Malignant Transformation Of Neurofibromas Research Articles

Malignant Degeneration of a Peripheral Nerve Sheath Tumor in the Neck Region.

Background: Malignant transformation of neurofibromas into malignant peripheral nerve sheath tumors (MPNST) is a rare but aggressive phenomenon, particularly in the head and neck region, and is associated with a poor prognosis. The primary treatment modality is surgical excision, often followed by radiotherapy. This is a case report of MPNST in the neck, with long-term follow-up. Case Presentation: A 26-year-old woman presented with a history of multiple progressively enlarging neck swellings for 8 years. The swellings were associated with mild pain and occasional bleeding. The patient had undergone 3 prior surgical excisions, with a fourth recurrence leading to complete excision and split-thickness skin grafting due to extensive raw surface area. Histopathological examination confirmed the diagnosis of MPNST. The patient subsequently received adjuvant chemoradiotherapy due to the aggressive nature of the pathology. Results: The patient has been under regular follow-up for 36 months, with no evidence of local, regional, or distant metastasis. Conclusion: Malignant transformation of neurofibromas is a rare entity, particularly in the head and neck. Early surgical intervention followed by adjuvant chemoradiotherapy provides effective long-term control of the disease and improved survival.

Neurofibroma Development in Neurofibromatosis Type 1: Insights from Cellular Origin and Schwann Cell Lineage Development

Simple SummaryNeurofibromas have been thought to originate from cells within the Schwann cell lineage, while no consensus has been reached so far about the specific time of initiation and the exact cellular origin. Moreover, the role of Schwann cell lineage transition in different developmental stages of neurofibromas, together with other determinant factors, remains controversial, despite intensive studies. In this review, we summarized the accumulating evidence about the full range of neurofibroma development based on cellular and molecular pathogenesis.Background: Neurofibromatosis type 1 (NF1), a genetic tumor predisposition syndrome that affects about 1 in 3000 newborns, is caused by mutations in the NF1 gene and subsequent inactivation of its encoded neurofibromin. Neurofibromin is a tumor suppressor protein involved in the downregulation of Ras signaling. Despite a diverse clinical spectrum, one of several hallmarks of NF1 is a peripheral nerve sheath tumor (PNST), which comprises mixed nervous and fibrous components. The distinct spatiotemporal characteristics of plexiform and cutaneous neurofibromas have prompted hypotheses about the origin and developmental features of these tumors, involving various cellular transition processes. Methods: We retrieved published literature from PubMed, EMBASE, and Web of Science up to 21 June 2022 and searched references cited in the selected studies to identify other relevant papers. Original articles reporting the pathogenesis of PNSTs during development were included in this review. We highlighted the Schwann cell (SC) lineage shift to better present the evolution of its corresponding cellular origin hypothesis and its important effects on the progression and malignant transformation of neurofibromas. Conclusions: In this review, we summarized the vast array of evidence obtained on the full range of neurofibroma development based on cellular and molecular pathogenesis. By integrating findings relating to tumor formation, growth, and malignancy, we hope to reveal the role of SC lineage shift as well as the combined impact of additional determinants in the natural history of PNSTs.

Abstract 1614: Creation of malignant peripheral nerve sheath tumor models deficient for polycomb repressive complex 2 and identification of therapeutic vulnerabilities

