Discussion:
Malignant peripheral nerve sheath tumors account for about 5-10% of soft tissue sarcomas and are derived from either peripheral nerve Schwann cells or pre-existing neurofibromas. Among the different histological variants, 10% of MPNST show foci of skeletal muscle differentiation (1-3). This subtype of MPNST with rhabdomyoblastic differentiation was first described in a patient with NF1 by Masson and Martin in 1932 (7). The term MTT was suggested in 1973 by Woodruff referring to the ability of the Triton salamander to regenerate supernumerary limbs containing muscle, bone and neural components after the implantation of the cut end of the sciatic nerve into the soft tissue of its back (8). Since then, less than 200 cases of MTT have been reported to date, many of them in patients with NF1 who have a 10% life time risk of malignant transformation from plexiform neurofibromas.
Although most MTT cases are diagnosed in patients under 35 years of age, few cases have been reported in children and adolescents (9-19). Main series have shown no gender predilection and, although widely distributed, the head, neck and trunk have been described as the most common locations. Those MTT associated with NF1 constitute over 50-70% of cases and display a young age, male predominance, and frequent head and neck involvement. Nevertheless, sporadic cases tend to affect female patients at older age and are frequently located on the trunk (1-3, 10, 13, 19, 20). Up to 8% of reported cases have been related to previous radiation (4-6). Other unusual locations such as intracranial fossa, spinal cord, mediastinum, uterus or epididymis have been described in the literature (17, 21-29). Our patient presented with a huge retroperitoneal mass, which is an uncommon finding with less than 20 similar cases reported to date (30-35).
The histogenesis of these composite tumors has not been clearly defined. They may reflect the capability of the nerve sheath cells to induce mesenchymal differentiation or may be explained by the potential of the neural crest to differentiate into both Schwann and muscular tumoral cells. Woodruff proposed three criteria to establish the diagnosis of MTT, including tumor origin in peripheral nerves of patients with known NF1, predominance of Schwann cell growth pattern and the presence of rhabdomyoblastic differentiation in the absence of extension or metastasis of a rhabdomyosarcoma (8). Further on, Daimaru suggested the omission of the first criteria to include sporadic cases (36). It is currently assumed that histological diagnosis must be supported by immunohistochemical findings. S-100 and Leu-7 proteins positivity reflect nerve sheath differentiation, whereas the positivity of actin, desmin, myogenin, MyoD1 and vimentin confirm rhabdomyoblastic differentiation (1).
The WES analyses performed in our patient revealed both SUZ12c.1214C>G and TP53 c.681delT mutations, both variants not previously described. SUZ12 inactivating mutations have been related with NF1 and CDKN2A loss of function in the progression of neurofibromas to MPNST, and somatic mutations inTP53 have been also demonstrated in most MPNST/MTT samples (37). Gains affecting MET have been related with the development of MPNST from plexiform neurofibromas and might involve RASderegulation contributing to therapy resistance (38). Our patient also presented with a MYC amplification, usual across many cancer types including MPNST by regulating proliferation, cell cycle and tumor vascularization (39).
As illustrated by the present case, the natural history of MTT is much more aggressive than MPNST. The percentage of patients with metastatic disease at diagnosis reaches 30-50% with pulmonary involvement being the most frequent location, whereas lymph node involvement has not been reported (1-3).
The therapeutic strategy for MTT is primarily based on wide surgical resection (R0). Although the role of radiotherapy is not well established, it should be considered after inadequate surgical excision or high risk of local recurrence due to large tumor size or high histological grade. Chemotherapy regimens may be reserved for disseminated or unresectable disease, second-line treatment or palliation (1-3, 13, 32). Despite a multidisciplinary approach the prognosis of MTT is very poor, with 5-year overall survival rates not exceeding 15%. Early local and distance metastasis occur in up to 50% of patients, especially in cases with large tumors, incomplete surgery, location in the trunk or retroperitoneum and associated NF1 (1-3, 10, 13, 20, 26, 32).
In conclusion, MTT is a very rare form of MPNST, typically associated with NF1, with an aggressive behaviour. No standard treatment has yet been accepted, although surgical resection followed by radiation therapy have demostyrated to be essential to achieve long term survival. The poor prognosis of this entity requires collaborative efforts to obtain biological information and develop new targeted therapeutic strategies in the future.
Conflicts of interest: none to declare.