Cdkn2a (Arf) loss drives NF1-associated atypical neurofibroma and malignant transformation.

Plexiform neurofibroma (PN) tumors are a hallmark manifestation of neurofibromatosis type 1 (NF1) that arise in the Schwann cell (SC) lineage. NF1 is a common heritable cancer predisposition syndrome caused by germline mutations in the NF1 tumor suppressor, which encodes a GTPase-activating protein called neurofibromin that negatively regulates Ras proteins. Whereas most PN are clinically indolent, a subset progress to atypical neurofibromatous neoplasms of uncertain biologic potential (ANNUBP) and/or to malignant peripheral nerve sheath tumors (MPNSTs). In small clinical series, loss of 9p21.3, which includes the CDKN2A locus, has been associated with the genesis of ANNUBP. Here we show that the Cdkn2a alternate reading frame (Arf) serves as a gatekeeper tumor suppressor in mice that prevents PN progression by inducing senescence-mediated growth arrest in aberrantly proliferating Nf1-/- SC. Conditional ablation of Nf1 and Arf in the neural crest-derived SC lineage allows escape from senescence, resulting in tumors that accurately phenocopy human ANNUBP and progress to MPNST with high penetrance. This animal model will serve as a platform to study the clonal development of ANNUBP and MPNST and to identify new therapies to treat existing tumors and to prevent disease progression.

The effect of surgical margins on outcomes for low grade MPNSTs and atypical neurofibroma.

BACKGROUND AND OBJECTIVES: While convention defines atypical neurofibroma as benign and low-grade malignant peripheral nerve sheath tumors (MPNSTs) as malignant, sparse outcomes data exist for these tumors. This study reviews clinical outcomes of surgically resected low-grade MPNST and atypical neurofibroma, focusing on the effect of surgical margins on outcome. METHODS: This study is a retrospective review of 23 patients who underwent surgical resection of a low-grade MPNST or atypical neurofibroma. Treatment characteristics of adjuvant therapy and surgical margin were noted. Endpoints of local recurrence, presence of metastatic disease, disease-specific survival, and overall survival were reviewed. RESULTS: Eighteen of 23 patients (78%) had microscopically positive margins on the resection. Disease-specific survival was 100% for both atypical neurofibroma patients and those with low-grade MPNST, regardless of surgical margin. Local recurrence in terms of recurrence of measureable disease occurred in 2/12 (16.7%) of LGMPNST patients and 1/11 (9.1%) of atypical NF patients, all of whom had microscopically positive surgical margins. CONCLUSIONS: In a study dedicated exclusively to "intermediate" nerve sheath tumors, no patients developed metastatic disease nor died of disease despite a high rate of microscopically positive surgical margins (78%). While positive margins did lead to increased rates of local recurrence, these data suggest that surgeons potentially can temper their zeal for negative surgical margins in the setting of low-grade MPNST and atypical neurofibroma, as surgical morbidity may be more important than a presumed survival benefit of wide resection.

Oncologic Accuracy of Image-guided Percutaneous Core-Needle Biopsy of Peripheral Nerve Sheath Tumors at a High-volume Sarcoma Center.

OBJECTIVES: Peripheral nerve sheath tumors (PNSTs) are clinically heterogenous, comprising benign (BPNST) and malignant (MPNST) variants. BPNSTs can be managed with nerve-sparing excision or observation. MPNSTs require radical resection and multidisciplinary oncologic management (1, 15). Image-guided core-needle biopsy (IGCNBx) is the well-established standard to obtain preoperative tissue diagnosis of soft tissue tumors. However, there has been resistance to performing IGCNBx of PNSTs because of the presumed risk of nerve injury and unknown accuracy in determining malignancy. We sought to define the accuracy and safety of IGCNBx in PNSTs. MATERIALS AND METHODS: All patients that underwent both IGCNBx and surgical resection of a PNST at our institution between 2002 and 2016 were analyzed. The accuracy of IGCNBx in determining malignancy was calculated, including subgroup analyses by histologic subtype and neurofibromatosis 1 status. Complication data were collected and analyzed. RESULTS: Among the 78 PNSTs with IGCNBx and postresection surgical pathology, 76% (n=59) had BPNST and 24% (n=19) had MPNST on postresection surgical pathology. IGCNBx accurately determined malignancy in 94% of cases. IGCNBx demonstrating schwannoma or MPNST were 100% accurate in determining malignancy. IGCNBx demonstrating neurofibroma or indeterminate results were 33% and 57% malignant on postresection surgical pathology, respectively. There were no long-term complications, including sensory or motor deficits, from IGCNBx. CONCLUSIONS: Percutaneous IGCNBx demonstrates 94% accuracy in differentiating benign from malignant PNSTs. IGCNBx demonstrating neurofibroma or indeterminate pathology should be interpreted with caution because of risk of malignant reclassification on surgical pathology. Our results reaffirm the safety of IGCNBx, as no patients experienced long-term complications.