Abstract We constructed models of nerve sheath tumors that arise in Neurofibromatosis Type 1 (NF1) patients and conducted therapeutics discovery using synthetic lethal pharmacogenomic screens. Given both plexiform neurofibromas and malignant peripheral nerve sheath tumors (MPNSTs) arise within the Schwann cell lineage, we developed a drug discovery pipeline to identify targeted therapeutics for treating NF1-related neoplasia. Using CRISPR/Cas9, immortalized human Schwann cell lines were created lacking the NF1 gene or NF1 and components of Polycomb Repressive Complex 2 (PRC2), such as SUZ12. ~80% of all MPNST harbor loss of function mutations in PRC2 genes, which is highly suggestive that perturbation of epigenetic homeostasis plays a role in malignant transformation of neurofibromas. Our models mimic the genetics of MPNSTs and allowed us to identify selectively lethal drugs which exploit vulnerabilities specific to these genetic drivers. We describe the identification of these novel drugs, extensive in vivo testing in models of MPNST, and mechanistic studies to explain why they act specifically on MPNSTs. We identified compounds showing selective lethality towards NF1/SUZ12 double mutant cells. These include drugs affecting epigenetic homeostasis, such as HDAC inhibitors (HDACi). Moreover, many of these drugs showed strong synergy when tested in combination with a MEK inhibitor (MEKi) against NF1/SUZ12 deficient human Schwann and MPNST cell lines. We investigated the mechanism of this synergy using genetics, transcriptome, and proteome analysis. Interestingly, these mechanistic studies revealed possible emerging avenues of resistance the cells are utilizing to compensate for and survive therapeutic intervention. For instance, proteomics analysis of PRC2 deficient MPNST cell lines treated with combination therapy of MEKi and HDACi indicates activation of specific survival and stress response pathways. Targeting these pathways in conjunction with the therapeutics we have identified could prevent emergence of resistance and tumor escape. Clinically interesting drug candidates were advanced and tested as single agents and in combination in multiple in vivo models of MPNST (including patient derived and cell line xenografts). The FDA approved drugs vorinostat (HDACi) and selumetinib (MEKi) have shown dramatic efficacy, with combination therapy exhibiting strong synergy in vivo. This includes durable responses in survival studies and the ability to dramatically shrink established tumors, with treated tumors showing markers of apoptosis. The discovery of novel agents effective against several models of MPNST is exciting as there are currently no approved targeted therapies for MPNSTs. Our results implicate targeting of epigenetic homeostasis, in combination with MEKi, as a major vulnerability of MPNSTs deficient for PRC2 activity. Citation Format: Kyle B. Williams, Alex Larsson, Justin Tibbits, Christopher L. Moertel, David A. Largaespada. Creation of malignant peripheral nerve sheath tumor models deficient for polycomb repressive complex 2 and identification of therapeutic vulnerabilities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1614.

First Reported Case of a Well-Differentiated Neuroendocrine Tumor (WDNET) Arising Within Diffuse Ganglioneuromatosis (DGN) in a Patient With Neurofibromatosis Type 1 (NF-1)

Abstract Case Report A 51-year-old female with NF-1 underwent flexible sigmoidoscopy, which revealed a 1.8-cm mass in the upper rectum. The noncircumferential mass was located predominantly at the posterior rectal wall and was suspicious for a neurofibroma. The biopsy revealed a WDNET arising in a ganglioneuroma that extended to the edges of the biopsy tissue. The patient underwent a segmental resection, and sections revealed residual grade 1 WDNET intimately admixed with DGN. The area of DGN also showed multifocal microscopic clusters of neuroendocrine cells limited to the lamina propria. Discussion NF-1 involves the gastrointestinal tract in 10% to 25% of affected individuals. DGN is a poorly circumscribed, frequently transmural gastrointestinal lesion composed of spindled and ganglion cells that may be seen in PTEN hamartomatous tumor syndrome, multiple endocrine neoplasia syndrome type 2B, and (less commonly) NF-1. Though malignant transformation of neurofibromas to malignant peripheral nerve sheath tumors is well documented in NF-1, malignant transformation of DGN is extremely rare. To our knowledge, this is the first reported case of a WDNET arising in DGN. In addition to being the first reported case of WDNET in this setting, this is the first case to describe microscopic neuroendocrine cell nests in DGN. Similar proliferations have been described in the setting of inflammatory bowel disease, termed microcarcinoid or neuroendocrine cell micronests, which are not thought to have malignant potential. However, given the presence of these microscopic neuroendocrine cell nests within the larger DGN lesions and adjacent to the WDNET, we hypothesize that in the setting of NF-1, microscopic neuroendocrine cell clusters may serve as a precursor of WDNET. While this is a rare situation, these novel findings should prompt careful examination for WDNET and microscopic neuroendocrine cell nests in future cases of DGN.

