Question

Do patients with neurofibromatosis type 1 (NF1) develop neoplasms differently or experience worse outcomes compared with the general population?

Findings

In this cohort study of 1607 patients with NF1 evaluated at an academic cancer center who developed neoplasms other than neurofibromas, patients developed neoplasms at a younger age and more frequently compared with general population estimates. Patients with undifferentiated pleomorphic sarcoma, high-grade glioma, malignant peripheral nerve sheath tumor, ovarian carcinoma, and melanoma had significantly lower disease-specific survival rates compared with patients with other neoplasms.

Meaning

These findings suggest that patients with NF1 develop several neoplasms, including gliomas and sarcomas, at a younger age, more frequently, and with worse outcomes compared with individuals without NF1 and that counseling and annual follow-up should be advised for these patients.

Importance

Neurofibromatosis type 1 (NF1) is a complex genetic disorder that is associated with not only neurofibromas, but also an increased susceptibility to other neoplasms.

Objective

To evaluate the prevalence of neoplasia and outcomes among patients with NF1.

Design, Setting, and Participants

This cohort study was conducted among patients with NF1 at a single academic cancer center from 1985 to 2020 with median (range) follow-up of 2.9 years (36 days to 30.5 years). Of 2427 patients evaluated for NF1, 1607 patients who met the National Institutes of Health consensus criteria for NF1 were included. This group was compared with estimates from Surveillance, Epidemiology, and End Results (SEER) Cancer Statistics Review 1975 to 2015 and SEER participants database unless otherwise specified. Data were analyzed from August 2018 to March 2020.

Main Outcomes and Measures

Disease-specific survival (DSS) was measured from diagnosis date to date of neoplasm-specific death or censorship and calculated using the Kaplan-Meier method. Survival curves were compared using the log-rank test. Deaths from disease were considered a DSS end point; other deaths were considered censored observations. Secondary outcome measures were comparisons of (1) overall survival of patients with NF1 with neurofibroma neoplasms vs those without nonneurofibroma neoplasms, (2) neoplasm prevalence in the NF1 group vs general population estimates, and (3) age at diagnosis in the NF1 group vs general population estimates for the most common neoplasms in the NF1 group.

Results

Among 1607 patients with NF1, the median (range) age at initial visit was 19 years (1 month to 83 years) and 840 (52.3%) were female patients. Among 666 patients who developed other neoplasms in addition to neurofibromas (41.4%), 295 patients (18.4%) developed glioma and 243 patients (15.1%) developed malignant peripheral nerve sheath tumor (MPNST), the most common neoplasms. Patients with NF1, compared with the general population, developed several neoplasms at a younger mean (SD) age (low-grade glioma: 12.98 [11.09] years vs 37.76 [24.53] years;P < .0001; high-grade glioma [HGG]: 27.31 [15.59] years vs 58.42 [19.09] years;P < .0001; MPNST: 33.88 [14.80] years vs 47.06 [20.76] years;P < .0001; breast cancer: 46.61 [9.94] years vs 61.71 [13.85] years;P < .0001). Patients with NF1 developed neoplasms more frequently compared with the general population (odds ratio, 9.5; 95% CI, 8.5-10.5;P < .0001). Among patients with NF1, significantly lower 5-year DSS rates were found among those with undifferentiated pleomorphic sarcoma (1 of 5 patients [20.0%]), HGG (8 of 34 patients [23.1%]), MPNST (72 of 228 patients [31.6%]), ovarian carcinoma (4 of 7 patients [57.1%]), and melanoma (8 of 12 patients [66.7%]) compared with those who had neoplasms classified asother (110 of 119 patients [92.4%]) (allP < .001) .

Conclusions and Relevance

This cohort study found that among patients with NF1, those who developed undifferentiated pleomorphic sarcoma, HGG, MPNST, ovarian carcinoma, or melanoma had significantly lower DSS rates compared with those who developed other neoplasms. This study also found that patients with NF1 developed some neoplasms more frequently and at a younger age compared with individuals without NF1. HGGs and MPNST were noteworthy causes of death among patients NF1. This information may be useful for NF1 patient counseling and follow-up.

