here, considering the morphologic features, the neoplasm should also be differentiated from a LCS. The neoplastic cells of LCS display overtly malignant cytology and linear nuclear grooves reminescent of Langerhans cell histiocytosis, a key feature to suggest this diagnosis [1
]. The neoplastic cells consistently express S-100 protein, and, unlike HS, CD1a [1
]. In addition, there is usually some immunostaining for CD68, lysozyme, and CD45. On electron microscopy, Birbeck granules and a variable number of lysosomes should theoretically be present in all cases in which adequate examination was carried out [1
Spindle to ovoid cell proliferation with occasional multinucleated cells can be observed in FDCS [1
]. The neoplasm forms fascicles, storiform patterns, and whorls [1
]. The neoplastic cells are strongly positive for one or more of the follicular dendritic cell markers, including CD21, CD23, and CD35. In addition, they express vimentin, fascin, clusterin, HLA-DR, and are variably positive for EMA, S-100 protein, and CD68 [1
]. Follicular dendritic cell sarcoma may occur in association with Castleman disease, usually the hyaline vascular type [1
]. A high proportion of cases of putative FDCS showing features of inflammatory pseudotumor have been associated with the Epstein-Barr virus [1
]. In these cases, Epstein-Barr virus encoded RNA (EBER) has been found in all of the spindle cells [1
]. In the case presented here, all neoplastic cells were negative for Epstein-Barr encoded RNA. Electron microscopically, the most distinctive ultrastructural feature of FDCS is the presence of numerous long, slender cytoplasmic processes connected by desmosomes.
Dendritic cell sarcoma, NOS, can mimic a HS with prominent spindle cell component. This is a diagnosis of exclusion, not well characterized morphologically and immunohistochemically. The neoplastic cells express CD1a and S-100 protein but lack cytoplasmic Birbeck granules [1
The overall appearance of HS may be indistinguishable from a diffuse large B-cell lymphoma or an anaplastic large cell lymphoma. Immunohistochemical markers are necessary to make a certain lineage distinction. In contrast to HS, diffuse large B-cell lymphoma constantly express various pan-B markers such as CD19, CD20, CD22, and CD79a, while anaplastic large cell lymphomas are positive for CD30, and ALK [1
Other tumors, such as carcinomas, melanomas, and soft tissue sarcomas, primary or metastatic, can be confused with HS and were excluded in our case by the lack of immunoreactivity for pancytokeratin, CAM 5.2, CK 903, TTF1, HMB45, MART-1/Melan A, CD99, CD117, smooth muscle actin, desmin, and myogenin.
Last but not least, HS may be confused with reticulohistiocytoma – an uncommon, incompletely characterized benign histiocytic proliferation of the skin and soft tissues. The lesion is composed of epithelioid histiocytes with abundant, densely eosinophilic cytoplasm, and, in contrast to HS, mild if any, nuclear atypia and low mitotic activity [13
Histiocytic sarcoma is a neoplasm with uncertain molecular pathogenesis. The neoplasm in our case showed a 57–80 hyperdiploid /46, XY  karyotype, including 3 to 4 copies of various chromosomes. Recent studies established a cooperative role of PTEN and p16(INK4A)/p14(ARF) in the development of HS [4
]. In addition, HS demonstrated germ-like clonal immunoglobulin and T-cell receptor genes [14
The biologic behavior of HS is typically aggressive with a poor response to therapy. In agreement with previous reports, the HS case presented here demonstrated high proliferative rate and extranodal spread [1
]. Stage of disease and possibly tumor size are considered significant prognostic indicators [1
]. Most patients die of progressive disease reflecting the high clinical stage at presentation [1
]. Sarcomas in the head and neck are best treated initially with surgery to obtain wide surgical margins. This may be limited due to neurovascular structures within the head and neck. Hence local recurrence in large sarcomas is a concern. Radiotherapy has been shown been shown to be an important adjunctive role in management of tumors were wide surgical margins are not possible. Chemotherapy regimens are more controversial. Due to the rarity of head and neck sarcomas there are no proven regiments. Most studies are retrospective reviews from different institutions. Chemotherapy like radiotherapy is used primarily for local control of disease. The patient's overall prognosis is influenced by grade and the ability to obtain wide margins, with improved survivability by controlling local recurrence and distant metastasis [15
In summary, HS is a rare neoplasm that may pose difficulty in pathologic diagnosis. Awarness of HS is important because these neoplasms may mimic other lymphoproliferative disorders in their clinical presentation and morphologic appearance. Even with immunohistochemical work-up, diagnosis may be missed as histiocytic markers are often not included in the routine pannel of antibodies used for investigation of spindle cell and undifferentiated neoplasms. The key feature suggestive of HS is the strong expression of one or more "histiocytic markers", including CD163, CD68, and lysozyme in the majority of neoplastic cells.
Although a few cases of extranodal FDCS have been described in the head and neck [12
], to our knowledge this is the first case of a HS arising in this area.