Once a poorly defined pathologic oddity, in recent years, gastrointestinal stromal tumor (GIST) has emerged as a distinct oncogenetic entity that is now center stage in clinical trials of kinase-targeted therapies. This review charts the rapid progress that has established GIST as a model for understanding the role of oncogenic kinase mutations in human tumorigenesis. Approximately 80% to 85% of GISTs harbor activating mutations of the KIT tyrosine kinase. In a series of 322 GISTs (including 140 previously published cases) studied by the authors in detail, mutations in the KIT gene occurred with decreasing frequency in exons 11 (66.1%), 9 (13%), 13 (1.2%), and 17 (0.6%). In the same series, a subset of tumors had mutations in the KIT-related kinase gene PDGF receptor alpha (PDGFRA), which occurred in either exon 18 (5.6%) or 12 (1.5%). The remainder of GISTs (12%) were wild type for both KIT and PDGFRA. Comparative studies of KIT-mutant, PDGFRA-mutant, and wild-type GISTs indicate that there are many similarities between these groups of tumors but also important differences. In particular, the responsiveness of GISTs to treatment with the kinase inhibitor imatinib varies substantially depending on the exonic location of the KIT or PDGFRA mutation. Given these differences, which have implications both for the diagnosis and treatment of GISTs, we propose a molecular-based classification of GIST. Recent studies of familial GIST, pediatric GIST, and variant forms of GIST related to Carney's triad and neurofibromatosis type 1 are discussed in relationship to this molecular classification. In addition, the role of mutation screening in KIT and PDGFRA as a diagnostic and prognostic aid is emphasized in this review.

Biology of gastrointestinal stromal tumors.

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(13)60106-3.pdf

Gastrointestinal stromal tumour

The prevalence of neurofibromatosis type 1 (NF1) is about 1/3,000. There are no known ethnic groups in which NF1 does not occur or is unusually common. The prevalence is somewhat higher in young children than in adults, a difference that probably results at least in part from the early death of some NF1 patients. NF1 is fully penetrant in adults, but many disease features increase in frequency or severity with age. The reproductive fitness of NF1 patients is reduced by about one-half. About half of all cases result from new mutations. The estimated rate of new NF1 mutations is unusually high, but the basis for this high mutation rate is not known. Am. J. Med. Genet. (Semin. Med. Genet.) 89:1-6, 1999.

Epidemiology of neurofibromatosis type 1

Purpose: To analyze the results of therapy for malignant peripheral nerve sheath tumor (MPNST) and to identify prognostic factors of survival, and of local and distant control of disease. Methods and Materials: From 1975 through 1993, 134 MPNSTs were diagnosed and treated at our institution. Tumor sites included extremities in 36 (27%) cases and non-extremities in 98 (73%). Median follow-up for survivors was 53 months (range: 7–280). There were 14 tumors of histologic grade I disease (10%), 43 of grade II disease (32%), 43 of grade III disease (32%), and 32 of grade IV (24%). Seventy-three patients (54%) underwent radiation therapy (RT) as part of their initial treatment of the primary tumor, including 14 (10%) who had brachytherapy and 16 (12%) who had intraoperative electron irradiation (IOERT) as part of their radiation course. Results: The 5- and 10-year survival rates were 52% and 34%, respectively. Local and distant failure rates at 5 years were both 49%. On univariate analysis, prognostic factors significantly related to survival (log-rank: p p = 0.023), and surgical margin status ( p = 0.0044) remained significant. For local control of disease, univariate analysis showed location of disease, surgical margin status, history of NF-1, history of prior irradiation, mitotic rate, radiation dose ≥ 60 Gy, and use of IOERT or brachytherapy to be significant prognostic factors. On multivariate analysis, only surgical margin status (p = 0.0024), RT dose ( p = 0.021), and use of IOERT or brachytherapy ( p = 0.016) remained significant. For distant control of disease, significant prognostic factors on univariate analysis included tumor size, stage, tumor grade, mitotic rate, presence or absence of necrosis, and histologic subtype. On multivariate analysis, tumor size ( p = 0.0065), grade ( p = 0.036), and histologic subtype ( p = 0.001) remained significant. Patients with perineurial MPNSTs had a much lower rate of distant metastasis and a better overall survival as compared with other histologic subtypes. Conclusion: Management of patients with MPNST involves a multi-modality approach. The goal of surgery is complete resection with negative margins. Adjuvant irradiation to doses ≥ 60 Gy and the inclusion of IOERT or brachytherapy are associated with improved local control of disease.

