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Flashcards in GI Deck (322):
1

Acute liver failure can have 3 categories of histologic manifestations: necrosis with marked inflammatory activity, necrosis with little or no inflammation, or extensive microvesicular steatosis with little necrosis or inflammation. What etiologies fall under each category?

-Necrosis with marked inflammatory activity: idiosyncratic drug reactions, autoimmune hepatitis, viral hepatitis, Wilson disease. -Necrosis with little or no inflammation: acetaminophen toxicity, herpes simplex hepatitis, vascular diseases, Wilson disease. -Extensive microvesicular steatosis with little necrosis or inflammation: Reye syndrome, acute fatty liver of pregnancy, drugs (such as valproate and antiretrovirals).

2

Bile duct hamartomas, bile duct adenomas, and bile ductular proliferation.

Bile duct hamartoma or von Meyenburg complex is a type of ductal malformation that often occurs sporadically or as part of the spectrum of polycystic liver disease. It is commonly multifocal and located in or near the periphery of portal tracts. This lesion is usually small (0.5 cm), gray or white, and irregularly shaped. It consists of dilated, small to medium-sized ductular structures that usually contain inspissated bile. The ductules are separated by dense collagen and lined by cuboidal to flattened epithelium that shows no or minimal cytologic atypia. Bile duct adenoma is less common than bile duct hamartoma. It is typically noted in a subcapsular location but can be seen deep in the hepatic parenchyma. Bile duct adenomas may occur singly or as multiple lesions. This lesion is typically small (2 cm), white or gray, and firm. Microscopically, it consists of relatively uniform ductules lined by bland cuboidal epithelium and separated by fibrotic stroma, sometimes containing dense chronic inflammation. Mucinous differentiation and neuroendocrine cells can be found in bile duct adenomas. Since they are neoplasms, bile duct adenomas can display mild nuclear enlargement and atypia, but they lack marked variation in nuclear size and shape. Bile ductular proliferation is a reactive process that occurs in noncirrhotic or cirrhotic liver (especially when cirrhosis is associated with large areas of fibrosis). It can be seen as a reaction to obstruction of bile flow, a reaction to infarction, or as a sequela of tumor ablation. The reactive ductules usually show a uniform lobular architecture with bland, atrophic, flattened biliary epithelium. Acute inflammation is commonly present. Metastatic pancreatic adenocarcinoma can be difficult to differentiate from the benign biliary lesions mentioned above, especially on frozen section.

3

Carney Triad.

Characterized by the presence of at least 2 of the following 3: Gastric epithelioid leiomyosarcoma (now called GIST), extraadrenal paraganglioma, pulmonary hamartoma/chondroma. Primarily affects young women. Not familial.

4

Dieulafoy disease.

AKA Dieulafoy lesion, Dieulafoy ulcer, caliber persistent artery, gastric aneurysm, gastric arteriosclerosis, submucosal arterial malformation, cirsoid aneurysm, and solitary exulceration simplex. Defined as an abnormally large artery that retains a large caliber as it approaches the mucosa. The mean diameter of pathogenic arteries at the level of the muscularis mucosae is ~1mm, versus normal arteries having a diameter of ~0.1mm. There is also an accompanying vein. MC location is the lesser curvature of the stomach, b/c the submucosal arteries of the lesser curvature are direct branches of the left gastric artery, whereas in the rest of the stomach, the submucosal vessels are of much smaller caliber b/c of their serial branching. The disease usually occurs in males, and there is a wide age range at time of occurrence.

5

Differential diagnosis for spindle cell neoplasms of the GI tract?

GISTs, leiomyosarcoma, schwannoma, solitary fibrous tumor, desmoid-type fibromatosis, metastatic melanoma.

6

Dysplasia of the biliary tract, considered as preinvasive biliary neoplasia, has been noted in __% to __% of patients with invasive carcinoma, __% of patients with sclerosing cholangitis, and incidentally in __% to __% of cholecystectomy specimens.

Dysplasia of the biliary tract, considered as preinvasive biliary neoplasia, has been noted in 40% to 60% of patients with invasive carcinoma, 30% of patients with sclerosing cholangitis, and incidentally in 1% to 3.5% of cholecystectomy specimens.

7

Examples of pseudoneoplastic lesions in the alimentary tract and their related neoplastic mimes.

Pseudocarcinomatous epithelial hyperplasia (adenocarcinoma). Enteritis/colitis cystica profunda (adenocarcinoma). Adenomyoma of duodenum (well-differentiated adenocarcinoma). Tumefactive chronic pancreatitis (well-differentiated ductal adenocarcinoma). Mycobacterial pseudotumors (sarcomas). Bacillary angiomatosis (hemangiomas). Florid lymphoid hyperplasia (lymphomas). Hepatic bile duct hamartoma (metastatic adenocarcinoma). Hepatic focal nodular hyperplasia (fibrolamellar hepatocellular carcinoma). Inflammatory cloacogenic polyp (tubulovillous adenoma). Xanthogranulomatous cholecystitis (sarcomatoid carcinoma).

8

Gallbladder carcinoma epidemiology.

Gallbladder carcinoma shows female predominance (F:M = 3–4:1). The mean age of patients is 65 years. It is more common in some Latin American countries such as Chili, Mexico, and Bolivia. In the United States, Native and Hispanic Americans have a higher rate of gallbladder cancer than other ethnic groups. Gallbladder carcinomas are associated with gallstones (80%), porcelain gallbladder (20%), and abnormal choledochopancreatic duct junction.

9

In what pattern does hepatocellular carcinoma stain with pCEA?

Canalicular pattern. This pattern results from cross-reactivity with biliary glycoprotein I and is demonstrated in 90% of HCCs and is not seen with monoclonal CEA. Similar to pCEA, villin and CD10 also show a canalicular pattern of staining.

10

List mesenchymal lesions of the GI tract with typical histologic and anatomic locations.

Inflammatory fibroid polyp; submucosal; antrum, small bowel, colon, esophagus. GIST; mural (muscularis propria); stomach, small bowel, colon, esophagus. Inflammatory myofibroblastic tumor; mesenteric, rarely mural; colon, small bowel, stomach, esophagus. Schwannoma; mesenteric, rarely mural (muscularis propria); stomach, colo-rectum, esophagus, small bowel. Fibroblastic polyp; mucosal; left colon. Mesenteric fibromatosis; mesenteric, retroperitoneal; small bowel, colon, stomach secondary involvement. Perineurioma; mucosal, submucosal; left colon, jejunum. Synovial sarcoma; mucosal, submucosal; esophagus, stomach. F and I dendritic cell sarcoma; mesenteric or, rarely, mural; stomach, duodenum, small bowel, colon. Leiomyosarcoma; mural; rare - found from esophagus to rectum.

11

List pathologic processes characterized by infiltrates of eosinophilic cells in the alimentary tract.

Malakoplakia. Crystal-storing histiocytosis (plasma cell dyscrasias, lymphoproliferative disorders, clofazimine-induced histiocytosis, eosinophilic colitis). Russell bodies gastritis. Granular cell tumor. Decidual reaction. Histiocytic infiltrate or infections.

12

List pathologic processes characterized by infiltrates of foamy cells in the alimentary tract.

Xanthoma. Muciphages. Whipple disease. Infections (Histoplasmosis, Rhodococcus equi, Mycobacterium avium-intracellulare complex). Melanosis coli. Hereditary metabolic storage disorders.

13

List pseudoneoplasms of the GI tract according to location (entire alimentary tract, esophagus, stomach, and intestines).

Entire alimentary tract: inflammatory fibroid polyp, xanthoma, lipoma-like lesions, ectopias and heterotopias, pseudotumors due to infections, benign signet ring cell infiltrates. Esophagus: fibrovascular polyp, melanosis of the esophagus, pseudodiverticulosis. Stomach: gastritis cystica profunda, inverted hyperplastic polyp, Russell bodies gastritis. Intestines: mucosal prolapse-related lesions, malakoplakia, tumefactive endometriosis, prolapsing mucosal folds of diverticular disease, hypertrophic and papilla, elastofibromatous lesions.

14

List type and sites (in decreasing order of frequency) of heterotopias of the GI tract.

Gastric; upper esophagus, duodenum, Meckel diverticulum, rectum. Pancreatic; antrum, ampulla, Meckel diverticulum, remaining segments of intestine. Sebaceous glands; throughout esophagus. Salivary glands; rectum, perianal. Prostate gland; anal canal. Thyroid and parathyroid glands; upper esophagus.

15

M:F of intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma?

M=F for intrahepatic cholangiocarcinoma, and M>F for extrahepatic cholangiocarcinoma.

16

Metastatic Crohn disease.

MCD is an entity characterized by cutaneous, noncaseating granulomas at sites anatomically separate from the GI tract. It is the least common dermatologic manifestation of Crohn disease. In adults, the age of onset of MCD ranges from approximately 29 to 39 years, and the majority of patients have a previous diagnosis of Crohn disease. Twenty percent of patients with MCD may present without classical manifestations of Crohn disease. In these patients, Crohn disease manifests in 2 months to 4 years after the initial presentation of MCD. Cutaneous lesions of MCD may present as papules, plaques, nodules, and ulcerations, which may involve the arms, legs, genitalia, and face. Lesions have also been noted to have predilection for the moist environment of skin folds, including submammary and abdominal creases as well as the perineal and inguinal regions. MCD may present as a solitary lesion or occur in multiple sites and may be painless or tender upon palpation. In the pediatric population, MCD typically presents from the ages of 10 to 14, with about 50% of these patients having concurrent Crohn disease. Of these patients, approximately one-half have active gastrointestinal symptoms. In children who present with MCD lesions without evidence of Crohn disease, subsequent onset of gastrointestinal manifestations occurs from 9 months to 14 years after the initial presentation of MCD. The genitalia appear to be the most common area of involvement in children with MCD; the most common cutaneous manifestation presents as labial, penile, and/or scrotal swelling with or without accompanying erythema. Genital ulcerations have also been reported. MCD presents microscopically as sterile, noncaseating granulomatous inflammation located primarily in the superficial papillary and deep reticular dermis with occasional extension into the subcuticular fat. The granulomas consist of Langerhans giant cells, epithelioid histiocytes, lymphocytes, and occasional plasma cells. The underlying etiology of MCD is currently unknown. It has been suggested that antigens or immune complexes stemming from the GI tract in primary Crohn disease travel through the circulatory system and deposit in the skin, creating perivascular granulomatous features seen on microscopic examination of MCD lesions. Autoimmune cross-reactivity has also been suggested, where antibodies specific to antigens in the GI tract that may be responsible for inflammatory Crohn disease react with skin antigens of similar structure. The differential diagnosis of MCD consists of any granulomatous entities that may involve the skin, including but not limited to cutaneous sarcoidosis, erythema nodosum, pyoderma gangrenosum, hidradenitis suppurativa, mycobacterial disease, and foreign body reaction.

17

Morphologic features to distinguish reactive atypia from dysplasia in gallbladder.

Acute inflammation and/or ulceration; + in RA, - in D. Intraepithelial neutrophils; + in RA, - in D. Abrupt transition between normal and atypical epithelium; - in RA, + in D. Fine nuclear chromatin; - in RA, + in D. Prominent nucleoli; + in RA, -/+ in D. Surface maturation; + in RA, -/+ in D. Loss of polarity; - in RA, + in D. History of instrumentation; + in RA, - in D.

18

Relationship of EGFR and KRAS to colorectal carcinomas?

The EGFR signaling pathway is overexpressed in ~80% of CRCs. When EGF, as well as several other ligands, occupies the EGFR, it activates a signaling pathway cascade through the downstream effectors of the mitogen-activated protein kinases (MAPK) pathway. These effectors (KRAS, BRAF, ERK, and MAPK) influence cellular proliferation, adhesion, angiogenesis, migration, and survival. Blocking EGFR with cetuximab (Erbitux) or panitumumab (Vectibix) blocks all downstream effects of this receptor and is the basis of these therapeutic agents. ~30-40% of CRCs harbor mutations in KRAS that yield a constitutively active protein, where blockage of the EGFR does not affect the downstream signaling cascade of the MAPK pathway. KRAS mutations typically occur in codons 12 or 13 (exon 2) or in codon 61 (exon 3) of the KRAS gene. Only patients whose CRCs carry a wild-type sequence of KRAS have a favorable response to cetuximab or panitumumab; patients with mutations in codons 12 or 13 do not benefit. Hence, the NCCN guidelines with the recommendation that mutation analysis of the KRAS gene on the primary tumor or a site of metastasis should be part of the pretreatment workup for all patients with stage-IV CRC.

19

Sarcomatoid carcinoma of the esophagus.

AKA carcinosarcoma, pseudosarcoma, pseudosarcomatous squamous cell carcinoma, spindle cell carcinoma, and polypoid carcinoma, reflecting the uncertainty of its pathogenesis. Sarcomatoid carcinoma represents ~2% of esophageal carcinomas. Most authors believe the sarcomatous component results from metaplasia of carcinoma cells, others believe that 2 distinct malignancies coexist, and others believe the sarcomatoid component is of epithelial origin. More common in men, age is usually 60-70 years. ~60% arise in the midesophagus, ~33% in the distal, and <10% in the proximal. Grossly, these tumors are polypoid masses, commonly attached to the wall by a pedicle, but occasionally the tumors have a broad base. The surrounding mucosa is normal. Cut surface is white-gray, soft, and fleshy. Microscopically, these tumors are biphasic, containing a mixture of carcinoma and malignant sarcomatoid elements, with the latter generally forming the bulk of tumor. The epithelial component is usually squamous in nature and ranges from in situ or minimally invasive to infiltrating nests admixed with spindle cells. The sarcomatous component is typically composed of undifferentiated, spindled cells arranged in a fascicular or storiform pattern. These cells are embedded in an undifferentiated matrix that is edematous and contains scattered collagen fibers. Stromal differentiation has been reported with bizarre giant cells and with osseous and cartilagenous differentiation. The epithelial component is cytokeratin positive. The mesenchymal component is strongly vimentin positive; it may occasionally have cytokeratin immunoreactivity, but when present is almost always focal and less intense. The sarcomatoid cells are occasionally reactive with actin and desmin. The prognosis is much better than that of common squamous cell carcinoma b/c the sarcomatoid carcinoma tumors tend to grow into the lumen rather than the wall. Despite their size (up to 15 cm), they typically invade no deeper than the lamina propria or the submucosa. Usually treated surgically with esophagogastrectomy. Metastases may be carcinomatous, sarcomatoid, or mixed.

