Malignant peripheral nerve sheath tumor with rhabdomyosarcomatous differentiation (malignant triton tumor)

Malignant peripheral nerve sheath tumors arise from Schwann cells or within existing neurofibromas and have a strong association with type 1 neurofibromatosis. These tumors are histologically diverse and may contain malignant areas of divergent mesenchymal differentiation, the most common of which is skeletal muscle (rhabdomyosarcoma). Malignant peripheral nerve sheath tumor with rhabdomyosarcomatous differentiation is also known as malignant triton tumor. Malignant triton tumor has a worse prognosis than classic malignant peripheral nerve sheath tumor does, and the correct diagnosis requires attention to the clinical history and knowledge of the complexities regarding its differential diagnosis. In this review we discuss the clinical, histopathological, immunohistochemical, and prognostic features of this rare neoplasm.     

BRAF mutation,TERT promoter mutation,and HER2 amplification in sporadic or neurofibromatosis-related neurofibromas and malignant peripheral nerve sheath tumors: do these molecules have a signature in malignant transformation?

Peripheral nerve sheath tumors may occur sporadically or related to neurofibromatosis (NF). Unless the mechanisms of tumorigenesis in NF related malignant peripheral nerve sheath tumors (MPNST) are better understood, it remained unclear in sporadic cases. We aimed to investigate the genetic route for malignancy in both individuals with NF-1 and sporadic ones to open a way for targeted therapies in the future. We investigated the role of HER2 with Dual ISH DNA Probe Cocktail test, BRAF mutation (exon 15) and TERT promoter mutation frequency with Sanger sequencing method in respectively 25 sporadic neurofibromas, 25 NF-1 related neurofibromas and 25 MPNST cases from two institutes. Categorical data were analyzed and summarized as frequency and percentage. Statistical analysis was done with SPSS v.22 statistical package, and the statistical significance level was considered as 0.05. We identified TERT promoter mutation only in one sporadic MPNST (4%) and no BRAF mutation in any case. HER2 amplification is found in 10/25 (40%) MPNST cases. No mutations or gene amplification detected in neurofibromas (p < 0.001). MPNSTs are sarcomas with poor prognosis and limited treatment options. TERT promoter mutations and HER2 amplification may play a putative role in therapeutic purposes.     

Culture of cytogenetically abnormal schwann cells from benign and malignant NF1 tumors

Dermal and plexiform neurofibromas are benign peripheral nerve sheath tumors that arise in neurofibromatosis type 1 (NF1). NF1 patients also have an increased risk of malignant peripheral nerve sheath tumors (MPNSTs), thought to arise in a subset of plexiform neurofibromas. Plexiform neurofibroma pathogenesis is poorly understood, despite the serious clinical problem posed by these tumors. The Schwann cell is hypothesized to be the cell type initially mutated and clonally expanded in plexiform neurofibromas. To test this hypothesis and search for genetic alterations involved in tumorigenesis, we established Schwann cell cultures from plexiform and dermal neurofibromas. Cytogenetic abnormalities were identified in 4/6 plexiform cultures (including one from a plexiform with a sarcomatous component) and 0/7 dermal neurofibroma Schwann cell cultures. There were no consistent chromosomal regions involved in the abnormal karyotypes, suggesting that plexiform tumors are heterogeneous and may bear a variety of primary and/or secondary genetic changes. This is the first study to show successful culturing of genetically abnormal Schwann cell lineages from plexiform neurofibromas. Thus, we present the strongest evidence yet to support the theory that the Schwann cell is the central component in the development of plexiform neurofibromas. This is a key finding for NF1 research, which will lead to further studies of the genetic and biochemical pathogenesis of these Schwann cell tumors. Genes Chromosomes Cancer 27:117-123, 2000.     

Molecular analysis of malignant triton tumors.

