A 55-year-old man with a cerebral mass

A 55-year-old man presented with recent onset of dizziness and left lower limb weakness. Magnetic resonance imaging revealed a relatively circumscribed mass in the left frontal lobe extending to the corpus callosum and contralateral hemisphere, with conspicuous perilesional edema and contrast enhancement (Figure 1). A whole-body computerized tomography (CT) scan did not reveal any other lesions. The patient underwent partial excision of the mass. F-18 fluorodeoxyglucose–positron emission tomography (PET) imaging demonstrated hypermetabolism in the residual brain mass, but no evidence of any lesion outside the central nervous system.

Microscopic examination revealed a hypercellular neoplasm mainly composed of large cells exhibiting irregular or indented, frequently nucleolated, nuclei, and eosinophilic cytoplasm, and characterized by brisk mitotic activity (Figure 2A; Box 1) and necrosis. Additionally, scattered binucleated or multinucleated cells were observed (Figure 2A). Some neoplastic cells exhibited hemophagocytic activity, consisting of engulfment of fragmented neutrophils or red blood cells in the cytoplasm (Figure 2B), whereas others displayed a brown cytoplasmic pigment (Figure 2C). Perl's staining revealed the presence of iron deposits in these cells (Figure 2D). Immunohistochemistry showed that the tumor cells were diffusely positive for CD68 (Figure 2E), CD163 (Figure 2F), and CD45, and negative for CD3, CD20, CD30, ALK, Langerin (CD207), CD21, myeloperoxidase, CD34, CD117, HMB45, Melan-A, CKAE1-AE3, GFAP, and OLIG2. CD4 (Figure 2G) and S100 positivity was observed in some neoplastic cells (Figure 2). Ki-67 labeling index was 40%. Immuno-expression of BRAF p. V600E was absent. CD3 immunostaining revealed abundant infiltration of small lymphocytes (Figure 2H).

Histiocytic sarcoma (HS).

HS is an exceedingly rare and aggressive hematopoietic tumor that primarily affects the lymph nodes, skin, gastrointestinal tract, or soft tissues, and can occur in individuals of varying ages, ranging from infancy to older adulthood. Primary HS of the central nervous system (CNS) is extremely uncommon, with fewer than 40 cases reported in the English literature [1]. Herein we present an additional case, which was considered as primary HS of the CNS owing to the lack of localization outside the CNS on CT and PET scans. According to the World Health Organization classification of CNS tumors, HS is defined as a malignant proliferation of cells showing morphological and immunophenotypic features of histiocytes and no other lines of differentiation. Histologically, HS is characterized by large cells with irregular nucleolated nuclei and eosinophilic cytoplasm, and brisk mitotic activity. An infiltrate of lymphocytes surrounding tumor cells, along with the presence of large pleomorphic cells and CD45 positivity may suggest anaplastic large-cell lymphoma or diffuse large B-cell lymphoma. However, the absence of immunostaining for CD30, ALK, and B-cell lineage markers excludes these diagnoses. Hemophagocytosis is a useful clue for the histological diagnosis of HS [2], and suggests histiocytic derivation of the tumor, which should be confirmed by the immunohistochemical expression of at least two histiocytic markers (CD68, CD163, CD4, lysozyme). A similar phenomenon, called emperipolesis, consisting of intact, undigested, blood cells in the cytoplasm of large histiocytic cells, is present in Rosai-Dorfman disease. This is a clonal proliferation of large histiocytes, that similarly to histiocytic neoplastic cells of HS, is positive for S100, CD68, and CD163 and can affect the CNS. However, in contrast to HS, Rosai-Dorfman disease does not feature brisk mitotic activity and necrosis. HS should also be distinguished from other histiocytic neoplasms, such as Langerhans cell or dendritic cell sarcomas, which can be ruled out by the negative Langerhans (CD1a and Langerin) and dendritic cell (CD21, CD35) markers. Myeloid sarcoma, which can also be positive for CD45 and express CD68 and CD163 in cases with monocytic differentiation, should also be considered in the differential diagnosis of HS, and can be excluded by the immunohistochemical negativity of myeloid markers (myeloperoxidase, CD34, CD117). The presence of brown pigment in the cytoplasm of neoplastic cells may suggest malignant melanoma. However, the absence of expression of melanocytic markers (SOX10, HMB45, Melan-A), together with Perl's stain which unequivocally demonstrates that the brown pigment corresponds to hemosiderin deposits likely derived from hemophagocytosis, rule out this diagnosis. Finally, according to the World Health Organization classification of CNS tumors, it is essential to exclude other tumor lineages (epithelial, mesenchymal, or glial) in order to diagnose HS. Negativity for cytokeratins, GFAP, and OLIG2 excludes metastatic carcinoma and gliomas. HS may feature molecular alterations involving the MAPK–ERK and PI3K–AKT–MTOR signaling pathways. Both BRAF activating mutations, including the BRAF p. V600E mutation, and BRAF rearrangements have been identified in HS, and may serve as potential therapeutic targets [1, 3].

S. A. drafted the manuscript. G. K. R. and V. B. reviewed and edited the draft. All the authors approved the final version of the manuscript.

Valeria Barresi is supported by the University of Verona, Italy (FUR 2023).

The authors declare no conflicts of interest.

All data related to this case were identified.