Gastrointestinal stromal tumors

Previously, stromal tumors were thought to be smooth muscle neoplasms. After the discovery of the gain-of-function mutation in the c- KIT Ptoto oncogene by Hirota (Werner 2020) in 1998, a GIST could be reliably distinguished from other histopathological subtypes of mesenchymal tumors.

The term "gastrointestinal stromal tumors" was coined by Mazur et al (Rammohan 2013).

In 2000, the first patient who had metastatic GIST was treated with imatinib. A remarkable response was seen (van der Zwan 2005).

Gastrointestinal stromal tumor (GIST) is a distinct entity within soft tissue sarcomas (Kasper 2015). GIST are potentially malignant (Hohenberger 2021) mesenchymal tumors of the gastrointestinal tract that develop from an intestinal Cajal cell or its precursor (Herold 2022).

GISTs can vary in size, from a few millimeters to 30 cm. The average size is between 5 - 8 cm (Rammohan 2013).

The usual TNM- classification for malignant tumors has no clinical added value for GIST (Hohenberger 2021).

The risk for metastases and tumor-associated deaths can be determined using the modified table according to Miettinen and Lasota:

• Group 1:
  • Mitotic count ≤ 5 / 50 HPFs.
  • Tumor diameter ≤ 2 cm
  • gastric GIST none (0)
  • jujunal and ileal GIST none (0)
  • duodenal GIST none (0)
  • rectal GIST none (0)
• Group 2:
  • Mitotic count ≤ 5 / 50 HPFs.
  • Tumor diameter > 2 cm ≤ 5 cm
  • gastric GIST very low (1.9%)
  • jujunal and ileal GIST low (4.3 %)
  • duodenal GIST low (8.3 %)
  • rectal GIST low (8.5 %)
• Group 3 a:
  • mitotic count ≤ 5 / 50 HPFs
  • Tumor diameter > 5 cm ≤ 10 cm
  • gastric GIST low (3.6 %)
  • jujunal and ileal GIST medium (24 %)
  • duodenal GIST no data
  • rectal GIST no data
• Group 3 b:
  • mitotic count ≤ 5 / 50 HPFs
  • tumor diameter > 10 cm
  • gastric GIST medium (12 %)
  • jujunal and ileal GIST high (52 %)
  • duodenal GIST high (34 %)
  • rectal GIST high (57 %)
• Group 4:
  • mitotic count ≥ 5 / 50 HPFs
  • Tumor diameter ≤ 2 cm
  • gastric GIST 0 (very low number of cases)
  • jujunal and ileal GIST 50 % (very low number of cases)
  • duodenal GIST no data
  • rectal GIST high (54 %)
• Group 5:
  • mitotic count ≥ 5 / 50 HPFs
  • tumor diameter > 2 cm ≤ 5 cm
  • gastric GIST medium (16 %)
  • jujunal and ileal GIST high (73 %)
  • duodenal GIST high (50 %)
  • rectal GIST high (52 %)
• Group 6 a:
  • mitotic count ≥ 5 / 50 HPFs
  • Tumor diameter > 5 cm ≤ 10 cm
  • gastric GIST high (55 %)
  • jujunal and ileal GIST high (85 %)
  • duodenal GIST no data
  • rectal GIST no data
• Group 6 b:
  • mitotic count ≥ 5 / 50 HPFs
  • tumor diameter > 10 cm
  • gastric GIST high (86 %)
  • jujunal and ileal GIST high (90 %)
  • duodenal GIST high (86 %)
  • rectal GIST high (71 %)

(Hohenberger 2021)

The risk in terms of prognosis can be assessed using the modified Fletcher classification:

• Very low risk:
  • Tumor size < 2.0 cm, mitotic index ≤ 5, localization of primary tumor: anywhere.
• Low risk:
  • tumor size 2.1 - 5.0 cm, mitotic index ≤ 5, localization of primary tumor: anywhere
• Medium risk:
  • tumor size 2.1 - 5.0 cm, mitotic index > 5, localization of primary tumor: stomach
  • tumor size < 5.0 cm, mitotic index 6 - 10, localization of primary tumor: anywhere
  • tumor size 5.1 - 10.0 cm, mitotic index ≤ 5, localization of primary tumor: stomach
• High risk:
  • Tumor size: all sizes, mitotic index: all indices, tumor rupture.
  • tumor size >10.0 cm, mitotic index all indices, localization of primary tumor: anywhere
  • tumor size: all sizes, mitotic index > 10, localization of primary tumor: anywhere
  • tumor size > 5.0 cm, mitotic index > 5, localization of primary tumor: anywhere
  • tumor size 2.1 - 5.0 cm, mitotic index > 5, localization of primary tumor: not in stomach
  • Tumor size 5.1 - 10.0 cm, mitotic index < 5, localization of primary tumor: not in stomach (Akahoshi 2018).