[Results of surgical management of spinal neurinomas and neurofibromas at Yaounde]. / Resultats du traitement chirurgical des neurinomes et neurofibromes spinaux a Yaounde.

BACKGROUND: Spinal neurinomas and neurofibromas are poorly studied in Sub-Saharan Africa. AIM: The objective of this study was to report the results of the surgical management of these tumours in Yaoundé. METHODS: This was a retrospective study done at the Yaoundé General and Yaoundé Central Hospitals from the 1st of January 1995 to the 1st of January 2005. The inclusion criteria: medical files which had the results of pre and post operatory clinical examinations, neuroradiologic and histopathologic examinations, the post operatory report. The follows up of at least six months. The functional outcome was evaluated using the Karnofsky scale. RESULTS: Of the 62 patients operated for an intraspinal tumor, 12 (19.35%) were selected (nine neurinomas, two neurofibromas, one neurofibrosarcoma). The mean age was 40.66 years +/- 13.20 with a sex ratio of 0.71. The average duration of symptoms before the diagnosis was 17.83 months +/- 5.81; the most frequent symptom was radicular pain (six cases). Five patients were paraplegic. The average Karnofsky score was 50.00 +/- 12.79 before surgery and 70.83 +/- 23.53 after. The situation of the tumor was cervical (four cases), dorsal (six cases) and lumbar (two cases). The tumor was extradural, intradural, intra and extradural in six, four and two cases respectively. Tumor excision was macroscopically complete in nine cases and partial in three. Five patients were well enough after treatment to continue their professional activities. CONCLUSION: The diagnosis of neurinomas and neurofibromas are late in our environment, resulting to poor surgical results.

Radiation-Induced Schwannomas and Neurofibromas: A Systematic Review.

OBJECTIVE: Radiation-induced benign peripheral nerve sheath tumors are uncommon late complications of irradiation. We conducted the largest systematic review of individual patient data. METHODS: We performed a systematic search of PubMed databases and compiled a comprehensive literature review. Kaplan-Meier analysis was used to investigate survival, and statistical significance was assessed with a log-rank test. RESULTS: We analyzed 40 cases of radiation-induced benign peripheral nerve sheath tumors. The histologic distributions were 28 schwannomas, 11 neurofibromas, and 1 ganglioneuroma. The average age of radiation exposure for development of primary lesions was 14.9 ± 15.5 years, and the latency period between radiotherapy to the onset of secondary tumors was 24.5 ± 12.7 years. The average irradiation dose delivered was 26.3 ± 20.3 Gy. The median overall survival for all cases was not reached (95% confidence interval, 22-not reached) months, with 10-year survival rates of 65.2%. Surgical negative margin was a positive prognostic factor for radiation-induced benign peripheral nerve sheath tumors. CONCLUSIONS: The risk of incidence of secondary benign peripheral nerve sheath tumors in patients treated with radiotherapy should be considered in long-term follow-up periods. At present, complete surgical resection is the main stay for the treatment of radiation-induced benign peripheral nerve sheath tumors.

EGFR-Stat3 signalling in nerve glial cells modifies neurofibroma initiation.

Neurofibromatosis type 1 (NF1) is an inherited disease in which affected patients are predisposed to develop benign Schwann cell (SC) tumours called neurofibromas. In the mouse, loss of Nf1 in the SC lineage causes neurofibroma formation. The tyrosine kinase receptor EGFR is expressed in Schwann cell precursors (SCP), which have been implicated in plexiform neurofibroma initiation. To test if EGFR activity affects neurofibroma initiation, size, and/or number, we studied mice expressing human EGFR in SCs and SCP in the context of mice that form neurofibromas. Neurofibroma number increased in homozygous CNP-hEGFR mice versus heterozygous littermates, and neurofibroma number and size increased when CNP-hEGFR was crossed to Nf1fl/fl;DhhCre mice. Conversely, diminished EGFR signalling in Nf1fl/fl;DhhCre;Wa2/+ mice decreased neurofibroma number. In vivo transplantation verified the correlation between EGFR activity and neurofibroma formation. Mechanistically, expression of CNP-hEGFR increased SCP/neurofibroma-initiating cell self-renewal, a surrogate for tumour initiation, and activated P-Stat3. Further, Il-6 reinforced Jak2/Stat3 activation in SCPs and SCs. These gain- and loss-of function assays show that levels of tyrosine kinase expression in SCPs modify neurofibroma initiation.

