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.