GIST are among the rarely occurring tumors of the gastrointestinal tract (Hübner 2018). The incidence of GIST is 1: 100,000 (Herold 2022). Nevertheless, they are the most common mesenchymal neoplasms of the gastrointestinal tract (Rammohan 2013). Males are affected slightly more often than females (van der Zwan 2005), 8.3 cases per 1 million versus 5.7 cases per 1 million (Hübner 2018).

Among malignant tumors of the small intestine, GIST occurs with a frequency of up to 13% (Zeuß 2016).

The cause of GIST is unknown. Very rarely, it occurs in families (Herold 2022). The mode of inheritance is then autosomal dominant (Rammohan 2013).

However, it is often found (in up to 5% [Rammohan 2013]) in patients with neurofibromatosis type 1 (Herold 2022). Here, it mostly occurs in the small intestine without KIT mutation (Rammohan 2013).

It also occurs as part of the Carney triad in young women together with pulmonary chondromas and paragangliomas (Rammohan 2013) and in Carney- Stratakis syndrome also together with pulmonary chondromas and paragangliomas (Hübner 2018 / Lehnert 2015).

KIT protein is expressed by Cajal cells, mast cells, germ cells and hematopoietic cells. KIT is involved in cell growth, differentiation and survival. Binding of KIT ligand induces autophosphorylation and dimerization. These in turn trigger a cascade of intracellular signals involved in tumorigenesis (van der Zwan 2005).

Pathogenetically, we find:

- in approx. 90 % an activating mutation in tyrosine kinase receptor c-kit (CD 117)

- in approx. 60 % of them in KIT exon 11

- in approx. 5 % a mutation of the PDGFR- alpha- gene (receptor for platelet-derived growth factor alpha [Kasper 2015])

- the rest is a so-called wild type without mutation (Herold 2022).

The age of onset is between 50 - 70 years of age (Herold 2022).

GIST can develop from the esophagus to the rectum throughout the gastrointestinal tract (Rammohan 2013).

There are:

- 10 % in the esophagus (Rammohan 2013)

- 50 % in the stomach

- 25 % in the small intestine

- 10 % in the colon (Herold 2022).

Metastasis is hematogenous to liver, peritoneum and in rare cases extra-abdominal. Metastasis is already found in 50% of patients at diagnosis (Herold 2022).

In about 2 / 3 of the patients the following symptoms occur:

• Bleeding (the most common symptom at 30-40% [Rammohan 2013]).
  • gastrointestinal as hematemesis or melena (due to erosions into the GIT- lumen)
  • intra-abdominal due to ruptured GIST
• Symptoms of obstruction (such as dysphagia, bile duct obstruction, small bowel intussusception [Rammohan 2013]).
• Perforation (Herold 2022).

Accidentally discovered in approximately 20% of all GISTs and an additional 10% at autopsy (Rammohan 2013).

Diagnostics include imaging (see d.), biopsy, and mutation analysis (Herold 2022). The biopsy should not be taken percutaneously preoperatively because of the significant risk of rupture of the tumor and the additional risk of dissemination (Rammohan 2013).

Imaging should include endoscopic sonography, contrast CT or MRI. In unclear cases, PET- CT is recommended (Herold 2022).

Endoscopic sonography

Endoscopic sonography can be used to assess the depth of invasion. In addition, tissue samples can be obtained this way (Rammohan 2013).

Contrast CT or MRI.

On contrast CT, tumors present as a well-demarcated soft tissue mass with heterogeneous enhancement (Rammohan 2013).

Response to therapy is also assessed by contrast CT scan. The CHOI- criteria or the RECIST (Response Evaluation Criteria in Solid Tumors) serve as measures.

The CHOI- criteria have been shown to be superior in assessing for response with tyrosine kinase inhibitors (TKIs) (Rammohan 2013).

RECIST- criteria:

- Complete response: disappearance of all lesions.

- Partial response: reduction of the longest diameters by 30%.

- Progressive disease: increase in longest diameters by 20%.

- Stable evolution: neither partial response nor progressive disease criteria are present (Rammohan 2013).