Characterisation of malignant peripheral nerve sheath tumours in neurofibromatosis-1 using heterogeneity analysis of 18F-FDG PET

PurposeMeasurement of heterogeneity in 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) images is reported to improve tumour phenotyping and response assessment in a number of cancers. We aimed to determine whether measurements of 18F-FDG heterogeneity could improve differentiation of benign symptomatic neurofibromas from malignant peripheral nerve sheath tumours (MPNSTs).Methods18F-FDG PET data from a cohort of 54 patients (24 female, 30 male, mean age 35.1 years) with neurofibromatosis-1 (NF1), and clinically suspected malignant transformation of neurofibromas into MPNSTs, were included. Scans were performed to a standard clinical protocol at 1.5 and 4 h post-injection. Six first-order [including three standardised uptake value (SUV) parameters], four second-order (derived from grey-level co-occurrence matrices) and four high-order (derived from neighbourhood grey-tone difference matrices) statistical features were calculated from tumour volumes of interest. Each patient had histological verification or at least 5 years clinical follow-up as the reference standard with regards to the characterisation of tumours as benign (n = 30) or malignant (n = 24).ResultsThere was a significant difference between benign and malignant tumours for all six first-order parameters (at 1.5 and 4 h; p < 0.0001), for second-order entropy (only at 4 h) and for all high-order features (at 1.5 h and 4 h, except contrast at 4 h; p < 0.0001–0.047). Similarly, the area under the receiver operating characteristic curves was high (0.669–0.997, p < 0.05) for the same features as well as 1.5-h second-order entropy. No first-, second- or high-order feature performed better than maximum SUV (SUVmax) at differentiating benign from malignant tumours.Conclusions18F-FDG uptake in MPNSTs is higher than benign symptomatic neurofibromas, as defined by SUV parameters, and more heterogeneous, as defined by first- and high-order heterogeneity parameters. However, heterogeneity analysis does not improve on SUVmax discriminative performance.

Histopathologic evaluation of atypical neurofibromatous tumors and their transformation into malignant peripheral nerve sheath tumor in patients with neurofibromatosis 1—a consensus overview

Patients with neurofibromatosis 1 (NF1) develop multiple neurofibromas, with 8% to 15% of patients experiencing malignant peripheral nerve sheath tumor (MPNST) during their lifetime. Prediction of transformation, typically from plexiform neurofibroma, is clinically and histologically challenging. In this overview, after a consensus meeting in October 2016, we outline the histopathologic features and molecular mechanisms involved in the malignant transformation of neurofibromas. Nuclear atypia alone is generally insignificant. However, with atypia, loss of neurofibroma architecture, high cellularity, and/or mitotic activity >1/50 but <3/10 high-power fields, the findings are worrisome for malignancy. We propose the term "atypical neurofibromatous neoplasms of uncertain biologic potential (ANNUBP)" for lesions displaying at least 2 of these features. This diagnosis should prompt additional sampling, clinical correlation, and possibly, expert pathology consultation. Currently, such tumors are diagnosed inconsistently as atypical neurofibroma or low-grade MPNST. Most MPNSTs arising from neurofibromas are high-grade sarcomas and pose little diagnostic difficulty, although rare nonnecrotic tumors with 3-9 mitoses/10 high-power fields can be recognized as low-grade variants. Although neurofibromas contain numerous S100 protein/SOX10-positive Schwann cells and CD34-positive fibroblasts, both components are reduced or absent in MPNST. Loss of p16/CDKN2A expression, elevated Ki67 labeling, and extensive nuclear p53 positivity are also features of MPNST that can to some degree already occur in atypical neurofibromatous neoplasms of uncertain biologic potential. Complete loss of trimethylated histone 3 lysine 27 expression is potentially more reliable, being immunohistochemically detectable in about half of MPNSTs. Correlated clinicopathological, radiologic, and genetic studies should increase our understanding of malignant transformation in neurofibromas, hopefully improving diagnosis and treatment soon.