20

Small intestinal bacterial overgrowth.

SIBO is a common cause of chronic diarrhea and malabsorption. It results from colonization of the proximal small bowel by gram-negative aerobic and anaerobic bacteria that are normally restricted to the colon or, less frequently, from overgrowth of oropharyngeal flora. A predisposition to SIBO exists in diverse conditions where there is altered anatomy from prior surgery (eg, blind loop syndrome) or stricture or where there is impaired gut motility and prolonged orocecal transit time. The gold standard for diagnosis is a small intestinal aspirate culture showing growth of at least 10^5 colony-forming units of bacteria per milliliter (CFU/mL) of duodenal or jejunal fluid. Cultures of small-bowel mucosal biopsies can be substituted when there are inadequate luminal secretions. Histologically, mild or moderate villous blunting is the only change seen, and this is seen in only ~50% of symptomatic pts with the culture diagnosis of SIBO. The high rate of histologically "normal" biopsies does not negate the pathogenic role of bacterial overgrowth in symptomatic pts. It has been hypothesized that excess colonic flora within the small intestine can impede fat digestion by deconjugating bile acids and hindering the formation of micelles, that these bacteria can induce vitamin B12 deficiency, and that they can result in osmotic or secretory diarrhea through the production of organic acids. All of these proposed mechanisms can coexist with microscopically health small bowel mucosa.

21

What % of colorectal adenocarcinomas express nuclear CDX2 and apical/luminal/cytoplasmic villin?

Nearly 100%.

22

What 2 CK immunostains can be used to distinguish cholangiocarcinoma and hepatocellular carcinoma?

CK7 and CK19. Cholangiocarcinoma is CK7+ CK19+, while hepatocellular carcinoma is CK7- CK19-.

23

What are some non-gastrointestinal manifestations of Crohn disease?

Along with the characteristic GI findings of this disease, patients with Crohn disease may also present
with extraintestinal manifestations including ocular findings, musculoskeletal pathology, and mucocutaneous manifestations. Mucocutaneous findings are the most frequent extraintestinal manifestation of Crohn disease; 22% to 44% of patients present with mucocutaneous changes, which may be categorized as granulomatous skin disease, oral manifestations, cutaneous changes secondary to nutritional deficiencies, and cutaneous disorders that have been associated with Crohn disease (eg, pyoderma gangrenosum, erythema nodosum, erythema multiforme, and epidermolysis bullosa acquisita). Included within the granulomatous cutaneous category are perianal, peristomal, and perifistular inflammatory lesions, which are contiguous with the gastrointestinal tract and are the most common cutaneous manifestations of Crohn disease.

24

What are the current endoscopic and histologic criteria of the mucosal esophagogastric junction?

For endoscopy:
1. The distal end of esophageal longitudinal mucosal veins.
2. The proximal end of gastric longitudinal mucosal folds.
3. The squamocolumnar junction in most Japanese and Chinese subjects.
For histology:
1. The distal end of squamous mucosa.
2. The distal end of deep esophageal glands and ducts.
3. The distal end of multilayered epithelium.
In patients with active esophagitis, ulcers, or hiatal hernias, endoscopy #1 and #2 landmarks may not be determined with certainty, and patients should be treated with PPIs before endoscopy.
In a healthy person, the SCJ overlaps with mucosal EGJ; however, in patients with ulcers, hiatal hernias, and columnar-lined epithelium, the SCJ is not stable and cannot be used as the landmark for the true mucosal EGJ. In most Japanese and Chinese individuals, the SCJ overlaps with the EGJ, so the SCJ may be used as a surrogate landmark of the mucosal EGJ in these populations. However, that seems not to be the case in other populations.

25

What do GISTs stain + for?

CD117 (c-kit) (>95%), and may stain + for CD34, SMA, desmin, nestin, and S100. DOG-1 (Discovered On GIST-1)/PDGFR-alpha is useful for c-kit negative GISTs. Up to 47% of small bowel GISTs and 10-14% of rectal and esophageal GISTs stain for SMA.

26

What is CD117/c-kit?

A transmembrane TK receptor involved in mitogenic signaling. Stains GISTs in a strong, diffuse, pancytoplasmic, and sometimes membranous pattern. Some GISTs show a cytoplasmic "dotlike" pattern, and these are more likely to be extraintestinal or show epithelioid morphology. CD117 also stains mast cells, some hematopoietic precursor cells, melanoma, renal cell carcinoma, and seminoma.

27

What is seen histologically in skin and GI biopsies from patients with acute GVHD?

The skin biopsy initially shows epidermal basal vacuolization and focal epidermal apoptosis with lymphoid infiltration. Bullae formation with epidermal separation can extend to erythroderma, and necrosis is observed in later stages. In grade I, there is vacuolization of the basal keratinocytes; in grade II, there are dyskeratotic keratinocytes and basal cell vacuolization; in grade III, there is increased keratinocyte necrosis and focal basal layer clefting; in grade IV, there is necrosis of the entire epidermis and complete separation from the dermis. There are various degrees of lymphocytic infiltration. The microscopic findings of early GVHD are similar to erythema multiforme, while the severe form resembles toxic epidermal necrolysis.
The GI biopsy shows diffuse edema and mucosal swelling followed by variable crypt cell apoptosis ("exploding" crypts) and a mixed chronic and predominantly lymphoplasmacytic infiltrate, and there can be crypt dropout. In grade I, there is increased crypt apoptosis; in grade II, there is apoptosis with crypt abscess; in grade III, there is crypt necrosis; in grade IV, there is total denudation of mucosal areas. The immunosuppressive drug mycophenolate mofetil can cause variable GI mucosal injury patterns, including GVHD-like changes.
In the skin and GI tissue affected by GVHD, the mechanism of apoptosis is likely similar and caused by alloreactive T lymphocytes targeted to alloantigen on recipient tissue.

28

What types of metaplasia occur in the biliary tract?

Two major types of metaplasia occur in the biliary tract: gastric and intestinal. Gastric metaplasia is the most common type of metaplasia and is found in about 50% of gallbladders removed for chronic cholecystitis or cholelithiasis. The lesion appears to begin in the base of the crypt as buds or branches. Secondary branches then occur and are arranged either in a lobular or a diffuse pattern. Gastric metaplasia recapitulates the gastric pyloric or antral mucosa. Morphologically, pyloric gland metaplasia shows small branching glands that are composed of columnar or cuboidal cells with abundant bubbly cytoplasm. Pyloric gland metaplasia can be indistinguishable from pyloric gland adenoma, except that adenoma usually forms a discrete lesion grossly. An arbitrary cutoff of 5 mm has been used to separate these 2 lesions. Intestinal metaplasia is noted in around 30% of gallbladders excised for cholelithiasis. The incidence of intestinal metaplasia appears to increase with age and with the duration of gallstone disease. The initial lesion begins as a few goblet cells at the tips of the mucosal folds rather than the base of the crypts. This is followed by a downward progression of the lesion, possibly reaching the Rokitansky-Aschoff sinuses. When fully developed, the intestinal metaplasia consists of variable amounts of goblet or columnar cells with a brush border. Paneth and endocrine cells can also be found. Although metaplastic cells can show pseudostratification and mild nuclear atypia, the presence of only basal pseudostratification and the absence of significant atypia favor metaplasia over dysplasia. In addition, squamous metaplasia, a rare type of metaplasia, can be seen in the gallbladder and biliary tract. Squamous metaplasia tends to be associated with gallstones and can lead to squamous dysplasia or squamous cell carcinoma.

29

What is enteric hyperoxaluria?

It is the most common etiology of oxalate nephropathy and is caused by fat and/or bile acid malabsorption, leading to steatorrhea. Under normal conditions, calcium and oxalate complex with each other in the colonic lumen and are excreted in the feces. In the setting of fat malabsorption, high levels of free fatty acids are present in the intestinal lumen and bind calcium, thereby reducing the amount of free calcium available to bind oxalate. This results in high intestinal levels of free oxalate, which is readily absorbed by the colonic epithelium and ultimately precipitates as calcium oxalate crystals in the kidney. In addition, the presence of high levels of free fatty acids and bile salts enhances colonic mucosal permeability to oxalate, further promoting oxalate absorption. Enteric hyperoxaluria can be seen in patients with inflammatory bowel disease, pancreatic insufficiency, following bowel surgery (including jejunoileal bypass and rou-en-Y gastric bypass), and use of gastrointestinal lipase inhibitors such as orlistat.

30

Sclerosing mesenteritis is an idiopathic inflammatory and fibrotic process which has been referred to by a variety of names, including...

Sclerosing mesenteritis is an idiopathic inflammatory and fibrotic process which has been referred to by a variety of names, including refractile mesenteritis, lipogranuloma of the mesentery, primary liposclerosis of the mesentery, multifocal subperitoneal sclerosis, mesenteric panniculitis, and mesenteric lipodystrophy.

31

Hep-Par 1, MOC31, p-CEA, and GPC-3 stains for diagnosis of HCC and differentiation from adenocarcinomas.

Expression of Hep-Par 1 with negative MOC31 in the appropriate clinical and morphological setting confirms the diagnosis of HCC. Hep-Par 1 has high sensitivity for HCC. Hep-Par 1 is negative in most adenocarcinomas originating in the pancreas, biliary tree, breast and colorectum. Strong expression has been noted in lung and gastroesophageal adenocarcinomas, but is generally accompanied by strong MOC31 expression. Hepatoid adenocarcinomas of the gastrointestinal tract are also positive for Hep-Par 1. If the staining with Hep-Par 1 is weak or absent, but suspicion of HCC persists based on clinical and imaging findings, other markers of hepatocellular differentiation can be sought such as polyclonal CEA (p-CEA) or glypican-3 (GPC-3). p-CEA shows a canalicular pattern of staining, which is considered pathognomonic of HCC. In contrast, most adenocarcinomas show luminal or cytoplasmic pattern of staining with p-CEA. Both Hep-Par 1 and p-CEA have low sensitivity for poorly-differentiated HCC (around 50%). GPC-3 can be helpful in this situation as it has higher sensitivity for poorly-differentiated HCC. MOC31, a cell surface glycoprotein is negative in >90% of HCC, while majority of adenocarcinomas are positive. This antibody along with one or more hepatocellular markers is extremely useful for the diagnosis of HCC.

32

Membranoproliferative glomerulonephritis is a well-known manifestation of hepatitis ___. In the setting of malignancies, MPGN is often associated with ___, and is less common observed with solid tumors.

Membranoproliferative glomerulonephritis is a well-known manifestation of hepatitis C. In the setting of malignancies, MPGN is often associated with non-Hodgkin lymphoma, and is less common observed with solid tumors.

33

What tumors are seen in the subtypes of MEN syndrome?

MEN1: Pancreatic tumors (gastrinoma 50%, insulinoma 20-30%, VIPoma 12%, glucagonoma 33%), parathyroid adenomas, pituitary adenomas. MEN 2A: Medullary thyroid carcinoma, parathyroid adenomas, pheochromocytoma. MEN 2B: Medullary thyroid carcinoma 85%, pheochromocytoma 50%, mucosal neuroma 100%, marfanoid body habitus 80%. FMTC: Medullary thyroid carcinoma 100%.

34

Biliary atresia. Epidemiology and classification.

Biliary atresia is an inflammatory cholangiopathy of infancy that results in progressive fibrosis and obliteration of extrahepatic and intrahepatic bile ducts and represents the main indication for liver transplant in young children. The portoenterostomy/Kasai procedure is the only form of therapy that can be offered to these patients besides liver transplant. The reported incidence of biliary atresia shows some regional variability, being higher in Asia and the Pacific region. Biliary atresia is broadly classified into 2 main forms. The first form is the embryonic/fetal, "early," or syndromic form (10-20% of cases), which is associated with a high frequency of additional congenital malformations (including asplenia, polysplenia, cardiovascular defects, situs inversus, intestinal malrotation, small-intestinal atresia, anomalous choledochopancreatic ductal junction, and various positional abnormalities of the portal vein and hepatic artery), and is referred to as biliary atresia-splenic malformation (BASM) syndrome. Cystic dilatation of biliary remnants may be seen in a small minority of cases of fetal-type biliary atresia (5-10% of cases) and these cases are referred to as cystic biliary atresia. The second form is the perinatal/postnatal, "late," or nonsyndromic form (80-90% of cases), generally occuring as an isolated abnormality.

35

What can cause false-positives or false-negatives in liver biopsies for biliary atresia?

False-positives can be seen with total parenteral nutrition-associated liver disease, and alpha 1-antitrypsin deficiency. False-negatives can be seen with early age at biopsy (<5-6 portal tracts).

36

Susceptibility to celiac disease is primarily associated with which human leukocyte antigen alleles?

Susceptibility to celiac disease is primarily associated with the HLA-DQ2 allele (~95% of patients with CD), and also associated with HLA-DQ8 (~5% of patients with CD).

37

Pathogenesis/immunology of celiac disease.