Triton tumors are rare variants of malignant peripheral nerve sheath tumor (MPNST) with muscle differentiation, often seen in patients with neurofibromatosis 1 (NF1). Individuals affected with NF1 harbor mutations in the NF1 tumor suppressor gene and develop neurofibromas and MPNSTs. The NF1 gene is expressed in Schwann cells and its expression is lost in schwannian neoplasms, suggesting a role in malignant development. Separately, there is evidence that p53 suppressor gene mutations are involved in MPNSTs. To determine the role of the NF1 and p53 genes in the development of the malignant Triton tumor we examined 2 such tumors, 1 from a 3-year-old boy without clinical manifestations of NF1 and another from a 24-year-old man with NF1. Histological analysis of these tumors showed both neural and muscle differentiation with S-100 and desmin immunoreactivity, respectively. Reverse transcribed RNA polymerase chain reaction (RT-PCR) of NF1 mRNA showed NF1 expression in the sporadic tumor. Strong nuclear immunoreactivity for p53 was observed throughout the malignant population in both tumors. This was confirmed by loss of heterozygosity for p53 in the non-NF1 patient, suggesting that p53 is involved in both hereditary and sporadic Triton tumors. The finding of preserved NF1 gene expression in the non-NF1-related Triton tumor suggests that different genetic events predispose to the development of this rare neoplasm in sporadic cases.     

Mediastinal tumors of peripheral nervous system origin.

A wide spectrum of benign and malignant tumors of peripheral nervous system origin can arise in the mediastinum. These neoplasms are more frequent in the posterior mediastinum and can develop from peripheral nerves, sympathetic and parasympathetic ganglia, and neural tube embryonic remnants. The clinicopathologic features of mediastinal schwannomas, melanotic schwannomas, neurofibromas, ganglioneuromas, granular cell tumors, malignant tumors of peripheral nerve sheath origin, malignant melanocytic tumors of peripheral nerve sheath origin, neuroblastomas, ganglioneuroblastomas, and pigmented neuroectodermal tumors of infancy are reviewed.     

Pathology of tumors of the peripheral nerve sheath in type 1 neurofibromatosis.

The two main peripheral nerve sheath tumors found in patients with neurofibromatosis, type 1 (NF1), are neurofibroma, a benign tumor, and malignant peripheral nerve sheath tumor (MPNST). The tumors are related in that most MPNSTs are thought to arise by malignant transformation of neurofibromas. Such an event occurs in about 2% of NF1 patients. There are five forms of neurofibroma; three of them-localized cutaneous neurofibroma when multiple, plexiform neurofibroma, and massive soft-tissue neurofibroma-are highly specific for NF1. Only two forms of neurofibroma, plexiform and localized intraneural neurofibroma, are significant precursors of MPNST. Massive soft-tissue neurofibromas are worrisome in that they may mask MPNST arising from one of the mentioned neurofibromas. The vast majority of MPNSTs are high-grade malignant tumors with a high rate of distant metastasis. The overall 5-year survival rate for patients with MPNSTs ranges from 34% to 52%. MPNSTs generally are solitary, deep-seated globoid or fusiform tumors. They are firm, fleshy, tan, and often focally to extensively necrotic, and they invade surrounding soft tissue. On histological examination, MPNSTs are most often hypercellular, hyperchromatic, fasciculated, and mitotically active tumors. Low-grade tumors account for only about 10-15% of cases. Twenty percent of MPNSTs have unusual and potentially misleading histological features, such as epithelioid cells and divergent mesenchymal or glandular differentiation. Am. J. Med. Genet. (Semin. Med. Genet.) 89:23-30, 1999.     

Microscopic intraneural perineurial cell proliferations in patients with neurofibromatosis type 1

Benign peripheral nerve sheath tumors (PNSTs) showing more than one line of differentiation (hybrid PNSTs) have been increasingly recognized, mainly due to awareness of their existence and as a consequence of increased use of immunohistochemisty during the last decade. Two recent studies suggested overrepresentation of hybrid tumors among benign PNSTs in patients with neurofibromatosis type 1 (NF-1). This study was performed to assess the presence of perineurial cells in microscopic (early) neurofibromatous lesions and normal-looking peripheral nerves in specimens from 5 patients with NF-1 using markers of perineurial cell differentiation (epithelial membrane antigen, claudin-1, and glucose transporter 1). In 2 patients, multiple normal looking nerve fibers as well as hypertrophied nerves and microscopic tumor nodules showed variable intraneural perineurial cell proliferations that frequently occupied the whole nerve fascicle resulting in multiple microscopic reticular perineurioma-like nodules (microscopic hybrid neurofibromatosis/perineuriomatosis). None of the cases showed the onion skin pattern of intraneural perineurioma. However, other nerve fibers within the same specimens showed normal compact rim of perineurium without any detectable intraneural perineurial cells. Both patients had concurrent multiple larger PNSTs (plexiform neurofibromas, hybrid neurofibroma/perineurioma and lesions with features intermediate between the 2 types). One specimen harboring high-grade malignant PNST and 2 specimens with large solitary neurofibromas displayed no intraneural perineurial cells. These observations suggest that intraneural perineurial proliferations are part of the early lesions in the setting of constitutional NF-1 inactivation and support the concept of pure and hybrid perineuriomatous lesions as novel member of the spectrum of PNSTs in NF-1.     

