A 36-year-old male applied for life insurance. Three years prior to application, he had a history of a gastrointestinal bleed resulting in a Hemoglobin of 5.3 g/dl (53 g/L). A work-up found a 5.3-cm ulcer and gastrointestinal stromal tumor in the gastric antrum. The tumor was resected without any neoadjuvant or adjuvant therapy. The pathology report demonstrated a 2-cm tumor with a mitotic count <5 mitoses per 50 HPFs (high powered fields) and one lymph node negative for tumor. The gastric ulcer was benign, with good response to treatment. The rest of the work-up was negative for invasive or metastatic disease.
What is GIST and what are the mortality implications?
The gastrointestinal stromal tumor arises from the subepithelial stromal or mesenchymal layer of the Gastrointestinal (GI) tract. GISTs were originally classified as another type of tumor: leiomyoma, leiomyoblastoma, leiomyosarcoma or schwannoma. But, in 1998 the discovery of gain-of-function mutations in the c-kit proto-oncogene in GISTs allowed them to be distinguished reliably from other histopathological subtypes of GI mesenchymal tumors. They are now described as a distinct clinical and histopathological entity: a soft tissue sarcoma arising in mesenchymal tissues.
The cause of most GIST lesions is unknown. Some families have GISTs caused by a DNA mutation passed down from parent to offspring, but most DNA mutations in GISTs are sporadic or acquired and not inherited.
Most patients with GIST have a mutation in an oncogene called c-kit. The c-kit gene is found in all cells of the body. It directs the cell to make a protein called KIT, which causes the cell to grow and divide. Usually the c-kit gene in interstitial cells of Cajal (ICCs) is inactive. In most GISTs, the c-kit gene is mutated and is always active resulting in an overexpression of KIT, which may explain why the cancer forms. A small percentage of GISTs will have overexpression of KIT without an identifiable c-kit mutation, and the molecular basis remains undefined.
In about 5% to 10% of GISTs, the cancer cells have a mutation in a different gene called PDGFRA (platelet derived growth factor receptor alpha). These PDGFRA positive GISTs lack overexpression of KIT. And still another subset have oncogenic mutations downstream from KIT functioning, and are often called wild-type tumors. Several of the heritable genetic syndromes linked to GIST are wild-type tumors:
- The Carney triad syndrome, comprising gastric GIST, paraganglioma and pulmonary chondroma
- Carney–Stratakis syndrome
- Type-1 neurofibromatosis
Sarcomas are uncommon cancers, affecting approximately 50 people per million population annually in the United States. Of these, GIST is among the most common, affecting 10 to 15 people per million per year, but accounts for less than 1% of all gastrointestinal tumors.
While most GISTs occur in the stomach (60-70%) and the small intestine (20-30%), they can occur in any part of the GI tract and have even been found in the mesentery, the omentum and the peritoneum.
The median age at diagnosis is around 60–65 years, with a wide range. Occurrence in children, adolescents and younger patients is very rare, although pediatric GISTs represent a distinct subset, marked by female predominance, absence of KIT/PDGFRA mutations, usually gastric origin, often multifocal, and often with lymph node metastases.
Up to 75% of GISTs are discovered when they are less than 4 cm in diameter and are either asymptomatic or associated with nonspecific symptoms. They are frequently diagnosed incidentally during radiologic studies, endoscopy or surgical procedures performed to investigate GI tract disease or to treat an emergent condition such as hemorrhage, obstruction, or perforated viscus.
Clinical manifestations of GISTs are as follows:
- Vague, nonspecific abdominal pain or discomfort
- Early satiety or a sensation of abdominal fullness
- Anorexia, weight loss, nausea, anemia, and nonspecific GI
The following tests are typically ordered in the work-up:
CT scanning – for initial evaluation and surveillance of recurrence.
EUS (Endoscopic ultrasonography) – determines size and extent of the tumor.
