Therapeutic Consequences from Molecular Biology for Gastrointestinal Stromal Tumor Patients Affected by Neurofibromatosis Type 1

Abstract

Purpose: Patients affected by neurofibromatosis type 1 (NF-1) have an increased risk of developing gastrointestinal stromal tumors (GIST). NF-1–associated GISTs are usually wild type for c-KIT and platelet-derived growth factor receptor-α (PDGFR-α) mutations and harbor a different oncogenic molecular mechanism. The lack of data on imatinib activity raises the question whether to enroll these patients in clinical trials. We analyzed a large series of NF-1 related GISTs to discuss the therapeutic implications. Materials and Methods: Clinical, pathologic (IHC to CD34, S100, bcl-2, PDGFRA), and molecular features (exons 9, 11, 13, 14, 17 in c-kit and exons 12, 14, 18 in PDGFRA) of 28 patients were analyzed. Results: The most common site of primary lesions was the small bowel (75%). Twelve patients (43%) had multiple tumors. Most tumors belonged to the high (30.5%) or intermediate risk group for malignant behavior (39%). Three patients developed peritoneal and liver metastases; another four had peritoneal spread only. All tumors were immunohistochemically strongly positive for CD117. Three primary KIT/PDGFRA activating mutations were found. Three metastatic patients treated with imatinib experienced progression, and only one had temporary stable disease. Median survival after starting treatment with imatinib was 21 months. Conclusions: This study is the largest series available and confirms that KIT/PDGFRA mutations in NF-1–associated GISTs are sporadic. Prognosis of metastatic tumors is poor, and imatinib response rate is low. Patients with NF-1–GIST of high or intermediate risk should not be eligible for adjuvant trials of imatinib. Imatinib should not be used in a neoadjuvant intent in these patients, and molecular analysis of activating mutations is strongly recommended.

Classification of gastrointestinal stromal tumor syndromes

“…Of note, these studies have substantial discrepancy of tumor-proliferative status, mitotic count and tumor size, which may explain the different outcomes. We emphasize that greater experience will be necessary in this area, and the role of adjuvant treatment with imatinib in NF-1 syndromal cases remains debatable (Mussi et al 2008).…”

“…In one cohort, reported by Miettinen et al, these patients enjoyed an overall good prognosis, with only five out of 35 patients dying of metastatic disease (Miettinen et al 2006). Conversely, two case reports have stated that NF-1-mutated GISTs either only showed an initial response to imatinib (Lee et al 2006) or were completely resistant to imatinib (Mussi et al 2008). Of note, these studies have substantial discrepancy of tumor-proliferative status, mitotic count and tumor size, which may explain the different outcomes.…”

“…There is no clear female predominance in these patients. From a therapeutic standpoint, NF-1-related GISTs have not responded well to imatinib (Mussi et al 2008). While there is no reported efficacy of imatinib, there is a report of a response to sunitinib (Kalender et al 2007).…”

Neoplasms Associated with Germline and Somatic NF1 Gene Mutations

“…On immunohistochemical staining, 95% are positive for CD117, 70% for CD34, and 40% for smooth muscle actin [56]. GISTs spread by the hematogeneous route, with the most common sites of metastases being the liver, lung, peritoneum, and lymph nodes [66].…”

Surgical management of localized soft tissue tumors

“…[68][69][70] The extent of surgery should be determined on a case-by-case basis, taking into account the risk of recurrence, the lack of benefit from available tyrosine kinase inhibitors, and the actual behavior of the underlying disease.…”