A 37‐Year‐Old Pregnant Female with Multifocal Brain Lesions

CLINICAL HISTORY

A 36‐year old right‐handed female patient in the 21st week of pregnancy presented to the Neurology emergency department due to double vision, hypoesthesia on the right side of her face, headache, nausea and weight loss. The symptoms had started 4 months previously, when she was going through an IVF (in vitro fertilization) procedure, with nausea and weight loss. She became pregnant a few weeks after the symptoms started. Neurological examination revealed right abducens nerve palsy and sensory loss in the area of the right maxillary and mandibular nerve. MRI, T1 weighted sequence, showed multiple lesions in the ventricular system, and one in the region of the right trigeminal nerve, which could have been metastases (Figure 1a, 1b—arrows pointed the tumors). The complete blood count showed mild anemia. A lumbar puncture was performed, which revealed normal opening pressure, mild pleocytosis (6 leucocytes) and slightly elevated proteins. There were no malignant cells in the CSF, chest X‐ray, abdomen and breast ultrasound were unremarkable. The neurosurgeon suggested biopsy of the lesions next to the trigeminal nerve but only after the delivery. The patient did not consider abortion. Her neurological condition slowly deteriorated and a caesarean section was performed at the 30th week of pregnancy followed immediately by a biopsy of the lesion in the region of the right trigeminal nerve. She gave birth to a girl weighed 1400 g. After the delivery the patient's condition started to deteriorate at a more rapid pace with a worsening of headache with vomiting, disorientation and gait instability. A head CT scan showed obstructive hydrocephalus and open ventricular drainage was performed after which the headaches subsided. She started treatment with radiotherapy. Seven weeks after delivery and 10 months after the beginning of her symptoms she became unconscious with nonreactive pupils and was admitted to the intensive care unit. The CT scan showed hematocephalus and obstructive hydrocephalus. She died at the same day.

Figure 1.

 

BIOPSY FINDINGS

Small pieces of tissue from the right gasserian ganglion, approximately 1 cubic centimeter, were sent for examination. Microscopically, the ganglion was heavily infiltrated by tumor cells with abundant slightly granular cytoplasm and moderately polymorphic nuclei, occasionally with nuclear grooves and distinct nucleoli. Mitotic figures were present (Figure 1c‐arrows pointed the ganglion cells, and 1d). Immunohistochemical workup came out as follows: tumor cells were negative for epithelial (CK7, CK20, AE1/AE3, EMA), melanoma (melan A, HMB‐45, S‐100), lymphomas markers (CD3, CD20, CD79a, CD138), markers of Langerhans cells (CD1A, langerin), neuroepithelial/neuroendocrine markers (chromogranin, Syn38, CD56, and GFAP), germ cells markers (OCT4 in SALL4), markers for the tumors of urogenital tract (PAX8) and markers for estrogen and progesterone receptors, but were strongly positive for CD68 (Figure 1e—arrows pointed at the ganglion cells), CD4, CD45 and CD45RO. The Ki‐67 proliferation index was 40%. Additionally, two more immunoreactions, CD163 and PU1, were done in another laboratory and came out positive. What is your diagnosis?

DIAGNOSIS

Multifocal histiocytic sarcoma of the CNS (primary or metastatic?)

POST MORTEM FINDINGS

The formalin fixed brain weighed 1490 g. Coronal sections showed scattered grayish tumors up to 2 cm in diameter, located in the body of both lateral ventricles attached to the ependymal surface. Smaller tumors were present in the fourth ventricle, infiltrating the cerebellum and medulla (Figure 2a and 2b, respectively). The aqueduct and fourth ventricle were filled with blood due to secondary hemorrhages in the brainstem. The spinal cord was macroscopically unremarkable but, on microscopic examination, the spinal roots were infiltrated by tumor cells, which focally entered the spinal cord parenchyma as well as subarachnoid space, which was also infiltrated by tumors cells intracranially. The feature of erythrophagocytosis by tumor cells was frequently evident (Figure 2c and 2e). The right oculomotor nerve was thicker than the left one due to tumor cell infiltration (Figure 2d). Severe tumor cell infiltration was present in the reminder of the intracranial part of the left trigeminal nerve, as well. Extra axial spread of the tumor cells was evident only in the liver, with disseminated tumor cells creating only two macroscopically visible foci, and pituitary gland (Figure 2e and 2f, respectively). All tumors described showed the same microscopic features as those in the biopsy specimen.

Figure 2.

 

DISCUSSION

Histiocytic sarcoma (HS) is a rare neoplasm that usually arises in the lymph nodes, skin and the intestinal tract 4. HS is usually a disease of adults, with a peak incidence in the fifth decade 2. According to the World Health Organisation, HS is defined as a neoplastic proliferation of cells with morphological and immunophenotypic characteristics of mature tissue histiocytes. A diagnosis of HS requires verification of the histiocytic lineage and exclusion of other hematopoietic and non‐hematopoietic malignancies. Immunohistochemistry should include histiocytic markers (CD68, lysozyme, CD11c, CD14 and CD163, the last named being regarded as a specific HS marker) which confirm the diagnosis, as well as markers that exclude possible differential diagnoses of anaplastic large cell lymphoma, diffuse large cell B‐cell lymphoma, peripheral T cell lymphoma, Langerhans cell histiocytosis, carcinoma, melanoma and glial tumors.

Primary HS of the brain is extremely rare, with only 16 cases reported in the literature (all references are in the electronic version), of which 11 presented as a single lesion and 5 with multifocal lesions 1, 2, 3, 4. The age of presentation in these cases ranged from 20 months to 69 years, without a gender predominance. The clinical symptoms were nonspecific (weakness, dizziness, headache, vomiting) and also depended on the localization of the tumor 4. Of the six reported cases with multifocal lesions (including the current case) there were four females ranging in age from 37 to 55 years and two males of age 11 and 44 years, with a short survival time of 3 weeks to 8 months in spite of aggressive treatments 1, 2, 4. Most cases of HS were treated with combined surgery, chemotherapy and radiation therapy. All the cases had an aggressive course with survival time up to 10 months, except a case with primary leptomeningeal HS with disease‐free survival longer than 3 years following treatment with surgery, radiotherapy and chemotherapy 3.

There is a little data about the metastatic potential of primary CNS HS. Our case is the first described case of primary CNS HS with spontaneous extra axial metastasis to the liver and pituitary gland. The current case is the second reported case of primary CNS HS with autopsy, that revealed multifocal intraventricular HS with extensive infiltration of the subarachnoid space, right oculomotor and trigeminal nerves, spinal nerve roots, in particular the roots of the cauda equina and brain parenchyma of cerebrum, cerebellum and medulla at the sites of the tumor ependymal attachments.

In conclusion, primary CNS HS is a very rare neoplasm and difficult to diagnose without biopsy and immunohistochemistry. The presence of large, polymorphic histiocytes with polymorphic nuclei and occasional multinucleated cells should raise suspicion of HS but a wide panel of immunostains is necessary to achieve a correct diagnosis. HS expresses one or more histiocytic markers and does not express markers of other cell lineage. The disease is extremely aggressive with poor prognosis. There is no agreement on the most appropriate treatment because the disease is rare and the number of reported cases is limited.