Among autoimmune diseases, CD is one of the few where the offending antigen is known (gluten). Gluten is mostly made up of 2 groups of proteins: ethanol-soluble gliadins and ethanol-insoluble glutenins. Gliadin contains large amounts of the amino acids proline and glutamine. It is known that alpha-gliadin among other peptides is toxic to celiac patients. The pathogenesis of CD involves a CD4+ T-cell mediated immune response to gliadin peptides, activation of a CD8+ T-cell intraepithelial innate immune response, and production of antibodies against tissue transglutaminase, as well as anti-gliadin, anti-reticulin, and anti-endomysial antibodies. In 1997, tissue transglutaminase type II was identified as the major autoantigen of CD (and also the epitope recognized by anti-endomysial antibodies). Tissue transglutaminase is an 85-kDa enzyme that is expressed in multiple tissues. Gliadin can serve as a substrate of transglutaminase, which is activated upon injury of inflammation of the small bowel, and in the process becomes cross-linked to transglutaminase, thereby creating a neoantigen, which induces an immune response to the self-protein (transglutaminase). Moreover, tissue transglutaminase can selectively deamidate gliadin peptides, leading to enhanced T-cell stimulatory activity. The ensuing inflammatory cascade produces inflammatory cytokines, proteinases, and other tissue-damaging mediators that induce mucosal tissue damage, leading to the characteristic histopathologic alterations.

38

Serologic testing in celiac disease.

The most sensitive antibody tests detect IgA-class antibodies against tissue transglutaminase (tTGA) and endomysium (EMA). The anti-gliadin antibodies are no longer considered sensitive or specific enough to be used for routine clinical detection of CD, except in children younger than 18 months of age, because anti-gliadin IgA antibodies are considered to be the first autoantibodies to appear after intestinal exposure to a gluten-containing diet. Serologic IgA tTGA antibody testing is considered to be the most sensitive method for detecting CD, with sensitivity approaching 97% in clinical practice, while IgA EMA antibodes are highly specific markers for CD, approaching 100%. The presence of titers of both tTGA and EMA antibodies have been shown to correlate with the degree of mucosal damage. Seronegative CD does occur, accounting for up to 15% of all CD patients. Recently, a new test for detecting antibodies against deamidated aliadin peptides (DGP) was introduced, which displays promising results and a high specificity (99%). DGP IgA testing may have greater sensitivity for the detection of adequate adherence to a gluten-free diet.

39

How is celiac disease most commonly classified?

In 1992, Marsh introduced a grading scheme to classify the morphologic spectrum of gluten-sensitive enteropathy. In 1999, Oberhuber modified some of the parameters and published a modified scheme. The Marsh-Oberhuber classification described 5 interrelated states of small-intestinal mucosal injury (types 0-4). Increased IELs (intraepithelial lymphocytes) are defined as = or >30 IELs/100 enterocytes. Type 0: Preinfiltrative, normal small-intestinal mucosa with no increase in IELs. Type 1: Infiltrative type, which is characterized by a normal villous and crypt architecture (normal villous to crypt ratio of >3:1) and an increased number of IELs. Type 2: Infiltrative-hyperplastic type, which is characterized by a normal villous architecture and crypt hyperplasia with an increased number of IELs. Type 3: Destructive (flat mucosa) type of CD lesion. It is divided into 3 different subgroups depending on the degree of villous atrophy. Type 3a: Mild villous atrophy with villous to crypt ratio of <1:1, and in increased number of IELs. Type 3c: Total villous atrophy with completely flat mucosa and an increased number of IELs. Type 4: Atrophic type (also referred to as the hypoplastic lesion) is characterized by flat mucosa with only a few crypts visualized and near-normal IEL counts. It is usually found in patients with refractory sprue, ulcerative jejunoileitis, and enteropathy-associated T cell lymphoma.

40

Differential diagnosis of small bowel mucosa with normal villous architecture and increased intraepithelial lymphocyte counts.

Celiac disease. Food hypersensitivity. Peptic ulcer disease. H. pylori-associated gastroduodenitis. Drugs (NSAIDs, PPIs). Infections (viral enteritis, Giardia, Cryptosporidium). Immune dysregulation (SLE, RA, Hashimoto thyroiditis, autoimmune enteropathy). Immunodeficiency (common variable immune deficiency). Graft-versus-host disease. Bacterial overgrowth. Lymphocytic and collagenous colitis. Irritable bowel syndrome.

41

Differential diagnosis of small bowel mucosa with villous atrophy and with/without increased intraepithelial lymphocyte count.

Celiac disease. Infections (tropical sprue). Refractory sprue. Collagenous sprue. Immune dysregulation (autoimmune enteropathy). Immunodeficiency (common variable immune deficiency). Graft-versus-host diesease. Inflammatory bowel disease (Crohn disease). Drugs (mycophenolate mofetil, colchicine). Chemoradiation therapy. Nutritional deficiency. Eosinophilic enteritis. Bacterial overgrowth. Lymphoma.

42

What is refractory celiac diasease (RCD)?

A subgroup of patients with CD (~5%) may develop RCD, a condition that has also been referred to as refractory sprue, which is characterized by persistent symptoms and severe villous atrophy not responding to a gluten-free diet for at least 6 months. Both primary and secondary forms of the disease have been described. The diagnosis of RCD is made after exclusion of other small-bowel diseases, such as tropical sprue, common variable immune deficiency, or autoimmune enteropathy. RCD may be subdivided into 2 subtypes (RCD type 1 and RCD type 2). Cases of RCD type 1 display a normal IEL phenotype, that is, CD3+ and CD8+. In cases of RCD type 2, the IELs show an aberrant phenotype in that intracytoplasmic CD3 expression is noted, but surface CD3, and often CD8, are not present; additionally, a clonal T-cell receptor gene arrangement is detected. RCD type 1 often responds to therapy with immunomodulatory agents and patients have a low risk of progression to lymphoma, whereas RCD type 2 either has a transient response or is refractory to immunosuppressive agents, and patients often manifest ulcerative jejunitis and are at an increased risk for enteropathy-associated T cell lymphoma. Patients with type 2 RCD have a very poor prognosis with a 5-year survival rate of <50%.

43

What is collagenous sprue?

CS is a rare type of small-bowel enteropathy associated with chronic diarrhea and severe malabsorption, typically affecting middle-aged or elderly females. Histologically, CS is characterized by villous atrophy, crypt hyperplasia, and a thick subepithelial collagen band (>10 um) that entraps small capillaries and cellular elements in the lamina propria. A significant percentage (40-86%) of patients with CS have celiac disease, especially refractory celiac disease. However, a clear etiology of this disorder in some cases remains undetermined. Patients with CS were thought to have a uniformly poor prognosis with high morbidity (due to severe malnutrition) and mortality, but recent studies have shown that with current therapeutic management strategies, including active monitoring for adherence to a gluten-free diet and/or use of immunomodulatory drugs, patients with CS can have good clinical outcomes.

44

Alpha-1-antitrypsin deficiency genetics.

AAT deficiency is the most common genetic cause of liver disease in children and a major cause of hereditary liver dysfunction in adults, second only to hereditary hemochromatosis as the leading genetic cause of liver disease in adults. AAT is a glycoprotein produced predominantly in hepatocytes that functions as an inhibitor of serine proteases. AAT deficiency is caused by mutations in the SERPINA1 gene on chromosome 14q31-32.3 and is inherited in an autosomal recessive pattern. The genetic mutation results in a conformational abnormality (misfolding) of the AAT glycoprotein, abnormal retention of a polymerized form in the endoplasmic reticulum of hepatocytes, and low serum levels of AAT (approximately 15% normal). The normal allele is designated PiM and the two most common variant alleles are PiS and PiZ, resulting from single base pair mutations in exons III and V, respectively. The resultant amino acid substitutions in the AAT protein alter the net charge of the protein and allow detection of the normal type (MM), carrier types (MS, MZ) and deficiency variants (SS, SZ, ZZ) by isoelectric focusing (Pi (protease inhibitor) typing). Hepatic cirrhosis is most often associated with PiZZ type.

45

Alpha-1-antitrypsin deficiency epidemiology.

AAT deficiency has an incidence of approximately 1 in 4000 livebirths, with 3.4 million AAT-deficient individuals and 116 million carriers worldwide. Although generally considered to be a disease of Caucasians from northern Europe, AAT deficiency is known to occur in all racial groups and is underdiagnosed, particularly in non-Caucasian populations. AAT deficiency results in severe liver disease in only approximately 3 – 10% of affected individuals, suggesting a role for other modifier genes and concurrent environmental factors potentiating the progression of liver disease. Age at presentation is highly variable, from the neonatal period to adulthood. Signs and symptoms of liver disease in infancy include neonatal cholestasis, conjugated hyperbilirubinemia, abdominal swelling, and poor feeding, whereas the more slowly progressive forms manifesting in late childhood or adulthood typically produce fatigue, poor appetite, abdominal swelling, asymptomatic hepatomegaly and/or splenomegaly, jaundice, pruritis, peripheral edema, and abnormal elevation of liver enzymes.

46

Mechanisms of injury in alpha-1-antitrypsin deficiency, and types of systemic disease associated with alpha-1-antitrypsin deficiency.

The pathologic consequences of deficient alpha-1-antitrypsin are primarily restricted to the lungs and liver. In the lung, deficiency of serum alpha-1-antitrypsin results in unopposed proteolytic destruction of alveolar tissue by neutrophil elastase, and therefore results in progressive panacinar emphysema, typically presenting in the fifth or sixth decade of life in non-smokers and fourth decade of life in smokers. Other pulmonary manifestations include chronic bronchitis, bronchiectasis, and asthma. In the liver, endoplasmic reticulum storage of the abnormal protein results in progressive liver injury, hepatitis, liver failure, and cirrhosis. The pathogenesis of liver cell injury is thought to be secondary to mitochondrial injury, activation of autophagy, and caspase activation leading to apoptosis. Hepatocellular carcinoma is also an associated complication. Other reported systemic diseases associated with AAT deficiency include necrotizing panniculitis, glomerulonephritis, arterial aneurysms, gastrointestinal bleeding, rheumatoid arthritis, anti-proteinase3-associated vasculitis (Wegener granulomatosis), and other immune-mediated vasculitis.The pathologic consequences of deficient alpha-1-antitrypsin are primarily restricted to the lungs and liver. In the lung, deficiency of serum alpha-1-antitrypsin results in unopposed proteolytic destruction of alveolar tissue by neutrophil elastase, and therefore results in progressive panacinar emphysema, typically presenting in the fifth or sixth decade of life in non-smokers and fourth decade of life in smokers. Other pulmonary manifestations include chronic bronchitis, bronchiectasis, and asthma. In the liver, endoplasmic reticulum storage of the abnormal protein results in progressive liver injury, hepatitis, liver failure, and cirrhosis. The pathogenesis of liver cell injury is thought to be secondary to mitochondrial injury, activation of autophagy, and caspase activation leading to apoptosis. Hepatocellular carcinoma is also an associated complication. Other reported systemic diseases associated with AAT deficiency include necrotizing panniculitis, glomerulonephritis, arterial aneurysms, gastrointestinal bleeding, rheumatoid arthritis, anti-proteinase3-associated vasculitis (Wegener granulomatosis), and other immune-mediated vasculitis.

47

Differential diagnosis of alpha-1-antitrypsin deficiency in neonates and in adults.

In neonates, the differential diagnosis of AAT deficiency is dependent on the histologic pattern, but includes extrahepatic biliary atresia (duct proliferation pattern), neonatal giant cell (viral) hepatitis (hepatocellular necrosis pattern), and Alagille syndrome (bile duct paucity pattern). In adults, the differential diagnosis of chronic hepatitis and cirrhosis is broad and includes alcoholic cirrhosis, hepatitis B or C viral infection, non-alcoholic fatty liver disease, autoimmune hepatitis, Wilson’s disease, and hereditary hemochromatosis.

48

At the cellular level, how can one tell the right side of the colon and the left side of the colon apart?

The lamina propria that surrouonds the crypts nomally contains eosinophils, lymphocytes, plasma cells, and a few histiocytes. It is important to know where the biopsy came from in the colon to determine if the cellularity is within normal range. Relative to the left colon and rectum, the right colon contains greater numbers of inflammatory cells in the lamina propria. Normally there are many more plasma cells and eosinophils in the lamina propria of the right colon. The closer one gets to the ileocecal valve, the more inflamed the lamina propria looks. The left side of the colon contains significantly fewer cells within the lamina propria, and the surface epithelium contains more goblet cells and fewer absorptive cells relative to the right colon. Lamina propria eosinophilis are ~3x more numerous in the ascending relative to the descending colon. Eosinophils also show seasonal and geographic variability. In the right colon, Paneth cells are a normal constituent, and in children they may even be present in the normal transverse colon. When Paneth cells are encountered in the left colon and rectum, their presence provides a useful marker of previous mucosal injury. Occasional intraepithelial lymphocytes, typically T cells, are a normal finding. There should be ~1 lymphocyte for every 20 epithelial cells. There tend to be a few extras on the right side as compared with the left side.

49

What are some histologic features to distinguish acute self-limited colitis from acute-onset Crohn's disease?

The most reliable histologic criteria for distinguishing ASLC from acute-onset UC are the preservation of crypt architecture and the lack of plasmacytosis in the lamina propria in ASLC. The presence of either or both of these features should make one think of a chronic colitis and not ASLC. Small granulomas, usually secondary to crypt rupture, may be encountered in ASLC and should not lead one to an automatic diagnosis of CD.

50

Are colonic pseudomembranes pathognomonic for C. difficile infection?

C. difficile infection can often be identified endoscopically and histologically by its characteristic pseudomembrane formation, but C. difficile infection does not always have pseudomembranes, as some cases have biopsy findings identical to those of any other generic acute self-limited colitis. If severe mucosal damage occurs, with coagulative necrosis and pseudomembranes, the histologic features may overlap with those of ischemic colitis or enterohemorrhagic E. coli infections.

51

Some bacterial colonic infections cause histologic changes that are characteristic of a given organism. What can be seen with Yersinia and Salmonella infections?

