Mucosa-associated lymphoid tissue (MALT) is scattered along mucosal linings to protect the body from an enormous quantity and variety of antigens. The tonsils, Payer patches within the small intestine, and the vermiform appendix are examples of MALT.
MALT includes

• Gut-associated lymphoid tissue (GALT)
• Bronchial/tracheal-associated lymphoid tissue (BALT)
• Nose-associated lymphoid tissue (NALT)
• Vulvovaginal-associated lymphoid tissue (VALT).

What is MALToma?

MALToma is a B cell lymphoma arising from the MALT. It is the most common primary GI lymphoma worldwide. NHL accounts for 2-3% of all malignancies, and MALTomas comprise approximately 5% of all NHLs.

What are the predominant sites of MALT-lymphoma?

• GI-Tract- Stomach (75%), small bowel (9%), Ileocaecal (7%), Multifocal (6%)
  Rectum (2%), Colon (1%)
• Lung
• Salivary Glands
• Ocular adnexa
• Skin

Why is MALToma a malignant condition?

• Monoclonality
• Non-random chromosomal aberration
• Histologic transformation to high-grade lymphoma
• Metastasis to lymph nodes/bone marrow.

Gastric MALTomas

Discuss the pathogenesis of gastric MALToma?

H. Pylori infection has been definitively established as a cause of MALTomas. 90% of MALToma pts are infected with H. Pylori.

• Infection by H Pylori
• Increase in MALT tissue
• Additional genetic mutations
• Malt lymphoma

What are the clinical features of gastric MALToma?

• Median age is 63 years with equal gender distribution
• Symptoms- epigastric pain, dyspepsia, nausea and vomiting and gastric bleeding. B symptoms can occur.
• The duration of symptoms preceding the diagnosis may range from a few days to six years.

How is MALToma diagnosed?

MALToma is usually diagnosed at endoscopy. MALToma can occur anywhere in the stomach. The most common site is antrum (41%) or multifocal (33%).
The endoscopic findings are erythema, erosions or ulcers. A mass lesion on OGD is unusual.

Discuss the staging investigations for gastric MALToma?

• Baseline bloods-LDH, B2 microglobulin (both could be elevated)
• OGD- with multiple biopsies from all the visible lesions & the non-involved areas with complete mapping of the organ
• CT Chest/Abdomen/pelvis
• Bone marrow biopsy
• EUS- for evaluation of depth of invasion and presence of perigastric lymph nodes. A deep infiltration of the gastric wall is associated with a higher risk of lymph node involvement and a lower response rate with antibiotic therapy alone.

Regardless of the presentation site- all the above diagnostic studies should be done.

Discuss the staging system for MALToma?
The best staging system is still controversial. Options are;

• Modified Blackledge staging system- recommended by International workshop held in Lugano, Switzerland.
• When EUS is available- TNM can also be employed
• Ann Arbor

Discuss the treatment of gastric MALToma?

Optimal therapy remains to be determined due to lack of controlled trials. However, the prognosis is excellent with overall survival rates of 80% to 95% at 5 years.

H. Pylori positive and localised disease (stage IE)

• HP eradication as sole therapy leads to durable remissions in 60-100%. This approach has been validated extensively, with more than 20 reported studies. Any of the highly effective antibiotic regimens proposed can be used. Thus far, no regimen has been proven to be superior in inducing lymphoma remissions. A second-line anti- Helicobacter therapy with different antibiotics may be needed in some instances.
• Breadth test 2 months after treatment to confirm eradication
• OGD with multiple biopsies every 6m for 2 years, then yearly to monitor the histologic regression.
• B cell clonality often persists (in upto 50%) following successful therapy to eradicate HP or following treatment with radiation therapy alone unlike successful treatment with chemoradiotherapy.The ultimate significance of persistent clonality in this setting is unclear. Histologic evaluation of repeated biopsies remains the fundamental follow up procedure despite the reproducibility problems. Whether the persistence of PCR detected B-cell monoclonality is associated with a higher risk of lymphoma relapse remains to be determined.
• Remission may take up to a year after HP eradication. So it may be worthwhile waiting 12 months before considering further therapy.