Study Population

We identified patients evaluated for NF1 or an NF1-related neoplasm from 1985 to 2020 (Figure 1;Table 1). An unblinded electronic health record review was performed by 2 research fellows (J.P.L. and K.L.S.). Patients identified with anInternational Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10)⁷ diagnosis code of neurofibromatosis or an NF1-defining lesion, such as malignant peripheral nerve sheath tumor (MPNST), optic pathway glioma, or neurofibromas, were included. Patients were included if they had sufficient documentation supporting NF1 clinical diagnosis according to the updated 1987 National Institutes of Health consensus criteria (eTable 1 in theSupplement).^8,9 Patients with incomplete data were excluded. Patient data were anonymized prior to analysis, and data abstraction was agreed upon prior to collection and reviewed during collection by the research team. In specific cases in which the 2 research fellows did not agree on the criteria of inclusion, a third blinded research expert (I.E.M.) was involved.

The primary outcome measure was disease-specific survival (DSS). Secondary outcome measures were comparisons of (1) overall survival of patients with NF1 with nonneurofibroma neoplasms vs those without nonneurofibroma neoplasms, (2) neoplasm prevalence in the NF1 group vs general population estimates, and (3) age at diagnosis in the NF1 group vs general population estimates for the most common neoplasms.

The date of neoplasm diagnosis was the date of histological confirmation following expert pathological evaluation. For patients not undergoing resection, the diagnosis date was the earliest date at which the neoplasm was noted on imaging.¹⁰ General population estimations for neoplasm prevalence, median diagnosis age, and 5-year DSS were obtained from the Surveillance, Epidemiology, and End Results (SEER) Cancer Statistics Review 1975 to 2015; the SEER participants database (1985-2017); and several large studies.^{3,11,12,13,14,15,16,17,18,19,20,21,22} Type of treatment received for specific neoplasms, including surgical treatment, chemotherapy, and radiation therapy, were recorded. Surgical treatment was defined as surgical resection of the specific neoplasm, chemotherapy was defined as any systemic agent used to treat the specific neoplasm, and radiation therapy was defined as neoplasm-specific treatment using forms of radiation.

Statistical Analysis

Comparisons of neoplasm prevalence in the NF1 group with the general population were calculated using SEER prevalence data and large population databases referenced inTable 2. Hypothesis tests were 2-tailed analyses. The odds ratios (ORs) and 95% CIs of specific neoplasms in patients with NF1 compared with the general population were calculated using the χ² test with Yate correction and Woolf logit method (Table 2). To compare mean age at diagnosis for specific neoplasms, we used SEER*Stat statistical software version 8.3.5 (US Department of Health and Human Services) to query data from SEER registries for patients diagnosed with glioma, glioblastoma, anaplastic astrocytoma, pilocytic astrocytoma, anaplastic oligodendroglioma, ependymoma, astrocytoma, breast cancer, or MPNST from 1985 through 2017. Two-sample Wilcoxon rank-sum test and t test were used to compare the mean age at diagnosis of both groups.

Deaths from disease were considered a DSS end point; other deaths were considered censored observations. Causes of death were determined based on the documentation of the electronic health record. The causes of death were reviewed by the research team composed of physicians (J.P.L., Y.C., and K.E.T.). We calculated DSS using the Kaplan-Meier method; survival curves were compared using the log-rank test. We measured DSS from diagnosis date to date of neoplasm-specific death or censorship.P values were 2-sided, andP < .05 was considered statistically significant. Owing to the concern for type I error from multiple secondary analyses, we adjusted our significance threshold toP < .001 for secondary analyses. Statistical analyses were performed using SPSS statistical software version 22.0 (IBM) from August 2018 to March 2020.