FDG-PET scanning – highlights metastases, establishes baseline metabolic activity, and assesses response to treatment.
Immunohistochemistry – Availability of KIT immunohistochemistry made the diagnosis easier, but does not identify all GISTs. West et al. and Espinoza et al. identified DOG1 which has been found in 97% of GIST making it more sensitive than KIT.
It is widely accepted that the terms benign or malignant are not applicable to GIST as all are potentially malignant. Instead, tumor size, mitotic rate, and presence of metastases determine prognosis.
Figure 1 – FDG-PET scanning
Outcomes in patients with GISTs are highly dependent on the clinical presentation and the histopathological features of the tumor.
Most GISTs remain ‘silent’ until reaching a large size. Symptoms vary according to location and size.
Larger GISTs are associated with complications such as GI hemorrhage, GI obstruction, and bowel perforation.
Aggressive GISTs have a defined pattern of metastasis to the liver and throughout the abdomen or both. Lymph node metastasis is not common. Spreading to the lung and bone in advanced cases has been reported. Metastasis often occurs 10-15 years after initial surgery.
Small esophago-gastric lesions, less than 2 cm in size when diagnosed as GIST, are considered low risk. There is no consensus, but the National Comprehensive Cancer Network suggests an endoscopic ultrasound assessment, usually with fine needle aspiration or core needle biopsy, then annual follow-up. Excision is reserved for lesions that increase in size or become symptomatic.
Standard treatment of localized GISTs > 2 cm in size is complete surgical excision of the lesion, without dissection of clinically negative lymph nodes. A laparoscopic approach is discouraged in patients with large tumors, because of the risk of tumor rupture, which is associated with a very high risk of relapse.
The presence of a KIT mutation in more than 75% of GISTs was the seminal finding to define a specific sarcoma subtype based on activation of a specific receptor tyrosine kinase. This led to therapy with tyrosine kinase inhibitors, such as imatinib.
Tyrosine kinase inhibitors are now standard treatment in metastatic GIST. Patients with intermediate or high risk of recurrent GIST, should also be strongly considered for adjuvant treatment with imatinib.
The risk of relapse following surgery can be substantial, as defined by available risk classifications.
Adjuvant treatment with imatinib for 3 years was associated with improved relapse-free and overall survival compared with 1 year of therapy in a randomized trial in high-risk patients.
When surgery is likely to result in major functional sequelae (e.g. total gastrectomy or abdomino-perineal resection of rectum) imatinib is usually administered prior to surgery.
The TNM classification for staging GISTs has several limitations, and its use is not recommended. Prognostic factors of proven value are the mitotic rate, tumor size, tumor site, and presence or absence of tumor rupture.
Recently, Stotz M et al. suggested that Inflammatory blood count biomarkers may improve recurrence risk stratification and inform long-term prognosis of GIST patients after curative surgery. A low Hemoglobin, and elevations in the white blood cell count, NLR (neutrophil/lymphocyte Ratio) and dNLR (derived NLR) were associated with a poor overall survival in GIST patients in multivariate analysis.
Gastric GISTs have a better prognosis than small bowel or rectal GISTs.
Tumor rupture through a serosal surface is an adverse prognostic factor and should be recorded, whether it took place before or during surgery.
Table 1 - Modified NIH risk classification for primary GIST (after Joensuu)
| Tumor size (cm) || Mitotic Index (per 50 HPFs) ||Primary tumor site|
|Very low risk|| <2.0 ||≤5|| Any|
|Low risk||2.1-5.0||≤5|| Any|
|High risk ||Any
Prognostic contour maps have been generated through a number of series of GIST patients not treated with adjuvant therapy. These maps incorporate the mitotic index and tumor size as continuous non-linear variables, while tumor rupture is considered in addition to tumor site. They have been validated against pooled data from 10 series and 2,560 patients from the literature.