Non-neurogenic sarcomas in four children and young adults with neurofibromatosis type 1

It is well known that children and young adults with neurofibromatosis type 1 (NF1) have a higher risk for non-neurogenic sarcomas than the general population, in addition to an increased risk for malignant peripheral nerve sheath tumor. When non-neurogenic sarcomas occur in early childhood, a subsequent malignant peripheral nerve sheath tumor can occur as a second malignant neoplasm, especially after alkylating agent chemotherapy and irradiation. This report includes the clinicopathologic features of non-neurogenic sarcomas and secondary malignant peripheral nerve sheath tumor in the context of four cases of NF1. The purpose is to emphasize that early diagnosis of NF1 and recognition of potential manifestations of non-neurogenic sarcomas are important for clinical care of these patients and their families.     

Clinic-based study of plexiform neurofibromas in neurofibromatosis 1

Individuals with neurofibromatosis 1 (NF1) develop both benign and malignant tumors at an increased frequency. One of the most common benign tumors in NF1 is the plexiform neurofibroma. These tumors cause significant morbidity and mortality on account of their propensity to grow and affect adjacent normal tissues. To determine the clinical profile of plexiform neurofibromas in NF1, we conducted a retrospective review of 68 NF1 patients with plexiform neurofibroma. In our series, 44% of tumors were detected by 5 years of age and most were located in the trunk and extremities. Only two patients developed malignant peripheral nerve sheath tumors in their preexisting plexiform neurofibromas. Lastly, we demonstrate that there were no specific clinical features of NF1 associated with the presence of plexiform neurofibroma. These results underscore the importance of careful serial examinations in the evaluation of patients with NF1.     

Peripheral nerve sheath tumors of the head and neck

The head and neck region is a common location for benign peripheral nerve sheath tumors (PNST) and a rare site for malignant PNST. The diagnostic distinction between schwannoma (neurilemmoma) and benign neurofibroma remains clinically and prognostically important. Most benign PNST are schwannomas, and these do not have a recognized malignant potential. Malignant PNST arise de novo or from benign neurofibromas. The definitive diagnosis of malignant PNST may be difficult or impossible using only routine light microscopy. Electron microscopy and immunohistochemistry are special techniques that may be helpful. The prognosis in patients with malignant PNST depends heavily on the extent of surgical excision, size of the primary tumor, and presence or absence of von Recklinghausen's neurofibromatosis.     

Neurofibromatosis- and schwannomatosis-associated tumors: Approaches to genetic testing and counseling considerations

Neurofibromatosis (NF) and schwannomatosis (SWN) are genetic conditions characterized by the risk of developing nervous system tumors. Recently revised diagnostic criteria include the addition of genetic testing to confirm a pathogenic variant, as well as to detect the presence of mosaicism. Therefore, the use and interpretation of both germline and tumor-based testing have increasing importance in the diagnostic approach, treatment decisions, and risk stratification of these conditions. This focused review discusses approaches to genetic testing of NF- and SWN-related tumor types, which are somewhat rare and perhaps lesser known to non-specialized clinicians. These include gastrointestinal stromal tumors, breast cancer, plexiform neurofibromas with or without transformation to malignant peripheral nerve sheath tumors, gliomas, and schwannomas, and emphasizes the need for inclusion of genetic providers in patient care and appropriate pre- and post-test education, genetic counseling, and focused evaluation by a medical geneticist or other healthcare provider familiar with clinical manifestations of these disorders.     

Childhood neurofibromatosis: risk factors for malignant disease

Forty-five children with both neurofibromatosis and malignant tumors were compared with a pediatric population with neurofibromatosis without tumors to ascertain if any of the clinical manifestations of this disorder were associated with either tumor development or histology. No such factors emerged except that, in most of the optic glioma patients, the neurofibromatosis mutation was paternally inherited. Concordance of histologic tumor types was seen when malignancies occurred in affected family members, similar to that noted in the literature. Although cancer is independent of the other manifestations of neurofibromatosis and these manifestations may vary among family members, it appears that malignant tumors are often concordant when they occur within a family.     