Survival

The median (range) survival after diagnosis with a nonneurofibroma neoplasm for the NF1 group was 15.5 years (7.0 days to 46.6 years); Patients who were not diagnosed with a nonneurofibroma neoplasm had excellent outcomes, and we were not able to calculate median survival; the 25-year overall survival (OS) was 84.80% (95% CI, 75.00%- 94.60%). The survival curve did not cross 50% survival. The 5-year OS (SD) was significantly worse in patients with NF1 and nonneurofibroma neoplasms compared with patients without additional neoplasms (63.10% [0.05%] vs 99.60% [0.01%];P < .0001) (Figure 2). Among 666 patients with NF1 who developed nonneurofibroma neoplasms, 261 patients (39.2%) died, with mean (SD; range) age at death 40 (18; 1-90) years. Among 941 patients with NF1 who did not develop additional neoplasms, 23 patients (2.4%) died, with mean (SD; range) age at death of 44 (19; 15-78) years. Among patients with NF1, significantly lower 5-year DSS rates were found among those with undifferentiated pleomorphic sarcomas (UPSs; 1 of 5 patients; [20.0%]), HGG (8 of 34 patients [23.1%]), MPNST (72 of 228 patients [31.6%]), ovarian carcinoma (4 of 7 patients [57.1%]), and melanoma (8 of 12 patients [66.7%]) compared with those who had neoplasms classified asother (110 of 119 patients [92.4%]) (allP < .001) (Table 2;Figure 2). No difference in DSS was found for other neoplasms when we compared the NF1 group with the general population.

Among patients with NF1 without nonneurofibroma neoplasms, 12 patients presented with more serious multisystemic complications that were associated with significant morbidity and mortality. These patients died at a younger mean (SD) age (29 [8] years); causes of death included complications from facial or airway neurofibromas for 3 patients, deep neurofibroma resection for 3 patients, neurological deficits from neurofibromas for 3 patients, unknown causes for 2 patients, and pneumonia for 1 patient.

Glioma

Gliomas were the most common neoplasm in the NF1 group, found in 295 patients (18.4%). Within this subgroup, LGGs were the most frequently occurring, found in 267 patients (16.6%) (Table 2); OPG was the most prevalent subtype of LGG, found in 178 (11.1%) patients. Among patients with NF1 and a known OPG, 27 patients (15.2%) developed more than 1 LGG. Among patients with OPG, 56 patients (31.5%) received chemotherapy and 24 patients (13.5%) received additional radiotherapy (Table 3). Of 178 children with NF1 and radiographically identifiable OPGs, 68 (38.2%) developed signs or symptoms of the tumor. Among 89 patients with NF1 and non-OPG LGG, 33 patients (37.1%) received surgical resection. Twenty-eight patients developed HGG (1.7%), and among those, 6 patients (21.4%) developed HGG with a prior non-OPG LGG. The mean (SD) age at diagnosis of HGG for patients with NF1 was 27.31 (15.59) years vs 58.42 (19.09) years for the general population (OR 82; 95% CI, 56.6-119.5;P <.001; eTable 3 in theSupplement); 18 patients with HGG (64.3%) underwent surgical resection, of whom 16 patients (89.0%) received multimodality therapy (Table 3). Among patients who developed HGG, 9 patients received chemoradiation alone and 1 patient received chemotherapy only (eAppendix in theSupplement).

Sarcoma

Among patients in the study group, 285 patients (17.7%) developed sarcomas. The most frequently occurring sarcoma subtype, MPNST, was diagnosed in 243 patients (15.1%). Of those, 5 patients (2.1%) developed 2 separate primary MPNSTs at the time of this study. All 248 MPNSTs developed from neurofibromas, and 79 patients with MPNST (32.9%) presented with metastatic disease at diagnosis (eTable 2 in theSupplement). Among patients with NF1, MPNSTs were diagnosed at a younger mean (SD) age compared with the general population (33.88 [14.80] years vs 47.06 [20.76] years;P < .0001) (eTable 3 in theSupplement). Among patients with MPNST, 223 patients (91.7%) underwent resection for MPNST; among these patients, 187 patients (83.9%) received neoadjuvant or adjuvant therapy (Table 3). Two patients with poor performance status at MPNST diagnosis received palliative care.

