Gastritis, Gastric Cancers, and Submucosal Tumors: Gastric Tumors MALT NET GIST

0:00Welcome to Board Pearls. This is episode two of two of the Gastritis, Gastric Cancers, and Submucosal Tumors chapter, in the Stomach and Small Bowel Disorders module. This episode is the gastric tumors: adenocarcinoma split by Lauren type, MALT lymphoma versus the more aggressive large B-cell lymphoma, the three types of gastric neuroendocrine tumor, and the GIST as the model targeted-therapy cancer. In each one, the histology and the molecular driver are the discriminator, so that's what to hold onto.

0:32Start with gastric adenocarcinoma and the Lauren split, because it's the framework almost every downstream decision falls out of. It divides the cancer into two types that behave like two different diseases. The intestinal type forms recognizable gland-like structures. The diffuse type has no glands, just poorly cohesive cells that infiltrate the wall, with signet-ring cells as the giveaway. The intestinal type is the cancer at the bottom of the H. pylori cascade from episode one: it arises in older patients, favors men, sits in the distal stomach, accumulates a series of molecular hits, and tracks the high-incidence regions where H. pylori and salt-and-processed-meat exposures overlap. The diffuse type is a different animal, arising from non-atrophic mucosa, with equal sex distribution, at younger ages, at similar rates worldwide, and with a worse prognosis. Its driver is loss of the E-cadherin protein, encoded by CDH1, and since E-cadherin is what holds cells together, losing it is what gives the diffuse type its non-cohesive infiltrating pattern.

1:42That split has direct consequences, one of them inherited. Signet-ring cells in a young patient, or anyone with a first-degree relative who had diffuse gastric cancer, triggers germline CDH1 testing and the hereditary diffuse gastric cancer workup, and carriers are offered prophylactic total gastrectomy, because surveillance can't reliably catch the disease before it spreads. The trigger to recognize on a stem is signet-ring histology in someone in their thirties or forties with that family history. And linitis plastica is the diffuse-type variant to flag, the worst-prognosis presentation, where infiltrating cells thicken and stiffen the whole wall into a rigid leather-bottle stomach that won't inflate, usually metastatic by diagnosis. Its biopsy trap is that surface forceps biopsies often miss it because the cells are deep, so a rigid, non-distensible stomach with non-diagnostic superficial biopsies needs deeper sampling.

2:38The risk factors span both types with some skew, the unifying idea being that chronic mucosal injury plus high-risk diet and microbial exposure drives the intestinal type while non-atrophic E-cadherin loss drives the diffuse type. H. pylori is a definite carcinogen for both, with the more virulent strains carrying higher risk, and atrophy, extensive and incomplete metaplasia, adenomatous polyps, prior partial gastrectomy, family history, smoking, and a high-salt low-produce diet round it out. Presentation is usually advanced because early symptoms are vague, indistinguishable from ulcer dyspepsia, with the alarm features being weight loss, dysphagia from proximal tumors, vomiting from antral obstruction, and bleeding. The paraneoplastic signs to name are migratory thrombophlebitis, acanthosis nigricans, and a sudden eruption of seborrheic keratoses, and the four metastatic exam landmarks are the left supraclavicular node, the umbilical nodule, the rectal-shelf pelvic deposit, and the ovarian signet-ring metastasis.

3:43Staging runs in an order where each step rules a management arm in or out. Endoscopy with biopsy makes the diagnosis. Endoscopic ultrasound gives the most accurate depth and node staging by reading the wall layers, where the tumor runs from confined to the inner layers, to the muscle, to the outer coat, to through the serosa or into adjacent organs. CT of chest, abdomen, and pelvis looks for distant spread, most often liver and peritoneum, with PET in selected cases. And a staging laparoscopy with peritoneal washings is added before any curative surgery, because cross-sectional imaging routinely misses peritoneal disease, which matters most for the diffuse type. Molecular profiling at diagnosis is now mandatory in advanced disease and is the biggest shift in the field: you test HER2, PD-L1, microsatellite instability or mismatch-repair status, and Epstein-Barr status, and increasingly claudin 18.2, because each one selects a targeted therapy.

4:44For resectable disease, the favored answer is perioperative FLOT chemotherapy, the four-drug regimen given before and after surgery, which replaced the older regimens by improving survival, with surgery being subtotal gastrectomy for distal tumors or total for proximal and diffuse-type disease, both with a D2 lymph node dissection. Very early cancer confined to the superficial layers with favorable features, differentiated, non-ulcerated, small, and without lymphovascular invasion, can be removed endoscopically. In metastatic disease the molecular profile earns its place: HER2 amplification adds trastuzumab, a positive PD-L1 score adds a checkpoint inhibitor to chemotherapy, mismatch-repair-deficient tumors are exquisitely sensitive to checkpoint inhibitors regardless of PD-L1, and claudin 18.2 expression selects zolbetuximab. Survival in advanced disease stays poor, which is why prevention through H. pylori eradication and surveillance of premalignant conditions is the highest-impact intervention.