CHOI- criteria:

- Signs of response to therapy: 10% decrease in tumor size and 15% decrease in tumor density (Rammohan 2013).

PET

PET can detect minute metastases that may not be detectable on CT / MRI. Differentiation between active tumor tissue and scar or necrotic tissue is also possible in this way.

Routine PET examination of the postoperative course of the disease is currently not recommended (Rammohan 2013).

Laboratory chemistry reveals anemia at most; otherwise, the laboratory values are usually unremarkable (Herold 2022).

A biopsy is not mandatory in cases of high-grade GIST with primary resectability without organ loss. According to the guideline, a biopsy is recommended depending on the localization from a tumor size of approximately 3 cm (Hohenberger 2021).

- Histological processing of the biopsy

- Immunohistochemistry: Here, KIT (CD 117) is found positive in approx. 90%.

- Determination of the mutation number per HPF

- Mutation analysis: This is used to plan a drug therapy (imatinib resistance is found in approx. 10 %).

(Herold 2022)

Three microscopic morphologies are found in GIST:

- spindle cell type (70 %)

- epithelioid type (20 %)

- mixed type (10 %)

(van der Zwan 2005 / Akahoshi 2018)

- Leiomyomas

- Leiomyosarcomas

Differentiation is possible by immunocytological examination (Schubert 2016).

- Perforation of the GIST

- Metastases to peritoneum, mesentery, omentum, liver (Rammohan 2013).

Patients who already have metastatic GIST and do not have a drug-sensitive mutation in the KIT or PDGFRA gene should be treated at a GIST-experienced center (Hohenberger 2021).

GIST usually do not respond to radiotherapy. However, there are single case reports in which palliative radiotherapy together with a tyrosine kinase inhibitor were effective (Werner 2020).

For gastrointestinal stromal tumors, treatment with imatinib (Herold 2022), trade name Gleevec (van der Zwan 2005), is recommended. This is a tyrosine kinase inhibitor (Gnant 2008).

Neoadjuvant therapy:

Tumor response by neoadjuvant therapy can be demonstrated by PET as early as 48 h with a significant reduction in tumor metabolism. Tumor regression is visible on CT after approximately 2 - 3 months. Neoadjuvant treatment should be continued until tumor remission can no longer be achieved(Hohenberger 2021).

Dosage recommendation: imatinib 400 mg / d (Rammohan 2013).

Adjuvant Therapy:

Treatment with imatinib can be equally adjuvant - depending on the classification of risk in the case of e.g. large tumor, tumor localization, high mitotic rate. This can prolong both recurrence-free and overall survival (Herold 2022).

Adjuvant therapy with imatinib should be given for at least a 3-year period.

Dosage recommendation imatinib in adjuvant: 400 mg / d (Werner 2020).

At diagnosis, metastasis is already present in approximately 50% of patients with GIST. If the tumor is already inoperable, immediate treatment with tyrosine kinase inhibitors is recommended (Herold 2022).

Dosage recommendation: Imatinib 400 mg / d

It has been shown in studies that approximately 80% with metastatic GIST respond to treatment (van der Zwan 2005).

If progression occurs, the dose can be increased or switched to another TKI such as sunitinib (dosing recommendation: 50 mg / d each for 4 weeks, then 2 weeks off therapy [Hohenberger2021]).

If the treatment with sunitinib also does not respond, should be switched to regorafenib (dosage recommendation: 160 mg / d each for 3 weeks, then 1 week break [Hohenberger 2021]).

[Herold 2022)

If a KIT exon 9 mutation exists, a dose increase to 2 x 400 mg imatinib / d is recommended (Herold 2022), as significantly better progression-free survival and a significantly higher remission rate have been shown under this dosage (Hohenberger 2021).

Patients with a PDGFRA- D842V mutation do not respond to imatinib and sunitinib. Only dasatinib has been shown to have some efficacy in a small cohort of patients (n = 50) (Werner 2020).

In patients who do not yet show metastasis, primary surgery should be performed with the goal of R0 resection, possibly with along with neoadjuvant chemotherapy (see "Internal Therapy").

(Herold 2022)

During surgery, rupture of the tumor must be avoided at all costs. Complete resection is possible in approximately 85% of patients (Rammohan 2013). GIST should always be resected with a safety margin (Werner 2020).

Systematic lymphadenectomy is usually not necessary because of the low frequency of lymph node metastases. The only exception is patients with SDH-deficient GIST and clinical v. a. lymph node involvement (Hohenberger 2021).

