GI

Question 2

Diagnosis?

Inheritance pattern?

Gene?

Most common mutation?

Pathophysiology?

Symptoms?

Answer 2

Hereditary Hemochromatosis

• homozygous autosomal recessive
• HFE gene
• C282Y
• HFE protein in small intestinal cells, regulation of iron uptake. Mutation –> unregulated uptake of iron regardless of need
• liver, pancreas, heart, pituitary, and skin –> hepatomegaly, diabetes, cardiomyopathy, amenorrhea, and hyperpigmentation

Question 4

• __ testing has now become the serologic test of choice for evaluation of celiac disease, largely replacing the __ for initial testing.
• Genetic testing for __ is utilized in selected cases as part of the clinical evaluation of celiac disease.
  
  • __ is present in approximately 95% of patients with celiac disease and most of the remaining 5% are positive for __.
  • __testing is not diagnostic of celiac disease (present in approximately __ of the Caucasian population), but absence of these haplotypes virtually excludes celiac disease.

Answer 4

Celiac disease

• IgA antitissue transglutaminase (tTG) testing has now become the serologic test of choice for evaluation of celiac disease, largely replacing the more labor-intensive (although similarly accurate) antiendomysium antibody for initial testing.
• Genetic testing for HLA DQ2 and DQ8 is utilized in selected cases as part of the clinical evaluation of celiac disease. HLA DQ2 is present in approximately 95% of patients with celiac disease and most of the remaining 5% are positive for HLA DQ8. Although positive DQ2/DQ8 testing is not diagnostic of celiac disease (present in approximately one-third of the Caucasian population), absence of these haplotypes virtually excludes celiac disease.

Question 5

In typical cases of celiac disease, intraepithelial lymphocytes are CD__+/CD__+.

Abnormal lymphocyte populations (with __ phenotype) may be seen in cases of refractory celiac disease and these patients are at increased risk for development of __.

• Histopathologic features of celiac disease include )__, and variable architectural abnormalities, including __.
• Most or all features of celiac disease, including intraepithelial lymphocytosis and variable amount of villous atrophy, may be present in cases of __.

Answer 5

Celiac disease

• In typical cases of celiac disease, intraepithelial lymphocytes are CD3+/CD8+. Abnormal lymphocyte populations (with CD3+/CD8- phenotype) may be seen in cases of refractory celiac disease and these patients are at increased risk for development of enteropathy-associated T cell lymphoma.
• Histopathologic features of celiac disease include intraepithelial lymphocytosis (characteristically showing a “tip-heavy” distribution), and variable architectural abnormalities, including villous atrophy (ranging from none to total) with variable crypt hyperplasia and expansion of the lamina propria by chronic inflammatory cells, especially plasma cells. None of the previous findings, however, are specific for celiac disease and clinical correlation is required to establish this diagnosis.
• Most or all features of celiac disease, including intraepithelial lymphocytosis and variable amount of villous atrophy, may be present in cases of tropical sprue. Correlation with clinical (i.e., traveling to tropical regions) and laboratory findings (negative celiac disease workup) are generally required to establish this diagnosis.

Question 6

• The prevalence of celiac disease is higher in __ and __ than in the general population.
• Patients with celiac disease (also known as gluten-sensitive enteropathy) are at risk for developing __.

Answer 6

Celiac disease

• The prevalence of celiac disease is higher in patients with Down’s syndrome and diabetes mellitus than in the general population.
• Patients with celiac disease (also known as gluten-sensitive enteropathy) are at risk for developing enteropathy-associated T-cell lymphoma.

Question 7

4 forms?

Virus?

Stain?

Answer 7

Kaposi sarcoma involving stomach

Four forms of Kaposi sarcoma (KS) are described:

(1) classic form, an indolent, primarily cutaneous disease typically affecting older men of Mediterranean ancestry
(2) endemic form, primarily affecting HIV-negative children in Africa
(3) iatrogenic form, affecting organ transplantation patients on immunosuppressive therapy
(4) HIV-associated cases.

