A young man with multifocal brainstem leptomeningeal disease

A 19-year-old man presented with right eye ptosis, horizontal binocular diplopia, and right facial paresthesia. Neurological examination was consistent with right third, fourth, fifth, and sixth cranial neuropathies. Head MR imaging revealed multifocal leptomeningeal enhancement along bilateral cranial nerves and an enhancing mass at the right-sided prepontine cistern (Figure 1A). Chest and abdominal CT scans showed no significant abnormalities.

Three months later, he developed progressive bilateral lower extremity weakness. Spine MR imaging revealed diffuse leptomeningeal enhancement of the spinal cord and cauda equina, and enhancing intramedullary lesions at dorsal T4 and right-sided T10 thoracic levels (Figure 1B). Follow-up head MR imaging showed progressive leptomeningeal enhancement and newly developed ependymal enhancement in the fourth ventricle, frontal horns of bilateral lateral ventricles, and septum pellucidum.

An initial biopsy from the prepontine mass showed lymphohistiocytic proliferation with atypical cells, which, alongside immunohistochemical (IHC) testing, favored a benign histiocytic lesion. A bone marrow biopsy was negative for malignancy. Some cerebrospinal fluid (CSF) analyses revealed atypical mononuclear cells. A subsequent biopsy via L2 lumbar laminectomy showed lymphohistiocytic proliferation, comprising atypical histiocytes (positive for CD163 and CD68/PG-M1; negative for S100, CD1a, and ALK/ALK1/D5F3), together with Ki-67-positive atypical cells, small CD3-positive T cells, and small CD20-positive B cells (Figure 2A). In-situ hybridization (ISH) for Epstein–Barr virus early RNA (EBER) was negative.

Given the relentless clinical and radiological progression, a tentative diagnosis of malignant histiocytosis was made. The patient had been treated with multiple courses of high-dose methotrexate-based chemotherapy but showed negligible neurological improvement. He subsequently developed the neurogenic bladder with recurrent urinary tract infections and later obstructive hydrocephalus. Eventually, he received comfort care and died 33 months after the initial presentation.

At autopsy, the central nervous system (CNS) showed an infiltrative neoplasm extensively involving the craniospinal leptomeninges and ventricular system and invading the cranial nerves, spinal nerve roots, cauda equina, subpial brain/spinal cord parenchyma, and subependymal brain parenchyma (Box 1, Figure 2B). The non-cohesive large neoplastic cells had pleomorphic vesicular/hyperchromatic nuclei, prominent nucleoli, and abundant pale-eosinophilic cytoplasm (Figure 2C). There was high mitotic activity, multinucleated cell formation, hemophagocytic activity, apoptosis, and focal necrosis.

On IHC testing, most of the neoplastic cells were positive for CD163 (Figure 2D) and CD68/PG-M1 (Figure 2E). The neoplastic cells were negative for lysozyme, myeloperoxidase, CD1a, CD3, CD4, CD20, CD21, CD30, CD45/LCA, CD123, ALK/ALK1/D5F3, cytokeratins/AE1/AE3, epithelial membrane antigen, melan-A, and neurofilament/2F11. Small subsets of the neoplastic cells in the CNS parenchyma and pia mater were positive for S100 and GFAP with weak/moderate immunoreactivity, probably representing phagocytosis. The Ki-67 proliferation index was approximately 80% (Figure 2F). Leukocytes scattered among the neoplastic cells were CD3-positive T cells, myeloperoxidase-positive myeloid cells, and CD20-positive B cells. The neoplastic cells were negative for EBER ISH.

There was no histopathologic evidence of hematolymphoid neoplasms in the bone marrow, spleen, lymph nodes, or other extra-craniospinal organs. Both lungs were involved by bronchopneumonia.

Primary CNS histiocytic sarcoma, with diffuse leptomeningeal involvement.

Histiocytic sarcoma (HS) is defined as a malignant hematolymphoid neoplasm of histiocytic lineage, with histologic and immunophenotypic features of non-dendritic non-Langerhans histiocytes and without other lines of differentiation [1, 2]. HS accounts for <1% of all hematolymphoid neoplasms, affects adults preferentially, and exhibits aggressive clinical courses [1].

Primary CNS-HS is exceedingly rare, with <40 cases reported in the literature [1]. We report a very unusual case of primary CNS-HS presenting initially as brainstem leptomeningeal disease. Only three cases with similar presentations have been reported [2]. The differential diagnosis includes chronic leptomeningitis, metastasis from systemic cancer, leptomeningeal involvement by primary CNS neoplasm, and primary leptomeningeal neoplasm (e.g., diffuse large B-cell lymphoma) [2, 3]. Subsequently, our patient's disease progressed to the spinal leptomeninges and CNS parenchyma. Neither CSF analyses nor tissue biopsies yielded the diagnosis during life. The histopathologic diagnosis of CNS-HS was proven at autopsy with the aid of IHC testing.

Making a histopathologic diagnosis of HS may be straightforward for ample amounts of tissue from readily accessible organs or unlimited tissue at autopsy, with prominent nuclear atypia of neoplastic cells and characteristic IHC profiling. By contrast, diagnosing HS is challenging for scant tissue from neurosurgical biopsy because admixed reactive leukocytes may obscure HS cells [1, 2]. As HS is rare, pathologists may not consider it. A broad IHC panel is crucial to exclude other neoplasms with morphologic similarity. DNA methylation profiling is complementary to the standard diagnostic tools to guide, refine, or deliver tumor-type diagnoses; nonetheless, the performance of machine-learning classifiers depends on the representativeness of tumor datasets used for training (e.g., in the case of CNS-HS) [1].

Clinical data collection: PS-S, PT. Radiological data collection: OT, TP. Pathological data collection: BK, PB, VP, VS. Manuscript draft preparation: BK, PS-S, VS. All authors reviewed and approved the final manuscript.

The authors declare no conflicts of interest.

This work was approved by the Human Research Ethics Committee, Faculty of Medicine Ramathibodi Hospital, Mahidol University (COA. MURA2022/722).