Intra-cerebellar schwannoma with various degenerative changes: a case report and a systematic review

Schwannoma, also known as neurilemoma or neurinoma, is a benign nerve sheath tumor arising from differentiated Schwann cells [1, 2]. Intra-cranial schwannomas account for 5–8% of intra-cranial tumors [2], and approximately 90% of them arise in cerebellopontine angles in relation to the vestibular nerve. Sub-tentorial intra-cerebral schwannomas are very rare, and to date, only 20 cases of cerebellar schwannomas have been reported in the English literature [3‐18]. In this report, we present a case of schwannoma, without a family history of neurofibromatosis, arising within the cerebellar hemisphere with remarkable degenerative changes on histology.

A few days after amputation of the left lower leg because of arteriosclerosis obliterans, a 61-year-old man presented with worsening disorientation and was referred to our institution. He had been undergoing treatment for hypertension and diabetes mellitus for around a year and undergoing artificial dialysis due to chronic renal failure for 4 years. He had no symptoms and no family history of neurofibromatosis. Neurological examination demonstrated disorientation in date and time, and finger-nose-finger and heel-knee-shin dysmetria on the left side but no hearing disturbance. A computed tomography scan revealed a cystic lesion (6.5 cm in the largest diameter) in the left hemisphere of the cerebellum with a mural nodule (2.5 cm) with enhancement and focal calcification, in addition to hydrocephalus (Fig. 1a, b). Magnetic resonance imaging demonstrated that the cystic lesion was hypointense on T1-weighted images and hyperintense on T2-weighted images (Fig. 1c, d). The tumor was well defined, and no peritumoral brain edema was observed. The lesion was more than 5 mm from the left acoustic nerves, and the nodular component was located just inside the skull. T2 star-weighted images showed hemorrhage within the cyst and in the mural nodule (Fig. 1e). Fluid-attenuated inversion-recovery images showed hydrocephalus with periventricular hyperintensity (Fig. 1f). Pre-operative differential diagnoses included hemangioblastoma, low-grade well-circumscribed glioma, and metastatic tumor of unknown primary origin. The patient underwent suboccipital craniotomy. The surface of the tumor was moderately swollen (Fig. 2a). The discharge of brownish fluid during drainage of the cystic component implied a history of intra-cystic bleeding. The tumor had feeders from the superior cerebellar artery, and most of the boundary was clear. The tumor was resected totally after detachment from the cerebellum (Fig. 2b). The post-operative clinical course was good, and hydrocephalus improved. A 5-year follow-up demonstrated no recurrence or neurological dysfunction.

Histopathological examination of the tumor tissue showed proliferation of tumor cells with large nuclei intermingled with various sized blood vessels (Fig. 3a, b). The tumor cells were pleomorphic, with polygonal or spindle shapes, and harbored eosinophilic cytoplasm and hyperchromatic nuclei (Fig. 3c). The size of the nuclei also varied, and intra-nuclear cytoplasmic inclusions were occasionally observed. Nucleoli were occasionally observed and mostly inconspicuous. Cellular areas and hypo-cellular areas were intermingled, and a meshwork of fine fibers was observed in the hypo-cellular areas (Fig. 3d). Most tumor cells harbored abundant cytoplasm with a low nuclear-cytoplasmic ratio, and no mitosis was detected. Various intra-cytoplasmic inclusions were observed, including eosinophilic granular inclusions or hyaline bodies, concentric cytoplasmic inclusions, and yellow-brownish lipofuscin granules (Fig. 2d). The lipofuscin granules showed various colors, from faint pinkish to dark brown (Fig. 3e). Cells with eosinophilic granular inclusions or hyaline bodies tended to be distributed around hemosiderin-laden macrophages or hypo-cellular areas. Hyalinization was diffusely observed in the wall of the blood vessels and intra-tumoral extracellular matrix (Fig. 3f, g). On the periphery of the tumor, hemorrhage, aggregation of hemosiderin-laden macrophages, and cystic areas were observed (Fig. 3a). Calcification was occasionally observed. Neither Rosenthal fibers nor neuronal differentiation were observed within the tumor. The cerebellum surrounding the tumor showed reactive gliosis and mild atrophy, as well as scattered Rosenthal fibers (Fig. 3h). Immunohistochemical analyses showed that the tumor cells were diffusely positive for S-100 protein (Fig. 3i), vimentin, and neuron-specific enolase and focally positive for glial fibrillary acidic protein (Fig. 3j). Tumor cells were negative for Olig2 (Fig. 3k), synaptophysin, chromogranin, neurofilament, NeuN, epithelial membrane antigen, CD34, IDH1 (R132H), Melan A, and Inhibin alpha. The Ki-67 labeling index was less than 1%, with only a few positive cells (Fig. 3l). Considering various degenerative changes of the tumor tissue and the immunohistochemical features, the final pathological diagnosis of schwannoma with marked degenerative changes (a so-called ancient schwannoma) was made.