5:44Gastric lymphoma is a small share of gastric tumors but occupies a big share of the exam, because the management of its two types diverges sharply at the first decision. MALT lymphoma is the indolent low-grade one with H. pylori at the center; large B-cell lymphoma is the aggressive high-grade one that doesn't respond to eradication and needs combination chemoimmunotherapy, and it's the most common primary gastric lymphoma. The discrimination is what the stem tests, because the treatments are so different.

6:13The pathogenesis of MALT is the mechanism they favor. Normal stomach has essentially no organized lymphoid tissue, but chronic H. pylori infection induces it, and within that tissue, H. pylori-reactive T cells provide help that supports nearby B-cell proliferation, which over years goes from a reactive expansion to a monoclonal low-grade marginal-zone lymphoma. Because those malignant B cells initially depend on that antigen-driven T-cell help, eradicating H. pylori removes the help and a meaningful proportion of MALT lymphomas regress, which is why it's the one gastric malignancy where antibiotics are curative in early disease. So first-line therapy for stomach-confined MALT is eradication, which achieves histologic remission in most early-stage cases, confirmed off the acid blocker by breath or stool test rather than serology, with follow-up endoscopy to watch for regression. Many patients in remission still have a detectable monoclonal population on molecular testing, but that alone doesn't predict relapse and doesn't change management.

7:14The translocation known as t(11;18) is the defining trick. It creates a fusion that constitutively activates the survival pathway, so those malignant B cells no longer depend on H. pylori signaling, which means t(11;18)-positive MALT lymphomas do not respond to eradication, and the translocation is over-represented in eradication non-responders and deeper or nodal disease. So testing for it at diagnosis is essential for planning. The four situations that move a patient to second-line therapy are t(11;18)-positive disease, H. pylori-negative MALT, higher-stage disease, and persistent disease after adequate eradication, and second-line is involved-site radiation, which gives high local control for localized disease, or rituximab, the anti-CD20 antibody, alone or with chemotherapy for more advanced disease. Surgery has essentially no first-line role. The large B-cell lymphoma is the aggressive form, which may arise on its own or transform from a prior MALT, presenting as large ulcerated masses, diagnosed by large B-cell morphology and CD20 positivity, staged with endoscopic ultrasound plus CT and marrow, and treated with R-CHOP, with eradication added on the assumption that inflammation drove it but never substituting for the chemoimmunotherapy. Endoscopic ultrasound matters in both, because submucosal spread can extend beyond what surface biopsies catch, and finding a hidden high-grade component changes therapy from antibiotics to R-CHOP.

8:55Gastric neuroendocrine tumors come in three types, and the type sorts by gastrin and the background mucosa, which then dictates management. Types one and two are gastrin-driven and arise on a background of high gastrin; type three is gastrin-independent and behaves like an aggressive cancer. Type one is the most common and arises in autoimmune atrophic gastritis: the low acid removes the brake on gastrin, the high gastrin is a growth signal to the enterochromaffin-like cells, and over years that produces small, multiple tumors in the body and fundus on atrophic mucosa, with high gastrin and high pH because the parietal cells are gone. Its malignant risk is low, so management is endoscopic resection of larger lesions and surveillance of smaller ones, rarely needing wide surgery, and it doesn't cause carcinoid syndrome because it releases histamine that the liver clears. Type two arises in Zollinger-Ellison syndrome, almost always with MEN1, the same growth effect of high gastrin on those cells, but here the mucosa is hyperplastic and the acid is high because the parietal cells are intact, so gastrin is high and pH is low; risk is again low, and the priority is managing the underlying gastrinoma and searching for the other MEN1 tumors.

10:06Type three is the sporadic, gastrin-independent one, and it's the dangerous one, and the point worth making click is that a gastric neuroendocrine tumor with a normal gastrin is the highest-risk type. Here's why that isn't paradoxical: in types one and two the high gastrin is the driver and the tumor is a reactive proliferation, so take away the drive and it's biologically passive, whereas in type three there's no drive to remove, the proliferation is autonomous, which is why it's larger, more invasive, and more often metastatic at diagnosis, arising on normal mucosa with a normal gastrin. It frequently spreads to nodes and liver, can cause an atypical carcinoid syndrome, and needs formal surgical resection with lymphadenectomy like an adenocarcinoma, with endoscopic resection acceptable only for small low-grade lesions. Grade drives prognosis across all three, by the proliferation marker Ki-67 and mitotic count, with the high-grade neuroendocrine carcinomas managed with platinum chemotherapy like small-cell lung cancer. Imaging for type three is CT or MRI plus DOTATATE PET, and one caveat on the carcinoid screen: a foregut tumor like this lacks the enzyme to make much serotonin, so a flat urinary 5-HIAA is the expected pattern, not a reassuring one.