• Human herpesvirus-8 (HHV-8) is thought to play a major role in all forms of KS.
• Histology
  
  • proliferation of relatively bland spindle to epithelioid cells forming slitlike spaces containing red blood cells
  • +/- eosinophilic, PAS-positive hyaline inclusions within tumor cells
• monoclonal antibody to HHV-8 latent nuclear antigen (LANA) is a highly sensitive and specific marker of HHV-8 infection in paraffin-embedded tissue sections of KS
  
  • other spindle cell lesions, such as spindle cell hemangioma, dermatofibrosarcoma protuberans, and pyogenic granuloma, are LANA negative

Question 8

Helicobacter pylori and Gastric Carcinoma

Answer 8

Helicobacter pylori and Gastric Carcinoma

• sixfold increased risk of gastric carcinoma in individuals infected with H. pylori.
• Infection and gastric cancer risk are high in Japan and Colombia.
• Africa, where the infection rate is also high, the gastric cancer rate is very low.
• This so-called African enigma remains unexplained.
• CagA and VacA genes are being studied as possible oncogenes. CagA-positive H. pylori strains are associated with alterations in the gastric epithelial cell cycle and apoptosis, more severe mononuclear and neutrophilic infiltrates, and more severe glandular atrophy and intestinal metaplasia. VacA-positive strains are frequently isolated from distal gastric cancers.
• Host factors include certain interleukin-1β subtypes, tumor necrosis factor-α expression, and genetic polymorphisms of mucin (MUC-1) and human leukocyte antigens (HLA).
• Known environmental risk factors are excessive dietary salt and inadequate intake of fruits and vegetables.

Question 9

Answer 9

Spirochetosis.

• Intestinal spirochetosis is a noninvasive infection by spirochetes, most commonly Brachyspira pilosicoli and Brachyspira aalborgi, which proliferate along the colonic epithelial surface.
• Although thought to represent an incidental finding in some cases, spirochetosis has been associated with diarrhea, anal discharge, and abdominal pain in immunosuppressed individuals, especially in the setting of HIV/AIDS (definite cause-effect relationship still uncertain because of the concomitant infections and other confounding factors in these cases).
• Prevalence of 2% to 16% in Western countries, being significantly higher in developing countries. Most commonly seen in homosexual men with HIV/AIDS.
• Gross/endoscopic appearance of the mucosa is usually normal.
• This infection must be suspected and a “fringed,” basophilic line is seen along the apical border of colonicytes (including colonocytes within crypts). Organisms along the epithelial surface are highlighted by silver stains (Warthin-Starry and Steinter stains). Alcial blue pH 2.5 and PAS stains can also be used, while Gram stains usually fails to highlight these organisms.

Question 10

Answer 10

Listeria villitis

• placenta and fetus are infected with Listeria via the hematogenous route
• important cause of second trimester abortion
• acquired by the mother from consumption of contaminated meat or unpasteurized dairy
• premature delivery or stillbirth
• most common in pregnant women, immunocompromised hosts, the elderly, and newborns

Question 11

What causes pipestem fibrosis in the liver?

Answer 11

Schistosomiasis and Pipestem Fibrosis

• Symmers fibrosis refers to the dense, rounded, and fibrotic portal tracts that are seen on the cut surface of the liver in late schistosomiasis.
• Early changes in schistosomiasis include schistosomal granulomas within portal vein branches, sometimes with an extensive surrounding eosinophil infiltrate and corona of degranulated bright red eosinophil granules (Hoeppli-Splendore effect).
• Later changes in schistosomiasis include portal tract fibrosis, loss of portal vein lumina, and acquisition of schistosomal finely granular black pigment in Kupffer cells and portal macrophages.
• Acid-fast stain is useful to apply to suspected schistosomal granulomas or other suspicious areas because the outer cuticle and lateral spike of Schistosoma mansoni and other species are positive on acid-fast bacilli.

Question 12

DDx?

Answer 12

Fibrin Ring Granulomas and Q Fever

• Fibrin ring granulomas (also called “donut granulomas”) are lobular granulomas that are distinguished from other types of granulomas by their central, seemingly empty space (a lipid vacuole) surrounded by strands of fibrin with outer lymphocytes and macrophages.
• Fibrin ring granulomas are chiefly formed as a result of infections, the most frequent association being with Q fever (C. burnetii infection).
• The histologic differential diagnosis of fibrin ring granulomas includes cytomegalovirus, Leishmania spp., hepatitis A virus infection, and allopurinol toxicity. These granulomas have been considered a nonspecific reaction, chiefly to infections.
• Fibrin ring granulomas are typically located within the lobular parenchyma and are not within portal tracts. Their central empty hole and surrounding strands of fibrin are histologically distinct from sarcoid granulomas, which are usually fibrosing and often clustered adjacent to portal tracts, and drug-related granulomas, which lack the central vacuole and sometimes contain eosinophils.

Question 13

Dx in infant?

Increased risks?

Tx?

