Gastrointestinal stromal tumor

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Classification according to ICD-10
C15.- Malignant neoplasm of the esophagus
C16.- Malignant neoplasm of the stomach
C17.- Malignant neoplasm of the small intestine
C18.- Malignant neoplasm of the colon
C19.- Malignant neoplasm of the retroperitoneum and peritoneum
ICD-10 online (WHO version 2019)

As gastrointestinal stromal tumor (GIST) is a rare malignant connective tissue tumor ( sarcoma ) of the gastrointestinal tract (GI tract, from gr. Gaster "stomach" and lat. Intestine "gut"), respectively. Gastrointestinal stromal tumors occur most frequently in the stomach area and cause unspecific symptoms. Treatment is usually based on complete surgical removal of the tumor, which may be supplemented by drug treatment with the tyrosine kinase inhibitor imatinib . The prognosis is determined by the size, lymph node involvement , degree of metastasis and differentiation or the mitotic activity of the tumor.

frequency

The incidence of gastrointestinal stromal tumors is given in various studies with ten to 20 new cases per million population and year. Men are affected slightly more often than women. The median age of onset is 60 to 70 years. A US study showed a slightly higher probability of illness and also mortality among African Americans.

localization

Relative frequency of gastrointestinal stromal tumors in the sections of the gastrointestinal tract

The stomach is the most common site of GIST manifestation with around 60%, followed by the small intestine (30%), colon (<5%), rectum and anal canal (<5%) and esophagus (3%).

Tumors that meet the criteria of a GIST morphologically and immunohistochemically but show no relation to the walls of the gastrointestinal tract are also rarely observed. Such neoplasms are also known as extra-gastrointestinal stromal tumors (eGIST) and must be differentiated from metastatic settlements. Preferred places of manifestation of eGISTs are the mesentery , large network and retroperitoneum . Individual case reports document the occurrence of eGISTs in many other locations (including pancreas , uterus , fallopian tubes , ovaries , diaphragm , external genitals).

metastasis

GISTs metastasize primarily to the liver and within the abdominal cavity, but occasionally also form deposits in bones, skin and soft tissues. Lymph node involvement is comparatively rare and apparently mainly observed in young patients.

Cause and development of the disease

The disease entity was first described in 1983 on the basis of new immunohistochemical findings, after GISTs had previously often been classified as leiomyosarcomas , leiomyomas , leiomyoblastomas or schwannomas because of their light microscopic similarity to smooth muscle or neural neoplasms . Recent research suggests that the tumor is derived from pluripotent mesenchymal stem cells , which show properties of the interstitial Cajal cells . The latter are cells of mesenchymal origin located in the muscular wall of the gastrointestinal tract, which show features of smooth muscles as well as autonomous nerve cells and which have a pacemaker function in the context of gastrointestinal peristalsis .

A significant contribution to the delimitation of gastrointestinal stromal tumors as an independent tumor entity was the detection of mutations of the c-Kit - proto-oncogene in these tumors in 1998 .

Essential condition for the development of most gastrointestinal stromal tumors are gain-of-function (GOF) mutations that constitutively activated for forming growth factor - receptors lead to the cell surface. These usually arise somatically as a new mutation, but in rare cases also occur in the germline and are then hereditary.

They mostly affect the KIT receptor (approx. 90%), and in a minority of cases (approx. 5%) the PDGFA (platelet derived growth factor A) receptor. Normally, these receptors are only activated after binding a specific molecule ( ligand ), also called stem cell factor in the case of the KIT receptor , and then transmit a signal that promotes cell growth and proliferation . In the case of certain structural changes of these receptors caused by mutations, however, their permanent activation occurs even in the absence of a ligand, so that the balance between cell growth and proliferation on the one hand and cell death ( apoptosis ) on the other hand is shifted in the direction of the former and an abnormal cell growth and a Tumor formation results.

No known mutations are found with a small percentage of gastrointestinal stromal tumors. One speaks here of the wild type of the tumor; the mechanisms involved in tumor development remain incomprehensible in these cases.

Association with other diseases and familial forms

In a small proportion of cases, there may be a relationship with hereditary diseases.

In the rare familial GIST syndrome, constitutively activating mutations in the KIT or PDGFA genes are already present in the germline of those affected, i.e. H. also in their germ cells (sperm or egg cells) so that they can be passed on to children. In the cases observed so far, there was usually an autosomal dominant mode of inheritance, so that the offspring of an affected person also have a 50% probability of being carriers of the defective gene. Familial c-KIT mutations, in addition to an increased incidence of GISTs, apparently result in variable accompanying symptoms (increased skin pigmentation , nevi , urticaria pigmentosa ).

In the case of the rare Carney-Stratakis syndrome , which is also hereditary in an autosomal dominant manner , an association with GISTs and paragangliomas has been observed. The cause here are mutations in genes that code for subunits of succinate dehydrogenase (SDH).