Surgical Treatment of Sacral Neurogenic Tumor: A 10-year Experience with 64 Cases.

OBJECTIVE: To explore the outcomes of surgical treatment of sacral neurogenic tumors METHODS: Between 1 January 2003 and 31 December 2012, data on 64 patients with sacral neurogenic tumors treated with surgery were retrospectively analyzed. The mean age of the 64 cases (35 males and 29 females) was 37.2 years (range, 21-69 years); 38 had neurilemmomas and 26 neurofibromas. Thirty-four of the tumors involved S 1 and S 2 , 11 S 3 or lower, and 19 were single presacral soft tissue masses. Tumors were removed via anterior, posterior or combined anteroposterior approaches. Patients with unstable sacroiliac joints underwent iliolumbar fixation. RESULTS: Depending on the extent of tumor involvement, one of three surgical approaches was used: a single anterior approach (19 patients), single posterior approach (25 patients), or a combined anteroposterior approach (20 patients). The mean operation time was 3 h (range, 2-6 h) and the mean blood loss 878 mL (range, 400-3120 mL). The mean duration of follow-up was 58.2 months (range, 24-93 months). These surgeries had the following complications. Three patients had massive intraoperative hemorrhage and posterior back pain and discomfort postoperatively. One patient had intraoperative ureteral injuries requiring intraoperative ureteral catheterization. In two patients, the tumor involved the S 1 nerve roots bilaterally, necessitating their removal, which resulted in obvious lower limb motion and sphincteric dysfunction. In 13 patients with unilateral tumor involvement of the nerve roots of S 1 and lower spinal levels, only the contralateral nerve roots of the S1 and lower levels were preserved; eight of these patients had impaired bladder and bowel function. Posterior incisions failed to heal in 10 patients, secondary wound healing occurred in nine of them and one required a gluteus maximus myocutaneous flap. Three patients developed postoperative cerebrospinal fluid leaks that were and alleviated by waist belt compression bandaging and placing them in the Trendelenburg position. Eight patients developed tumor recurrences postoperatively; pathological examination of the tissue excised in the second surgeries revealed malignant changes in the three patients with neurilemmomas. There were no intraoperative deaths. Rod fractures occurred in three of the 18 patients requiring iliolumbar reconstruction. CONCLUSIONS: The clinical characteristics of sacral neurogenic tumors make them easy to diagnose. The approach to resection should be determined by the location and size of the tumor. Patients with huge tumors may lose considerable blood intraoperatively and a have higher risk rate of postoperative complications.

p53 expression in neurofibroma and malignant peripheral nerve sheath tumor. An immunohistochemical study of sporadic and NF1-associated tumors.

Malignant peripheral nerve sheath tumors (MPNST) are highly malignant sarcomas arising either de novo or in transition from neurofibroma. Although relatively little is known of the molecular genetic alterations that underlie their formation, recent DNA sequencing studies have demonstrated the presence of p53 mutations in some MPNST. This tumor-suppressor gene has been implicated in the progression of a variety of human malignancies, including sarcomas. Employing the anti-p53 monoclonal antibody Do-7, this retrospective immunohistochemical study of p53 gene overexpression in MPNST found reactivity to be present in 68% and to be significant in degree in 57%. In contrast, although some degree of p53 overexpression was present in 48% of neurofibromas, none stained strongly and only 1 of the 27 (4%), a cellular example, showed significant staining. No difference in the frequency or degree of p53 staining was noted between MPNSTs from patients with or without neurofibromatosis 1. The observed overexpression of the gene product, possibly the reflection of a p53 gene mutation, suggests a role for p53 in the progression of neurofibroma to MPNST. Although the prognostic of p53 overexpression in MPNST remains to be confirmed, in the present series immunopositive tumors were associated with a shorter median patient survival (18 months) than were tumors showing no reactivity (82 months) (P = .02).