Answer 13

Infant of a diabetic mother

• 3-10% of all pregnancies are affected by abnormal glucose regulation
• increased risk of growth abnormalities, respiratory distress, hypoglycemia, and congenital anomalies
• If maternal blood glucose is tightly controlled, the risk of adverse events is markedly decreased (but is still increased over baseline).
• Nesidioblastosis generally refers to congenital hyperinsulinism with an abnormal microscopic appearance of the pancreas.
• If severe, near-total pancreatectomy may be needed (rare).

Question 14

Who gets it?

Endoscopy?

Histology?

DDx?

Answer 14

Gastric antral valscular ectasia (GAVE)

• older women, history of autoimmune conditions
• presents with anemia due to chronic blood loss
• Endoscopically,(“watermelon stomach”) longitudinal raised red mucosal stripes along the antrum and pylorus
• Microscopically, thrombi within dilated mucosal vessels
• Associated less specific histologic features include regenerative epithelial changes and fibromuscular hyperplasia of the lamina propria.
• spare the gastric body (in contrast with portal hypertensive gastropathy, which also involves the gastric body).
• Abnormal antral motility and mucosal prolapse are thought to be involved in the pathogenesis of this disease.

Question 15

Dx?

Histology?

Subtypes?

Stains?

Children and young adults with multiple__ and diabetes?

Most likely to progress an special staining?

Answer 15

Hepatocellular Adenoma (Liver Cell Adenoma)

• benign tumor of hepatocytes
• Histology
  
  • thickened cords of hepatocytes
  • interspersed blood vessels (thin venous and arterial profiles are seen)
  • NO bile ducts
• subclassified into four groups based on genomic classification:
  
  • type 1, HNF-1α mutations, with large droplet steatosis and without atypia
  • type 2, β-catenin mutations, with atypia and features that may transition to hepatocellular carcinoma
  • type 3, interleukin-6 ST mutations, including inflammatory or telangiectatic adenoma
  • type 4, no known mutation, with no specific features
• to distinguish it from carcinoma
  
  • reticulin (which should show preserved reticulin framework throughout, in contrast to the “paucireticulin” pattern seen in hepatocellular carcinoma
  • possibly CD34 (should show limited expression near pseudo–portal tracts).
• immunostains can be added
  
  • trio of glypican-3, glutamine synthetase, and heat shock protein 70 (which all should be negative)
• Children and young adults with multiple adenomas (adenomatosis is defined as ≥10 adenomas) and diabetes are very likely to haveHNF-1α mutation and maturity-onset diabetes of the young type 3.
• Adenomas with suspicious features for the development of or transition to hepatocellular carcinoma (nuclear atypia, pseudoglandular growth, increased mitotic activity, focal loss of reticulin) and harboring β-catenin mutations should demonstrate glutamine synthetase expression and nuclear overexpression of β-catenin on immunohistochemical staining.

Question 16

Adult Dx?

DDx?

Icreased prevalence in what population?

Histology?

Answer 16

Postinfantile Giant Cell Hepatitis

• rare in adults (in contrast to multinucleated giant hepatocytes in a neonatal liver biopsy specimen, a frequent change).
• affects only centrilobular hepatocytes
• Histologic DDx:
  
  • autoimmune hepatitis
  • HCV infection with or without HIV coinfection
  • drug hepatotoxicity
  • primary sclerosing cholangitis (less common)
• prevalence is slightly more than 2% in chronic hepatitis C

Question 17

Dx?

Where do they most commonly occur?

Age?

Answer 17

Lymphangioma of the small intestine and mesentery

• Lymphangiomas occur most commonly in the head and neck area of young children. They can, however, occur in the gastrointestinal tract of children and adults. Although they are often asymptomatic, it can present with symptoms of intestinal obstruction.
• The cystic spaces represent dilated lymphatic vessels lined by endothelial cells that are positive for CD31 and factor VIII-related antigen. Cystic lymphangiomas are benign lesions that are usually cured by surgical excision
• Intestinal lymphangiectasia may be primary or secondary. Patients present with protein-losing enteropathy and malabsorption, hypoalbuminemia, hypogammaglobulinemia, and lymphopenia, resulting in secondary immunodeficiency. Primary disorders, which result from congenital obstruction to lymph flow or abnormal lymphatic structures, may be limited to intestinal lymphatics or may involve multiple organs. Secondary lymphangiectasia may be central, resulting from cardiac disease or from local obstruction to lymphatics due to a wide variety of causes.