Confirmation of mutation landscape of NF1-associated malignant peripheral nerve sheath tumors.

The commonest tumors associated with neurofibromatosis type 1 (NF1) are benign peripheral nerve sheath tumors, called neurofibromas. Malignant transformation of neurofibromas into aggressive MPNSTs may occur with a poor patient prognosis. A cooperative role of SUZ12 or EED inactivation, along with NF1, TP53, and CDKN2A loss-of-function, has been proposed to drive progression to MPNSTs. An exome sequencing analysis of eight MPNSTs, one plexiform neurofibroma, and seven cutaneous neurofibromas was undertaken. Biallelic inactivation of the NF1 gene was observed in the plexiform neurofibroma and the MPNSTs, underlining that somatic biallelic NF1 inactivation is likely to be the initiating event for plexiform neurofibroma genesis, although it is unlikely to be sufficient for the subsequent MPNST development. The majority (5/8) of MPNSTs in our analyses demonstrated homozygous or heterozygous deletions of CDKN2A, which may represent an early event following NF1 LOH in the malignant transformation of Schwann cells from plexiform neurofibroma to MPNST. Biallelic somatic alterations of SUZ12 was also found in 4/8 MPNSTs. EED biallelic alterations were detected in 2 of the other four MPNSTs, with one tumor having a homozygous EED deletion. A missense mutation in the chromatin regulator KDM2B was also identified in one MPNST. No TP53 point mutations were found in this study, confirming previous data that TP53 mutations may be relatively rare in NF1-associated MPNSTs. Our study confirms the frequent biallelic inactivation of PRC2 subunits SUZ12 and EED in MPNSTs, and suggests the implication of KDM2B.

Intraoral presentation of multiple malignant peripheral nerve sheath tumors associated with neurofibromatosis-1

Neurofibromatosis-1 (NF-1) is a relatively common autosomal dominant disease characterized by multiple cutaneous fibromatoses and café au lait spots. It is associated with the mutation of NF-1 gene, a tumor suppressor gene located on chromosome 17q11.2. Hence, it can be considered as a familial cancer predisposition syndrome in which the affected individuals are at increased risk of developing malignancies. Intraoral neurofibromas associated with NF-1 are quite common, but the occurrence of malignant peripheral nerve sheath tumor (MPNST) in the oral cavity is very rare. Oral MPNST can occur either de novo or by malignant transformation of neurofibromas or very rarely can represent a metastatic lesion. Here, we present a case of MPNST involving the maxillary region, in a patient with NF-1. Since MPNST often creates a diagnostic dilemma, histopathologic criteria for the diagnosis of MPNST are also discussed.

Apolipoprotein D is down-regulated during malignant transformation of neurofibromas

Apolipoprotein D (apoD) expression was studied in nonneoplastic peripheral nerve, neurofibromas (NFs), and malignant peripheral nerve sheath tumors (MPNSTs) by quantitative polymerase chain reaction, in situ hybridization, and immunohistochemistry. Multiplex quantitative polymerase chain reaction for messenger RNA was performed on a series of formalin-fixed and paraffin-embedded specimens that included 9 MPNSTs, 12 NFs, and 4 normal peripheral nerves. The average apoD expression was 108-fold decreased (DeltaCt = -7.3) in the MPNSTs compared with the NFs (P < .05). ApoD expression levels were 3.0-fold elevated (DeltaCt = 1.7) in the NFs compared with nonneoplastic peripheral nerve (P < .05). In situ hybridization for apoD RNA was performed on a separate series of 10 cases in which each microscopic section included both MPNST and the NF from which it arose. These studies confirmed elevated apoD expression in NFs compared with MPNSTs and demonstrated that this expression was variable among individual cells within the NFs. Differential expression by immunohistochemistry could only be demonstrated in selected areas, most likely because apoD protein is a small molecule that is secreted out of the cell into the extracellular space and plasma. ApoD expression initially increases a small amount with the formation of NFs from nonneoplastic peripheral nerve and subsequently decreases markedly as NFs transform into MPNSTs. This expression pattern may serve as a marker for cell cycle inhibition during peripheral nerve tumorigenesis.

