A rare case of intracranial malignant triton tumor arising in the middle cranial fossa: a case report and review of the literature

Introduction

Malignant triton tumors (MTTs) are a rare subtype (accounting for less than 10%) of malignant peripheral nerve sheath tumors (MPNSTs) showing rhabdomyosarcomatous differentiation and following a particularly aggressive clinical course [24]. In a recent metanalysis, only 124 cases of MTT were reported between 1973 and 2010 in the English and French literature [24]. Since then, 38 further cases of MTT have been reported [9,10,11,13-15,17,18,20, 22,25-27,31-34], of whom only few had an intracranial location [1,3,6,7,11,12,19,34,35].
About one half of cases are related to neurofibromatosis type 1 (NF-1), and previous exposure to radiation is a recognized risk factor [37].
We describe a rare case of intracranial malignant triton tumor, probably arising from the left oculomotor nerve sheath, which eroded the middle cranial fossa and progressed into the infratemporal fossa. To our knowledge, only nine intracranial cases have been reported so far [1,3,6,7,11,12,19,34,35].

Case report

A 74-year-old woman presented to the Emergency Unit for left facial pain and blush, strabismus with diplopia, left mydriasis and ptosis. Her remote history was irrelevant, apart from reporting exposure to radiation during the Chernobyl nuclear disaster in 1986. Indeed, she was living at the time in a rural Ukrainian area northern of Kiev, where she remained until she moved to Western Europe in about 2000.
An emergent computed tomography (CT) scan revealed an extremely large intra-extracranial petroclival lesion, extending from the middle cranial fossa into the infratemporal fossa through a wide skull erosion (Fig. 1). Cranial magnetic resonance imaging (MRI) confirmed the presence of the lesion, which was well delimited from the brain, hyperintense in T2 and inhomogeneously contrast enhanced (Fig. 2).
The patient underwent surgery and a subtotal removal of the intracranial component of the neoplasm was performed. After the surgery, facial pain disappeared and she could quickly resume her previous activities. Histology revealed a high-grade sarcoma (FNCLCC grade 3) with necrosis, neoplastic areas with positivity for S100, heterologous osteocartilaginous areas and skeletal muscular differentiation (positive stain for desmin and myogenin). In conclusion, histology disclosed an intracranial MPNST with skeletal muscle differentiation (the so-called MTT) (Fig. 3).
MPNST arising from a peripheral nerve may be associated with a pre-existing benign nerve sheath tumor, or may occur in patients with NF-1. When, as in this case, these aspects are absent, the diagnosis is based on the constellation of histological and immunohistochemical features.
Despite the close relation between MTT and NF-1, no genetic studies were performed because of the absence of any other stigmata of the disease, such as café-au-lait spots, axillary freckling, Lisch nodules, cutaneous neurofibromas, optic glioma or familiarity for NF-1. No synchronous metastases were shown at a full-body radiologic examination.
The patient underwent adjuvant conformational radiotherapy at a total dose of 50 Gy scheduled in 20 sessions, while no chemotherapy was proposed. Despite the treatment, the progression-free survival was only 2.5 months and the overall survival was 4 months.