Question 18

Answer 18

Primary Sclerosing Cholangitis with Ductopenia

• A young adult with cholestatic serum liver tests (particularly isolated alkaline phosphatase elevation) should be investigated for primary sclerosing cholangitis (PSC) and its frequently accompanying background of inflammatory bowel disease.
• The most diagnostic lesions found in PSC include periductal “onion-skin” fibrosis and fibroobliterative lesions (i.e., fibroobliterative cholangitis—round or ovoid scars that replace former bile ducts).
• The presence of chronic portal and periportal inflammation in PSC underscores the point that PSC sometimes may resemble chronic hepatitis, including the presence of interface hepatitis.
• Alternative differential diagnoses of ductopenia include primary biliary cirrhosis (PBC), usually seen in middle-aged women; drug-induced liver injury (e.g., amoxicillin and clavulanic acid); and syndromic and nonsyndromic paucity of intrahepatic bile ducts in infants and children.
• A definitive diagnosis of PSC should be rendered by radiologic assessment of the extrahepatic and intrahepatic bile ducts. Serum perinuclear antineutrophilic cytoplasmic antibody is often elevated in patients with PSC.
• In a liver specimen that otherwise appears to be consistent with PSC because there is periductal fibrosis and other seemingly diagnostic features, if plasma cells are unusually prominent and the periductal inflammation is particularly dense, an important additional consideration is IgG4-associated cholangitis. IgG4-associated cholangitis should be excluded by immunostaining with antibody to IgG4 and by evaluation of the individual’s serum IgG4 level.

Question 19

DDx?

Answer 19

Acute Hepatitis

• Acute hepatitis (either viral or drug-related) is characterized by diffuse lobular necroinflammation, with ballooning and apoptosis of hepatocytes, disarray of liver cell plates, and diffuse portal and sinusoidal inflammation (chiefly lymphocytes).
• The major causes of acute hepatitis include hepatitis viruses (A through E) and drugs (usually idiosyncratic or unpredictable agents); alternative, herbal, and recreational agents should be considered.
• Histologic determination of the cause is often difficult. Helpful additional features favoring drug-induced liver injury include abundant eosinophils, bile duct damage, granulomas, and otherwise atypical histologic features for acute hepatitis.
• Autoimmune hepatitis may rarely appear on histology as acute hepatitis. Features that may raise suspicion for autoimmune liver disease include prominence of central perivenulitis (inflammation and liver cell dropout around central veins, with inflammation prominently lymphocytes and plasma cells), plasma cell prominence within the portal and periportal inflammatory infiltrates, and the presence of bridging necrosis (central-to-portal bridging necrosis).

Question 20

Answer 20

Isospora

• I. belli is a protozoan known to infect only humans. Ingestion of contaminated food or water containing oocysts causes disease, which is usually self-limited in healthy individuals.
• I. belli infection is rare among immunocompetent individuals. Immunocompromised patients are susceptible to more severe infections.Isospora organisms have been detected in the stool of 0.2% to 3% of patients with AIDS.
• The differential diagnosis includes other protozoan infections such as Microsporida and Cryptosporidium. Morphologic features are used to differentiate such organisms.
• Histologically, Isospora infection of the small bowel is characterized by mucosal atrophy with shortening of villi and crypt hypertrophy. Lamina propria eosinophilia is a distinct feature that is not usually present in other protozoan infections. I. belli organisms measure approximately 30 μm and are identified in and beneath enterocytes.

Question 25

How do the following stain with CDX-2?

• Poorly differentiated colonic carcinomas
• Gastric carcinomas
• Normal gastric surface epithelium
• Intestinal type adenocarcinomas arising in the genitourinary tract
• Barrett’s epithelium may be positive
• Mucinous adenocarcinomas of the ovary
• Mucinous and large cell neuroendocrine lung carcinomas

Answer 25

CDX-2

• CDX-2, a homeobox transcription factor involved in gastrointestinal development, is a useful marker for tumors of gastrointestinal origin.
• Poorly differentiated colonic carcinomas are often CDX-2 negative.
• Gastric carcinomas are usually positive, although normal gastric surface epithelium is CDX-2 negative.
• Pancreato-biliary neoplasms stain weakly or not at all with anti-CDX-2.
• Intestinal type adenocarcinomas arising in the genitourinary tract are usually positive; Barrett’s epithelium may be positive; mucinous adenocarcinomas of the ovary show patchy, but often strong, CDX-2 staining.
• A subset of mucinous and large cell neuroendocrine lung carcinomas may show patchy, but strong, staining for CDX-2.