Clinic‐based study of plexiform neurofibromas in neurofibromatosis 1

Individuals with neurofibromatosis 1 (NF1) develop both benign and malignant tumors at an increased frequency. One of the most common benign tumors in NF1 is the plexiform neurofibroma. These tumors cause significant morbidity and mortality on account of their propensity to grow and affect adjacent normal tissues. To determine the clinical profile of plexiform neurofibromas in NF1, we conducted a retrospective review of 68 NF1 patients with plexiform neurofibroma. In our series, 44% of tumors were detected by 5 years of age and most were located in the trunk and extremities. Only two patients developed malignant peripheral nerve sheath tumors in their preexisting plexiform neurofibromas. Lastly, we demonstrate that there were no specific clinical features of NF1 associated with the presence of plexiform neurofibroma. These results underscore the importance of careful serial examinations in the evaluation of patients with NF1. Am. J. Med. Genet. 92:132–135, 2000. © 2000 Wiley‐Liss, Inc.     

Advancing RAS/RASopathy therapies: An NCI‐sponsored intramural and extramural collaboration for the study of RASopathies

RASopathies caused by germline pathogenic variants in genes that encode RAS pathway proteins. These disorders include neurofibromatosis type 1 (NF1), Noonan syndrome (NS), cardiofaciocutaneous syndrome (CFC), and Costello syndrome (CS), and others. RASopathies are characterized by heterogenous manifestations, including congenital heart disease, failure to thrive, and increased risk of cancers. Previous work led by the NCI Pediatric Oncology Branch has altered the natural course of one of the key manifestations of the RASopathy NF1. Through the conduct of a longitudinal cohort study and early phase clinical trials, the MEK inhibitor selumetinib was identified as the first active therapy for the NF1‐related peripheral nerve sheath tumors called plexiform neurofibromas (PNs). As a result, selumetinib was granted breakthrough therapy designation by the FDA for the treatment of PN. Other RASopathy manifestations may also benefit from RAS targeted therapies. The overall goal of Advancing RAS/RASopathy Therapies (ART), a new NCI initiative, is to develop effective therapies and prevention strategies for the clinical manifestations of the non‐NF1 RASopathies and for tumors characterized by somatic RAS mutations. This report reflects discussions from a February 2019 initiation meeting for this project, which had broad international collaboration from basic and clinical researchers and patient advocates.     

Schwann cells harbor the somatic NF1 mutation in neurofibromas: evidence of two different Schwann cell subpopulations

Neurofibromas are one of the most characteristic features of neurofibromatosis type 1 (NF1), an inherited autosomal-dominant neurogenetic disorder affecting 1 in 3500 individuals worldwide. These benign tumors mainly consist of Schwann cells (SCs) and fibroblasts. Recent evidence demonstrates that somatic mutations at the NF1 gene are found in neurofibromas, but it has not been demonstrated whether SCs, fibroblasts and/or both cell types bear a somatic loss of NF1. We recently established a cell culture system that allows selective expansion of human SCs from neurofibromas. We cultured pure populations of SCs and fibroblasts derived from 10 neurofibromas with characterized NF1 mutations and found that SCs but not fibroblasts harbored a somatic mutation at the NF1 locus in all studied tumors. Furthermore, by culturing neurofibroma-derived SCs under different in vitro conditions we were able to obtain two genetically distinct SC subpopulations: NF1(-/-) and NF1(+/-). These data strongly support the idea that NF1 mutations in SCs, but not in fibroblasts, correlate to neurofibroma formation and demonstrate that only a portion of SCs in neurofibromas have mutations in both NF1 alleles.     