Yersinia may show stellate foci of necrosis within lymphoid aggregates and aphthous lesions in the area of the appendix and ileocecal valve. The reactive lymphoid tissue in this region may lead to intussusception. Salmonella (typhoid fever) may have a characteristic gross appearance with raised longitudinal folds with ulcerated mucosa overlying hyperplastic Peyer patches. The biopsy findings in such cases can show aggregates of macrophages filled with cellular debris.

52

The enterohemorrhagic strain of E. coli, O157:H7, is associated with a spectrum of clinical presentations, the most unusual of which is that of an afebrile illness. What are clinical symptoms and histologic features on biopsy?

Often despite a high volume of diarrhea, only a few leukocytes are present in the stool, and the bacteria cannot be grown on routine culture. Therefore, a high index of suspicion is necessary clinically. Patients may develop nonbloody diarrhea, hemolytic uremic syndrome, an acute abdomen, and TTP. This strain is highly virulent, and only a very small number of viable bacteria are required to produce symptomatic infection. The histologic features of enterohemorrhagic E. coli are typically similar to the pattern of injury associated with acute ischemic colitis. The presence of fibrin thrombi within lamina propria capillaries may be a clue to the diagnosis. Imaging may also suggest ischemic colitis, with thumbprinting on plain films, and edematous thickening of the colonic wall. Although any segment or the entire colon may be involved, the presence of right-sided injury should raise the question of E. coli rather than ischemic colitis or IBD. Inflammation and injury are usually contiguous rather than segmental with E. coli.

53

The normal basement membrane of the colon measures __ to __ um in thickness, whereas in collagenous colitis the thickness of the collagen usually ranges from __ to __ um.

The normal basement membrane of the colon measures 2 to 5 um in thickness, whereas in collagenous colitis the thickness of the collagen usually ranges from 10 to 30 um.

54

What is diversion colitis?

Defunctioning of the large bowel by ileostomy or colostomy is performed for a number of conditions, including CD, fecal incontinence, idiopathic constipation, and sphincter-saving operations for large-bowel neoplasia. Diversion colitis is the colitis that develops in the bypassed or excluded segments of the colon. Although diversion colitis is often an incidental finding in asymptomatic patients, some patients may present with mucoid or bloody discharge or abdominal pain. The colitis occurs 3 to 36 months following bypass and completely regresses within 3 months of reestablishment of the fecal stream. A deficiency of short-chain fatty acis is thought to be the cause of diversion colitis. Short-chain fatty acids are the main source of energy for colonocytes, and they are usually derived from fermentation of dietary starches by normal colonic bacterial flora. Once the fecal stream is diverted, dietary starches are no longer present. This lack of colonocyte nutrition leads to an inflammatory reaction. The inflammation can be reversed by giving short-chain fatty acids via enemas several times a week, or by reestablishing the fecal stream.

55

What are pathologic features of diversion colitis?

The gross and endoscopic features of diversion colitis include erythema, friability, edema, and nodularity with aphthous ulcers. Histologically, diversion colitis has the potential to take on a wide spectrum of changes ranging from mild colitis to those reminiscent of severe active chronic UC. The hallmark of the condition relates to the grossly apparent nodularity, which corresponds to large lymphoid aggregates with prominent germinal centers. The remaining features of diversion colitis are more variable. In some instances, the inflammation may mimic severe UC with crypt distortion and marked chronic inflammation of the lamina propria. In other cases, patchy cryptitis and aphthous lesions may mimic CD. Because of the nonspecific nature of these histologic changes, it is imperative that the pathologist knows that he or she is looking at material from a diverted segment of colon (most often a Hartmann pouch).

56

Lynch syndrome has mutations in what genes?

The hallmark of Lynch syndrome is a genetic mutation in one of the family of DNA mismatch repair (MMR) protein genes (MLH1, MLH3, MSH2, MSH6, PMS2). These proteins function to repair errors in replication of DNA at short repetitive sequences (microsatellites). Lynch syndrome is associated with a high risk of colon and endometrial cancers, as well as increased risk of urothelial, small bowel, hepatobiliary, and pancreatic cancer. Further, 10-15% of sporadic colon, endometrial, and gastric tumors may harbor a somatic, non-germline MMR mutation or loss of expression.

57

Do colon cancers with MMR loss have a more favorable prognosis?

Colon cancers with MMR loss tend to have a somewhat more favorable prognosis and differ in chemotherapy sensitivity as compared with cancers from other molecular backgrounds.

58

What is spirochetosis?

Human intestinal spirochetosis is defined histologically by the presence of spirochetal microorganisms attached to the apical cell membrane of colorectal epithelium. Human intestinal spirochetes include Brachyspira aalborgi and Brachyspira pilosicoli. Incidence is common in poorly developed areas, but low where living standards are high. Homosexuals and HIV+ individuals are at high risk. Most patients are asymptomatic, but children, homosexual and HIV+ men are more likely to be symptomatic regardless of invasion. The bacteria can be highlighted using silver stains, PAS, Giemsa, Alcian-blue (pH 2.5) and by immunohistochemistry. Intestinal spirochetosis often coexists with other enteric pathogens, including Entamoeba histolytica, Enterobius vermicularis, Helicobacter pylori, Shigella flexneri and Neisseria gonorrhoeae.

59

Up to __% of hepatic angiomyolipomas contain areas of extramedullary hematopoiesis.

Up to 40% of hepatic angiomyolipomas contain areas of extramedullary hematopoiesis (in contrast to renal AMLs, EMH is a frequent feature).

60

How do carcinoid tumors of pulmonary, gastric and duodenal, ileal, appendiceal, and rectal types stain with TTF-1, CDX-2, and PDX-1 (Pancreatic and Duodenal Homeobox factor-1)?

Pulmonary carcinoids are positive for TTF-1 (only sometimes though) and negative for the others. Gastric and duodenal carcinoids are mostly positive for PDX-1 and negative for the others. Ileal carcinoids are positive for CDX-2 and negative for the others. Appendiceal carcinoids are positive for CDX-2 and negative for the others. Rectal carcinoids are negative for TTF-1 and CDX-2 and and almost all are negative for PDX-1.

61

What are MANECs?

Mixed AdenoNeuroendocrine Carcinoma is the term used for tumors with features of adenocarcinoma and neuroendocrine carcinoma, each comprising at least 30% of the mass (WHO 2010). MANECs can occur in any organ of the GI tract, and they are notably seen in the appendix as a malignant counterpart of the goblet cell carcinoid.

62

How has the grading system for GI tract NECs changed from the 2004 to 2010 WHO?

The 2010 grading system emphasizes mitotic count and Ki-67 index (It is recommended that these parameters are assessed over 50 hpf.). Grade 1 NET: < or =2% Ki-67 index. Grade 2 NET: 2-20 mitoses/10 hpf and/or 3-20% Ki-67 index. Grade 3 NET: >20 mitoses/10 hpf and/or >20% Ki-67 index. Most notably, NE lesions of the GI tract are graded and staged separately in the 2010 system. The 2004 system incorporated metastasis, gross invasion, size, vascular invasion, mitotic activity and proliferative rate, which resulted in a change in terminology from "tumor" to "carcinoma" based on the presence of metastasis for tumors of identical grade. Now, NE "tumors" represent G1 and G2 lesions, regardless of the stage.

63

Mesenchymal hamartoma of liver.

MH is an uncommon tumor that occurs almost exclusively in children; most cases are diagnosed in the first two years of life. It is the third most common liver tumor in this age group, following hepatoblastoma and infantile hemangioma. In most cases, serum AFP is normal or mildly elevated. MH may be solid or cystic, the latter being formed as a result of degeneration of the loose mesenchymal tissue. Extramedullary hematopoiesis is a frequent finding. The stroma tends to be more fibrotic in the rare adult cases. In some cases the mesenchymal component may dominate, with sparse ductal elements. The ductal elements express CK7 and lack CK20. The stromal cells are positive for SMA and vimentin.

64

Where is the most common extranodal site of lymphoma involvement?

GI tract.

65

Primary intestinal follicular lymphomas typically present in what specific location?

It typically presents in the second portion of the duodenum, and less frequently, in the jejunum. It appears endoscopically as one or more small polyps. Although typically asymptomatic, it may present with bowel obstruction. Staging must be performed to exclude GI involvement by a more widespread follicular lymphoma, such as one involving retroperitoneal lymph nodes. Patients with confirmed primary intestinal follicular lymphoma seem to have excellent survival and may not require treatment.

66

What is the relationship between ulcerative jejunitis, celiac disease, and enteropathy-associated T-cell lymphoma?

There is considerable overlap between the inflammatory condition known as ulcerative jejunitis, which occurs in patients with refractory celiac disease, and early EATL. Identical T-cell clones have been found in patients with refractory celiac disease, ulcerative jejunitis, and subsequent EATL, suggesting that these represent a spectrum of the same neoplastic process.

67

What is IPSID?

ImmunoProliferative Small Intestinal Disease is a rare disorder that is considered a variant of MALT lymphoma with nearly complete plasmacytic differentiation. Its name results from its preferential involvement of the small intestine, but it is also known as IgA heavy chain disease, because the neoplastic cells in about one-half of cases produce an abnormal, truncated IgA heavy chain that is missing the variable and the first constant regions and that can be found in the serum. The plasma cells will be positive for CD138 but negative for kappa and lambda light chains. IPSID is suspected to result from Campylobacter infection, and early cases have a relatively high rate of response to broad-spectrum antibiotics. Although it was thought that IPSID was entirely an inflammatory process, it has been now confirmed as a clonal process. It is relatively common for IPSID to progress to a high-grade lymphoma indistinguishable from DLBCL.

68

What are the first, second, and third most common tumors of the liver seen in children under 3 years of age?

First: Hepatoblastoma. Second: Infantile hemangioma. Third: Mesenchymal hamartoma.

69

Hepatoblastoma is the most common malignant liver tumor in children and comprises ~__% of the pediatric malignant neoplasms. Nearly 90% of cases occur between __ months and __ years of age. The two morphologic subtypes of HB are __ (55%) and __ (45%).

Hepatoblastoma is the most common malignant liver tumor in children and comprises ~1% of the pediatric malignant neoplasms. Nearly 90% of cases occur between 6 months and 5 years of age. The two morphologic subtypes of HB are epithelial (55%) and epithelial-mesenchymal (45%).

70

What is lipofuscin?

Lipofuscin is the name given to finely granular yellow-brown pigment granules composed of lipid-containing residues of lysosomal digestion. It is considered one of the aging or "wear-and-tear"pigments, found in the liver, kidney, heart muscle, adrenals, nerve cells, and ganglion cells. It is specifically arranged around the nucleus, and is a type of lipochrome. Lipochrome is a form of pigment associated with amber and gold tones in the eyes of mammals. The term carotenoid is sometimes considered a synonym of lipochrome, but that term usually refers to specific molecules, while lipochrome refers to accumulations of varied molecules. Lipofuscin appears to be the product of the oxidation of unsaturated fatty acids, and may be symptomatic of membrane damage, or damage to mitochondria and lysosomes. Aside from a large lipid content, lipofuscin is known to contain sugars and metals, including mercury, aluminum, iron, copper, and zinc.

71

What is ceroid?

A golden, waxy (from cera, Latin for wax; eidos, Greek for form), alcohol-insoluble pigment. It is acid-fast and sudanophilic. It is a complex of oxidized polyunsaturated lipid pigment(s) (?polymer of oxidized lipid and protein?) resulting from the peroxidation of unsaturated lipids that are similar or identical to lipofuscin. Ceroid accumulates in macrophages of the heart, (cirrhotic) liver, GI tract, nervous system, muscles, and brain in the elderly and is thus termed "wear and tear" pigment.

72

How is microvesicular steatosis defined?

In cellular pathology, steatosis (also called fatty change, fatty degeneration or adipose degeneration) is the process describing the abnormal retention of lipids within a cell. It reflects an impairment of the normal processes of synthesis and elimination of triglyceride fat. Excess lipid accumulates in vesicles that displace the cytoplasm. Microvesicular steatosis is defined by multiple small lipid droplets (liposomes) in the hepatocyte without nuclear dislocation, as compared with macrovesicular steatosis, which is usually composed of a large cytoplasmic lipid vacuole that displaces the nucleus peripherally.

73

What is peliosis?

The Greek word "pelios" means "discoloured by extravasated blood," or "livid". Peliosis is a pathological entity characterized by the gross appearance of multiple cyst-like, blood-filled cavities within parenchymatous organs. The classical pathoanatomical concept is based upon the opinion that peliosis exclusively develops in organs belonging to the mononuclear phagocytic system (liver, spleen, bone marrow, and lymph nodes). However, a paucity of studies indicates that other organs such as lungs, parathyroid glands, and kidneys may be affected too. Since the disease may culminate in spontaneous rupture of the affected organ and thus may mimic a violent death at autopsy, peliosis is far more than just another morphological curiosity.

74

What is peliosis hepatis?

Peliosis hepatis is characterised by randomly distributed multiple blood-filled cavities throughout the liver. The size of the cavities usually ranges between a few millimeters to 3 cm in diameter. The pathogenesis of peliosis hepatis is unknown. There are several hypotheses as to cause: it arises from sinusoidal epithelial damage, from increased sinusoidal pressure due to obstruction in blood outflow from the liver, or from hepatocellular necrosis. The condition is typically asymptomatic and is discovered following evaluation of abnormal liver function tests. However, when severe it can manifest as jaundice, hepatomegaly, liver failure and hemoperitoneum. Disease associations include… Infections: HIV, Bacillary peliosis (caused by Bartonella), Staphylococcus aureus. Chronic conditions: End stage renal failure, Kwashiorkor, tuberculosis and other chronic infections. Malignancy: Monoclonal gammopathies, Hodgkin disease, malignant histiocytosis, seminoma, hepatocellular adenoma, hepatocellular carcinoma. Renal transplants: It can be found in up to 20% patients, can be related to azathioprine or cyclosporine use, and may be associated with increased risk of transplant rejection. Drugs and toxins: Corticosteroids, androgens, azathioprine, tamoxifen.