H. Pylori negative, failed antibiotic treatment, non gastric locations or extensive disease (IIE-IV) or extensive mucosal disease.

No definite guidelines exist, as there are no published randomized studies. A choice can be made between conventional therapeutic modalities.

• The standard of care for localised disease (HP negative or failed antibiotic treatment) is radiation therapy (30Gy in 4 weeks). More than 90% long term disease-free survival.
• Surgery was once the cornerstone, but the role is limited at present. As MALToma is a multifocal disease, a total gastrectomy will be needed. This is associated with significant morbidity.
• Systemic disease; Chemotherapy for MALTomas has not been studied extensively. Historically, the chemotherapy used for low-grade NHLs has been used. HP eradication should be used anyways in all cases

What is the prognosis?

MALTomas are indolent neoplasms with a fairly good prognosis. Gastric MALTomas have a stage-dependent prognosis. The cure rate may be as high as 90% for stage IE disease and is approximately 30-40% for extensive stage IIIE or IVE disease.

It is an uncommon mesenchymal tumour of GIT, arising from interstitial cells of Cajal. They express CD34, Actin and recently recognized as almost uniformly c-kit (CD117) +
Histologic subtypes include spindle, epitheloid and mixed. Until recently, there were no appropriate diagnostic tests. CD 117 is now used as a diagnostic tool.

Discuss the pathogenesis of GIST?

• C-Kit or KIT proto-oncogene-àc-kit receptor (memb TK)
• CD117 molecule is part of C-kit receptor.
• Normally, this receptor is activated by stem cell factor
• In GIST- c-kit receptor is permanently switched on– unregulated cell proliferation

Discuss the epidemiology of GIST?

• 0.1-3% of all GI cancers
• Incidence 1-2/100,000 based on historical data (difficult to interpret due to changing diagnostic criteria in the past)
• Estimates now of 200-2000 new cases/year in England and Wales with updated diagnostic criteria.

Discuss the clinical presentation of GIST?

• Abdominal pain, GI bleed, mass, Obstruction.
• Site of primary tumour- Stomach (50%), Small bowel (25%), Colon (10%), Oesophagus (5%), Extraintestinal (7%)
• Primary tumour only (46%), metastatic disease (47%)
• Frequently metastases to liver, rarely to regional lymph nodes and virtually never to lungs.

Discuss the diagnosis of GIST?

• Endoscopy- subepithelial mass
• CT scan- Solid mass that enhances brightly with IV contrast
• EUS- most accurate
• EUS FNA/ biopsy- used selectively

Discuss the clinical Behaviour of GIST?

• All GISTs are potentially malignant
• Any symptomatic GIST is potentially aggressive
• No uniform prognostic guidelines. Poor prognosis is associated with-
  • Increasing tumour size
  • GIST with high mitotic rate
  • Metastatic disease at presentation

Discuss the management of GIST?

• Surgical resection is the treatment of choice. 67% of primary tumours are resectable. However 50% recur in 5 years (most often: intraabdominal, liver)
• Recurrent disease treated as metastatic disease i.e. no role of further surgery
• Continued surveillance may be needed after surgery
• Advanced or metastatic disease- NICE recommends;
  • Imatinib (Gleevac) – 400mg/day first line treatment in CD117+unresectable or metastatic disease. Rapid dramatic response
  • Assess responders every 12 weeks. Continue therapy until tumour ceases to respond.
  • Side effects- nausea and vomiting, fluid retention, cramps, fatigue, GI or intraabdominal bleed- 5%
  • 2 year survival nearly 80%. 2year progression free survival 50%

Discuss stomach GIST?

• Most common in Fundus
• Small lesions <1cm with EUS benign- F/U repeat OGD &EUS at 6m and 12m
• Surgery- if tumour becomes symptomatic, shows structural changes or enlarges >1cm.

