A 43‐Year‐Old Female with Multifocal Cerebral Lesions

Clinical History

A 43‐year‐old woman presented with a six month history of progressive nocturnal nausea and vomiting, resulting in 30 kilograms of weight loss. Subsequently, she developed gradual cognitive decline and a cerebellar syndrome with gait ataxia and nystagmus. MRI showed multifocal lesions localized periventricularly, parenchymal and in the pons on contrast‐enhanced T1‐weighted images (figure 1a). Examination of cerebrospinal fluid (CSF), whole body positron emission tomography computerized tomography (PET‐CT) scan and bone marrow biopsy did not show extra cranial involvement. The differential diagnosis consisted of metastatic melanoma, lymphoma, multiple sclerosis, meningoencephalitis or a granulomatous infection. Stereotactic biopsy of the lesions was performed.

Figure 1.

 

Pathology

Morphologically, the tumor was composed of large atypical cells with wide eosinophilic, partially vacuolated and granular cytoplasm containing eccentrically placed enlarged polymorphic nuclei with prominent nucleoli. Multi nucleated giant cells were also observed as well as mitoses and atypical mitosis. (figures 1b and 1c) The percentage of Ki67‐positive proliferating cells was approximately 20%. Immunohistochemical staining showed that neoplastic cells were positive for hemapoietic lineage, CD45 (figure 1d) and histiocytic markers (CD163 (figure 1e), CD68, and CD4). There was no expression of Langerhans cell (CD1a), myeloid (MPO, CD15, CD34), B cell (CD20, CD79a, PAX5), T cell (CD3, CD2, CD5, CD30, ALK‐1), or melanocytic (MelanA) markers. Also markers for mesenchymal malignancies and sarcomas (rhabdomyosarcoma, synovial sarcoma) were negative. Molecular studies demonstrated that the T and B cell receptor genes were in germ‐line configuration. What is your diagnosis?

Diagnosis

The tumor was classified as histiocytic sarcoma.

Discussion

Histiocytic sarcoma was first described in 1970 by Mathe et al. 3 Histiocytic sarcomas (HS) are rare malignancies of hematopoietic origin, and are thought to derive from mononuclear phagocytic cells or histiocytes. They most commonly involve the intestinal tract, soft tissues of skin, but any organ may be involved. Clinical manifestations depend on the involved organs. In the central nervous system (CNS) HS can involve any site, including the brain parenchyma, spinal cord and meninges.

Extensive immunohistochemisty work‐up is essential for a correct diagnosis. It should include markers to confirm HS as well as stains to exclude carcinoma, malignancies of mesenchymal origin, other non Hodgkin lymphoma's and follicular dendritic cell tumors from the differential diagnosis. A recent literature review by So et al demonstrated only 17 histological proven cases of CNS‐HS, of which five occurred in children. 4 An extensive search yielded one additional case report of true CNS‐HS. 1 Based on these few cases, CNS‐HS tumors behave aggressively with very poor prognosis. Known attempted treatments in CNS‐HS tumors include irradiation, chemotherapy and surgical excision. The preferred initial therapy is surgery in patients with a single lesion. Overall survival of more than 12 months was shown in three CNS‐HS cases and these all involved a single localized lesion that could be resected as part of trimodality treatment. (1&4)

Multifocal and hence unresectable disease, like in our patient, was reported in five adult cases. Chemotherapy treatment in previous cases of multifocal CNS‐HS includes vinblastine, cladribine, high dose methotrexate, temozolomide and cytarabine (Ara‐C). Reported survival ranged from two months after treatment with whole brain irradiation and chemotherapy to four and ten months after diagnosis despite treatment with steroid‐ and chemotherapy. (1&4) Our case confirms this dismal prognosis, and steroid‐ and chemotherapy (Ara‐C) resistance. Of interest, a remarkable radiologic response without clinical improvement was reached after only 6 Gray irradiation. In malignant glioma, it is known that irradiation might increase the permeability of the blood brain barrier, thereby possibly overcoming chemotherapy resistance. 2 Whole‐brain irradiation may improve the responses to chemotherapy, albeit the rate of neurotoxicity is high. 4 However, there are no data on combined chemoradiotherapy in CNS‐HS. Our patient died three months after diagnosis.