In addition, an increased incidence of GISTs has been observed in patients with type 1 neurofibromatosis who have mutations in the NF1 gene.

Since in all of these hereditary forms the causal mutation is already present at birth and in all body cells, familial GIST forms manifest themselves more frequently at a young age and sometimes multicentrically. In this context, Cajal cell hyperplasias have been described as possible precursor lesions of GIST. There is also evidence that GIST patients are increasingly developing other malignant tumors at the same time (e.g. adenocarcinomas of the large intestine and stomach , lymphomas of the stomach).

In the non-hereditary Carney triad , an association of GISTs, paragangliomas and chondromas of the lungs is observed.

Symptoms

The symptoms caused by GIST are non-specific. At the time of diagnosis, about 75% of patients have symptoms. These include abdominal pain (36%), gastrointestinal bleeding (25%), deterioration in general condition (24%), indigestion (16%), iron deficiency anemia (15%), nausea and vomiting (12%) as well as constipation or diarrhea (9 %). A tumor in the abdomen can only be felt in about 8% of patients.

Diagnosis

Ultrasound image of a histologically confirmed gastrointestinal stromal tumor (GIST, 2-3) anterior to the pancreas (1). cross-section
Endoscopy: gastrointestinal stromal tumor in the stomach area.

There are currently no pioneering laboratory tests that could confirm or rule out the diagnosis of GIST. According to the current state of knowledge, the tumor does not form any factors that can be detected in the blood and used for early diagnosis as part of a screening .

The majority of GISTs are accessible to an endoscopic examination ( esophagogastroduodenoscopy , colonoscopy ), whereby a biopsy can be taken if necessary .

Imaging methods such as sonography , conventional X-rays after administration of contrast media, computed tomography and magnetic resonance tomography make a significant contribution to tumor diagnosis and determination of tumor spread . The positron emission tomography (PET) using 18 F-2-fluoro-2-deoxy-D-glucose is especially suitable for the detection of metastases .

The actual diagnosis is made through a histological examination of the surgical specimen or a biopsy by a pathologist. Immunohistochemical examinations (c-kit (CD117), CD34, DOG1) are of great importance here, as only they allow the differentiation of some morphologically very similar differential diagnoses with sufficient certainty.

Differential diagnosis

When making a diagnosis, a number of other benign (e.g. leiomyoma , lipoma , schwannoma ) and malignant tumors (e.g. leiomyosarcoma , adenocarcinoma , lymphoma , neuroendocrine tumors ) as well as non-neoplastic lesions of the gastrointestinal tract such as one should be considered arteriovenous malformation or ectopic pancreatic tissue .

pathology

Histological picture of a GIST
Immunohistochemical staining for c-Kit (CD117)

Macroscopically, GISTs appear as gray-white, solidified to pithy soft, spherical or slightly lobed tumors with a size of 0.5–40 cm. The mean tumor size in symptomatic patients at the time of diagnosis is approximately 6.0 cm. Typically, the tumor is found in the wall of a gastrointestinal hollow organ, below the mucous membrane ( submucosal ) and protruding it. The mucous membrane covering often appears intact, but it can also be broken up like an ulcer. Necrosis and bleeding within the tumor mass occur as well as sometimes pronounced cystic changes.

Histologically , GISTs show either a purely spindle-cell (69%), epitheloid (12%) or mixed spindle-cell / epitheloid (20%) picture. Immunohistochemically, the vast majority of GISTs express the markers c-Kit (CD117; 87%) and PDGFA (66%). Smooth muscle markers can also be detected in 30–80% of cases; however, the most reliable of these, desmin , is only expressed by a minority of GISTs. CD 34 positivity can be demonstrated up to 70% of the time.

classification

With the 7th edition of the TNM classification of malignant tumors (valid from January 2010), standardized criteria for clinical and pathological tumor classification of the GIST are now available for the first time:

T (primary tumor)

TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
T1 Tumor 2 cm or less in greatest extent
T2 Tumor more than 2 cm, but not more than 5 cm in its greatest extent
T3 Tumor more than 5 cm, but not more than 10 cm in its greatest dimension
T4 Tumor more than 10 cm in greatest extent

N (regional lymph nodes)

NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastases
N1 Regional lymph node metastases

M (distant metastases)

M0 No distant metastases
M1 Distant metastases

treatment

Treatment is usually based on the complete surgical removal of the tumor, which can also be carried out minimally invasively ( laparoscopically ) in the case of smaller tumors . Since GISTs rarely develop lymph node metastases, routine removal of the regional lymph nodes is not necessary according to common doctrine.