11:23The last tumor is the GIST, the closing topic because its molecular biology, its ultrasound appearance, and its drug selection line up in one tight package. It arises from the interstitial cells of Cajal, the pacemaker cells that generate the gut's slow wave, which is why it shows up wherever those cells live, most often the stomach then the small intestine. The molecular biology is what makes it teachable: most GISTs have an activating KIT mutation, whose protein is detected as CD117, a smaller share have a PDGFRA mutation, and the rest are wild-type for both and driven by other pathways, including the succinate-dehydrogenase-deficient GISTs of certain syndromes and the neurofibromatosis-associated ones. The mutation matters because it picks the drug: most KIT-mutant GISTs respond to imatinib, but one particular PDGFRA mutation, D842V, is intrinsically imatinib-resistant and needs avapritinib, and the wild-type ones are often imatinib-resistant but tend to behave indolently.

12:28On endoscopy it's a subepithelial mass with normal overlying mucosa bulging into the lumen, sometimes with central ulceration that bleeds, and the bleeding smooth submucosal mass with central umbilication is the prototype stem. Endoscopic ultrasound is the diagnostic anchor because it shows both the layer of origin and the character, and the key discriminator is that the GIST arises from the fourth layer, the muscle layer, as a hypoechoic mass continuous with it, which separates it from the other submucosal lesions. Sampling gives tissue for the CD117 and DOG1 stains, positive in essentially all GISTs, plus mutation analysis. Risk is stratified because it drives whether to operate on a small lesion and whether to add adjuvant drug, and the two big factors are size and mitotic count, captured by the rule of fives: under five centimeters and under five mitoses is low-risk, over five in one is intermediate, over five in both is high-risk, with small-bowel location and tumor rupture worsening the risk. Management by size and risk: resect all gastric GISTs over two centimeters and all non-gastric ones regardless of size, while a small gastric GIST without high-risk ultrasound features can be surveilled. Surgery is a wedge resection with clear margins, and there's no lymph node dissection, because GIST doesn't spread to regional nodes, which is a recurring trap.

13:51Imatinib is the tyrosine kinase inhibitor that transformed GIST and remains the favored answer for advanced and high-risk resected disease, given daily, with the exon-eleven mutations responding best and the exon-nine ones needing a higher dose. It doesn't eradicate the tumor, so it's continued indefinitely in metastatic disease, given for three years as adjuvant therapy after resection of high-risk tumors, and used before surgery to shrink large or awkwardly located tumors. The D842V PDGFRA mutation needs avapritinib instead. And after imatinib fails, the sequence is sunitinib, then regorafenib, then ripretinib, which covers a broad range of resistance mutations and so sits at the end. Imatinib, sunitinib, regorafenib, ripretinib in that order is the sequence to know, with avapritinib carved out for D842V.

14:46So hold the episode together by histology and driver at each step. Adenocarcinoma splits on Lauren type, which drives the molecular profile, which drives therapy: intestinal type from the cascade with HER2 in a subset, diffuse type from CDH1 loss with the hereditary syndrome and linitis plastica to flag, resectable disease getting perioperative FLOT with a D2 dissection, and metastatic disease driven by HER2, PD-L1, mismatch repair, and claudin 18.2. Lymphoma splits on grade: MALT is indolent and H. pylori-driven with eradication curative in most early cases and t(11;18) marking the non-responders, while large B-cell lymphoma gets R-CHOP, not antibiotics. Neuroendocrine tumors split on gastrin: type one from atrophic gastritis with high gastrin and high pH, type two from ZES with high gastrin and low pH, both low-risk, and type three sporadic with a normal gastrin on normal mucosa, the dangerous one treated like adenocarcinoma. And the GIST is the targeted-therapy story: a fourth-layer hypoechoic mass from the interstitial cells of Cajal, a KIT or PDGFRA mutation that picks the drug, the rule of fives plus site and rupture for risk, and the imatinib-sunitinib-regorafenib-ripretinib sequence with avapritinib for D842V.

16:08That sets up chapter eight on gastric and small-bowel motility, where the focus shifts from tumors to mechanics: gastroparesis as the common endpoint of vagal injury or loss of those same pacemaker cells, the four-hour emptying study anchoring the diagnosis, and the treatment running from diet to prokinetics to the endoscopic pyloromyotomy.

16:27For the full chapter, the practice vignettes, and the topic-tagged question bank, head to board pearls dot com. You'll find the rest of the series on Apple Podcasts, Spotify, or wherever you listen to podcasts. That brings us to the end of episode two of two of chapter seven, and I'll see you in the next one.