Discuss pre Imatinib outcomes for GIST?

• All GIST
  • 5year survival 28-43%
  • Median survival 19 months
• Single primary tumour completely resected
  • 5year survival 50-65%
  • Median survival 66months
• Metastatic disease or recurrent disease
  • Median survival 9-12 months
• Chemotherapy- not effective

Discuss the mutated Tyrosine kinases in GIST: PDGFRa (platelet derived growth factor receptor)?

• Subset of GIST tumour without kit mutations (KIT-WT)
• PDGFRa was constitutively phosphorylated in KIT-WT GIST
• Approximately 30% of KIT-WT GIST had PDGFRa mutation

Is an identified KIT mutation requisite to treat GIST with Imatinib?
Studies have correlated response to Imatinib to the presence of kit mutation, however not absolute

What about the minority of GIST tumours that do not have kit or PDGFRa mutation? Should they be offered Imatinib?

Imatinib may have an indirect mode of action by boosting NK cell activation in pts with GIST (ass with prolonged progression free survival)

What are the causes of gastric subepithelial masses?

Gastric subepithelial masses are most commonly GIST.
Gastric lipomas are a rare cause of gastric subepithelial masses, accounting for <1% of gastric intramural lesions.

What are the clinical features of gastric subepithelial masses?

They are mostly diagnosed incidentally at endoscopy

Discuss the diagnostic approach to gastric subepithelial masses?

• It is difficult to differentiate an intramural lesion from extramural compression with endoscopy alone.
• On endoscopy, lipomas have a yellow hue and often exhibit a pillow sign when probed with closed biopsy forceps, and may also exhibit some mobility. A recent study showed that the pillow sign (indents when depressed using biopsy forceps) had 98% specificity but only 40% sensitivity in identifying lipomas.
• Once a gastric subepithelial lesion is seen, an EUS is needed to define it further. A CT scan may also help to differentiate whether the lesion is intramural or extramural.

Link 2 to teaching module

Based on BSG guidelines 2010

What are the clinical features of gastric polyps?

Gastric polyps are mostly asymptomatic (>90%) and are typically found incidentally at OGD. Larger polyps can present with bleeding, anemia, abdominal pain or gastric outlet obstruction.

What are the types of gastric polyps?

• Fundic gland polyps
• Hyperplastic
• Adenomatous
• Hamartomatous polyps (Juvenile polyp, Peutz-Jeghers syndrome and Cowden’s syndrome)
• Polyposis syndromes (non Hamartomatous polyps as in Juvenile polyposis, Familial adenomatous polyposis)
• Subepithelial masses presenting as polyp

Discuss Fundic gland polyps (FGP)?

• Observed in 0.8-23% of endoscopies
• Usually multiple (usually <10) transparent sessile polyps 1-5 mm in size
• Located in the body and fundus
• Uncertain cause. FGP may regress or even disappear in time
• Unlikely to be related to PPI use (however conflicting reports)
• Dysplasia occur in < 1% of sporadic FGPs

Discuss FGP and familial adenomatous polyposis (FAP)?

• FGPs are common in patients with FAP. In this context, they are usually multiple and ‘carpet’ the body of the stomach. Epithelial dysplasia occurs in 25-41% of FAP associated FGP.
• There is no clear evidence about the number of FGPs needed to warrant large bowel investigations. The presence of dysplastic foci should arouse suspicion of FAP.
• When considering lower GI investigation, remember a flexible sigmoidoscopy can diagnose almost all cases of FAP.

Discuss the management of FGP?

• Polypectomy is not required for sporadic FGPs.
• Although FGPs have reliable endoscopic features, biopsy of probable FGPs is recommended to exclude dysplasia or adenocarcinoma (and possible FAP) and to exclude the need for polypectomy as required for other types of polyp (moderate, net benefit, qualified).
• In patients with numerous FGP who are under 40 years of age, or where biopsies demonstrate dysplasia, colonic investigation should be performed to exclude FAP

Discuss hyperplastic polyps?