Among patients with NF1, 20 patients (1.2%) developed gastrointestinal stromal tumors (GISTs) and 13 patients (0.8%) developed embryonal rhabdomyosarcomas (ERMSs) (Table 2). Among these, 2 patients (10.0%) had metastatic GIST and 4 patients (30.8%) had metastatic ERMSs. Of the GISTs, none carriedc-kit orPDGFRA mutations, 13 tumors (65.0%) were located in the jejunum or ileum, and 6 tumors (30.0%) were located in the duodenum. Among ERMSs, 11 sarcomas (84.6%) were located in genitourinary system. A diagnosis of ERMS was made 3-fold more often in male patients with NF1 (10 male patients and 3 female patients with NF1 developed ERMS) compared with 1.5 fold more often among male patients in sporadic cases.²³ Other sarcomas in the NF1 group included UPS in 5 patients (0.3%), osteosarcoma in 4 patients (0.2%), leiomyosarcoma in 2 patients (0.1%), liposarcoma in 2 patients, and angiosarcoma in 1 patient (0.1%). Among patients with UPS, 2 patients (40.0%) had metastatic disease at diagnosis, whereas no patients had metastatic osteosarcoma, leiomyosarcoma, liposarcoma, or angiosarcoma at diagnosis; all patients diagnosed with UPS presented with a growing, painful mass and died from their disease. Among 4 patients with osteosarcoma, 2 patients (50.0%) showed now sign of progression after therapy and ultimately died of a synchronous primary MPNST.

Breast and Ovarian Carcinoma

In the study group, 47 patients (2.9%), including 46 female patients and 1 male patient, developed breast cancer. Mean (SD) age at diagnosis for breast cancer in patients with NF1 was 46.61 (9.94) years compared with 61.71 (13.85) years in the general population (eTable 3 in theSupplement). Of women who developed breast cancer, 18 women (38.3%) developed it at younger than age 50 years, including 2 women (4.3%) who were diagnosed in their 20s. All breast cancers were ductal carcinoma; tumor receptor status is included in the eAppendix in theSupplement. Among patients with breast cancer, 3 patients (6.4%) had metastatic breast cancer at diagnosis (eTable 2 in theSupplement). Female patients with NF1 also developed ovarian carcinoma at a younger age and more frequently compared with general population estimates (OR, 5.6; 95% CI, 2.8-11.1;P < .0001) (Table 2). Among 8 patients with NF1 and ovarian serious carcinoma, 3 patients (37.5%) had ovarian carcinomatosis at diagnosis and 5 patients (62.5%) had developed peritoneal and distant metastasis by last follow-up.

Pheochromocytoma and Neuroendocrine Tumors

In the study group, 36 patients (2.4%) developed endocrine neoplasms (Table 2); among these patients, 20 patients (1.2%) were diagnosed with pheochromocytoma. Of patients with NF1, 270 patients (16.8%) had hypertension by last follow-up. Of those, 20 patients (7.4%) had pheochromocytomas, among whom 2 patients (10.0%) were diagnosed with bilateral pheochromocytomas (eAppendix in theSupplement) and 2 other patients developed metastatic disease (eTable 2 in theSupplement). No difference in diagnosis age was found between the NF1 group and the general population. All patients with pheochromocytoma underwent surgical resection (Table 3). Among 666 patients who developed neoplasms, 9 patients developed neuroendocrine tumors (NET) (eTable 2 in theSupplement), among whom 8 patients (88.9%) underwent resection and 1 patient (11.1%) had metastatic NET at diagnosis. Among patients with pheochromocytoma, 1 patient was diagnosed with a rectal NET.

Melanoma

Melanoma was diagnosed in 15 (0.9%) patients, among whom 6 patients (40.0%) had metastatic disease at diagnosis and 5 patients (33.3%) with localized disease at the time of surgery developed metastases postoperatively. The median (range) thickness of the primary melanomas was 2.7 (0.9-50.0) mm. Among patients with melanoma, 1 patient was diagnosed with periocular melanoma in the left orbit.

Limitations

This cohort study has some limitations. First, some patients with NF1 may have received treatment elsewhere, although this would suggest a higher prevalence of neoplasia than that found in our analysis. Second, the patients lost to follow-up may be associated with changes in the outcome analyses. Third, 10.0% of our NF1 group was younger than age 8 years old at last follow-up, which may be associated with changes in rates of clinical characteristics and prevalence or risk of neoplasia in our group; these younger patients with NF1 may be associated with decreases in the true numbers of characteristics and patients at risk for non-NF neoplasia. Fourth, the mean age for patients with NF1 who did not develop additional neoplasms was similar to the mean age for those who did develop neoplasms. This may be associated with the small sample size. Despite these limitations, our study found neoplasia occurrence and patient outcome characteristics that may be used in the evaluation of neoplasia among patients with NF1.

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