Malignant Transformation of Neurofibromas in Neurofibromatosis 1 Is Associated with CDKN2A/p16 Inactivation

Patients with neurofibromatosis 1 (NF1) are predisposed to develop multiple neurofibromas (NFs) and are at risk for transformation of NFs to malignant peripheral nerve sheath tumors (MPNSTs). Little is known, however, about the biological events involved in the malignant transformation of NFs. We examined the CDKN2A/p16 gene and p16 protein in NFs and MPNSTs from patients with NF1. On immunohistochemical analysis, all NFs expressed p16 protein. The MPNSTs, however, were essentially immunonegative for p16, with striking transitions in cases that contained both benign and malignant elements. None of the benign tumors had CDKN2A/p16 deletions, whereas three of six MPNSTs appeared to have homozygous CDKN2A/p16 deletions. Methylation analysis and mutation analysis of CDKN2A/p16 in MPNSTs did not reveal any abnormalities. These results show that malignant transformation of NF is associated with loss of p16 expression, which is often secondary to homozygous deletion of the CDKN2A/p16 gene. The findings suggest that CDKN2A/p16 inactivation occurs during the malignant transformation of NFs in NF1 patients and raises the possibility that p16 immunohistochemistry may provide ancillary information in the distinction of NF from MPNST.

Expression of p27 kip and Other Cell Cycle Regulators in Malignant Peripheral Nerve Sheath Tumors and Neurofibromas : The Emerging Role of p27 kip in Malignant Transformation of Neurofibromas

There is little information regarding the status of cell cycle regulators in malignant peripheral nerve sheath tumors (MPNSTs) and neurofibromas (NFs). In this study, we investigated patterns of expression of p53 and pRB, cyclin-dependent kinase inhibitors (CKIs) p21 and p27, as well as cyclins D1 and E, in a cohort of 35 well-characterized MPNSTs and 16 NFs. These phenotypes were correlated with proliferative index, as assessed by Ki-67, as well as clinicopathological parameters of poor outcome. p53 nuclear overexpression was found in 10 of 35 (29%) MPNSTs, and it was lacking in NFs (P = 0.02). There were no differences in the patterns of expression of pRB, cyclin D1, and p21 between MPNSTs and NFs. However, p27 nuclear expression was present in most NFs, but it was absent in the majority of MPNSTs, which displayed cytoplasmic staining (P < 0.001). Nuclear cyclin E expression was more pronounced in MPNSTs than in NFs. We observed inverse patterns of expression for nuclear p27 and nuclear cyclin E expression. The staining profiles of cytoplasmic p27 and nuclear cyclin E expression were found to be statistically associated (P = 0.01). High Ki-67 expression was found in 20 of 34 (59%) MPNSTs but was absent in NFs (P < 0.001). Furthermore, detection of cytoplasmic p27 expression was found to be a prognostic factor for poor survival in MPNSTs (P = 0.03, relative risk = 2.4).

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.

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.

Case report: Periosteal neurofibroma mimicking osteochondroma

Neurofibromas may present within an inherited complex (von Recklinghausen's disease) or sporadically [1]. Both forms may present with orthopaedic problems, the commonest being scoliosis, pseudarthrosis and periosteal or intramedullary cystic change [2]. In addition, malignant transformation of neurofibromas may occur. We present the case of a 22-year-old female who had no family history or clinical evidence of von Recklinghausen's disease where a periosteal neurofibroma mimicked an osteochondroma on plain radiography.