Segmental neurofibromatosis in childhood

Segmental neurofibromatosis refers to individuals who have manifestations of neurofibromatosis type 1 (NF-1) limited to one area of the body. It results from a post-conceptional mutation in the NF-1 gene leading to somatic mosaicism. Although it is generally considered a rare condition, this report of 39 children with segmental NF-1 demonstrates that it is commonly seen in a pediatric NF-1 referral center. The mean age at diagnosis was 7.8 years (range: 2-25 years). Twenty-nine patients had only pigmentary manifestations of segmental NF-1, including seven who had only café-au-lait macules and 22 who had café-au-lait macules and freckling. Two patients had isolated plexiform neurofibromas; a third patient had a plexiform neurofibroma of the eyelid in addition to ipsilateral dysplasia of the sphenoid wing and Lisch nodules. A 12-year-old girl had an isolated tibial pseudarthrosis. An 8-year-old boy had an isolated optic pathway tumor, which behaved both biologically and radiographically as an NF1-associated tumor. While most children with segmental NF-1 have only localized pigmentary changes, some children will have isolated plexiform neurofibromas, pseudarthroses, or optic pathway tumors. Accurate diagnosis of segmental NF-1 is crucial for both management and genetic counseling.     

Two sporadic spinal neurofibromatosis patients with malignant peripheral nerve sheath tumour

We analyzed two unrelated male patients in whom neurofibromatosis type 1 (NF1) was not suspected until they presented with malignant peripheral nerve sheath tumours (MPNSTs) in their thirties and forties, respectively. Patient A presented with progressive peroneus paresis due to a rapidly growing MPNST in the thigh. MRI examination revealed multiple symmetrical spinal neurofibromas in this patient as well as in patient B who presented at the age of 42 with paraparesis and an MPNST at spinal level L4. Dermal features in both patients were strikingly mild, therefore both patients were considered belonging to the NF1-subform of spinal neurofibromatosis (SNF). The novel NF1 mutations identified, i.e. splice mutation, c.7675+1G > A, in patient A and two alterations, p.Cys1016Arg and p.2711delVal, located in trans in patient B support the notion that the phenotype of SNF may be related to mutations with possible residual functionality. The MPNSTs of both patients showed LOH affecting chromosome 17 including the NF1 locus. Furthermore, a truncating TP53 mutation was identified in the tumour of patient A. Both alterations are frequent findings in NF1-associated MPNSTs. To our knowledge these are the first MPNST patients with the clinical phenotype of SNF. The clinical course observed in these two patients suggests that nodular plexiform neurofibromas and spinal-nerve-root neurofibromas which may be asymptomatic for a long time and, hence, unrecognized in SNF patients bear the risk for malignant transformation.     

Neurofibromatosis 2: clinical and DNA linkage studies of a large kindred

At least eight provisional categories of neurofibromatosis have been proposed. Among these, neurofibromatosis 1 (von Recklinghausen's disease or peripheral neurofibromatosis) and neurofibromatosis 2 (central or bilateral acoustic neurofibromatosis) have been established as distinct disorders. We studied 15 affected male and 8 affected female members of one large kindred with neurofibromatosis 2. None of the patients met the diagnostic criteria for neurofibromatosis 1. Between the ages of 15 and 53 years, the patients had multiple central nervous system tumors of various types--mainly, bilateral acoustic neuromas. Two or more tumors eventually developed in 20 of the patients; 9 had evidence of only bilateral acoustic neuromas. Meningiomas and ependymomas were more common among the young patients; those who initially presented with acoustic neuromas were nearly a decade older. Intracranial nontumoral calcifications were present in most patients and were also found in symptom-free children. The presence of such lesions is probably a prodromic feature of neurofibromatosis 2. Simultaneous analysis of D22S1 and IGLV DNA markers for coinheritance with neurofibromatosis 2 indicates that the locus for the disease is near the center of the long arm of chromosome 22 (22q11.1----22q13.1). The eventual isolation of this disease gene may reveal a cause of the most common intracranial tumors in humans.     

Die Rolle der Neuropathologie bei familiären Tumorerkrankungen

Inherited cancer syndromes often involve the central and peripheral nervous system. For the surgical neuropathologist the possibilty in individual patients of a familial tumour syndrome needs to be considered in the case of special tumours such as malignant peripheral nerve sheath tumour (MPNST), medulloblastoma with extensive nodularity (MBEN) or even atypical teratoid/rhabdoid tumour (AT/RT) of the brain. Furthermore, tumour location and patient age may point to a familial tumour syndrome as in the case of neurofibromatosis type 2 (NF2) with typical bilateral vestibular schwannoma in young age. This short review discusses some of the diagnostic aspects in this field relating to neurofibromatosis type 1 and 2 (NF1, NF2), as well as the two rare tumors MBEN in Gorlin-Goltz syndrome and AT/RT in particular.