Discussion

MTT is a rare, aggressive subtype of MPNSTs with rhabdomyosarcomatous differentiation and poor prognosis [15]. This tumor was first described by Masson in 1932 in neurofibromatosis patients [23], but it received this name in 1973 [39], basing on the previous observation that triton salamander can generate supernumerary limbs, formed by striated muscle, bone and nervous tissue if sciatic nerve is implanted on its back [21]. Most reported cases are diagnosed in the middle age (30-50 years) [15,24]; although a male predominance has been reported [15], this finding is not confirmed by the largest metanalysis [24].
MTTs, as MPNSTs, may arise either de novo or in the context of a previous benign schwannoma [36]. The most widely accepted explanation for their occurrence is that Schwann cells, which arise from the neural crest, may retain some capacity of differentiating in mesenchymal components during neoplastic transformation [41]. Diagnostic criteria proposed originally for MTT were as follows: 1) the tumor arises along a peripheral nerve, or in the context of a ganglioneuroma, or in an NF-1 patient, 2) it has the characteristics of growth of a Schwann cell tumor, 3) rhabdomyoblasts can be demonstrated inside the tumor [39]. Nowadays, immunohistochemistry stains with positivity for S100, myoglobin, desmin, muscle-specific actin, sarcomeric actin and myogenin, as skeletal muscle markers, are essential for diagnosis [30].
NF-1 association is reported in 38-57% of cases [24,40]. Previous radiation exposure is reported in 8% of patients with MTT [24] and it is a recognized risk factor [2]. Moreover, even therapeutic irradiation can be a trigger to MTT formation: in fact, malignant progression from benign schwannoma to MTT following the radiation therapy has been reported [29]. Indeed, one case of progression of a vestibular schwannoma to a malignant triton tumor after stereotactic radiosurgery has been reported [6]. The relationship between radiation and Schwann cell transformation has been previously investigated: it is recognized that small doses of radiation may alter the architecture of this cell line [4], therefore inducing loss of chromosomal stability and transformation [5]. It has been postulated that radiationinduced MTTs occur 4 to 41 years after irradiation, due to the very slow turnover in peripheral nerve sheath [29].
MTTs usually present in the head, trunk and extremities, more rarely they occur in retroperitoneum, vertebral column and within the heart [15]. The previously reported finding, that head and neck location had a better prognosis [37], has not been confirmed by more recent studies [15].
The gold standard therapy is wide surgical excision, of course whenever possible, followed by the adjuvant radiation therapy [24]. There is no evidence of the effectiveness of chemotherapy; however, chemotherapeutic regimens such as PEI (cisplatin, etoposide, ifosfamide) as the first-line chemotherapy and IA (ifosfamide, adriamycin) or MAID (mesna, doxorubicin, ifosfamide and dacarbazine) have been proposed as the second-line treatment [38]. Favorable response to treatment with isotretinoin (a retinoid analogue) and interferon  were also reported, in cases in which retinoic acid receptors were present in the tumor specimen [16].
The outcome of MTT is generally poor. 5-year overall survival is only 14%, and median time to death is 13 months [24]. Distant metastases develop in about one third of cases, local progression or recurrence occur in 50%, and median time to recurrence/progression is 6 months [24].
Most important unfavorable prognostic factors are association with NF-1, age, size, presence of positive margins at surgery or histological examination, and location of the tumor in the trunk [15,24]. Intracranial MTTs have seldom been reported. Only nine cases were reported from 1987 to 2014 [1,3,6,7,11,12,19,34,35] (Table I). Mean patient age at diagnosis was 39 years, ranging from 3 to 57, and most patients were males (6/9). NF-1 association was found in only one third (3/9) of patients; previous radiation exposure was reported in one case, specifically represented by a MTT arising at the site of a vestibular schwannoma after stereotactic radiosurgery [6]. The cerebellopontine angle was the most common site of origin (4/9); in four cases, however, MTT seemed to arise directly from brain parenchyma.
Our case is the first MTT ever reported developing in the middle cranial fossa, extending towards the petroclival region and eroding the skull base to invade the infratemporal fossa, and probably arising from the third nerve sheath. Previous intense radiation exposure during the Chernobyl disaster, about 30 years prior to tumor presentation, might be considered as a trigger for neoplastic transformation. Precise details on the patient’s actual radiation exposure are not available, but most reliable information would indicate that, during the first 10 years after the accident, average effective doses of exposure in the neighboring areas ranged from 5 mSv (the reported level for Russian urban areas) to 11 mSv (the reported level for the rural areas of the Ukraine where the patient was living at the time and spent about 15 further years after the nuclear accident) [8,28].

Conclusions

In this report, we describe a rare case of intracranial MTT. To the best of our knowledge, it is the tenth case reported in the literature. Although very rare, intracranial MTTs are very aggressive tumors arising in young or middle-aged patients, often associated with NF-1 and a poor prognosis. Previous radiation exposure is a recognized risk factor as confirmed by our case.

Disclosure

The authors declare no conflict of interest.

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