Malignant peripheral nerve sheath tumor: analysis of treatment outcome

Neurofibromatosis 1 (NF1), also known as von Recklinghausen disease, is an autosomal dominant condition caused by mutations of the NF1 gene, which is located at chromosome 17q11.2. NF1 is believed to be completely penetrant, but substantial variability in expression of features occurs. Diagnosis of NF1 is based on established clinical criteria. The presentation of many of the clinical features is age dependent. The average life expectancy of patients with NF1 is probably reduced by 10-15 years, and malignancy is the most common cause of death. The prevalence of clinically diagnosed NF1 ranges from 1/2,000 to 1/5,000 in most population-based studies. A wide variety of NF1 mutations has been found in patients with NF1, but no frequently recurring mutation has been identified. Most studies have not found an obvious relation between particular NF1 mutations and the resulting clinical manifestations. The variability of the NF1 phenotype, even in individuals with the same NF1 gene mutation, suggests that other factors are involved in determining the clinical manifestations, but the nature of these factors has not yet been determined. Laboratory testing for NF1 mutations is difficult. A protein truncation test is commercially available, but its sensitivity, specificity, and predictive value have not been established. No general, population-based molecular studies of NF1 mutations have been performed. At this time, it appears that the benefits of population-based screening for clinical features of NF1 would not outweigh the costs of screening.

/pdf/nf1-gene-and-neurofibromatosis-1-28d3wsenox.pdf

NF1 Gene and Neurofibromatosis 1

BACKGROUND

The development of malignant and benign tumors in patients with neurofibromatosis type 1 (NF1) was investigated in a long term follow-up study of 70 adult NF1 patients living in Goteborg, Sweden, on January 1, 1978. Their mean age at that time was 44 years (range, 20-81 years). The 70 NF1 patients had previously been investigated in a population-based study.



METHODS

The first part of this study involved a cancer registry study. The authors compared the number of tumors in the 70 NF1 patients reported to the Swedish Cancer Registry during the period 1978-1989 with the number of tumors expected in the general population by matching the incidence rates of the two populations specific to age, time of follow-up, and gender. The 95% confidence interval for the risk quotient between the risk to the patients and the risk to the general population was estimated. The second part of the study was a clinical pathologic follow-up study. All living patients were offered a clinical reexamination in 1990. All hospital records for all the NF1 patients were reviewed, and death certificates were also reviewed when available.



RESULTS

Malignant tumors were reported to the Cancer Registry four times as often in the NF1 patient group as in the general population (95% confidence interval, 2.1-7.6) during the follow-up period 1978-1989. Before 1978, 5 of 70 patients (7%) had 6 malignant tumors; these patients were not included in the Cancer Registry study. Using all available clinical data on the 70 NF1 patients from their birth up to 1990, the authors found that 17 of 70 patients (24%) had developed a total of 19 malignant tumors, namely, 5 sarcomas (in 7% of patients), 13 carcinomas (in 16%), and 1 malignant melanoma (in 1%). Four pheochromocytomas (in 6% of patients), 2 adenomas, and 1 C-cell hyperplasia were diagnosed. Five gastrointestinal stromal tumors (in 7% of patients) were also diagnosed.



CONCLUSIONS

Malignant tumors were reported to the Swedish Cancer Registry significantly more often in the NF1 patients than was expected in the general population matched for age, gender, and time of follow-up. The development of tumors is part of the NF1 disease process, and this deserves attention both in the clinical setting and in family counseling dealing with complications of NF1 in adulthood. Cancer 1997; 79:2125-31. © 1997 American Cancer Society.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/%28SICI%291097-0142%2819970601%2979%3A11%3C2125%3A%3AAID-CNCR9%3E3.0.CO%3B2-N

Matilda Samuelsson

Papers

Malignant and benign tumors in patients with neurofibromatosis type 1 in a defined Swedish population