Gastrointestinal stromal tumours: ESMO–EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up

Gastrointestinal stromal tumours (GISTs) are rare tumours, with an estimated unadjusted incidence of around 1/100 000/year [1.Nilsson B. Bümming P. Meis-Kindblom J.M. et al.Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era–a population-based study in western Sweden.Cancer. 2005; 103: 821-829Crossref PubMed Scopus (1027) Google Scholar]. This only covers clinically relevant GISTs, since, if investigated, a much higher number of lesions ≤ 1 cm in diameter (microGISTs) can be found at histopathological examination of stomach tissue in middle-aged and elderly individuals. There is a slight prevalence in males. The median age is around 60–65 years, with a wide range. Occurrence in children is very rare. Paediatric GIST represents a clinically and molecularly distinct subset, marked by female predominance, absence of KIT/platelet-derived growth factor alpha (PDGFRA) mutations, frequent mutations or silencing of the four genes that encode the subunits of the succinate dehydrogenase (SDH) enzyme complex, gastric multicentric location and possible lymph node metastases [2.Pappo A.S. Janeway K.A. Pediatric gastrointestinal stromal tumors.Hematol Oncol Clin North Am. 2009; 23 (vii): 15-34Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar]. Some syndromes are linked to GISTs: •The Carney triad syndrome, marked by gastric GISTs, paraganglioma and pulmonary chondromas (these may occur at different ages) [3.Zhang L. Smyrk T.C. Young Jr, W.F. et al.Gastric stromal tumors in Carney triad are different clinically, pathologically, and behaviorally from sporadic gastric gastrointestinal stromal tumors: findings in 104 cases.Am J Surg Pathol. 2010; 34: 53-64Crossref PubMed Scopus (167) Google Scholar];•Carney–Stratakis syndrome, marked by a dyad of GIST and paraganglioma [4.Gaal J. Stratakis C.A. Carney J.A. et al.SDHB immunohistochemistry: a useful tool in the diagnosis of Carney–Stratakis and Carney triad gastrointestinal stromal tumors.Mod Pathol. 2011; 24: 147-151Crossref PubMed Scopus (162) Google Scholar, 5.Pasini B. McWhinney S.R. Bei T. et al.Clinical and molecular genetics of patients with the Carney–Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD.Eur J Hum Genet. 2008; 16: 79-88Crossref PubMed Scopus (363) Google Scholar]; and•Neurofibromatosis type 1(NF1), possibly leading to wild-type (WT), often multicentric GIST, predominantly located in the small bowel [6.Miettinen M. Fetsch J.F. Sobin L.H. Lasota J. Gastrointestinal stromal tumors in patients with neurofibromatosis 1: a clinicopathologic and molecular genetic study of 45 cases.Am J Surg Pathol. 2006; 30: 90-96Crossref PubMed Scopus (377) Google Scholar]. Families with germline autosomal dominant mutations of KIT are an extremely rare finding, presenting with multiple GISTs at an early age, possibly along with other associated features such as pigmented skin macules, urticaria pigmentosa and diffuse hyperplasia of the interstitial cells of Cajal in the gut wall. When small oesophagogastric or duodenal nodules < 2 cm in size are detected, endoscopic biopsy may be difficult and laparoscopic/laparotomic excision may be the only way to make a histological diagnosis. Many of these small nodules, if diagnosed as GISTs, will be either low-risk or entities whose clinical significance remains unclear. Therefore, the standard approach to patients with oesophagogastric or duodenal nodules < 2 cm is endoscopic ultrasound assessment and then follow-up, reserving excision for patients whose tumour increases in size or becomes symptomatic [IV, C]. As an option, the patient can choose to undergo a histological assessment, also depending on age, life expectancy and comorbidities. If follow-up is the choice, an evidence-based, optimal surveillance policy is lacking. A logical approach may be to have a short-term first control (e.g. at 3 months) and then, in the case of no evidence of growth, a more relaxed follow-up schedule may be selected. In a histologically proven small GIST, standard treatment is excision, unless major morbidity is expected. Alternatively, in the case of a likely low-risk GIST on biopsy, the decision can be made with the patient to follow up the lesion. However, an exception is the standard approach to rectal nodules represented by biopsy or excision after endorectal ultrasound assessment and pelvic magnetic resonance imaging (MRI), regardless of the tumour size and mitotic rate. In fact, the progression risk of a clinically significant GIST at this site is higher, its prognosis is significantly worse compared with most gastric GISTs and the local implications for surgery are more critical. A follow-up policy may be an option, to be discussed with the patient, in the case of small lesions and whenever the surgical risk is particularly high (comorbidities, age, etc.). The standard approach to tumours ≥2 cm in size is biopsy/excision, because they are associated with a higher risk of progression if confirmed as GIST [IV, C]. If there is an abdominal nodule not amenable to endoscopic assessment, laparoscopic/laparotomic excision is the standard approach. If there is a mass, especially if surgery is likely to be a multivisceral resection, multiple core needle biopsies are the standard approach. They should be obtained through endoscopic ultrasound guidance, or through an ultrasound/computed tomography (CT)-guided percutaneous approach. This may allow the surgeon to plan the best approach according to the histological diagnosis and avoid surgery for diseases which might not benefit (e.g. lymphomas, mesenteric fibromatosis and germ cell tumours). The risk of peritoneal contamination is negligible if the procedure is properly carried out. Moreover, lesions at risk in this regard (e.g. cystic masses) should be biopsied only in specialised centres. Immediate laparoscopic/laparotomic excision is an option on an individualised basis, especially if surgery is limited. If a patient presents with obvious metastatic disease, a biopsy of the metastatic focus is sufficient and the patient usually does not require a laparotomy for diagnostic purposes. The tumour sample should be fixed in 4% buffered formalin (Bouin fixative should not be used, since it prevents molecular analysis). Pathologically, the diagnosis of GIST relies on morphology and immunohistochemistry, the latter being positive for CD117 (KIT) and/or DOG1 (see Table 1) [7.Rubin B.P. Blanke C.D. Demetri G.D. et al.Protocol for the examination of specimens from patients with gastrointestinal stromal tumor.Arch Pathol Lab Med. 2010; 134: 165-170Crossref PubMed Google Scholar, 8.Novelli M. Rossi S. Rodriguez-Justo M. et al.DOG1 and CD117 are the antibodies of choice in the diagnosis of gastrointestinal stromal tumours.Histopathology. 2010; 57: 259-270Crossref PubMed Scopus (147) Google Scholar]. A proportion of GISTs (in the range of 5%) are CD117-negative. The mitotic count has a prognostic value and should be expressed as the number of mitoses on a total area of 5 mm2 [which replaces the former 50 high-power field (HPF) area]. Mutational analysis for known mutations involving KIT and PDGFRA can confirm the diagnosis of GIST, if doubtful (particularly in rare CD117/DOG1-negative suspect GIST). Mutational analysis has a predictive value for sensitivity to molecular-targeted therapy and to prognostic value. Its inclusion in the diagnostic work-up of all GISTs should be considered standard practice [II, A] (with the possible exclusion of < 2 cm non-rectal GISTs, which are very unlikely ever to be candidates for medical treatment). 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