• Majority of gastric polyps are hyperplastic in nature (30-93%)
• Sessile or pedunculated (< 2cms in diameter) usually in the antrum. Can be multiple throughout the stomach
• Multiple hyperplastic polyps occur in Menetrier’s disease
• Hyperplastic polyp formation is strongly associated with chronic gastritis (Helicobacter-associated gastritis, pernicious anaemia, reactive or chemical gastritis when adjacent to ulcer erosions and around gastroenterostomy stomas)
• Up to 80% of hyperplastic polyps regree after eradication of H pylori before endoscopic removal

Discuss the management of hyperplastic polyps?

• Hyperplastic polyps should be biopsied and an examination of the whole stomach should be made for mucosal abnormalities and any abnormalities biopsied. Hyperplastic polyps rarely undergo neoplastic transformation; however there is an increased risk of neoplasia in the surrounding abnormal gastric mucosa. The risk of adenocarcinoma in the surrounding mucosa is probably higher than in the polyp itself.
• Test for H Pylori and eradicate when present
• Symptomatic polyp or polyp with dysplastic foci should be removed

Discuss adenomatous polyps?

• These are true neoplasm’s and are precursors of gastric cancer
• Frequently solitary and can be found anywhere in the stomach (commonly in antrum)
• Frequently arise on a background of atrophic gastritis and intestinal metaplasia, but there is no proven association with H. Pylori infection.

Discuss the management of adenomatous polyps?

• Complete removal of the adenoma should be performed when safe to do so.
• An examination of the whole stomach should be made for mucosal abnormalities and any abnormalities biopsied (because there is a strong association between gastric adenoma and synchronous or metachronous gastric adenocarcinoma)
• Endoscopic follow-up is required following resection of gastric adenomas. Endoscopy should be repeated at 6 months for incompletely resected polyps or those with high grade dysplasia. Endoscopy can be repeated after 1 year for all other polyps
• There is no evidence as to whether gastric polyps need long term surveillance, and given the cost implications of such a programme, only a single gastroscopy 1 year after the removal of polyps with dysplasia is recommended (in the absence of polyp syndromes). Single repeat gastroscopy should also be performed at 1 year for all polyps with dysplasia that have not been removed.

Discuss the management of gastric polyps associated with polyposis syndromes?

BSG recommendations:

Discuss gastric polypectomy?

• Snare polypectomy and EMR in the stomach carry a high risk of complications. In the largest study, 7.2% patients had post-polypectomy bleeding, 80% of whom needed endoscopic therapeutic intervention. There is risk of perforation too.
• Therefore, given the risks of gastric polypectomy, it may be safer to only biopsy polyps in patients with co-morbidity or at risk of haemorrhage.
• Polyps <1 cm probably only require two biopsies, whereas larger polyps require three to four biopsies.
• The risks of polypectomy also require the clinician to be confident that polypectomy is indicated.
• Recommendations for gastric polypectomy
  • Any polyp with a dysplastic focus should be completely removed when safe to do so
  • Endoscopists performing gastric polypectomy should be competent to manage the complications of bleeding.
  • The decision to perform a polypectomy must be weighed against the risk of complications especially in elderly patients with concomitant illness.

BSG algorithm for the management of gastric polyps:

Reference:

BSG guidelines 2010: The Management of Gastric Polyps

The incidence of cancer of the cardia and gastroesophageal junction has been rapidly rising whereas cancer of the distal half of the stomach has declined rapidly over the recent few decades.

What are the risk factors for gastric cancer?

Helicobacter pylori infection, older age, male gender, diet including dry salted foods, atrophic gastritis, pernicious anemia, cigarette smoking, Menetrier’s disease, and familial polyposis

Discuss the pathogenesis of gastric cancer?