A major advance in the treatment of GIST was the introduction of the tyrosine kinase inhibitor Imatinib (Glivec®), a drug to be administered in tablet form for which response rates of over 50% have been proven in studies. Because of its systemic (whole-body) effectiveness, it is suitable for treating GISTs that have already metastasized. In addition, the adjuvant and neoadjuvant use of this substance is being tested. For tumors that do not respond adequately or not at all to this therapy, treatment with the multikinase inhibitor sunitinib (Sutent®) can be attempted. In addition to a possible primary (already existing at the start of treatment), the development of a secondary (developing during therapy) resistance of the tumor cells to the action of the kinase inhibitors is problematic. A possible cause for this is the development of secondary mutations in the KIT gene or a rhabdomyosarcomatous degeneration. In the case of resistance to imatinib and sunitinib, treatment with the tyrosine kinase inhibitor regorafenib (Stivarga®) can be attempted. The use of other substances, some of which have already been approved for other indications, such as sorafenib (Nexavar®), nilotinib (Tasigna®) or dasatinib (Sprycel®), is currently being tested .

Conventional cytotoxic chemotherapy with substances such as doxorubicin , ifosfamide , dacarbazine or temozolomide showed disappointing results with regard to the rate of tumor shrinkage in studies carried out before the introduction of imatinib. Scientific studies on the chemotherapy of GIST, which were treated after therapy with Imatinib and Sunitinib, are not yet available, but longer disease stabilization through classical chemotherapy is possible in this situation. GISTs also prove to be largely resistant to radiation therapy , which is therefore mainly used with a palliative objective, for example when a surgical procedure is not possible.

forecast

Gastrointestinal stromal tumors - especially those less than 2 cm in size and slowly growing (which represent the vast majority) - generally have a good prognosis. The surgery, which is now often performed laparoscopically, can usually be cured in the above-mentioned cases. This looks different with metastatic tumors. According to various studies, the disease-specific 5-year survival rate in patients with metastatic GISTs is between 30 and 60%, with large differences between localized tumors (median survival time of 5 years) on the one hand and metastatic or recurrent tumors on the other (median survival time of 10– 20 months). Correspondingly, tumors that cannot or cannot be completely removed for operational reasons have a poor prognosis. A tumor rupture (spontaneous or as part of the operation) also worsens the chances of healing because of the possibility of tumor seeding within the abdominal cavity. The same danger arises when the tumor grows onto the peritoneal covering ( serosa ) of the affected gastrointestinal hollow organ and breaks through it.

Important factors in estimating the prognosis that have also been validated in larger studies are, in particular, the size of the tumor and the rate at which the tumor cells divide ( mitotic activity ). The latter is determined by the examining pathologist by using the microscope to determine the number of mitotic figures in 50 visual fields at high magnification ("high power fields", HPF). From these parameters, a classification scheme was developed according to which tumors with a very low, low, intermediate and high risk of aggressive biological behavior ( relapse , metastasis ) can be distinguished:

risk Tumor size Mitotic activity
very low <2 cm <5/50 HPF
low 2-5 cm <5/50 HPF
intermediate <5 cm 6-10 / 50 HPF
5-10 cm <5/50 HPF
high > 5 cm > 5/50 HPF
> 10 cm any mitotic activity

The location of the tumor also seems to have an impact on the prognosis. GISTs of the stomach show a better prognosis than those of other locations. A scheme that takes this into account and is based on data from the follow-up of more than 1900 GIST patients divides the patient collective into 8 prognosis groups:

parameter % Proportion of patients with progressive disease / risk of
metastasis
group Tumor size
[cm]		 Mitoses
[50 HPF]		 stomach Duodenum Jejunum,
ileum		 rectum
1 ≤ 2 ≤ 5 0%
none		 0%
none		 0%
none		 0%
none
2 > 2 ≤ 5 ≤ 5 1.9%
very low		 8.3%
low		 4.3%
low		 8.5%
low
3a > 5 ≤ 10 ≤ 5 3.6%
low		 34%
high		 24%
moderate		 57%
high
3b > 10 ≤ 5 12%
moderate		 34%
high		 52%
high		 57%
high
4th ≤ 2 > 5 0% ? 50% 54%
5 > 2 ≤ 5 > 5 16%
moderate		 50%
high		 73%
high		 52%
high
6a > 5 ≤ 10 > 5 55%
high		 86%
high		 85%
high		 71%
high
6b > 10 > 5 86%
high		 86%
high		 90%
high		 71%
high

In the literature, unfavorable prognostic factors assessed differently with regard to their diagnostic significance and practicability are a high cell density within the tumor (cellularity), an epitheloid cell or mixed epitheloid cell / spindle cell histology and cell and nuclear atypia of the tumor cells.

Genetic Predictive Factors

According to various studies, specific mutations are independent prognostic factors. For example, patients in whom a certain section of the KIT gene is changed (mutation of exon 9) show, on average, a less favorable course of the disease than patients with other mutations (often mutation of exon 11). If there are no detectable mutations (genetic wild type of GIST), this is associated with a particularly poor prognosis.

Individual evidence

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