Path 17a:Congenital Anomalies, Esophagus, & Stomach

Chronic Helicobacter Pylori Gastritis

• Caused by a spiral-shaped or curved bacillus
• Closely associated with ulcers of the duodenum and stomach and chronic gastritis
• Associated with poverty, household crowding, and lower educational attainment in the US
• Infection typically occurs in childhood and persists for life
• Initial acute H. pylori gastritis is typically limited to the antrum
• Gastric response to initial infection is either normal or slightly increased acid secretion
• Progressing to chronic gastritis involving the gastric body and fundus causes loss of parietal cells and decreased acid secretion
• Continued injury and repair leads to intestinal metaplasia
• The constellation of findings including loss of parietal cells, decreased acid secretion, and intestinal metaplasia is referred to as atrophic gastritis

Cytotoxin-Associated Gene A (CagA)

• H. pylori can be CagA positive or negative
• CagA-positive strains have a higher tendency to colonize the gastric body and secrete pro-inflammatory cytokines like IL-8
• Pro-inflammatory cytokines attract neutrophils leading to mucosal damage, atrophic gastritis, metaplasia, dysplasia, and gastric carcinoma
• Areas with a high prevalence of gastric cancer tend to have a higher prevalence of H. pylori strains that are CagA positive vs. areas with a lower prevalence of gastric cancer

Pathologic Findings of Chronic H. Pylori Gastritis

• Silver stain shows dark squiggles lining up on the mucosal surface in the surface mucin.
• Crinkled appearance that resembles seagulls
• Exuberant neutrophilic response as the bacteria involve the epithelium which causes injury to epithelium
• Can develop a chronic inflammation response over time and a mucosal-associated lymphoid tissue arising as a result of the chronic infection
• Loss of parietal cells and an increased number of plasma cells
• Intestinal metaplasia, with goblet cells
• Goblet cells have pale blue-gray apical droplets of mucin

Gastric Adenocarcinoma

• Most common malignancy of the stomach, accounting for more than 90% of gastric cancers
• Two main types: intestinal type and diffuse type
• Intestinal type tends to be bulky, either a polypoid mass or a bulky ulcerated mass
• Diffuse type has an infiltrative, invasive pattern, apparent as thickening of the gastric wall, referred to as linitis plastica

Incidence of Gastric Adenocarcinoma

• Varies geographically
• High-incidence areas (more than 60 cases per 100,000 population) include East Asia, Eastern Europe, and Central and Latin America
• In high-incidence areas, the adenocarcinoma is usually intestinal type
• In high-incidence areas, the region of the stomach that's affected tends to be distal (antrum and pyloric regions)
• Lower-incidence areas (less than 15 cases per 100,000) include North America, Northern Europe, and Africa
• Decrease in incidence areas is due to a decrease in the intestinal type of adenocarcinoma
• Diffuse type is relatively more common in lower-incidence areas
• In lower-incidence areas, diffuse type tends to arise in the cardia of the stomach

Risk Factors for Intestinal-Type Adenocarcinoma

• Autoimmune gastritis, where autoantibodies attack parietal cells, leading to their loss, intestinal metaplasia, and atrophic gastritis
• Helicobacter pylori gastritis beginning with acute inflammation moving to atrophic gastritis setting the stage for dysplasia and carcinoma progression
• Smoking increases the risk, potentiating the effect of CagA-positive serotypes
• Diets high in meat, pickled, salted, or smoked foods
• Diets low in fruits and vegetables
• Gastric adenomas, with increased risk of progression to malignancy with increased size (larger than 2 cm)
• Familial adenomatous polyposis because they have increased gastric adenomas.

Pathogenesis of Intestinal-Type Adenocarcinoma

• Increased signaling via the Wnt pathway
• Can occur through loss of function of the APC tumor suppressor gene or gain of function of beta-catenin
• TP53 silencing
• HER2 amplification
• In a resting cell, APC joins with a destruction complex and degrades beta-catenin
• Beta-catenin cannot enter the nucleus and cause transcription of proliferative genes when degraded
• Beta catenin also has a role binding to e-cadherin
• When there is Wnt stimulation, the destruction complex is deactivated, beta-catenin concentration increases, and it can translocate into the nucleus and drive proliferation
• When APC is knocked out, the degradation complex is deactivated, beta-catenin is free to enter the nucleus, and proliferation occurs
• If beta-catenin becomes resistant to degradation, its concentration will increase, increasing its ability to drive proliferation