Schwannomas arise from differentiated Schwann cells [1, 2], and are subdivided into variants based on histological features, including conventional or classic, cellular, ancient, plexiform, and melanotic. The ancient variant is the third most common form of schwannoma variants, and secondary degenerative changes are evident along with an extreme degree of hyalinization of the vascular wall [2]. In the present case, along with hyalinization of the blood vessels, eosinophilic granular inclusions or hyaline bodies were diffusely observed. Granular inclusions such as those observed in the present case were reported to be frequently observed in intra-cranial schwannomas, especially acoustic schwannomas [19, 20], as products of degeneration, and tend to be distributed around the periphery of the Antoni B pattern or area with rich hemosiderin deposition. Pilocytic astrocytoma (PA) should be considered in the differential diagnosis of cerebellar tumors with remarkable degenerative changes. PA is frequently observed in the cerebellum, and is also known to accompany degenerative cellular atypia, vascular hyalinization, calcification, and eosinophilic granular bodies [1]. Immunohistochemical staining for Olig2 is useful in differentiating PA and schwannoma; the former is usually positive, and the latter is not [21]. Although pre-operative differential diagnoses did not include schwannoma, these findings, in combination with immunohistochemical staining for the S-100 protein and Olig2, led to the diagnosis of an ancient schwannoma in the present case.

We aimed to identify all full-text, peer-reviewed publications describing the detailed clinical findings in intracerebellar schwannoma. A systematic review was performed according to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) [22] (Fig. 4). Published studies pertaining to intracerebellar schwannoma were found by utilizing a thorough search strategy of PubMed, Scopus, Ovid MEDLINE, and Google Scholar databases from inception to February 1, 2022, with no language or regional restrictions. The term “Intracerebellar schwannoma” and “cerebellar schwannoma” was used for the search. The reference lists of chosen articles were searched to further identify relevant articles. The information that was extracted were as follows: author; year; clinical findings of the patients, including age, sex, tumor location, history of the diagnosis of neurofibromatosis, cystic change of the tumor detected by imaging study, dilation of ventricles and/or compression of ventricles. After removal of redundant reports, a total of 80 literatures were screened by the title/abstract, and 19 literatures were screened by full text. Finally a total of 17 eligible literatures with 20 cases were included to this study. To date, in combination with the present case, a total of 21 cases of cerebellar schwannoma have been reported in the English literature [3‐18, 23]. The patient characteristics and findings are summarized in Table 1. Age at diagnosis ranged from 9–79 years old (y.o.) (Mean: 47.0 y.o., Median: 49.0 y.o.), and the ratio of male/female was 0.5 (7/14 patients, respectively). Distribution of the age of onset is similar to the cases of intra-cranial vestibular schwannomas described in a previous report, meanwhile the male/female ratio is lower [24]. Based on diagnostic imaging, 16 cases were described to be accompanied by cystic changes, which is a common feature of classical or ancient schwannomas [25]. Among 21 cases of cerebellar schwannomas, 11 tumors were located across the cerebellar vermis, and 13 cases were reported to harbor dilation of the lateral ventricles and/or compression of the fourth ventricle because of growth of the tumor or expansion of cystic components. In the present case, pathological examination revealed the slow proliferative nature of the tumor cells, with no mitotic figures, a low Ki-67 labeling index, and remarkable degenerative changes. The nodular component of the tumor was just inside the skull, and the cystic component extended into the cerebellar parenchyma and pressed on the fourth ventricle. The rapid progression of cognitive dysfunction in the patient may be explained by the rapid expansion of the cystic component of the tumor, resulting in hydrocephalus due to compression of the fourth ventricle and cerebellar parenchyma.

The origin of intra-cerebellar schwannomas remains unclear. Some researchers suggest that the origin of intra-cerebellar schwannomas is Schwann cells in the perivascular plexus [15], and others suggest that specific soft membrane cells undergo metaplastic changes into Schwann cell-like cells and result in the formation of a schwannoma [26]. Either hypothesis can explain the pathogenesis of the schwannoma in the present case, and rapid expansion of the cystic component may make analysis of the pathogenesis difficult, because of destruction of the surrounding structures. The distribution and dynamics of the stem cells in the central nervous system has still not been fully elucidated [27]. To fully understand the pathogenesis of the intra-cerebellar schwannomas, detailed morphological analysis of the intact tumor and surrounding tissue is mandatory.

In this report, we presented a case of schwannoma arising within cerebellar hemisphere with remarkable degenerative changes. Although it’ rare, schwannoma should be listed in the differential diagnosis of the cystic lesion with heterogeneous histopathological morphology in the cerebellum.