Abdominal pain, nausea and vomiting are frequent complaints in the general population, triggering a staggering number of primary care and emergency room visits each year in the United States. Benign causes will underlie the vast majority of cases, but rarely, gastric neoplasms such as gastric adenocarcinoma, gastrointestinal stromal tumors or gastric neuroendocrine tumors will be discovered on subsequent diagnostic tests.
Here, we review the surgical oncologist’s perspective on salient clinical and therapeutic aspects of these uncommon but important clinical entities.
Gastric Adenocarcinoma
The incidence of gastric cancer in rising in the West, particularly in patients under 50 years of age.1 It is the fourth leading cause of cancer deaths in the world. Risk factors include environmental agents such as chronic infection with Helicobacter pylori, dietary consumption of salt and nitrosamines, obesity, smoking and alcohol. Underlying pathology such as atrophic gastritis and intestinal metaplasia may also contribute to patients with intestinal type histology.
While prior gastric surgery is felt to add some risk, a large nationwide cohort study recently demonstrated that bariatric surgery is actually associated with a reduction of gastroesophageal cancer incidence.2 As the gastric remnant will be inaccessible for endoscopic surveillance, attention to this region on subsequent axial imaging is paramount in patients with gastrointestinal symptoms.
Diffuse type gastric cancer, manifested by the classic linitis plastica or “leather bottle” appearance of the entire stomach, may occur within the context of hereditary syndromes including CDH1 mutations or de novo. It may be subtle on imaging and endoscopy but have a worse prognosis.
Due to the overall low incidence, there are no national guidelines in the United States to support screening endoscopy among healthy adults. As a result, gastric cancer here often presents in the locally advanced or metastatic setting. Patients may report abdominal discomfort, decreased oral intake, weight loss or anemia, or occasionally present with frank hematemesis or melena.
Figure 1 summarizes the workup and management of gastric adenocarcinoma. Initial evaluation should include a thorough assessment of nutritional and performance status, endoscopic biopsy and computed tomography of the chest, abdomen and pelvis with intravenous contrast. This will rapidly separate patients into anticipated early, locally advanced or metastatic disease.
Although not mandated, baseline positron emission tomography can be a useful tool to further exclude metastases and to monitor for eventual treatment response. For those without obvious radiographic metastatic disease, a baseline endoscopic ultrasound is critical to locate the primary lesion with respect to the gastroesophageal junction, evaluate for surrounding linitus plastica, identify the depth of invasion and assess for occult nodal involvement. Finally, because synchronous peritoneal metastases are present in up to 20% of patients on presentation, staging laparoscopy at the time of diagnosis is required to identify patients who are poor candidates for surgical resection but better served by expanded systemic therapy options including immunotherapy.
Discussion of cases at a robust multidisciplinary tumor board is strongly encouraged for optimal treatment planning. Very early gastric cancer (Tis or cT1a) with favorable characteristics may be amenable to endoscopic resection alone with close surveillance. Surgical resection is the mainstay of treatment for those rare patients with T1a or T1b tumors with no other disease noted.
The majority of Western patients present with T2 or greater, or N1 disease. These are excellent candidates for perioperative chemotherapy, first established as the standard of care by the MAGIC trial in 2006 and updated to the current standard of the four-drug “FLOT” regimen comprised of fluorouracil, leucovorin, oxaliplatin, and docetaxel, with four cycles given before and after curative intent gastrectomy.3,4 Surgery involves subtotal or distal gastrectomy for gastric body and antral cancers or total gastrectomy for proximal cancers of the cardia, fundus or proximal lesser curvature, with resection of all locoregional perigastric lymph nodes.
A minimally invasive approach is preferred if feasible, particularly with the advent of robotic surgery. Extent of nodal dissection has been long debated; current consensus suggests that a modified “D2” or extended nodal harvest to include the celiac, hepatic, splenic and left gastric artery stations may be associated with decreased gastric cancer specific survival but must be weighed against risks particularly in elderly patients.5 Surveillance is critical following completion of perioperative chemotherapy.
Within the last two years, a combination of systemic therapy, immune checkpoint inhibitors such as pembrolizumab (Keytruda) and nivolumab (Opdivo), and HER2 receptor targeted therapy have emerged as new personalized options for advanced gastric cancer. Patients with HER2 overexpression are candidates for fluorouracil with oxaliplatin or cisplastin, and trastuzumab and/or pembrolizumab.
The benefit of adding a targeted agent for HER2 was demonstrated in the ToGA trial.6 HER2 negative patients with PD-L1 CPS ≥ 5 should receive fluorouracil, oxaliplatin and nivolumab based on the results of Checkmate-649, which showed overall survival benefit of 13.1 months with this regimen compared to 11.1 months with chemotherapy alone.7
Patients who lack HER2 expression and have low PD-L1 expression may be candidates for immunotherapy as well, but data for a survival benefit is less robust. All patients with high microsatellite instability or deficient mismatch repair protein expression should be considered for immunotherapy since the first-ever disease site-agnostic FDA approval of pembrolizumab in 2017. Those with high tumor mutational burden should also be considered for immunotherapy, based on KEYNOTE-158.8
Of note, palliative care remains an essential component for patients with advanced gastric cancer who progress on therapy. Much work remains to help these patients achieve a two-year survival milestone.
Gastrointestinal Stromal Tumors
Gastrointestinal stromal tumors (GIST) are soft tissue sarcomas arising from esophagus to rectum. The most common location is in the stomach, which accounts for 60% of cases.
