Gastrointestinal stromal tumours: ESMO–EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up (2018)

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). Centralisation of mutational analysis in a laboratory enrolled in an external quality assurance programme and with expertise in the disease may be diagnosis is more for GIST, to confirm the diagnosis of GIST with an at a In GIST, for is to In GIST an syndrome should be Rossi S. M. et GIST is a for neurofibromatosis type 1 PubMed Scopus Google Scholar]. The of tissue is to allow molecular to be made at a for tumour to local and should be and for medical treatment or for medical treatment for medical treatment of of growth factor succinate in a of of growth factor succinate treatment is involving medical as as as should be carried in for and GISTs and/or expertise and a high number of patients The for node and of tumours the prognostic in GIST (see Table of for GIST from of of of to of KIT site in KIT or PDGFRA of and gastrointestinal stromal neurofibromatosis type growth factor tumour for from of with from in a GIST, gastrointestinal stromal neurofibromatosis type growth factor tumour for from of with from are the mitotic tumour size and tumour site GISTs have a prognosis small bowel or rectal is an prognostic factor and should be regardless of it or Mutational has not in risk at have a distinct GISTs have clinical and GIST with are associated with a prognosis and to risk have A risk by the of which the mitotic tumour size and tumour the prognostic in GISTs M. Lasota J. Gastrointestinal stromal tumors: on molecular and Pathol Lab Med. 2006; PubMed Google Scholar, M. Lasota J. Gastrointestinal stromal tumors: and prognosis at different Pathol. 2006; PubMed Scopus Google Scholar]. A all has on M. et and of a prognostic for after surgical of gastrointestinal stromal a 2009; Full Text Full Text PDF PubMed Scopus Google Scholar]. When these it is to that the mitotic and tumour size are that are through a of of GIST patients not with which the mitotic and tumour size as tumour is considered in to tumour site J. et of of gastrointestinal stromal tumour after an analysis of population-based Full Text Full Text PDF PubMed Scopus Google Scholar]. They have a that most the and the abdominal and pelvic is the of choice for and may be an rectal GISTs, and laboratory the work-up of the The of an tomography or is useful early of the tumour to molecular-targeted therapy is of The standard treatment of GISTs is surgical excision of the with no of clinically lymph If excision is the to follow the of surgery A] et of and surgery for gastric gastrointestinal stromal Google Scholar]. A approach is in patients have tumours, because of the risk of tumour which is associated with a very high risk of excision is the an excision whose are of tumour When surgery major and medical treatment is not the decision can be made with the patient to possible [IV, This is more for low-risk the of that surgery is associated with a worse If excision carried may be an option, the site of can be and major are not The risk of can be as by risk treatment with for 3 associated with a and in with 1 of therapy in patients in a M. et for stromal analysis of a Clin 34: PubMed Scopus (147) Google Scholar]. a that for a of 1 can in GISTs a diameter 3 cm with a et mesylate after of gastrointestinal stromal a 2009; Full Text Full Text PDF PubMed Scopus Google Scholar]. Therefore, therapy with for 3 is the standard treatment for patients with a significant risk of A is the risk is T. et treatment of GIST with or A on of the and the the the on GIST, the and the J 2009; Full Text Full Text PDF PubMed Scopus Google Scholar]. clinical are to of therapy in The benefit associated of may according to the type of being in patients with KIT mutations et of KIT and PDGFRA mutations on in patients with gastrointestinal stromal tumors with an analysis of a clinical PubMed Scopus Google Scholar, et and molecular features with after therapy of stromal the Clin PubMed Scopus Google Scholar]. Mutational analysis is to make a clinical decision There is a that PDGFRA GISTs should not be with the of sensitivity of this in and in [IV, the the of a higher of in the case of an KIT in GIST, to this in the for this [II, M. et mutations and for in patients with gastrointestinal stromal J 2006; Full Text Full Text PDF PubMed Scopus Google Scholar, et of and clinical in the North of mesylate for treatment of gastrointestinal stromal by and and Clin 2008; PubMed Scopus Google Scholar, Demetri G.D. et mutations and in patients with metastatic gastrointestinal stromal Clin PubMed Scopus Google Scholar]. may this which is not in the by regard to GIST, there is a on treatment in and GISTs [IV, This of sensitivity to and other in the as as which is often more of to sufficient and be to best in the rare In case of tumour at the of there is of tumour cells the peritoneal peritoneal disease can be to This the patient at a very high risk of peritoneal P. et of in patients with gastrointestinal stromal J 2010; PubMed Scopus Google Scholar]. Therefore, these patients should be considered for therapy [IV, The optimal of treatment in these is the these cells should be considered as If surgery is not or it be through surgery in the case of total and all other major with is standard A] J. Blanke C.D. et of mesylate for and gastrointestinal stromal early of Surg 2009; PubMed Scopus Google Scholar, P. P. et in gastrointestinal stromal tumors the Surg PubMed Scopus Google Scholar]. This may also be the case if the surgeon that the surgical is after (e.g. the risk of and tumour is A may be the of