A 32‐year‐old male with brainstem lesions

Clinical History

A 32‐year‐old male was admitted to the hospital with high fever and diarrhea. The clinical and laboratory investigations showed exsiccosis (dehydration) and highly increased values of liver enzymes. The patient died after three days due to sepsis following bronchopneumonia. In the patient's anamnesis (case history) the occurrence of a subarachnoid hemorrhage, after the rupture of a basilar aneurysm six years ago, as well as the subsequent development of psychiatric symptoms and dementia were reported.

Neuropathologic Findings

Brain sectioning revealed, apart from macroscopic findings easily identifiable as consequences of the subarachnoid hemorrhage in the past (multiple cortical infarcts, “coiled” basilar aneurysm etc.), three unusual yellowish microlesions in the left and right nucleus ruber (2 mm and 4 mm in diameter, respectively) and pons (<0.5mm in diameter). Histopathological examination showed that these lesions were of moderate cell density and had clearly defined, but irregularly borders (Figure 1). The Gomori silver stain revealed a well‐established network of reticulin fibers surrounding these cells (Figure 2A). The lesions consisted of ovoid to elongated cells that were positive for Vimentin, S100‐protein (Figure 2B) and myelin basic protein (MBP) (Figure 2C) but did not react for 2′,3′‐Cyclic‐Nucleotide 3′‐Phosphodiesterase (CNP). These cells were intermingled with some lipid‐laden macrophages. Within the lesions pre‐existing axons seemed to be largely preserved as visualized with an antibody detecting neurofilament protein (NF) (Figure 2D). The adjacent brain parenchyma showed reactive astrogliosis. The lesions did not react with antibodies staining for actin, desmin, EMA, synaptophysin, NeuN, Melan A, CD31, p53 or IDH‐1. The proliferation index estimated with Ki‐67 (MIB‐1) was low (approximately 1%). It is worth mentioning that all three lesions were located in the proximity of small stage III infarctions.

Figure 1.

 

Figure 2.

  

The conventional and immunohistochemical staining results of the microlesions were indicative of Schwann cell proliferations. Since such lesions have rarely been observed in the brain parenchyma and to rule out the possibility of multifocal intracerebral schwannomas, we decided to compare the acquired data with those of an intracerebral schwannoma taken from our archive. Histopathological examination of this tumor revealed, in contrast to the microlesions described above, a well‐demarcated tumor with regular borders to the adjacent brain parenchyma (compare Figure 3 with Figure 1). Nevertheless, intracerebral schwannoma displayed a similar storiform growth pattern, cytological appearance and abundant presence of reticulin fibers (compare Figure 4A with Figure 2A) and it was also positive for S100‐protein (compare Figure 4B with Figure 2B). However, on the contrary to the microlesions presented here, intracerebral schwannoma did not react at all for MBP (compare Figure 4C with 2C) and CNP and further showed a notable though expected absence of neurofilament positive axons within it (compare Figure 2D with Figure 4D). According to all previously reported cyto‐, histo‐ and immunohistochemical results of the present lesions the diagnosis of multiple intracerebral schwannomas could be excluded. What is the diagnosis?

Figure 3.

   

Figure 4.

  

Diagnosis

Multifocal intracerebral schwannosis.

Discussion

Schwannosis is recognized as a rarely occurring process that is considered to be a benign proliferation of Schwann cells with simultaneous partial myelination of central nervous system axons. It has been mainly observed in the spinal cord 4, 9, 10. Schwannosis was only reported once in the pontine parenchyma 6. The case present here is the first example of a multifocal manifestation of schwannosis in the brain stem, i.e. in the nucleus ruber and in the pons. Schwannosis seems to occur in response to various chronic (i.e. traumatic, neoplastic, degenerative, or compression producing) stimuli, possibly representing an attempted, though anomalous repair by inwardly migrated Schwann cells. Within this context, it is interesting that all three lesions were present close to small stage III infarctions.

Various hypotheses have been put forward with respect to the ontogenesis of schwannosis and the origin of the involved Schwann cells in the development of these lesions. O'Brien et al. 7 proposed the existence of a transitional zone between the central and peripheral nervous tissue compartments within the dorsal spinal nerve rootlets with a sharp discontinuity of different tissue types at its interface. While axons peripheral to the transitional zone are myelinated by Schwann cells and endoneurium mainly comprises the supporting tissue, axons central to the transitional zone are engulfed by oligodendrocytes and astrocytes which constitute the main cellular component of the surrounding neuropil. It has been further suggested that the transitional zone can become penetrable, thus allowing the migration of Schwann cells from the peripheral to the central nervous system via the dorsal root ganglia under particular conditions, especially after trauma of the spinal cord 7, 8, or even through penetrating blood vessels 8. It has been postulated in one study that the presence of Schwann cells in the CNS may delay regeneration following spinal cord injury 2 whereas two other studies have shown a supportive role for Schwann cells in the axonal elongation across transaction lesions in the spinal cords of adult rats 1, 3. An alternative hypothesis, put forward by Rubinstein 9, favors an ectopic derivation of the Schwann cells situated in the dorsal gray horn and its vicinity (zona terminalis of Lissauer) and in all cases described by him were found adjacent to schwannoma of the dorsal nerve root. According to this hypothesis these cells have been displaced centrally during ontogenesis and can potentially develop under specific stimuli to intramedullary schwannosis. In support of this statement is the frequent association of these lesions with other cellular ectopias, in particular those of ependymal cells 9. An alternative interpretation was given by Hori who proposed a regenerative reaction of peripheral nervous system elements in response to a local neoplastic lesion (e.g. ependymoma) that through its mass effect could result in focal spinal cord destruction or compression 4. Rubinstein 9 also described “angioneuromatosis” or “schwannosis of the spinal blood vessels” as a special form of schwannosis that involves the perivascular sheaths of the spinal blood vessels. This special type of schwannosis has been regarded as evidence of collateral regeneration from intra‐ or extramedullary neurites since they may also contain aberrant axons 9. These lesions could also lead to the development of microscopic neuromatous nodules with expansion of the perivascular space 9 or even become neoplastic, thus evolving into small true central schwannomas 5, 9.

Abstract

Schwannosis is a condition characterized by a benign proliferation of Schwann cells and an incomplete myelination of central nervous system axons following different chronic stimuli. It. has been mainly observed in the spinal cord. Various hypotheses have been put forward with respect to the appearance of Schwann cells inside the central nervous system since they exclusively populate the peripheral nervous system. According to these hypotheses, schwannosis seems to be either the result of aberrant migration under certain conditions, especially in response to spinal cord injury, or as a developmental abnormality in form of ectopia during ontogenesis. We report, for the first time, on the multifocal occurrence of this rare nosological entity in the brain stem. Furthermore we compare the histological and immunohistochemical profile of schwannosis to that of an intracerebral schwannoma taken from our archive.