A widely accepted model of gastric cancer describes a progression from chronic gastritis to chronic atrophic gastritis, to intestinal metaplasia, dysplasia, and eventually to adenocarcinoma. The following steps are described:

• Longstanding chronic superficial gastritis caused by chronic H. pylori infection leads to chronic atrophic gastritis and intestinal metaplasia.
• Gastric atrophy leads to loss of parietal cell mass and consequent hypochlorhydria. This causes increase in serum gastrin, a potent inducer of gastric epithelial cell proliferation.
• The increase in gastric pH permits colonization of bacteria capable of converting dietary nitrates to potent mutagenic N-nitroso compounds.
• Chronic inflammation also results in epithelial cell damage with increased free radical generation and increased cell turnover.

Hypochlorhydria due to gastric resection or autoimmune pernicious anemia will lead to similar chain of events.

Is Intestinal metaplasia (IM) reversible?
IM is a potentially reversible change. It occurs as a result of Helicobacter pylori infection
or other environmental stimuli. Epidemiological studies have shown that intestinal metaplasia in the stomach have a high cancer risk.

What are the clinical features of gastric cancer?

• Weight loss and persistent abdominal pain are the most common symptoms at initial diagnosis.
• Dysphagia in cancers arising in the gastric cardia or at the OG junction.
• Nausea or early satiety from gastric outlet obstruction or gastric stasis related to tumor infiltration of the stomach wall.
• Occult GI bleeding with or without iron deficiency anemia is common, while overt bleeding (ie, melaena or haematemesis) is seen infrequently.

How do you diagnose gastric cancer?

• Endoscopy and biopsies- The diagnosis of diffuse-type gastric cancer, so called “linitis plastica,” can be difficult as it may be associated with a relatively normal endoscopic appearance. Further these tumors tend to infiltrate the submucosa and hence superficial mucosal biopsies may be falsely negative.
• CT scan of chest/abdomen/pelvis to stage the disease.
• EUS is better than CT at assessing tumor depth (T stage) and perhaps lymph node involvement (N stage).
• PET-CT- The role of PET- CT in the staging of oesophago-gastric cancers is under evaluation. It is now increasingly being used in all cases of fit patients with an oesophageal or oesophago-gastric junction cancer which is suitable for radical treatment to detect occult stage IV disease.
• Laparoscopy is routinely used following CT and EUS in patients with T2 or greater gastric cancer prior to radical treatment. It is also considered in any patients where there is suspicion of peritoneal spread on CT or EUS such as in the presence of small volume ascites.
• Bone scan- Patients with advanced disease (>T2N0) who have not undergone full body PET-CT require a bone scan to exclude bony metastases.

Discuss TNM staging for gastric cancer?

T1- Tumor invades lamina propria or submucosa
T2- Tumor invades muscularis propria or subserosa
T3- Tumor penetrates serosa without invasion of adjacent structures.
T4- Tumour invades adjacent structures.

N1- Metastasis in 1 to 6 regional lymph nodes.
N2- Metastasis in 7 to 15 regional lymph nodes.
N3- Metastasis in more than 15 regional lymph nodes.

M0- No distant metastasis
M1- Distant metastasis.

Stage IA- T1N0M0, IB- T1N1M0/T2N0M0
Stage II- T1N2M0 /T2N1M0/T3N0M0
Stage III- T2N2M0/ T3N1-2M0/T4N0M0
Stage IV- Any N3 or M0 or T4N1M0

NB- The regional lymph nodes are the perigastric nodes, found along the lesser and greater curvatures, and the nodes located along the left gastric, common hepatic, splenic, and coeliac arteries. Involvement of other intra-abdominal lymph nodes, such as the hepatoduodenal, retropancreatic, mesenteric, and para-aortic, is classified as distant metastasis.

Discuss the management of gastric cancer?

How do you define a resectable gastric cancer?

• Surgical resection including regional lymphadenectomy is the treatment of choice for patients with stage I and II gastric cancer
• Stage III- All newly diagnosed patients with stage III gastric cancer should be considered candidates for clinical trials. However, Up to 15% of selected stage III patients can be cured by surgery alone, particularly if lymph node involvement is minimal (<7 lymph nodes). So, all patients with tumors that can be resected should undergo surgery.
• In practice, curative resectional procedures are confined to patients who at the time of surgical exploration do not have extensive nodal involvement.