75

What are acceptable (A) and unacceptable (U) criteria for liver transplantation based on frozen section histology for the following findings: macrovesicular steatosis, microvesicular steatosis, viral hepatitis, fibrosis, granulomas, nonspecific portal inflammation, necrosis, and malignancy.

Macrovesicular steatosis: A=Mild (particularly if the viral hepatitis status of the donor is unknown. Necrosis (ignore focal subcapsular necrosis): A=

76

How to distinguish lipofuscin, iron, and bilirubin in the liver?

Lipofuscin is located primarily in the centrilobular hepatocytes and is brown and finely granular. These features contrast with iron, which, in the early stages of hemochromatosis, is predominantly periportal in distribution. Iron appears as coarse, brown, refractile granules. Bilirubinostasis is a result of cholestasis, and is manifested as green to golden brown granules in perivenular hepatocytes. However, it is often associated with canalicular bile (often in zone 3 hepatocytes) and hepatocyte rosette formation in longstanding cases, helping to differentiate intracellular bile from lipofuscin.

77

What are the 4 subtypes of hemangioendothelioma?

Epithelioid, spindle cell, retiform, kaposiform.

78

Where in the pancreas are microcystic serous cystadenomas and oligocystic serous cystadenomas located? What is the sex predilection?

Microcystic serous cystadenomas most commonly occur in the body and tail and have a female predominance. Oligocystic serous cystadenomas most commonly occur in the head and body and have no sex predilection.

79

Solid-pseudopapillary neoplasm/solid-pseudopapillary tumor of pancreas. Gender prevalence and mean age. Common mutation seen in this neoplasm. Cell of origin. Current grading and staging systems.

SPNs occur mostly in females (~90%) with a mean age of presentation of 28-35. In males, the mean age at presentation tends to be 5-10 years older than that of females. This neoplasm has been shown to consistently harbor mutations in exon 3 of the beta-catenin gene, which leads to upregulation of known oncogenes such as cyclin D1. The cell of origin for SPN is unknown. Currently, no grading or staging schemes for SPN exist; if malignant features, such as invasion into adjacent structures, metastases, or malignant histology are present, the staging of these "solid pseudopapillary carcinomas" follows that of other exocrine pancreatic carcinomas.

80

Stains for solid-pseudopapillary neoplasm of the pancreas.

SPN stains positive for alpha-1 antitrypsin, PR, vimentin, alpha-1 antichymotrypsin, CD10, CD56, NSE, beta-catenin and cyclin D1. Alpha-1 antitrypsin will generally also stain the intracytoplasmic hyaline globules that are also typically PAS-positive. Vimentin and NSE stain in a diffuse manner. PR staining is present in both male and female patients. Nuclear staining of beta-catenin is seen due to mutations in the beta-catenin gene which leads to unusual nuclear accumulation of beta-catenin, and since beta-catenin mutations lead to cyclin D1 upregulation, cyclin D1 is usually positive in SPN. SPNs stain variably for cytokeratins and synaptophysin. Only in rare instances are positive staining results seen for S100, pancreatic enzymes (trypsin, amylase, chymotrypsin, etc.), or pancreatic hormones (insulin, glucagon, and somatostatin). Most report chromogranin to be negative in SPN. SPNs characteristically lose E-cadherin expression. CD99 has a characteristic paranuclear dotlike pattern.

81

How to differentiate pancreatic neuroendocrine tumor from pancreatic solid-pseudopapillary neoplasm.

Cytologically, PanNET and SPN are both composed of fairly uniform round cells with uniform nuclei, but PanNET cells tend to have the speckled chromatin pattern typical of neuroendocrine neoplsms. While pseudopapillae may be present in PanNETs, their presence, along wiht foamy cells and hyaline globules, should favor the diagnosis of SPN. In cases where morphology is insufficient in differentiating the two, IHC should be performed. PanNET stains strongly for chromogranin and synaptophysin, and will generally stain for the expressed pancreatic hormone. SPN has variable staining for synaptophysin, it is typically much weaker than in PanNET, and does not stain for chromogranin. In addition, loss of E-cadherin is present in nearly all cases of SPN, but is variable in PanNET. CD56 and NSE are positive in both and provide little diagnostic utility between the two. Lack of PR staining is another useful diagnostic finding in PanNET. CD99 is positive in most PanNETs, but it has a membranous staining pattern that allows for easy differentiation from the staining pattern seen in SPN, which is a paranuclear dotlike pattern.

82

Ulcerative colitis and Crohn disease. Which has a higher incidence of developing colorectal carcinoma?

Ulcerative colitis.

83

What 2 GI infections can mimic Crohn disease?

Various infectious agents can mimic Crohn disease, the common being infections due to Yersinia and Mycobacterium tuberculosis. Yersinia infections very closely mimic Crohn disease: both diseases can show ileo-colonic involvement, fissuring ulcers, granulomas and transmural inflammation. Similarly granulomatous infection with mycobacteria can closely mimic Crohn disease with granulomas. However, granulomas in Mycobacterial infections are also seen in draining lymph nodes, as opposed to Crohn where they are restricted mostly to the intestine. Transverse ulcers are more characteristic of mycobacterial infection as opposed to longitudinal ulcers and cobblestoning in Crohn disease. Infectious colitis may show diffuse colonic involvement, increased chronic inflammatory cells and neutrophils. In contrast to Crohn disease, neutrophils are often more prominent in the lamina propria compared to the crypts. The architecture is generally preserved.

84

Out of HAV, HBV, HCV, autoimmune, toxic, and ischemic causes of liver injury, which 2 cause the largest increase in transaminases?

Ischemia and toxic injuries lead to the most profound elevations in transaminases, sometimes >100x the upper limit of normal.

85

Out of HAV, HBV, HCV, alcoholic hepatitis, and toxic hepatitis, which 2 are the most common causes of jaundice?

HAV and alcoholic hepatitis are the most common causes of jaundice (~70%).

86

Lynch syndrome is the most common hereditary CRC syndrome. What are the 4 genes/proteins involved and what chromosomes are they on?

The four genes that are involved in encoding proteins that participate in DNA mismatch repair are: MLH1 (3p21), MSH2 (2p22-p21), MSH6 (2p16), and PMS2 (7p22). Tumors in patients with Lynch syndrome have a germline mutation of one allele of a DNA MMR gene and a somatic mutation in the other allele. The presence of two inactivating mutations results in defective DNA mismatch repair. If the MSI or DNA MMR IHC results show evidence of defective DNA MMR, then the patient may be evaluated further for Lynch syndrome by assessing a peripheral blood sample for germline mutations for one of the four DNA MMR genes.

87

Somatic BRAF mutations are (often seen/generally not seen) in tumors from those with Lynch syndrome.

Somatic BRAF mutations are generally not seen in tumors from those with Lynch syndrome. In patients with a BRAF mutation, LS can be ruled out in most cases.

88

What is the significance of the five common staining combinations seen in DNA mismatch repair protein IHC (MLH1, PMS2, MSH2, MSH6) in CRC? Give the MSI phenotype, clinical interpretation, and etiology.

Pattern #1: MLH1+, PMS2+, MSH2+, MSH6+; MSI phenotype is MSS or MSI-L; clinical interpretation is most likely sporadic CRC (Lynch syndrome very unlikely). Pattern #2: MLH1-, PMS2-, MSH2+, MSH6+; MSI phenotype is MSI-H; clinical interpretation is LS or sporadic CRC; etiology is germline hMLH1 mutation or hMLH1 promoter hypermethylation. Pattern #3: MLH1+, PMS2+, MSH2-, MSH6-; MSI phenotype is MSI-H; clinical interpretation is LS; etiology is germline hMSH2 mutation. Pattern #4: MLH1+, PMS2+, MSH2+, MSH6-; MSI phenotype is MSI-H; clinical interpretation is LS; etiology is germline hMSH6 mutation. Pattern #5: MLH1+, PMS2-, MSH2+, MSH6+; MSI phenotype is MSI-H; clinical interpretation is LS; etiology is germline PMS2 mutation.

89

Fibrolamellar hepatocellular carcinoma most commonly occurs in younger age groups; __% occur under the age of 40.

Fibrolamellar hepatocellular carcinoma most commonly occurs in younger age groups; 85% occur under the age of 40. However, one must recognize that in this age group conventional HCC is still more common.

90

In contrast to conventional HCCs, fibrolamellar HCC often does not have an elevated ___ level.

In contrast to conventional HCCs, fibrolamellar HCC often does not have an elevated AFP level.

91

What is the main differential diagnosis for fibrolamellar HCC?

The scirrhous variant of conventional HCC. Both tumors may have prominent fibrosis; however, the scirrhous variant of conventional HCC will not have lamellar fibrosis or the characteristic hepatocytes of FLM. The classic features of FLM are enlarged polygonal hepatocytes (~1.5x the size of a well-differentiated HCC hepatocyte) with markedly eosinophilic granular (from mitochondria) cytoplasm and macronucleoli (with a single large nucleolus).

92

Hepatic angiosarcoma has been associated with exposure to what agents?

Thorotrast (radiologic contrast material), arsenic (such as from insecticide exposure), and vinyl chloride (typically from polyvinyl chloride polymerization plants). However, since the use of these carcinogens has dramatically decreased, most current cases of hepatic angiosarcomas are sporadic in nature or are associated with anabolic steroid use.

93

What hematologic abnormalities may patients with hepatic angiosarcoma present?

Thrombocytopenia (secondary to entrapment of platelets in the tumor/Kasabach-Meritt syndrome). Microangiopathic hemolytic anemia (due to red cell fragmentation in the tumor). Disseminated intravascular coagulation.

94

Pulmonary enteric adenocarcinoma and how to differentiate from metastatic colorectal adenocarcinoma.

Enteric differentiation can occur in lung adenoCA and when this component exceeds 50%, the tumor is classified as pulmonary adenoCA with enteric differentiation. The enteric pattern shares morphologic and IHC features with CRC. In contrast to metastatic colorectal adenoCA, these tumors are histologically heterogeneous with some component that resembles primary lung adenoCA such as lepidic growth. The enteric pattern consists of glandular and/or papillary structures, sometimes with a cribriform pattern, lined by tumor cells that are mostly tall columnar with nuclear pseudostratification, luminal necrosis, and prominent nuclear debris. Poorly differentiated tumors may have a more solid pattern. These tumors show at least 1 IHC marker of enteric differentiation (CDX-2, CK20, or MUC2). Consistent positivity for CK7 and expression of TTF-1 in ~50% of cases help in the distinction from metastatic CRC. CK7 negative cases may occur. CDX-2 is reduced or absent in most poorly differentiated CRC and more than half show the high-frequency MSI phenotype. Although this type of tumor will rarely metastasize to lung, since IHC detection of MMR proteins (MLH1, MSH2, MSH6, and PMS2) gives a predictive value that is virtually equivalent to MSI testing, this may be worth testing in selected cases as MSI in primary lung adenoCA is extremely rare. Primary lung adenoCA that histologically resemble CRC but lack IHC markers of enteric differentiation are probably better regarded as lung adenoCA with enteric morphology rather than lung adenoCA with enteric differentiation.

95

Signet ring cells in the stomach. The differential diagnosis includes ___.

Lymphoma with artifactual signet ring cells due to cytoplasmic shrinkage (CD45 is usually positive in lymphoma). Metastases from breast or lung (clinical history, plus the use of appropriate immunostains such as TTF1 or GCDFP-15 is helpful). Reactive epithelial atypia associated with radiation treatment or chemotherapy. Xanthoma.

96

Peutz-Jeghers (hamartomatous) polyps overview.

Peutz-Jeghers polyps (hamartomatous polyps) are supported by broad bands of muscularis mucosa smooth muscle, which is thicker centrally, and resembles a Christmas tree at low power. The polyp has superficial columnar and goblet cells, but Paneth and endocrine cells at its base. Peutz-Jeghers polyps are large, pedunculated polyps of the gut almost always seen in association with Peutz-Jeghers syndrome. This rare autosomal dominant disorder is usually diagnosed at ages 20-30, with hamartomatous polyps in the small bowel (100%), stomach and colon (25%), and associated adenomatous lesions that may give rise to adenocarcinoma of the stomach, large or small bowel; adenoma malignum of the cervix, ovarian mucinous tumors, and carcinoma of the breast, lung and pancreas. The syndrome is also associated with sex-cord tumor with annular tubules (almost all patients) and melanotic pigmentation of the digits, genitalia, lips, oral mucosa, palms and soles. Peutz-Jeghers syndrome is caused by mutations in STK11/LKB1, a serine threonine kinase that may play a role in cell polarity.

97

What are etiologies of HCC?

Multiple risk factors can contribute to the development of this neoplastic process, such as viral hepatitis infection with HBV or HCV, cirrhosis (independently of cause), exposure to aflatoxin, use of anabolic steroids and tyrosemia.

98

What entities are in the differential diagnosis of HCC?

The differential diagnosis of HCC includes other hepatic lesions, such as focal nodular hyperplasia, angiomyolipoma, metastatic pancreatic or small bowel neuroendocrine tumors, and renal cell carcinoma.

99

The only primary liver lesion that is positive for HMB-45 is ___.

Hepatic angiomyolipoma.

100

IHC useful in liver and liver lesions.