A recurrence free survival calculator is available from Memorial Sloan Kettering Cancer Center located here:
https://www.mskcc.org/nomograms/gastrointestinal/stromal-tumor (assumes resected and no treatment with tyrosine kinase inhibitors).
The survival rates shown in Figure 2 are based on people treated many years ago, largely before these newer treatments such as tyrosine kinase inhibitors were used, so people being treated for GISTs today are likely to have a better outlook.
Based on people diagnosed between 2003 and 2009, the overall relative 5-year survival rate of people diagnosed with a malignant GIST was estimated to be about 76%:
- If the tumor was confined to the organ where it started, the 5-year relative survival was 91%.
- If it had grown into nearby tissue (or spread to nearby lymph nodes) when it was first diagnosed, the 5-year relative survival was around 74%.
- If it had spread to distant sites when it was first diagnosed, the 5-year relative survival was 48%.
In a large, randomized clinical trial performed in 946 patients with advanced GIST included between 2001 and 2002, treated with imatinib by a community of researchers from 58 institutions on two continents with a median follow-up of more than 10 years, slightly less than 10% and 15% of patients became long-term progression-free and long-term overall survivors, respectively.
Median OS was 3.9 years, and median PFS was 1.9 years (see Figure 2)
Figure 2 – Kaplan-Meier plots
De Matteo RP et al. studied 127 patients from 1983 to 2002 with localized primary GIST who underwent complete gross surgical resection of tumors originated in the stomach (58%) or small intestine (28%) in the absence of therapy with tyrosine kinase inhibitors with results shown in Figure 3.
Figure 3 – De Matteo RP et al. study
Returning to the case
According to the modified NIH risk classification and the results of De Matteo’s study summarized above, our case can be stratified as very low risk of recurrence or metastasis. However, due to the age and comparison to a similar non-affected population, mild to moderate excess mortality would be assigned.
Joensuu H. Risk stratification of patients diagnosed with gastrointestinal stromal tumor. Hum Pathol. 2008;39(10):1411–9
Joensuu H et al. Risk of recurrence of gastrointestinal stromal tumour after surgery: an analysis of pooled population-based cohorts. Lancet Oncol. 2012;13(3):265–74.
Cioffi A et al. GI Stromal tumors: 15 years of lessons from a rare cancer. J Clin Oncol 2015;33:1849-1854
Joensuu H, et al. One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial. JAMA. 2012;307(12):1265–72
Judson et al. UK clinical practice guidelines for the management of gastrointestinal stromal tumors (GIST) Clin Sarcoma Res (2017) 7:6
Casali PG et al. Ten-year progression free and overall survival in patients with unresectable or metastatic GI stromal tumors. J Clin Oncol 2017;35:1-11
West RB, Corless CL, Chen X, et al: The novel marker, DOG1, is expressed ubiquitously in gastrointestinal stromal tumors irrespective of KIT or PDGFRA mutation status. Am J Pathol 165:107-113, 2004
Espinosa I, Lee CH, Kim MK, et al: A novel monoclonal antibody against DOG1 is a sensitive and specific marker for gastrointestinal stromal tumors. Am J Surg Pathol 32:210-218, 2008
Dematteo RP, Gold JS, Saran L, et al. Tumor mitotic rate, size, and location independently predict recurrence after resection of primary gastrointestinal stromal tumor (GIST). Cancer 2008;112:608-15
Stotz M et al. (2016) Blood-Based Biomarkers Are Associated with Disease Recurrence and Survival in Gastrointestinal Stroma Tumor Patients after Surgical Resection. PLoS ONE 11(7): e0159448. doi:10.1371/journal.pone.0159448
Joensuu et al. Effect of KIT and PDGFA Mutations on Survival in Patients with Gastrointestinal Stromal Tumors Treated with Adjuvant Imatinib: An Exploratory Analysis of a Randomized Clinical Trial. JAMA Oncol. 2017;3(5):602-609