Is limb-sparing surgery applicable to neurogenic sarcomas of the extremities?

The presentation, treatment, and outcome of 12 patients with high-grade neurogenic sarcoma (NS) of the extremity were compared with those of 21 patients with high-grade extremity soft-tissue sarcoma of nonneural origin in a retrospective study from January 1976 to January 1988. Pain and neurologic deficit were more common in the NS group. Limb-sparing surgery was carried out with equal frequency in both groups. Local recurrence was six times more frequent in the NS group at three-year follow-up (59% vs 10%). Width of resection margin was the dominant prognostic variable bearing on local control after limb-sparing surgery. Anatomic and functional constraints tended to limit resection margin in patients with NS arising from mixed motor-sensory or predominantly motor nerves.

Long-term outcome after removal of spinal neurofibroma.

Spinal neurofibromas are uncommon, comprising approximately 3% of all spinal tumors. They occur both sporadically and in association with neurofibromatosis 1 (NF1; von Recklinghausen's disease). This study presents the clinical characteristics of 32 patients who underwent surgery for symptomatic spinal neurofibromas. Twenty-two of these patients showed clinical signs of NF1. The patients were typically younger (median age 31 years) than those with spinal schwannomas. The tumors were located mainly in the cervical region and tended to grow both extra- and intradurally. Patients with NF1 were prone to develop new spinal neurofibromas. A life-table analysis showed a reduced survival rate for these patients compared to that of the general population.

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.

[Diagnosis and treatment of primary retroperitoneal tumors].

New diagnostic imaging methods could shed much light on the diagnosis and treatment of retroperitoneal tumors. From 1978 to 1988, 98 patients were admitted. Eighty patients were treated by surgery and the diagnosis proved by pathology. In patients with primary malignant retroperitoneal tumors, 27 were completely resected and 18 received palliative resection. Of 18 benign tumors, 16 were completely resected. In these 80 patients, biopsy was done in 17 patients. In patients with malignant tumors, a 5-year survival rate of 14% was obtained. In the resected benign tumors, a 5-year survival of 100% was obtained. Local recurrence was the chief cause of death.

[Primary retroperitoneal tumor--an analysis of 303 cases].

Primary retroperitoneal tumor (PRT) is of a heterogeneous group of neoplasms of mesenchymal origin. From April 1964 through April 1992, 303 PRT cases were treated. Of the 288 cases with histological confirmation, 197 suffered from malignant tumors and 91 were benign. Since the PRT patients were usually symptomless, diagnosis was made late in the majority of patients. It resulted in low radical resection rate in both the malignant (36.9%) and the benign (84.6%) PRT owing to invasion to adjacent organs. The tumor recurrence rate was also high, being 74.2% for the malignant and 11.7% for the benign tumors. The overall 2-, 5-, and 10-year survival rates in the patients with malignant tumors were 55.3%, 19.5%, and 9.8%, respectively. The results of treatment were dependent primarily on completeness of tumor resection. Adjuvant radiotherapy could improve the survival rates but adjuvant chemotherapy did not help. In patients with tumor recurrence, operation remained to be the treatment of choice. If complete resection was impossible, the alternative was debulking operation followed by radiotherapy.

[Diagnosis and surgical management of mediastinal neurogenic tumors].

OBJECTIVE: To study the clinical manifestations, diagnostic methods, surgical management and prognosis of patients with neurogenic tumors of the mediastinum. METHOD: One hundred and ten patients with neurogenic tumors of the mediastinum were analyzed retrospectively. RESULTS: After operation, 2 patients died in hospitalization and 8 experienced such complications as Horner's syndrome or laryngeal recurrent nerve paralysis. In 102 patients with benign tumors, 2 patients had recurrence, and 4 patients with neurofibrosarcoma or malignant neurilemmoma died within 3 years postoperatively. CONCLUSIONS: Most neurogenic tumors of the mediastinum are benign and could be diagnosed by chest X-ray or CT. The clinical manifestations, diagnosis methods, surgical management of the dumbbell tumors differ from others. Minimal invasive surgery and video assist thoracoscopy surgery are of special value in treatment of the selected neurogenic tumors of the mediastinum. Benign neurogenic tumors rarely recur after complete resection, and malignant neurogenic tumors have poor prognosis.

Tumors of the peripheral nervous system.