The role of IHC is in the distinction of benign hepatocellular nodules from reactive hepatocytes; WD-HCC from benign hepatocellular nodules; poorly differentiated HCC from cholangiocarcinoma and metastases; and determination of histogenesis of malignant tumor; and of primary site of origin of malignant tumor. A panel of antibodies has more discriminant value. AFP expression usually indicates malignancy in a hepatocellular nodule and hepatocytic histogenesis of a malignancy. pCEA and CD10 stain bile canaliculi in better-differentiated HCC. HepPar1 is generally accepted as a hepatocytic marker. However, not all HCC stain uniformly and not all HepPar1-positive tumors are of hepatocytic origin or arise in the liver. Mature hepatocytes and hepatocellular nodules stain with CAM 5.2, CK 8, and 18 but not with CK 7, 19, 20, or AE1/AE3. Biliary epithelium expresses CK 7 and 19. CD 34 highlights sinusoidal capillarization. AFP, pCEA/CD10, and CD34 are useful for ascertainment of malignancy in hepatocellular nodules; HepPar1 and cytokeratins to be included if histogenesis is the issue. IHC results should be interpreted in the larger context of the case.

101

What are the 2 types of ulcers that can be seen in Crohn disease?

One type is aphthous ulcers (which may also occur in infectious enterocolitis), which are the characteristic ulcers which are formed over lymphoid tissue. As they enlarge, they develop a hemorrhagic rim. The small stellate aphthous ulcers develop into discontinuous linear or serpiginous ulcers and finally to wide based ulcers. A second type of ulcer that can be seen is the knife-like longitudinal fissures that can extend through the bowel wall and can result in fistulas, abscesses and peri-intestinal pseudotumors.

102

Epithelioid granulomas can be seen in Crohn disease in __% of resection specimens and __% of mucosal biopsy specimens. These epithelioid granulomas need to be differentiated from ___ granulomas.

Epithelioid granulomas can be seen in 60–90% of resection specimens and 30% of mucosal biopsy specimens. They should be differentiated from small mucosal granulomas related to crypt rupture, which can be seen in conditions other than Crohn disease. These are oriented around the crypts and may have mucin-containing macrophages (muciphages) and foreign body giant cells. Mucin stains have been used to identify them but are often not helpful. The epithelioid granulomas of Crohn disease can be found in any layer of bowel and their diagnostic value increases if they are found away from the ulceration.

103

Approximately __% of patients with Crohn disease develop adenocarcinoma.

Patients with Crohn disease are at a much higher risk of developing small intestinal and colorectal adenocarcinoma. Approximately 5% of patients with Crohn disease develop adenocarcinoma, and there is a positive correlation with the duration as well as the anatomical extent of the disease.

104

UC and Crohn disease. Which has a higher risk of developing CRC?

Patients with ulcerative colitis have a higher incidence of developing colorectal carcinoma than Crohn disease.

105

What is the most common endocrine tumor associated with MEN1?

Gastrinoma.

106

Pancreatic endocrine tumors have similar histologic features irrespective of the type of hormone produced, with a few exceptions, which are ___.

Stromal amyloid is commonly seen in insulinomas. Somatostatinomas are peculiar for containing glandular structures with psammoma bodies, but the latter are typically seen in duodenal rather than pancreatic tumors.

107

WHO 2010 classification of neuroendocrine tumors in GI tract and pancreas.

Low grade (G1): 20 mitoses/10 HPF, OR >20% Ki-67 index.

108

How are neuroendocrine tumors graded in GI tract and pancreas, and for lung and thymus?

For GI tract and pancreas, WHO 2010 classification: Low grade (G1): 20 mitoses/10 HPF, OR >20% Ki-67 index. For lung and thymus, WHO 2004 classification: Low grade (G1): 10 mitoses/10 HPF.

109

What is an Abrikossoff tumor?

AKA granular cell tumor AKA granular cell myoblastoma AKA granular cell nerve sheath tumor AKA granular cell schwannoma.

110

The genes PRSS-1, PST1, and CFTR have all been implicated as causes of recurrent ___.

The genes PRSS-1 (cationic trypsinogen), PSTI (pancreatic secretory trypsin inhibitor), and CFTR (cystic fibrosis transmembrane conductance regulator) have all been implicated as causes of recurrent pancreatitis.

111

What test is most specific and sensitive for pancreatic exocrine function?

Elastase-1. Fecal fat, chymotrypsin, and elastase-1 are all sensitive and specific, but with elastase being the most so.

112

What patterns of amylase, CEA, and CA 19-9 are seen in pancreatic pseudocyst, serous cystadenoma, mucinous cystadenoma, intraductal papillary mucinous neoplasm, and solid-pseudopapillary tumor?

Pancreatic pseudocyst: high amylase, low CEA, high CA 19-9. Serous cystadenoma: low amylase, low CEA, low CA 19-9. Mucinous cystadenoma: low amylase, high CEA, normal to high CA 19-9. Intraductal papillary mucinous neoplasm: high amylase, high CEA, normal to high CA 19-9. Solid-pseudopapillary tumor: low amylase, low CEA, low CA 19-9.

113

With cirrhosis, what characteristic finding is seen on serum electrophoresis?

Predominantly due to increased IgA, beta-gamma bridging is seen with cirrhosis. Cirrhosis can also show hypoalbuminemia with blunted alpha-1 and alpha-2 peaks.

114

What is the most common cause of mixed cryoglobulinemia?

Hepatitis C.

115

Hypovolemic hyponatremia is often due to ___. Euvolemic hyponatremia is often due to ___. Hypervolemic hyponatremia is often due to ___.

Hypovolemic hyponatremia is often due to water loss either through the kidneys or GI tract. Euvolemic hyponatremia is often due to drugs. Hypervolemic hyponatremia is often due to CHF, nephrotic syndrome, or cirrhosis.

116

For hepatitis, cirrhosis, biliary obstruction, space-occupying lesion, passive congestion, and fulminant failure, list the AST, ALT, LD, alk phos, total protein, albumin, bilirubin, and ammonia as L, N, or H.

Hepatitis: H, H, H, H, N, N, H, N. Cirrhosis: N, N, N, N to sl-H, L, L, H, H. Biliary obstruction: N, N, N, H, N, N, H, N. Space-occupying lesion: N or H, N or H, H, H, N, N, N-H, N. Passive congestion: sl-H, sl-H, sl-H, N to sl-H, N, N, N to sl-H, N. Fulminant failure: very H, H, H, H, L, L, H, H.

117

What are the 2 forms of GI anthrax?

Two types of GI anthrax are characterized by different symptoms: intestinal (e.g., nausea, vomiting, diarrhea) and oropharyngeal (e.g., neck swelling, difficulty swallowing). Shock and toxemia can characterize both forms of the disease, especially in the terminal stages.

118

How does GI anthrax occur?

This form of anthrax occurs by ingesting contaminated meat, in particular raw or undercooked, from infected animals. It has also been reported in association with animal-hide drums. The incubation period is 2–7 days.

119

What are fatality rates for the 3 forms of anthrax?

The fatality rate of inhalation anthrax approaches 90%, even with antibiotic therapy. Untreated cutaneous anthrax can have a fatality rate of up to 20%, but fatalities are rare (1%) with proper antibiotic treatment. The fatality rate for GI anthrax is 25%–60%.

120

Inhalation, cutaneous, and GI anthrax can be complicated by meningitis, which occurs in about _% of cases.

Inhalation, cutaneous, and GI anthrax can be complicated by meningitis, which occurs in about 5% of cases.

121

What is the so-called "anal glomerulus"?

So-called anal glomeruli are groups of small convoluted vessels are surrounded by connective tissue, which separates them from the surrounding loose tissue. Such structures probably represent thrombosed vessels with recanalization. The whole system has been referred to as the corpus cavernosum recti (although it is situated in the anal canal) and is more pronounced in the areas corresponding to the anal cushions (The anal lumen often forms more or less a triradiate slit when seen at anoscopy. Thus, three folds are seen, named the anal cushions.).

122

Glycogenic acanthosis is most often found in the (proximal/middle/distal) one-third of the esophagus.

Glycogenic acanthosis presents as white nodules or plaques, most often in the distal one-third of the esophagus. The lesions vary in size, can be up to 1 cm in diameter, and may coalesce to larger plaques. Macroscopically, they resemble monilial plaques or leukoplakia. Microscopically, there is hyperplasia of the cells of the prickle layer containing abundant glycogen.

123

What are Auerbach's and Meissner's plexi?

Auerbach's/myenteric plexus provides motor innervation to both layers of the tunica muscularis, having both parasympathetic and sympathetic input. A part of the enteric nervous system, Auerbach's/myenteric plexus exists between the longitudinal and circular layers of muscularis externa in the gastrointestinal tract. It is found in the muscles of the esophagus, stomach, and intestine. From Auerbach's/myenteric plexus, a secondary plexus (Meissner's submucosal plexus) is derived, and it is formed by branches that have perforated the circular muscular fibers. This plexus lies in the submucous coat of the intestine; it also contains ganglia from which nerve fibers pass to the muscularis mucosae and to the mucous membrane; its function is to innervate cells in the epithelial layer and the smooth muscle of the muscularis mucosae. Meissner's/submucosal plexus has only parasympathetic fibers and provides secretomotor innervation to the mucosa nearest the lumen of the gut.

124

What are areae gastricae?

They are grooves in the stomach mucosa that are fixed anatomical features and do not flatten out when the stomach is distended. Grossly (very close up), the surface of the mucosa is dissected by thin shallow grooves. Histologically, they appear as shallow depressions on an otherwise monotonously smooth surface.

125

What types of endocrine cells are present in the gastric antrum, and what types are present in the fundus?

In the antrum, ~50% of the endocrine cells are G cells (gastrin-producing), 30% are enterochromaffin cells (serotonin-producing), and 15% are D cells (somatostatin-producing). In the fundus, the majority of endocrine cells are enterochromaffin-like-cells that secrete histamine, with a smaller number of X cells (secretion product unknown) and enterochromaffin cells.

126

What is pyloric (or pseudopyloric) metaplasia?

It is thought to be the result of chronic gastritis, and consequently are more frequently encountered in elderly individuals. There is a replacement of the specialized acid- and enzyme-secreting cells of the fundic glands by mucus-secreting glands of the type present in normal pyloric mucosa. This change occurs in the zone of fundic mucosa adjacent to the histologic fundopyloric junction, and what were typical fundic glands now come to resemble typical pyloric glands.

127

How can jejunum and ileum be distinguished macroscopically?

Distal to the ligament of Treitz, the remainder of the small bowel is arbitrarily subdivided into the jejunum (proximal two-fifths) and ileum (distal three-fifths, terminating at the ileocecal junction). Although a discrete point demarcating the segments doesn't exist, there are features that gradually become more apparent from proximal to distal. The proximal jejunum has a thicker wall and is about twice the diameter of distal ileum. Jejunal segments have more prominent plicae circulares that can be palpated externally. The quantity of adipose tissue is greater in the ileum. Most of the jejunum lies within the upper abdominal cavity, whereas most of the ileum lies within the lower abdominal cavity and pelvis.

128

The submucosa of the GI tract lacks glands except at what 2 sites?

Esophagus and duodenum. Esophagus has submucosal glands that are considered to be a continuation of the minor salivary glands of the oropharynx. They are most concentrated in the upper and lower esophagus. The glands are drained by ducts, initially lined by a single layer of cuboidal epithelium, becoming stratified squamous in type, which open into the esophageal lumen. Duodenum has (mostly) submucosal Brunner's glands (about one-third of the glands are within the deep mucosa beneath the crypts, though). Brunner's glands begin just distal to the GE junction and gradually decrease in quantity along the duodenum with only scattered groups found distal to the ampulla of Vater.

129

Why is there increased incidence of ulcers and stomach cancer among blood group O secretors?

H. pylori binds H, Leb, and Ley antigens via BabA recognition of a terminal Fucα1–2Gal epitope.

130

How can you distinguish between a GI schwannoma and a bland spindled GIST?

GI schwannoma: commonly has a peripheral lymphoid cuff, frequent cell size variation, no skeinoid fibers, S100 positive in 100%, GFAP positive in 65-100%, CD117 negative. Bland spindled GIST: lacks peripheral lymphoid cuff, generally uniform cell size, may have skeinoid fibers, S100 positive in 5% (20% in small intestine), GFAP negative, CD117 positive in 74-95%.

131

What entities are in the differential diagnosis of an epithelioid GIST?

Poorly differentiated carcinoma. Melanoma/clear cell sarcoma. Glomus tumor. Gangliocytic paraganglioma. GI endocrine carcinoma. Extramedullary myeloid tumor. GI mucosal benign epithelioid nerve sheath tumor.

132

In women with Lynch syndrome, is the incidence of endometrial cancer or colorectal cancer greater?

Endometrial cancer. Lynch syndrome accounts for ~2-3% of CRC and 2.3% of EC, with an overall risk of developing CRC of 68% and EC of 62% in Lynch patients. However, when looking at the two genders separately, the risk of CRC for men is 83% versus 48% for women. Therefore, women with Lynch syndrome are at a substantially greater risk of developing EC than CRC.

133

Pancreatoblastoma. Ages affected?

Pancreatoblastoma has a bimodal distribution, with tumors presenting in both children (mean age 2.4 yrs) and adults (mean age 40 yrs), although the incidence (or perhaps simply its diagnosis) is more common in the young.

134

Pancreatoblastoma can occur sporadically, or in association with what genetic syndromes?

Beckwith-Wiedemann syndrome or familial adenomatous polyposis syndrome.

135

Microscopic appearance of pancreatoblastoma.

The diagnostic challenge in correctly identifying these lesions stems from their histologic heterogeneity. Microscopically, the tumor is organized into nests of primitive-appearing cells separated by dense, variably cellular stromal bands. There can be a variety of components, including those with endocrine differentiation, ductal differentiation, and even heterologous elements, such as bone and cartilage. The most characteristic histologic finding, and an important clue to the correct diagnosis, is the presence of squamoid corpuscles. These appear as variably sized foci of squamoid cells, which occasionally keratinize. They can be subtle and difficult to detect, or they can appear overtly squamous.

136

Entities in the DDx of pancreatoblastoma.