mitotic for risk for A biopsy with histological and mutational is to confirm the histological to to therapy with (e.g. PDGFRA and to the for KIT tumour after surgery is carried out. tumour assessment is to avoid surgery in the case of imaging it possible to the tumour very a particularly in the absence of mutational There are to the on to treatment it can be a or surgery and can be the patient from is the standard treatment for and metastatic disease A] C.D. Demetri G.D. M. et from a of mesylate for patients with or metastatic gastrointestinal stromal tumors Clin 2008; PubMed Scopus Google Scholar, C.D. Demetri G.D. et mesylate at in patients with or metastatic gastrointestinal stromal tumors the Clin 2008; PubMed Scopus Google Scholar, J. J. et in gastrointestinal stromal tumours with Full Text Full Text PDF PubMed Scopus Google Scholar, J. et of patients with stromal tumours to a of after progression on J 2005; Full Text Full Text PDF PubMed Scopus Google as as for patients with not is also the standard treatment for patients with metastatic disease have all lesions surgery is not as a approach in the metastatic The standard of is However, have that patients with tumours the KIT have significantly on a higher which is as standard treatment in this of of for the treatment of or metastatic gastrointestinal stromal tumors: a of Clin 2010; PubMed Scopus Google Scholar]. with a PDGFRA are to S. et al.Clinical and treatment in a of PDGFRA gastrointestinal stromal tumour J Full Text Full Text PDF PubMed Scopus Google and other and candidates for clinical on this is doubtful patients with GIST benefit from there are of of K.A. et treatment in patients with GIST of 2009; PubMed Scopus Google Scholar]. In the metastatic treatment with should be since treatment is by tumour lesions have A] et of in patients with gastrointestinal stromal tumours after 3 of an 3 2010; Full Text Full Text PDF PubMed Scopus Google Scholar]. When treatment is the patient should be to the of with as as with and and the best to should be by of and a policy of and should be in the case of that of are associated with a worse a with the has G.D. et are with clinical benefit in patients with gastrointestinal stromal Clin 2009; PubMed Scopus Google Scholar]. from its to the assessment of may be useful in the case patients that at a risk of major or patients with surgical to and progression on to the to the to of the tumour should be carried in the early of should be the since the risk of progression excision of metastatic disease has to be associated with a the patient is to it has this is to surgery or to patient J. et surgery in is it in all 2010; Full Text Full Text PDF PubMed Scopus Google Scholar, M. J. et of gastrointestinal stromal tumors after treatment with therapy Clin 2006; 24: PubMed Scopus Google Scholar, Blanke C.D. et of mesylate for and gastrointestinal stromal tumors: follow-up of Surg PubMed Scopus Google Scholar, S. P. P. et follow-up of patients with GIST in the of analysis of prognostic J Surg Full Text Full Text PDF PubMed Scopus Google Scholar]. not early because of for a small positive in which all patients peritoneal disease et there a of surgery in patients with or metastatic gastrointestinal stromal tumours to a in J Full Text Full Text PDF PubMed Scopus Google Scholar]. the surgical option should be individualised after the decision with the patient in the case of C]. excision of disease has not in surgery of such as the a has associated with a in the range as for treatment with Therefore, this may be a option for an patient with [IV, C]. (e.g. local such as or may be selected. In the case of tumour progression on an option may be to the to with the exception of mutations with the C.D. Demetri G.D. M. et from a of mesylate for patients with or metastatic gastrointestinal stromal tumors Clin 2008; PubMed Scopus Google Scholar, C.D. Demetri G.D. et mesylate at in patients with or metastatic gastrointestinal stromal tumors the Clin 2008; PubMed Scopus Google Scholar, J. J. et in gastrointestinal stromal tumours with Full Text Full Text PDF PubMed Scopus Google Scholar, J. et of patients with stromal tumours to a of after progression on J 2005; Full Text Full Text PDF PubMed Scopus Google Scholar]. is particularly useful in the case of a KIT GIST a higher not from the possibly in the case of in or in the case of molecular progression on imaging should be to the (see patient should be as a possible of tumour as as with In the case of confirmed progression or rare on to through and possibly standard treatment is A] G.D. et and of in patients with gastrointestinal stromal tumour after of a 2006; Full Text Full Text PDF PubMed Scopus Google Scholar]. The in of a have that a with a is and no has carried a clinical S. et al.Clinical of of in patients with gastrointestinal stromal tumour after J 2009; Full Text Full Text PDF PubMed Scopus Google Scholar]. This schedule be considered an option on an individualised C]. confirmed progression on a that at the of for 3 of can significantly This as it becomes is standard therapy for patients on or to to and A] G.D. P. et and of for gastrointestinal stromal tumours after of and an 3 Full Text Full Text PDF PubMed Scopus Google Scholar]. with a metastatic GIST should be considered for in clinical of or There is evidence that patients have on may benefit with the et of to control metastatic or gastrointestinal stromal tumours after of and a 3 Full Text Full Text PDF PubMed Scopus Google Scholar]. there is evidence that a treatment with a in the case of disease, may progression as to it no other option is at the at in a proportion of patients