For GIST that can be removed exclusively by organ resection, a response to imatinib should be verified preoperatively. In most cases, pretreatment with imatinib for 6-12 months reduces the size of the tumor to such an extent that a significantly reduced extent of surgery is required (Hohenberger 2021).

Cure can only be expected in small, completely resected GIST (Herold 2022). Nevertheless, recurrence or metastasis occurs in approximately 50% of patients after complete resection (Rammohan 2013).

Predictors at progression are:

- tumor size

- mitotic rate

- Tumor location:

GIST localized in the stomach, for example, have a better prognosis than small bowel GIST (van der Zwan 2005).

In advanced GIST, the median survival time is strongly dependent on:

- the molecular mutation analysis

- The response to drug therapy (Herold 2022).

The 5-year recurrence-free survival rate after surgery is approximately 59.9% (Akahoshi 2018).

Median survival of patients with advanced GIST have a 9-year survival rate of 35-49% with imatinib therapy (Rammohan 2013).

Follow-up

The goal of follow-up is early detection of local recurrence, peritoneal dissemination, and any liver metastases. A contrast CT should therefore be performed from the diaphragm to the inguinal region (Akahoshi 2018). A follow-up period of more than 10 years is recommended (Akahoshi 2018).

During the first 3 - 5 years, most recurrences occur. From there, intensive follow-up is required during this period (Rammohan 2013).

According to the Japanese clinical practice guideline for GIST by Nishida (2008), the recommended intervals for follow-up are as follows:

- GIST with very low and moderate risk should be followed up by CT every 6 - 12 months

- GIST with high risk or with metastases, peritoneal dissemination, infiltration of other organs, or injury to the pseudocapsule by CT every 4 - 6 months (Akahoshi 2018).

Werner (2020) recommends CT as the standard imaging modality:

- in patients with very low risk and R0 resection

- regular follow-up is not required

- for patients in the low-risk group with R0 resection

- every 6 months for a total of 5 years

- in patients of the medium- and high-risk group:

- until year 5 of disease follow-up every 3 months

- year 6 - 8: every 6 months

- year 9 - 13: 1 x yearly

1. Akahoshi K, Oya M, Shiratsuchi Y (2018) Current clinical management of gastrointestinal stromal tumor. World J Gastroenterol. 24 (26) 2806 - 2817
2. Gnant M, Schlag P M (2008) Chrirugic oncology: stargies and standards for practice. Springer Verlag Vienna / New York 290, 293
3. Herold G et al (2022) Internal medicine. Herold Publishers 478
4. Hohenberger P, Kasper B, Grünwald V (2021) Guideline program oncology: S3- guideline adult soft tissue sarcomas. AWMF- registration number: 032 / 04OL
5. Hübner J, Bruns J, Heinemann V (2018) German cancer society: gastrointestinal tumors. Elsevier Urban and Fischer Publishers 487
6. Kasper D L et al (2015) Harrison's Principles of Internal Medicine. Mc Graw Hill Education 102e - 3, 119e - 1, 119e - 2.
7. Lehnert (2015) Rational diagnostics and therapy in endocrinology, diabetology and metabolism. Georg Thieme Verlag Stuttgart 243
8. Nishida T, Hirota S, Yanagisawa A, Sugino Y, Minami M, Yamamura Y, Otani Y, Shimada Y, Takahashi F, Kubota T (2008) GIST guideline subcommittee: clinical practice guidelines for gastrointestinal stromal tumor (GIST) in Japan. Int J Clin Oncol. (13) 416 - 430
9. Rammohan A, Sathyanesan J, Rajendran K, Pitchaimuthu A, Perumal S K, Srinivasan U P, Ramasamy R, Palaniappan R, Govindan M (2013) A gist of gastrointestinal stromal tumors: A review. World J Gastrointest Oncol. 5 (6) 102 - 112.
10. Schubert J, Jenssen C (2016) Gastroenterological cytopathology. Walter de Gruyter Publishers Berlin / Boston 132 - 137.
11. Werner J (2020) Manual Gastrointestinal tumors: recommendations for diagnosis, therapy and follow-up. W. Zuckschwerth Verlag Munich 441 - 450
12. Zeuß D, Marth T (2016) DGIM Innere Medizin: Tumors of the small intestine. ePedia Springer Medizin.
13. van der Zwan S M, DeMatteo R P (2005) Gastrointetinal stromal tumor: 5 years later. In: Wiley Cancer: List of Issues - Wiley Online Library (104 (9) 1781 - 1788.