What is the type of surgery undertaken?

• Total gastrectomy is usually performed for lesions in the upper third of the stomach and subtotal gastrectomy for lesions in the lower two-thirds. The mortality of total gastrectomy is approximately twice that of a subtotal gastrectomy.
• Regional lymphadenectomy is undertaken with both total and sub total gastrectomy. Splenectomy is not routinely performed.
• EMR may be considered as a definite treatment option in Early Gastric Cancer (adenocarcinoma limited to the gastric mucosa and submucosa). H.Pylori should be eradicated in patients with early gastric cancer.

What is the role of chemoradiotherapy?

• Neoadjuvant chemotherapy remains investigational with no definite evidence of survival benefit and clinical trials are continuing. However, the UK MRC ST02 MAGIC trial reported a significant 5 year survival advantage for those patients receiving 3 courses of neoadjuvant ECF chemotherapy.  These patients had a 5 year survival of 36% compared to 26% for those patients having surgery alone.  Following the publication of this trial, a number of cancer centers offer neoadjuvant ECF chemotherapy to all suitable patients.
• Adjuvant chemotherapy/chemoradiotherapy is currently not standard practice for resected gastric cancer. However, the impressive result of the well conducted MAGIC trial is leading to the adoption of the adjuvant chemotherapy approach in much of Europe and other parts of the world.

Discuss unresectable or metastatic disease?

What is unresectable disease?
Any T4 lesion
Any N3 lesion
Any M lesion

What are the treatment options for unresectable gastric cancer?

• Chemotherapy is the usual treatment. It provides quality of life and survival benefit. The combination of epirubicin, cisplatin, and continuous infusion of 5-FU (ECF) appears to be one of the most active regimens.
• While chemotherapy is the most effective treatment modality for metastatic disease, it is often less successful for control of symptoms related to local tumor progression such as nausea, pain, obstruction, or bleeding. Palliative resection may be needed for patients with continued bleeding or obstruction. Palliative radiation therapy may also alleviate bleeding, pain, and obstruction.
• Endoscopic destruction (APC/Laser) of obstruction of the gastric cardia is very helpful to patients whose tumors have occluded the gastric inlet.

How do you treat recurrent gastric cancer?

Curative resection is not possible in patients with recurrent disease. Most such patients require will systemic chemotherapy or palliative RT.

What is the prognosis?
5 year survival rates;
IA — 78 percent IB — 58 percent
II — 34 percent
IIIA — 20 percent IIIB — 8 percent IV — 7 percent
What is the criterion for the diagnosis of familial gastric cancer?

What is familial gastric cancer?

Consensus criteria for the diagnosis of familial gastric cancer have been proposed by the International Gastric Cancer Linkage Consortium (IGCLC);
i. 2 cases of diffuse type gastric cancer in 1st/2nd degree relatives with one <50 years old OR
ii. 3 cases of diffuse type gastric cancer in 1st/2nd degree relatives of any age

Genetic testing is recommended to patients who fulfill the IGCLC criteria above, or those whose family history also includes other malignancies potentially related to E-cadherin gene CDH1 mutations including lobular breast cancer or signet ring cancer of the colon.

What is the role of primary prevention in gastric cancer?

• H.Pylori eradication is a potential strategy in the primary prevention of gastric cancer. Whether H. pylori eradication therapy can reverse or reduce the risk that precursor lesions (gastric atrophy, intestinal metaplasia, or gastric dysplasia) will progress is controversial. However, current data do suggest a role for screening and eradication strategies at least in some settings.
• Screening for H. pylori is not currently recommended in areas with a low-incidence of gastric cancer (UK) but it is reasonable to screen patients who have risk factors (previous gastrectomy, pernicious anemia, family history) for gastric cancer regardless of the baseline risk in the population.

Ref

1. British Society of Gastroenterology Guidelines for the management of Oesophageal and gastric cancer