Most nerve tumors (benign and malignant) do not arise from the nerves per se, but from the supporting cells; tumors arising from the cells of Schwann are termed schwannoma or neurilemmoma-benign or malignant. Surgical extirpation is the most effective treatment for these tumors. Radiation therapy can offer significant palliation and prolongation of life, but no cures have been observed. Benign tumors can be treated by local surgical extirpation; malignant tumors must be radically resected, including major amputation where indicated. Neurofibromatosis (von Recklinghausen's disease) is a genetic error of metabolism with a proclivity to produce multiple neurofibromas and, in about 10% of the patients, malignant neurilemmomas. Of 100 patients with malignant neurilemmomas treated by the author, 74 were considered determinate; among them, the 10-year "cure" rate was 32%. Patients with von Recklinghausen's disease had almost as good a 10-year survival rate as those with solitary malignant schwannoma (30% vs. 39%).

Postirradiation neurofibrosarcoma.

A known risk of radiation therapy is the induction of secondary neoplasms, most commonly osteosarcoma and fibrosarcoma. A recent addition to the list of postirradiation neoplasms is neurofibrosarcoma, a Schwann cell or fibroblastic malignancy arising in peripheral nerves, often associated with von Recklinghausen's disease. In a clinicopathologic review of 109 patients with neurofibrosarcoma seen at the Mayo Clinic from 1912 to 1981, the tumors in 12 cases were found to originate in areas that had previously been irradiated for benign or malignant disease. Seven of the 12 patients demonstrated stigmata of von Recklinghausen's disease. The mean latency period between irradiation and clinical presentation of the sarcoma was 15.6 years (range, 5-26 years). Eight patients experienced at least one recurrence; metastases were present in two, and nine patients died of their disease. The mean interval between initial diagnosis and death was 3.4 years. In summary, neurofibrosarcoma may arise secondary to radiation; animal studies on the effects of radiation on peripheral nerves support this concept. It is the authors' opinion that patients with von Recklinghausen's disease should not be unnecessarily irradiated, and that those who do receive radiation therapy should be carefully observed for the development of secondary neurofibrosarcoma.

Malignant peripheral nerve sheath tumors. A clinicopathologic study of 120 cases.

A review was done of 120 cases of malignant peripheral nerve sheath tumor (MPNST) seen during a 71-year period. Of the 120 patients, 52 were males and 68 were females with a mean age at diagnosis of 35.3 years; 12 patients were younger than 20 years. The series included 62 (52%) patients with neurofibromatosis, 13 (11%) with postradiation sarcomas, and 19 (16%) with metaplastic foci. The incidence of MPNST arising in neurofibromatosis was 4.6% in the current series and 0.001% in the general clinic population. Tumors greater than 5 cm and the presence of neurofibromatosis adversely affected the prognosis (P less than 0.05). When both features were present, survival was greatly decreased. Patients with tumor in the extremities did better than those with head or neck lesions. Metaplastic foci or previous radiation at the tumor site did not alter the prognosis. Each tumor was graded 1 to 4 on the basis of cellularity, pleomorphism, mitotic index, and necrosis. No significant correlation was noted between survival and either grade or mitotic rate. Survival was improved when total rather than subtotal resection was done. This was most marked in patients with a small lesion, which may reflect the difficulty in adequately excising large tumors. Adjuvant radiation or chemotherapy did not appear to affect survival. The MPNST is an aggressive uncommon neoplasm, and large tumor size, the presence of neurofibromatosis, and total resection are the most important prognostic indicators.

Malignant soft tissue tumors of nerve sheath origin.

Thirty-one patients with neurogenic sarcomas treated at Roswell Park Memorial Institute (RPMI) during a 10-year period were studied. The mean follow-up is 35.5 months. A specific nerve of origin could not be identified in 61.3% of patients. The most frequent site was the proximal lower extremity (38.7%). The only presenting symptom was enlarging mass in 67.7%. There was association with Von Recklinghausen's disease in 42% of the cases. Survival was significantly worse in tumors with Von Recklinghausen's disease (25.6%) compared to patients with solitary malignant schwannomas (50.9%). Twelve of 18 patients who had adequate surgical treatment initially remain disease-free, whereas only 2 of 11 patients referred following partial excision or recurrence remain disease-free (P less than 0.02). Eleven of 18 patients with grade I or II tumor are disease-free, whereas 2 of 10 patients with grade III tumor are disease-free (P less than 0.05). Resection of the sciatic nerve with wide excision is accompanied with a good functional result.