Morphology of Intestinal-Type Adenocarcinoma

• Tends to be bulky tumors
• May be a mass or an ulcerated tumor with heaped-up margins
• Grows along broad cohesive fronts
• Microscopically, glands and tubules may have apical mucin vacuoles and luminal mucin
• May present with iron deficiency anemia due to GI blood loss
• Large tumor mass with surface ulceration, may be how tumor presented
• Large adenomas may be right next to the tumor mass, suggesting it arose from such an adenoma

Morphology of Ulcerated Intestinal-Type Adenocarcinoma

• Central ulceration with large, heaped-up margins
• Retain ruble folds
• Benign peptic ulcer has ulcerated area and thickening surrounding the ulcer due to edema inflammation
• In section, benign peptic ulcer would show desmoplasia and fibrosis
• Histologically see incredible pleomorphism of the cells and mitotic figures
• Architectural features with cribriforming with punched-out appearances where there is no stroma between the glands

Diffuse-Type Adenocarcinoma

• No defined precursor lesions, unlike intestinal type
• Understanding comes from hereditary diffuse gastric cancer, due to autosomal dominant mutations in the CDH1 gene, which encodes E-cadherin
• E-cadherin's job is to hold the cells together so that they don't split apart
• Risk of gastric malignancy is so high in these individuals, it's recommended that they get a gastrectomy before the age of 30
• Sporadic diffuse-type adenocarcinomas also show loss of CDH1, either through epigenetic silencing or loss-of-function mutations

Findings of Diffuse Type Adenocarcinoma

• Gross: thickened gastric wall
• Can be picked up on radiologic image
• Endoscopist may not see anything, or may see a small ulcer and loss of the rugal folds
• Histologically, diffuse invasion of individual cells causes a profound desmoplastic reaction resulting in thickening of the wall and loss of rugal folds
• Section of formalin fixed resection show thick wall
• Low power show edema and small pink fibers with fibrillar quality
• This fibrillar quality is in reference to linis plastica
• At higher power, the inflammatory cells are classic signet ring cells
• Large mucin droplet pushing the nucleus to one side, resembling a signet ring
• Can look like foamy macrophages where nucleus is not in the plane of section
• Diagnosis is tricky to make and immunohistochemical stains are frequently used

Clinical Features of Gastric Adenocarcinoma

• Endoscopic screening in high prevalence areas used to identify early lesions
• Early diagnosis (intramucosal resection or partial gastrectomy) can save the patient
• Prognosis depends on depth of invasion and presence of metastases
• Diffuse gastric adenocarcinoma tends to dive quite deeply
• Because the incidence of gastric adenocarcinoma is low in the US, no screening is done and most individuals present at an advanced stage
• Overall survival is less than 30% in the US

Metastasis of Gastric Adenocarcinoma

• Virchow node: metastasis to a supraclavicular lymph node
• Sister Mary Joseph node: metastasis to the periumbilical lymph nodes
• Krukenberg tumor: metastasis from GI primaries to the ovaries
• Ovarian tumors will be mucinous and bilateral

Gastric Lymphoma

• Extranodal marginal zone B-cell lymphomas of mucosa-associated lymphoid tissue (MALTomas)
• H. pylori is the most common cause of MALT and commonly associated with gastric MALTomas
• MALT can be physiologic but lymphomas don't tend to arise in physiologic MALT, but will in inflammation-associated MALT

Development of Gastric Lymphoma

• Bacteria invade, antibacterial immune reaction occurs, and polyclonal B-cell proliferation occurs
• Chronicity leads to continued stimulation of B cells, which can develop additional mutations
• One of these B-cell clones can be supported by inflammatory cytokines secreted by H. pylori-specific T cells
• If H. pylori is diagnosed and treated at this point, lymphoma regression can occur
• If not, further clonal evolution can lead to distant spread and even progression to large B-cell lymphoma

Morphology Gastric Lymphoma

• Sheets of atypical lymphocytes push apart the glandular tissue
• Immune histochemical stain for CD20, a B-cell marker, will show that these are all B cells
• This is not a mixed inflammatory infiltrate trying to eradicate an infection; it is a clonal population of B cells