The diagnostic challenge in correctly identifying these lesions stems from their histologic heterogeneity. Commonly considered entities include acinar cell carcinomas, pancreatic endocrine neoplasms, poorly differentiated adenocarcinomas, and solid pseudopapillary tumors.

137

What is the most common malignancy associated with celiac disease?

Enteropathy-associated T-cell lymphoma.

138

Enteropathy-associated T-cell lymphoma is subclassified into what 2 types?

Classic type and type II, based on the assessment of histomorphology and immunophenotype.

139

Enteropathy-associated T-cell lymphoma is subclassified into classic type and type II, based on the assessment of histomorphology and immunophenotype. How do classic EATL and type II EATL differ in their epidemiology?

Classic EATL: Represents 80-90% of all EATL. Is a complication of celiac disease, with >90% having celiac disease-associated HLA-DQ2/-DQB. Patients with refractory celiac disease are at highest risk. Most common in Northern Europe (population has a high prevalence of celiac disease). Type II EATL: Represents 10-20% of all EATL. May be associated with celiac disease, but in most cases occurs sporadically in individuals with celiac-associated HLA types similar to those in the general population. Most common in Asia (celiac disease is uncommon in the population).

140

Enteropathy-associated T-cell lymphoma is subclassified into classic type and type II, based on the assessment of histomorphology and immunophenotype. How do classic EATL and type II EATL differ in their histopathologic appearance?

Both clinically present as multifocal involvement of the small intestine with ulcers, stenosis, and perforation. Classic type EATL: Variable morphology, frequently pleomorphic intermediate to large cells. Angulated nuclei. Prominent nucleoli. Areas of necrosis. Prominent background mixed inflammatory infiltrate. Type II EATL: Monotonous small- to intermediate-sized cells. Round nuclei. Inconspicuous nucleoli. Rare necrosis. Minimal background inflammatory cells.

141

Enteropathy-associated T-cell lymphoma is subclassified into classic type and type II, based on the assessment of histomorphology and immunophenotype. How do classic EATL and type II EATL differ in their immunophenotype?

Classic EATL: CD3+, CD5-, CD7+, 80% CD8-, >90% CD56-. Type II EATL: CD3+, CD5-, CD7+, 80% CD8+, >90% CD56+.

142

Enteropathy-associated T-cell lymphoma is subclassified into classic type and type II, based on the assessment of histomorphology and immunophenotype. How do classic EATL and type II EATL differ in their genetic aberrations?

Classic EATL: 86% +9q31.3 or -16q12.1. 73% +1q32.2-q41. 80% +5q34-q35.2 27% +8q24 (MYC). Type II EATL: 83% +9q31.3 or -16q12.1. 27% +1q32.2-q41. 20% +5q34-q35.2 73% +8q24 (MYC).

143

Villin IHC stain. What is the target? In what normal and disease states is there positivity? What are some uses of the stain?

Villin is an actin binding protein present in cytoskeleton of intestinal microvilli; has critical role in maintaining brush border organization. It is relatively specific for GI epithelium with brush border microvilli or adenocarcinomas derived from them. Positive staining (normal): Digestive tract epithelium, proximal renal tubules, hepatic bile ducts. Positive staining (disease): Colonic adenocarcinoma, renal cell carcinoma, pulmonary adenocarcinomas. Negative staining: Renal distal tubules, bronchiolar epithelium, pulmonary alveolar cells, bronchial gland cells. Uses: Primary bladder adenocarcinoma (villin-, CDX2-) vs. colorectal carcinoma to bladder. Ovarian adenocarcinoma (villin-) vs. colorectal adenocarcinoma.

144

What is the most common cause of renal failure in cirrhotic patients?

Spontaneous bacterial peritonitis.

145

At what wavelength light is bilirubin absorbance maximal?

450 nm.

146

What are the 4 main sources of alkaline phosphatase in the body?

Bile ducts, bone, placenta, intestine.

147

Put the 4 alkaline phosphatase isoenzymes into order of anodal mobility on electrophoresis.

Anodal mobility 1 = biliary. Anodal mobility 2 = bone. Anodal mobility 3 = placenta. Anodal mobility 4 = intestinal.

148

For the 4 alkaline phosphatase isoenzymes, list how strongly each is inhibited by L-phenylalanine and by heat/urea (sensitivity to heating parallels sensitivity to urea incubation, which is why they are grouped).

Biliary: -, +. Bone: -/+++. Placenta: +++/-. Intestinal: +++/+. For sensitivity to heat/urea, think "bone burns, placenta persists."

149

Hyperammonemia is nearly always due to ___.

Hyperammonemia is nearly always due to liver failure. However, particularly in children, it should raise suspicion for an inborn error of metabolism (especially urea cycle enzyme deficiencies).

150

Bilirubinuria indicates (conjugated/unconjugated) hyperbilirubinemia.

Bilirubinuria indicates conjugated hyperbilirubinemia, because unconjugated bilirubin, even when quite elevated, does not appear in urine.

151

Does direct spectrophotometry measure direct or indirect bilirubin?

Both, at the same time. This method is only capable of measuring total bilirubin.

152

In unconjugated hyperbilirubinemia... If the step affected is heme conversion to unconjugated bilirubin, the pathologic process is ___. If the step affected is delivery of unconjugated bilirubin to liver, the potential pathologic processes are ___. If the step affected is uptake of unconjugated bilirubin into hepatocyte, the potential pathologic processes are ___. If the step affected is conjugation of bilirubin in hepatocyte, the potential pathologic processes are ___.

In unconjugated hyperbilirubinemia... If the step affected is heme conversion to unconjugated bilirubin (increased production), the pathologic process is extravascular hemolysis. If the step affected is delivery of unconjugated bilirubin to liver, the potential pathologic processes are blood shunting (cirrhosis) or right heart failure. If the step affected is uptake of unconjugated bilirubin into hepatocyte, the potential pathologic processes are Gilbert syndrome and drugs such as rifampin. If the step affected is conjugation of bilirubin in hepatocyte, the potential pathologic processes are Crigler-Najjar syndrome and hypothyroidism.

153

In conjugated hyperbilirubinemia... If the step affected is transmembrane secretion of conjugated bilirubin into canaliculus (hepatocellular jaundice), the potential pathologic processes are ___. If the step affected is flow of conjugated bilirubin through canaliculi and bile ducts (cholestatic jaundice), the potential pathologic process is ___.

In conjugated hyperbilirubinemia... If the step affected is transmembrane secretion of conjugated bilirubin into canaliculus (hepatocellular jaundice), the potential pathologic processes are Dubin-Johnson syndrome, hepatitis, endotoxin (sepsis), pregnancy (estrogen), and drugs such as estrogen and cyclosporine. If the step affected is flow of conjugated bilirubin through canaliculi and bile ducts (cholestatic jaundice), the potential pathologic process is mechanical obstruction such as from PBC, PSC, tumor, stricture, or stone.

154

How can you distinguish hepatocellular jaundice from cholestatic jaundice based on alkaline phosphatase, transaminases, serum cholesterol, and pruritis?

Hepatocellular jaundice: alk phos 3x upper limit of normal, cholesterol normal, and pruritis absent. Cholestatic jaundice: alk phos >3x upper limit of normal, transaminases <3x upper limit of normal, cholesterol increased, and pruritis present.

155

In autoimmune hepatitis there is a polyclonal increase in Ig__, while in primary biliary cirrhosis there is a polyclonal increase in Ig__.

In autoimmune hepatitis there is a polyclonal increase in IgG, while in primary biliary cirrhosis there is a polyclonal increase in IgM.

156

What are 6 general causes of unconjugated neonatal hyperbilirubinemia?

Physiologic jaundice. Breast milk jaundice. Polycythemia. Hemolysis (HDN, hemoglobinopathies, inherited membrane or enzyme defects). Bowel obstruction (Hirschprung disease, cystic fibrosis, ileal atresia). Inherited disorders of bilirubin metabolism (Gilbert syndrome, Crigler-Najjar syndrome).

157

What are 6 general causes of conjugated neonatal hyperbilirubinemia?

Biliary obstruction (extrahepatic biliary atresia). Sepsis or TORCH infection. Neonatal hepatitis (idiopathic, Wilson disease, alpha-1 antitrypsin deficiency). Metabolic disorders (galactosemia, hereditary fructose intolerance, glycogen storage disease). Inherited disorders of bilirubin transport (Dubin-Johnson syndrome, Rotor syndrome). Parenteral alimentation.

158

Out of viral, toxic, ischemic, and alcoholic hepatitis, which tend to have AST:ALT over 1?

The AST:ALT is over 2 in 80% of patients with toxic, ischemic, and alcoholic hepatitis. It is usually <1 in viral hepatitis.

159

Out of alcoholic hepatitis, acute hepatitis A, acute hepatitis B, and acute hepatitis C, in which conditions does jaundice occur most frequently?

Jaundice occurs in 70% of patients with alcoholic hepatitis and acute hepatitis A, and occurs in 20-30% of patients with acute hepatitis B and acute hepatitis C.

160

What is the best indicator of prognosis in acute hepatic injury?

The PT is probably the best indicator of prognosis In acute hepatic injury, with PT prolongation >4 seconds indicating severe liver injury and an unfavorable prognosis. But bilirubin >15 mg/dL is also indicative of severe liver injury and an unfavorable prognosis.

161

Up to 10% of cases of acute pancreatitis are associated with normal levels of amylase, with this finding most common in people with hypertriglyceridemia-associated acute pancreatitis. Why?

Triglycerides competitively interfere with the amylase assay.

162

List non-pancreatic causes of hyperamylasemia.

Diabetic ketoacidosis, peptic ulcer disease, acute cholecystitis, ectopic pregnancy, salpingitis, bowel ischemia, intestinal obstruction, renal insufficiency, salivary gland pathology, and macroamylasemia. Amylase may also be raised somewhat by the administration of opioid analgesics, due presumably to contracture of the sphincter of Oddi.

163

What is macroamylasemia?

A benign acquired condition (associated with celiac disease, lymphoma, HIV infection, monoclonal gammopathy, rheumatoid arthritis, and ulcerative colitis) with an incidence of ~1%, in which apparently healthy individuals have markedly elevated serum amylase levels (with low urine amylase levels), due to Ig-amylase complexes.

164

What are the 2 isoenzymes of serum amylase?

Pancreatic and salivary. But when subjected to electrophoresis, 6 bands result, with the first three being salivary and the slowest three being pancreatic.

165

How many bands form when serum amylase is subjected to electrophoresis?

When serum amylase is subjected to electrophoresis, 6 bands result, with the first three being salivary and the slowest three being pancreatic.

166

Other than electrophoresis and monoclonal antibody assays, how can salivary and pancreatic amylase be differentiated?

An inhibition test: Salivary amylase is sensitive to inhibition by the wheat germ lectin, triticum vulgaris.

167

Serum amylase rises within __ to __ hours of the onset of acute pancreatitis and returns to normal in __ to __ days.

Serum amylase rises within 2 to 24 hours of the onset of acute pancreatitis and returns to normal in 2 to 3 days.

168

How much overlap is seen in the range of levels of amylase for acute pancreatitis vs other causes?

The degree of elevation tends to be higher in acute pancreatitis, but there is considerable overlap in the ranges. Pancreatitis causes amylase in the range of 250-1000 Somogyi units, while other causes are 200-500.

169

What are 2 additional markers of acute pancreatitis other than amylase and lipase?

Serum and urine trypsinogen-2 and elastase-1.

170

What tests are available for measuring pancreatic exocrine function?

Invasive: Secretin-CCK/secretin-pancreozymin test. Noninvasive: Fecal fat. Fecal elastase-1. Fecal chymotrypsin (bentiromide).

171

What is the secretin-CCK test?

An endoscope is introduced, and the duodenal concentrations of pancreatic exocrine products (bicarbonate, amylase, lipase, trypsin) are measured after IV administration of secretin and CCK.

172

A fecal fat test (72 hour fecal fat quantitation) is positive in pancreatic exocrine dysfunction. What other conditions will also result in a positive fecal fat test?

Severe ileal diseases (such as Crohn disease) or ileal resection.

173

What does the D-xylose test measure?

Small bowel mucosal absorptive capacity.

174

Pancreatic cysts: pseudocyst, serous cystadenoma, mucinous cystadenoma (mucinous cystic neoplasm), intraductal papillary mucinous tumor, solid-pseudopapillary tumor. What will the patterns for amylase, CEA, and CA 19-9 be for each?

Pseudocyst: inc, dec, inc. Serous cystadenoma: dec, dec, dec. Mucinous cystadenoma (mucinous cystic neoplasm): dec, inc, nl to inc. Intraductal papillary mucinous tumor: inc, inc, nl to inc. Solid-pseudopapillary tumor: dec, dec, dec.

175

CK-BB (CK1) is found primarily in the brain, with lesser amounts found in what other locations?

Stomach, bladder, and prostate.

176

MSI testing is performed by extracting DNA from paraffin-embedded neoplastic and nonneoplastic tissue. PCR is used to amplify 5 specific microsatellite regions: ___, ___, ___, ___, ___. These regions from the tumor are compared to those from nonneoplastic tissue to assess for differences in length, indicative of MSI.

MSI testing is performed by extracting DNA from paraffin-embedded neoplastic and nonneoplastic tissue. PCR is used to amplify 5 specific microsatellite regions: BAT25, BAT26 (both of which are regions of mononucleotide repeats), D2S123, D5S346, and D17S250 (regions of dinucleotide repeats). These regions from the tumor are compared to those from nonneoplastic tissue to assess for differences in length, indicative of MSI.

177

What tumors are seen in patients with vHL disease?

Hemangioblastomas (CNS and retinal), pheochromocytoma, clear cell RCC, pancreatic cysts, islet cell tumors, epididymal and ovarian cystadenomas, endolymphatic sac tumors.