with a Therefore, or of treatment progression with to which the patient has is an option [II, the other the of of of clinical should be because of the for have in in with of in only a of total is complex, and early in should be confirmed by an tumour in most patients may only in tumour on or these may tumour in tumour should be considered as the tumour an in the tumour size may be of the tumour if the tumour on is et of tomography and tomography in patients with metastatic gastrointestinal stromal at a with of tomography Clin PubMed Scopus Google Scholar]. The of lesions also be to the of Therefore, tumour size and tumour on or in or should be considered as for tumour has proven to be in early assessment of tumour and may be useful in there is or early of the is particularly useful (e.g. S. et of in gastrointestinal stromal patients with Med. PubMed Scopus Google Scholar]. However, a small proportion of GISTs have no The absence of tumour progression after of treatment is also considered as tumour M. J. et of progression as by in tumors in stromal tumors with the Clin 2009; PubMed Scopus Google Scholar]. the other tumour progression may not be by in the tumour In fact, in the tumour tumour lesions may be of tumour A progression is the the by which a of a becomes S. J. et al.Gastrointestinal stromal of after to 2005; PubMed Scopus Google Scholar]. There are no to the optimal follow-up policy of patients with occur more often to the and/or of lesions and other may be rare along the of metastatic disease with of The mitotic likely the at which assessment on the mitotic tumour size and tumour site may be useful in the follow-up patients have a from the of patients may have a this is much follow-up The optimal follow-up are not As an in patients undergo a follow-up with an abdominal or for 3 therapy (with a clinical follow-up to the to the of unless then on of therapy 3 for 2 years, then 5 from and for an 5 low-risk tumours, the of a follow-up is not if this may be carried with abdominal or for 5 low-risk GISTs not require follow-up, the risk is not is a factor to especially in low-risk GIST, with abdominal being an L. P. et of a follow-up in patients by gastrointestinal stromal J Full Text Full Text PDF PubMed Scopus Google Scholar]. have by in with the for rare in with the standard for They are to the standard approach to treatment and on and are to to the according to the of are represented by the of the and by all to the of considered to be are as may be to the patient as for a decision in of as as evidence not is the the of disease, and are to the the The relevant has by the A of is in Table of evidence and of have the in Table considered standard clinical practice by the of and ultrasound assessment and then follow-up is the standard approach for patients with oesophagogastric or duodenal nodules < 2 cm [IV, is the standard approach to tumours 2 cm in size [IV, analysis 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 of standard treatment of GISTs is surgical excision of the with no of clinically lymph excision is the to follow the of surgery surgery major and medical treatment is not the decision can be made with the patient to possible [IV, therapy with for 3 is the standard treatment of patients with a significant risk of GISTs should not be with [IV, treatment should be in and GISTs [IV, at a very high risk of peritoneal (in case of tumour at the of should be considered for therapy [IV, surgery with no major is not with is standard of is the standard treatment of and metastatic disease is also the standard treatment for patients with metastatic disease have all lesions surgery is not as a approach in the metastatic The standard of is treatment of patients with KIT is of the metastatic treatment with should be unless or patient to of metastatic disease should be individualised after the decision with the patient in the case of excision of disease should be considered for an patient with [IV, the case of tumour progression on of the can be to (with the exception of the case of confirmed progression or rare on standard treatment is at the of for 3 of is the standard therapy for patients on or to to and or of treatment progression with to which the patient has is an option [II, gastrointestinal stromal neurofibromatosis type growth factor no succinate in a Table of evidence and of from the of of the of of from at of quality for or of or with a of or of such or of with or control case of evidence for with a clinical or evidence for with a clinical evidence for or benefit does not the risk or the evidence or for not evidence or for of the of C.A. of the for cell PubMed Scopus Google Scholar]. in a GIST, gastrointestinal stromal neurofibromatosis type growth factor no succinate has for from and by has from has or from and has for and and by and has and from and and from has from and has for and has from and and and from and has for and being a of the for and from and is a of the for and has for and has by has in for and has by has and from and has from and has from and has for from and from and and from and from and has from and has with in with and has from and to clinical has by and and has and from and has with and in and is a for and has from for has being a for for the of a tumour has from and and for has from and has from and has on for and and has from has on for and and has from and has for from and has as a of for has from has or for is a of of has from and has from has from and from and from and has for and has from has and/or from and has and from and has from and for or and have no of and have not of to stromal for treatment and of Oncol PDF