Question 26

GASTRIC STROMAL TUMORS RISK ASSESSMENT

Answer 26

GASTRIC STROMAL TUMORS RISK ASSESSMENT

• Mitotic activity: >5/50hpf
• Tumor size: >10 cm
• Tumoral necrosis

Question 27

CARNEY’S TRIAD

Answer 27

CARNEY’S TRIAD

1. Multiple gastric stromal tumors*
2. Functioning, extra-adrenal paraganglioma
3. Pulmonary chondroma

*Succinate dehydrogenase-deficient, wild type for KIT/PDGFRA, often epithelioid morphology

Question 28

GI and PANCREATIC NEUROENDOCRINE TUMORS

• Grade 1:
• Grade 2:
• Grade 3:

Answer 28

GI and PANCREATIC NEUROENDOCRINE TUMORS

• Grade 1: <2 mf/10 hpf or <2% Ki67
• Grade 2: 2-20 mf/10 hpf or 3-20% Ki67
• Grade 3: > 20 mf/10 hpf or > 20% Ki67

Question 29

Location?

IHC?

A/W?

Answer 29

PSAMMOMATOUS CARCINOID

• Almost exclusively seen in the ampullary/periampullary location
• Immunoreactive for somatostatin (but somatostatinoma syndrome rare)
• Neurofibromatosis type 1

Question 30

GANGLIOCYTIC PARAGANGLIOMA * clinical course * location * Histologic triad

Answer 30

GANGLIOCYTIC PARAGANGLIOMA * benign course * exclusively in duodenum * Histologic triad 1. Zellballen nests 2. Epithelioid ribbons and nests 3. Fibrillary matrix with ganglion-like cells

Question 31

NEOPLASTIC POLYPOSIS

Answer 31

NEOPLASTIC POLYPOSIS * Familial Adenomatous Polyposis * Gardner Syndrome * Turcot Syndrome

Question 32

GASTRIC ADENOMAS

Answer 32

GASTRIC ADENOMAS * Intestinal type: high risk, seen in background of intestinal metaplasia * Foveolar type: low risk, seen in normal background; more commonly seen in FAP * Pyloric gland type: high risk, seen in background of intestinal metaplasia

Question 33

FAMILIAL ADENOMATOUS POLYPOSIS * CLASSICAL * ATTENUATED

Answer 33

FAMILIAL ADENOMATOUS POLYPOSIS * CLASSICAL * Autosomal dominant * Germline APC mutation * \> 100 polyps throughout * Cancer: 40 years age * ATTENUATED * Autosomal dominant * Germline APC mutation * \< 30 polyps, right-sided * Cancer: 55 years age

Question 34

HAMARTOMATOUS POLYPOSIS

Answer 34

HAMARTOMATOUS POLYPOSIS * Peutz-Jegher * Juvenile Polyposis * Cronkite-Canada * Cowden

Question 35

Answer 35

PEUTZ-JEGHER SYNDROME * Hamartomatous gastrointestinal polyps with aborizing smooth muscle * Primarily small bowel * Mucocutaneous pigmentation * Increased risk for GI, breast and pancreatic cancers

Question 36

JUVENILE POLYPOSIS

Answer 36

JUVENILE POLYPOSIS * Juvenile retention polyps * Dysplasia present in 30% cases * Increased risk for colorectal and gastric cancers * No mucocutaneous lesion

Question 37

CRONKITE-CANADA SYNDROME

Answer 37

CRONKITE-CANADA SYNDROME * Juvenile retention polyps, intervening mucosa abnormal * Ectodermal changes, including hair and nails * Nonfamilial, onset late adulthood * Protein-losing enteropathy

Question 38

COWDEN DISEASE

Answer 38

COWDEN DISEASE * Retention polyps, often with ganglion cells * Mucocutaneous lesions, including facial trichilemmomas * Increased risk for malignancies, including breast and thyroid * PTEN mutation

Question 39

MSI COLORECTAL CANCERS MORPHOLOGIC FEATURES

Answer 39

MSI COLORECTAL CANCERS MORPHOLOGIC FEATURES * Right sided * Poorly differentiated (medullary) and/ormucinous * Tumor-infiltrating lymphocytes (TIL), Crohn’s-like nodular lymphoid aggregates

Question 40

COLORECTAL MESENCHYMAL POLYPS

Answer 40

COLORECTAL MESENCHYMAL POLYPS * Leiomyoma * Schwannoma * Granular cell tumor * Polypoid ganglioneuroma