Portrait of a multifaceted disease

With the introduction of the new active ingredient avapritinib for the targeted treatment of gastrointestinal stromal tumors into the German market, this clinical picture is once again coming more into focus. In the course of the last years, correct and differentiated diagnostics, in particular also genetic diagnostics, have brought to light some new findings that are also of therapeutic relevance in the era of targeted therapies.

Gastrointestinal stromal tumors (GISTs) are the most common neoplasms of non-epithelial origin in the digestive tract and usually occur subepithelially in the stomach or upper small intestine. They sometimes affect other parts of the gastrointestinal tract, the omentum, mesentery or peritoneum [1,2]. With a cumulative proportion of 1%, mesenchymal tumors represent only a small subgroup of all primary gastrointestinal cancers, but in Switzerland about 120 new GIST diagnoses are made annually – and unfortunately often only in advanced, already metastasized stages [2,3]. As people age, their risk of developing GIST also increases. On average, affected individuals are 64 years old when the tumor is discovered. In addition, men are affected slightly more often than women, and black skin color is also considered a risk factor [4]. While clinical diagnoses are comparatively rare, with an incidence of 7-15 per million population annually, precursors of malignant disease appear to be common [4,5]. For example, autopsy studies found small GISTs in about one-third of the stomachs studied. This suggests that probably only a few tumors reach a clinically relevant size and develop malignant potential [6].

Characteristic genetics

In the diagnosis and therapy of gastrointestinal stromal tumors, much has been achieved in recent years and decades, thanks in particular to the discovery of characteristic molecular alterations. The genetic profile is remarkably constant within the clinically heterogeneous disease. For example, approximately 82% of tumors have activating mutations in the KIT gene and 8% have alterations in the platelet-derived growth factor receptor alpha (PDGFRA) gene. Both encode receptor tyrosine kinases. Approximately 10% of cases are so-called wild-type GISTs without classic KIT or PDGFRA mutation[3]. These are particularly common in younger patients and those with a family history [7]. The majority of the clinical picture arises from spontaneous mutations; only 5% of gastrointestinal stromal tumors form in the context of autosomal dominant inherited syndromes such as familial GIST syndrome, neurofibromatosis type 1, and Carney-Stratakis syndrome [7].

Even in the absence of a KIT mutation, there is often overexpression of KIT receptor tyrosine kinase, which can be detected by immunohistochemistry and potentially plays an important role in tumorigenesis [2]. Only about 5% of all GISTs are KIT negative by immunohistochemistry [7]. Contrary to the earlier assumption that GISTs arise from smooth muscle cells, they are a proliferation of the so-called Cajal cells. These are also known as “intestinal pacemaker cells” and are involved in transmitting signals from the autonomic nervous system to the smooth muscle of the digestive tract [8].

The diagnosis often comes (too) late

The typically asymptomatic course means that many GISTs are not recognized and treated until they reach an advanced stage [3]. Depending on the tumor size and location, affected individuals sometimes suffer from bloating, pain, indigestion or bleeding. However, incidental detection during endoscopic or imaging examinations often precedes definite symptoms.

CT with intravenous as well as oral contrast administration is recommended for initial diagnosis and staging [7]. This serves to characterize the tumor more precisely and to search for possible metastases, which are most frequently found in the liver, peritoneally or omentally. In rare cases, regional lymph nodes or the lungs are also involved [7]. Depending on individual conditions, MRI is used as an alternative or as a supplement. In unclear situations, endoscopic examination may also be helpful, but it is not possible to differentiate between GIST and leiomyoma, as both appear as submucosal masses [7]. Also, no reliable statement can be made as to whether the tumor mass is intra- or extramural. By means of endoscopic ultrasound, on the other hand, the correct identification of the source tissue is possible and the taking of a biopsy can be significantly simplified [7].

After the initial imaging, it is crucial for further clarification whether the found mass exceeds the size of 2 cm [7,9]. Since small foci are usually low-risk tumors of unclear clinical significance and the risk they pose does not justify the often difficult biopsy procedure, endosonographic follow-up is sufficient [9]. Although there are no clear guidelines for the optimal follow-up, a timely first control after about three months is considered useful by the European Society of Medical Oncology (ESMO). The interval may subsequently be prolonged in the case of size-stationary space-occupying lesions [9]. Rectal GISTs less than 2 cm are an exception. These have a significantly worse prognosis and should be removed regardless of their size [9].

Because the risk of progression of GISTs larger than 2 cm is comparatively greater, they should be biopsied or, where easily possible, removed altogether. The differentiated pathological diagnosis allows a better prognosis assessment as well as the choice of the optimal therapy for non-resectable or metastatic tumors. In particular, immunohistochemical evidence of KIT and DOG1 overexpression is of great importance. Genetic tumor analysis can not only help in unclear cases, i.e. KIT/DOG1-negative GISTs, but is also gaining therapeutic importance with the increasing use of various targeted agents and is now part of the diagnostic standard [9]. Furthermore, in accordance with the rapid development of oncologic therapies, tissue preservation should be considered [9].

Stage appropriate therapy

The therapy of GISTs depends on their stage. Thus, in localized disease, complete resection, if possible, is recommended. Rupture of the tumor should be avoided at all costs, as this very often leads to recurrences [9]. If complete resection is not possible, downstaging can be targeted with neoadjuvant imatinib administration. In all cases with a high risk of recurrence, adjuvant imatinib therapy should also be administered for three years in the presence of an imatinib-sensitive mutation [9].

The tyrosine kinase inhibitor (TKI) imatinib also has an important role to play in the treatment of metastatic GISTs. This was previously used in all advanced GISTs due to lack of alternatives, even if the tumor did not have an imatinib-sensitive mutation. Sunitinib and regorafenib were then used in further lines of therapy, as well as experimental approaches in clinical trials [9]. Avapritinib is a new TKI that has already been approved in Germany for the treatment of gastrointestinal stromal tumors with the generally imatinib-resistant (PDGFRA)-D842V mutation [9,10]. If there is a good response to TKI treatment, it should be continued until progression occurs, as discontinuation is often followed by rapid disease progression [11]. Resection during the course is possible [9].

Regardless of stage, gastrointestinal stromal tumors should be treated at a center with adequate experience in the field. The ongoing development of new targeted agents also holds great potential for the treatment of GIST sufferers, even if it makes diagnostics increasingly complex.

Uncertain forecast

It is extremely difficult to predict the clinical behavior of GISTs. Tumor size, location, and histologic mitotic count are clues that are incorporated into appropriate prognostic models [9]. For example, medium-sized tumors of the small intestine and those of the rectum appear to be prognostically less favorable than those of the stomach. In principle, however, every GIST has malignant potential and thus even small tumors should not be underestimated [1]. Purely on the basis of the mutation status, no statements can be made regarding the prognosis; this mainly influences the response to various therapeutic options [7]. Overall, 5-year overall survival in GIST is approximately 65%, ranging from 41 to 77% depending on stage [4].

With extremely heterogeneous courses and limited data, the clinical picture of gastrointestinal stromal tumors still poses great challenges to practitioners and researchers today. While genetic diagnostics are already well established, implications for treatment need further investigation. Effective agents for the treatment of advanced-stage tumors that do not respond to imatinib are also lacking. With the approval of avapritinib, which may soon also be granted in Switzerland, a first step has been taken here, which will hopefully be followed by others in the near future.

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