Derived from the precursors to the interstitial cells of Cajal, gastric GISTs present with bleeding or abdominal pain, or sometimes are incidentally found on an endoscopy. They have a range of behavior, and while often indolent and asymptomatic rarely can lead to progressive peritoneal and hepatic metastases. Endoscopic biopsy alone may miss a bulky submucosal lesion, so endoscopic ultrasound with fine needle aspiration is often needed for tissue diagnosis.
Small gastric GISTs less than 2 cm may be observed, though in young, fit patients with easily resectable 1-2 cm tumors, minimally invasive partial gastrectomy should be considered. GISTs greater than this size should be considered for upfront surgery if morbidity is low: minimally invasive partial gastrectomy avoiding impingement of the gastroesophageal junction or need for intestinal reconstruction. Robotic surgery appears to allow increased technical ease of accessing and resecting posterior and/or proximal lesions. Tumors that will involve major or total gastrectomy or potentially multivisceral resection need to be considered for upfront medical therapy for downsizing. Tumor mutational analysis will help contribute to decision-making.
The vast majority of lesions have mutations in KIT or PDGFRA, which are amenable to treatment with imatinib (Gleevec). Following resection, pathologic findings will determine risk assessment based on size and mitotic rate. One year of adjuvant imatinib was shown to increase recurrence-free survival in patients with tumors greater than 3 cm in ACOSOG Z9001, and this has since been extended to three years based on an observed 92% five-year survival rate in these patients in SSG XVIII/AIO.9,10
In the metastatic setting, treatment with imatinib is recommended based on mutational analysis. A minority of patients will have PDGFRA mutation D842V, which responds to the recently approved avapritinib (Ayvakit). Those who lack KIT or PDGFRA mutations and are found to have SDH deficiency will not benefit from imatinib but may respond to other tyrosine kinase inhibitors; additionally, these patients require genetic testing and, if positive, plasma metanephrines to exclude paraganglioma. In rare circumstances, young, high-functioning patients with metastatic GIST can be considered for cytoreductive surgery for palliation and disease control. Liver-directed therapy remains an option for consideration in isolated or symptomatic liver metastases for palliation.
Gastric Neuroendocrine Tumors
Neuroendocrine tumors (NETs) or “carcinoids” arise from enterochromaffin cells and are rarely encountered in the stomach. Like GISTs, these malignancies are usually submucosal in location and may be indolent but can have variable behavior. The majority of gastric NETS are type 1 lesions, which arise in the setting of hypergastrinemia from chronic atrophic gastritis. The fasting serum gastrin level will be high, and this triggers the development of multifocal NETs that are usually indolent and can be managed with endoscopic resection alone.
In severe cases refractory to medical management, antrectomy can be considered. Type 2 gastric NETs occur in patients who have elevated gastrin levels due to a concomitant gastrinoma either in the pancreas or duodenum as a part of Zollinger-Ellison syndrome. The primary gastrinoma should be identified with comprehensive imaging and resected with partial duodenectomy or Whipple procedure as indicated.
Type 3 gastric NETs occur with normal gastrin levels and are historically felt to have an aggressive course with early nodal and/or hepatic metastases. Formal gastrectomy with nodal harvest is generally recommended.
With the increasing availability of highly sensitive somatostatin receptor PET-CT imaging, it is likely that more accurate staging and prognostication can be offered at presentation and during the surveillance period.
Although rare, gastric neoplasms are identified on radiographic and endoscopic workup of many different symptoms. Multidisciplinary assessment of histologic features, staging workup and patient-specific factors allows for optimal treatment planning and long-term oncologic outcomes.
References
- Bergquist JR, Leiting JL, Habermann EB, et al. Early-onset gastric cancer is a distinct disease with worrisome trends and oncogenic features. Surgery. 2019 Oct;166(4):547-555.
- Lazzati A, Poghosyan T, Touati M, et al. Risk of Esophageal and Gastric Cancer After Bariatric Surgery. JAMA Surg. 2023 Mar 1;158(3):264-271.
- Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006 Jul 6;355(1):11-20.
- Al-Batran SE, Homann N, Pauligk C, et al. Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial. Lancet. 2019 May 11;393(10184):1948-1957.
- Degiuli M, Reddavid R, Tomatis M, et al. D2 dissection improves disease-specific survival in advanced gastric cancer patients: 15-year follow-up results of the Italian Gastric Cancer Study Group D1 versus D2 randomised controlled trial. Eur J Cancer. 2021 Jun;150:10-22.
- Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010 Aug 28;376(9742):687-97.
- Janjigian YY, Shitara K, Moehler M, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 2021 Jul 3;398(10294):27-40.
- Marabelle A, Fakih M, Lopez J, et al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol. 2020 Oct;21(10):1353-1365.
- Corless CL, Ballman KV, Antonescu CR, et al. Pathologic and molecular features correlate with long-term outcome after adjuvant therapy of resected primary GI stromal tumor: the ACOSOG Z9001 trial. J Clin Oncol. 2014 May 20;32(15):1563-70.
- Joensuu H, Eriksson M, Sundby Hall K, et al. One vs Three Years of Adjuvant Imatinib for Operable Gastrointestinal Stromal Tumor: A Randomized Trial. 2012;307(12):1265–1272. doi:10.1001/jama.2012.347
Malini D. Sur, MD, FACS
Dr. Sur is a board-certified surgical oncologist at the Atlanta Liver and Pancreas Surgical Specialists of Northside Hospital Cancer Institute. After graduating from Harvard College, Dr. Sur completed her doctorate and surgical residency at Mount Sinai School of Medicine in New York. She then pursued her fellowship in surgical oncology at the University of Chicago. Dr. Sur has expertise in robotic surgery. Her interests include hepatobiliary and pancreatic cancers, gastric neoplasms and neuroendocrine tumors.
