Clinical, histopathologic, molecular and therapeutic findings in a large kindred with gastrointestinal stromal tumor

Abstract

Germ-line mutations in the KIT receptor tyrosine kinase gene have been described in families with a propensity to develop gastrointestinal stromal tumor (GIST). There is limited information from large kindreds regarding median age at diagnosis, detailed histopathology, clinical effects of imatinib therapy and chromosomal abnormalities of the KIT gene. We identified a large kindred with GIST. Each family member was interviewed and appropriate medical records and radiographic imaging were obtained. Archival tumor tissue was obtained to confirm diagnosis, extract genomic DNA and perform fluorescent in situ hybridization cytogenetics of the KIT gene. Fifteen of 79 individuals with GIST were identified in this kindred. There were 8 males, the mean age at diagnosis was 53.9 (range 45-71) years. Histopathology revealed microscopic proliferation and nodularity in the myenteric plexus, spindled morphology, diffuse Kit but variable CD34 staining and low mitotic rates in the setting of metastatic disease. A deletion of codon 579 in exon 11 of the KIT gene was identified in tumor and normal tissue of this family. Mutation and cytogenetic analysis revealed homozygous loss of the wild-type KIT sequence in tumor from one individual. Four of 4 individuals treated with imatinib are alive and without progression while 9 of 11 individuals not treated with imatinib are deceased. This study describes a kindred with a propensity to develop GIST in an autosomal dominant pattern. Germ-line deletion of KIT codon 579 in GIST is associated with clinical benefit from imatinib, limited utility of mitoses to predict malignant potential, and a novel homozygous deletion of this codon in one individual. ' 2007 Wiley-Liss, Inc.

Gastrointestinal Stromal Tumor: Advances in Diagnosis and Management

“…Because most reported familial GIST kindreds are small, it is difficult to accurately compare the behavior of GISTs arising in the familial setting with sporadic GISTs. Although some reports suggest that these tumors appear to be indolent, in a study by Kleinbaum et al, 75 2 patients presented with metastases at the time of diagnosis despite having variable mitotic activity. The authors, 75 therefore, believed that patients with familial GISTs should be categorized as being at high risk for metastasis, irrespective of the tumor size and mitotic activity.…”

“…These mutations are identical to those found in sporadic tumors and are inherited in an autosomaldominant pattern. [73][74][75][76] Every family member who harbors a germline KIT mutation will develop one or more GISTs, usually at a younger age than those with sporadic tumors. Clinically, many members of familial GIST syndrome kindreds manifest with cutaneous findings that include hyperpigmentation (especially perineal), increased numbers of nevi, and mast cell disease in the form of urticaria pigmentosa or even systemic mastocytosis.…”

Familial Gastrointestinal Stromal Tumor Syndrome: Report of 2 Cases with KIT Exon 11 Mutation

“…The current report describes 2 additional cases of a mutation of p.Asp579del in exon 11 of KIT, adding 2 kindreds to the 3 previously reported families with familial GIST syndrome demonstrating this mutation. [18][19][20] Mutations causing familial GIST syndrome have no clear differentiating factors from mutations causing sporadic GIST, and the mutation of p.Asp579del has also been documented in sporadic GIST. 21 The p.Asp579del mutation is not within the region of high-frequency mutations noted at positions 556 to 560 in exon 11 of KIT in patients with GIST.…”

“…Nine of the 11 family members who did not receive imatinib eventually died from metastatic GIST, whereas all 4 patients receiving imatinib achieved stable disease for more than 4 years. 20 Typically, sunitinib is a second-line therapy following treatment failure with imatinib.…”

Update on the treatment of gastrointestinal stromal tumors (GISTs): role of imatinib

“…[52][53][54] Affected kindreds with familial GIST may present with multi-focal disease, and in some cases associated with cutaneous and mucous membrane hyperpigmentation, urticaria pigmentosa, mast cell disease and diffuse spindle cell hyperplasia in the myenteric plexus of the gastrointestinal tract. Carney's triad is a rare and possibly familial tumor syndrome.…”