178

MEN1 manifests with pituitary adenomas, parathyroid adenomas, and pancreatic islet cell tumors. What are nonendocrine lesions associated with MEN1?

Facial angiofibromas, collagenomas, lipomas, and meningiomas.

179

Hereditary hemochromatosis is an autosomal recessive disorder resulting from mutations in the HFE gene. What is the most common HFE mutation (seen in 70-100% of patients diagnosed with the disease)?

C282Y.

180

For the following clinical syndrome(s), give the causative agent(s) (list most common first): bacteremia in patients with colon cancer.

C. septicum, S. bovis.

181

For the following clinical syndrome(s), give the causative agent(s) (list most common first): bacterial peritonitis (spontaneous - cirrhosis with ascites and secondary - ruptured bowel).

Spontaneous: S. pneumoniae. Secondary: mixed - E. coli, enterococci, B. fragilis, other anaerobes.

182

For the following clinical syndrome(s), give the causative agent(s) (list most common first): gastroenteritis (with short incubation period (1-8 h), fried rice, traveler's diarrhea, hamburgers in fast food restaurants, antibiotic-associated colitis, viral).

With short incubation period (1-8 h): S. aureus, B. cereus. Fried rice: B. cereus. Traveler's diarrhea: E. coli (ETEC). Hamburgers in fast food restaurants: E. coli (EHEC). Antibiotic-associated colitis: C. difficile. Viral: Rotavirus, Norwalk virus, enteric adenoviruses.

183

The genetic defect implicated in the pathogenesis of Wilson disease is localized to chromosome 13, and involves the gene encoding ___.

The genetic defect implicated in the pathogenesis of Wilson disease is localized to chromosome 13, and involves the gene encoding the protein ATP7B. ATP7B is an ATP-dependent copper transport protein that plays a pivotal role in the biliary excretion of copper and in the incorporation of copper into apoceruloplasmin to form ceruloplasmin, the major circulating copper carrying protein.

184

What are typical liver copper concentrations in Wilson disease?

Quantitative hepatic copper concentration can be performed on formalin-fixed paraffin embedded tissue to secure the diagnosis. Concentrations are typically greater than 250 ug/g (4 micromol/g) of dry liver weight.Wilson disease is not excluded based solely on a hepatic copper concentration less than 250 ug/g since approximately 15 percent of Wilson disease patients fall below this cutoff. On the other hand, a copper concentration greater than 250 ug/g is virtually diagnostic unless the patient has chronic cholestatic liver disease, which is usually clinically distinct from Wilson disease.

185

Laboratory evaluation in patients with PBC is significant for ___, ___, and ___. Histologic findings include ___.

Laboratory evaluation in patients with PBC is significant for a positive antimitochondrial antibody (specifically the M2 type), elevated IgM, and elevated alkaline phosphatase. Histologic findings include a chronic non-suppurative, destructive cholangitis, which may eventually progress to cirrhosis.

186

What conditions result in the greatest decrements of serum albumin?

Hepatic synthetic function is poorly reflected in the albumin, since only in end-stage liver disease is serum albumin noticeably decreased. The greatest decrements in serum albumin are seen in protein-losing conditions such as protein-losing enteropathy and nephrotic syndrome.

187

Is alpha-1-antitrypsin deficiency detectable with SPEP?

SPEP can be used to screen for AAT deficiency, in which the serum will display a markedly diminished alpha-1 band.

188

What are causes of increased or decreased serum ceruloplasmin levels?

A falsely normal or increased ceruloplasmin may be seen in inflammatory states (ceruloplasmin is an acute phase reactant) or pregnancy. Decreased ceruloplasmin is seen with Wilson disease, hepatic failure, malnutrition, and Menke syndrome.

189

When can fibrinogen appear in SPEP, and where does it appear?

Fibrinogen is supposed to be absent from serum, most of it having been consumed in the clot. However, if the specimen clots incompletely (such as in a heparinized patient), fibrinogen may be seen in the SPEP straddling the beta/gamma interface and misinterpreted as an M protein. Other causes of fibrinogen in serum include patients with dysfibrinogenemia, APL syndrome, liver disease, or vitamin K deficiency.

190

Fibrinogen can sometimes be present in serum (heparinized patient with incompletely clotted specimen, dysfibrinogenemia, APL syndrome, liver disease, or vitamin K deficiency) and appear as a pseudo-M-spike on SPEP. What can be done to remedy this interference?

Absolute ethanol can be used in vitro to selectively precipitate fibrinogen and obviate this interference.

191

What is the pattern for cirrhosis seen on SPEP?

Beta-gamma bridging (attributed mainly to increased serum IgA) is the hallmark of cirrhosis. Additional features include hypoalbuminemi and blunted alpha-1 and alpha-2 bands.

192

What is schistosomiasis (AKA bilharzia)?

Schistosomiasis is caused by digenetic blood trematodes. The three main species infecting humans are Schistosoma haematobium, S. japonicum, and S. mansoni. Two other species, more localized geographically, are S. mekongi and S. intercalatum. In addition, other species of schistosomes, which parasitize birds and mammals, can cause cercarial dermatitis in humans.

193

What are geographic locations of the main Schistosoma species?

S. mansoni is found in parts of South America and the Caribbean, Africa, and the Middle East; S. haematobium in Africa and the Middle East; and S. japonicum in the Far East. S. mekongi and S. intercalatum are found focally in Southeast Asia and central West Africa, respectively.

194

What is the vector for Schistosoma spp?

There is no vector; there is direct penetration of skin by free-swimming cercaria. Infection occurs when skin comes in contact with contaminated freshwater in which certain types of snails that carry the parasite are living. The parasite leaves the snail and enters the water where it can survive for about 48 hours.

195

What is the vector for Fasciola hepatica?

F. hepatica (AKA common liver fluke or sheep liver fluke) has no vector. People usually become infected by eating raw watercress or other water plants contaminated with immature parasite larvae, or from contaminated water (by drinking it or washing food with it).

196

What are risk factors for development of hepatoblastoma?

GSD type 1a, hereditary tyrosinemia, HBV infection, and chronic cholestasis disorders including biliary atresia, progressive familial hepatic cholestasis type 2 (ABCB11 disease), and Alagille syndrome.

197

What are risk factors for development of HCC in children?

GSD type 1a, hereditary tyrosinemia, HBV infection, and chronic cholestasis disorders including biliary atresia, progressive familial hepatic cholestasis type 2 (ABCB11 disease), and Alagille syndrome.

198

Can mesenchymal hamartoma of liver and infantile hemangioendothelioma cause elevated AFP levels?

Yes.

199

What feature of the cysts in mesenchymal hamartoma of liver distinguishes it from choledochal cysts and Caroli disease?

The cysts in MHL do not communicate with the biliary tree, whereas the latter 2 entities by definition do communicate with the biliary tree.

200

What is the relationship between mesenchymal hamartoma of the liver and undifferentiated embryonal sarcoma?

Rarely, UES has arisen either in a preexisting MHL or following incomplete excision of MHL.

201

What genetic abnormalities have been identified in mesenchymal hamartoma of liver?

Aneuploidy in some, as well as balanced translocation involving a common breakpoint on the long arm of chromosome 19 (band 19q13.4) with alternative partners on chromosomes 11 and 15.

202

What is Alagille syndrome (AGS) AKA syndromic paucity of interlobular bile ducts AKA arteriohepatic dysplasia?

AGS is a multisystem disorder with AD inheritance and variable penetrance and expressivity. The traditional diagnostic criteria have consisted of paucity of the interlobular bile ducts in association with 3 of 5 major findings, including chronic cholestasis, cardiac disease (most frequently peripheral pulmonary artery stenosis), skeletal manifestations (short stature, butterfly vertebrae), ocular abnormalities (most commonly posterior embryotoxon, a circular opacity of the posterior peripheral cornea), and characteristic facial features (triangular face with a prominent forehead, deep-set eyes, a pointed chin, and a straight nose with a bulbous tip). Mutations are in the JAGGED1 (JAG1) gene.

203

What is the mutation in Alagille syndrome?

Mutations are in the JAGGED1 (JAG1) gene, which encodes a cell surface protein that functions as a ligand in the Notch signaling pathway regulating cell proliferation and differentiation. The precise mechanisms by which JAG1 mutations cause AGS is still incompletely understood. JAG1 mutations have been identified in >90% of clinically diagnosed probands; additionally, NOTCH2 mutations have been detected in the small minority of AGS patients lacking JAG1 mutations.

204

In Alagille syndrome, abnormalities in which organ system causes the most mortality?

Hepatic complications do contribute significantly to the morbidity of AGS but it is the cardiovascular sequelae that are most directly responsible for the early mortality. Specifically, intracardiac anomalies, which affect ~25% of AGS patients (most commonly tetralogy of Fallot).

205

What translocations are seen in clear cell sarcoma of soft parts and in clear cell sarcoma (gastrointestinal)?

Clear cell sarcoma of soft parts: t(12;22)(q13;q12) - EWSR1-ATF1. Clear cell sarcoma (gastrointestinal): t(2;22)(q33;q12) - EWSR1-CREB1.

206

For bone tumors, metastases are far more common than primary bone tumors in a ratio of __:1. The 5 most common primary sites are ___.

For bone tumors, metastases are far more common than primary bone tumors in a ratio of 25:1. The 5 most common primary sites are lung, breast, prostate, kidney, and thyroid. After lungs and liver, skeleton is 3rd most frequent site of metastatic disease.

207

Peutz-Jeghers syndrome is an autosomal dominant condition caused by inactivating mutations in the serine-threonine protein kinase 11 (STK11) gene, also called LKB1, on chromosome 19p13.3. Mutations in STK11 are found in ~__% of familial cases and ~__% of sporadic cases.

Peutz-Jeghers syndrome is an autosomal dominant condition caused by inactivating mutations in the serine-threonine protein kinase 11 (STK11) gene, also called LKB1, on chromosome 19p13.3. Mutations in STK11 are found in ~70% of familial cases and ~30-70% of sporadic cases.

208

In Peutz-Jeghers syndrome, hamartomatous intestinal polyps can be present throughout the GI tract, but the most common site is ___. Median age for development of polyps is __ yo. The lifetime risk of small intestinal polyps in PJS is __%, and the risk of intussusception in PJS is __%. Colon polyps occur in __%, stomach polyps in __%, and rectal polyps in __%.

In Peutz-Jeghers syndrome, hamartomatous intestinal polyps can be present throughout the GI tract, but the most common site is small intestine (jejunum > ileum > duodenum). Median age for development of polyps is 11-13 yo. The lifetime risk of small intestinal polyps in PJS is 90%, and the risk of intussusception in PJS is 50%. Colon polyps occur in 53%, stomach polyps in 49%, and rectal polyps in 32%.

209

How is Peutz-Jeghers syndrome diagnosed?

PJS is diagnosed clinically by the presence of 2 or more of the following three criteria: 2 or more PJS-type hamartomatous polyps. Mucocutaneous pigmentation. Familial history of PJS.

210

Peutz-Jeghers syndrome patients are at increased risk of cancer (__% of patients by age 70), including GI cancer (__x relative risk), pancreatic cancer, lung cancer, and breast cancer (__x relative risk, affecting 8% of patients by age 40, and 31% of patients by age 60).

Peutz-Jeghers syndrome patients are at increased risk of cancer (85-93% of patients by age 70), including GI cancer (50x relative risk), pancreatic cancer, lung cancer, and breast cancer (20x relative risk, affecting 8% of patients by age 40, and 31% of patients by age 60).

211

List syndromes in which intestinal polyps may be seen in children.

Polyposis syndromes include Peutz-Jeghers syndrome, juvenile polyposis, PTEN hamartoma syndromes (Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome), and familial adenomatous polyposis. Intestinal polyps may also be seen in MEN type 2B, Gorlin syndrome, and NF type 1.

212

Although most juvenile polyps in children are sporadic, a subset of these patients develop numerous polyps (juvenile polyposis) due gene to mutations in ___ or ___. In this syndrome, juvenile polyps may develop dysplasia and eventually carcinoma.

Although most juvenile polyps in children are sporadic, a subset of these patients develop numerous polyps (juvenile polyposis) due gene to mutations in SMAD4 or BMPR1A. In this syndrome, juvenile polyps may develop dysplasia and eventually carcinoma.

213

What are the criteria for diagnosis of juvenile polyposis?

>5 juvenile polyps in the colorectum OR multiple JP throughout the GI tract OR one or more JP and a positive family history of JP syndrome.

214

The PTEN hamartoma syndromes include ___ syndrome and ___ syndrome, both resulting from mutations in the tumor suppressor gene phosphatase and tensin homolog (PTEN) on chromosome 10q23.3. These syndromes are associated with increased risk of breast and thyroid carcinomas.

The PTEN hamartoma syndromes include Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome, both resulting from mutations in the tumor suppressor gene phosphatase and tensin homolog (PTEN) on chromosome 10q23.3. These syndromes are associated with increased risk of breast and thyroid carcinomas.

215

What are the 3 main subtypes of hepatic adenoma based on immunophenotypic/molecular studies?

Cellular atypia/beta-catenin mutated adenoma. Steatotic/hepatocyte nuclear factor 1-alpha mutated adenoma. Telangiectatic/inflammatory adenoma. Those HA not fitting these three main subtypes are labeled as "unclassified" HA.

216

Patients with familial adenomatous polyposis develop juvenile nasopharyngeal angiofibromas __x more frequently than an age-matched population.

Patients with familial adenomatous polyposis develop juvenile nasopharyngeal angiofibromas 25x more frequently than an age-matched population.

217

In addition to colorectal polyps, ~__% of patients with FAP also develop gastric and duodenal polyps. Other systemic manifestations of FAP include osteomas (__%), congenital hypertrophy of the retinal pigment epithelium (__%), desmoid-type fibromatosis (__%), and dental abnormalities. Risk of malignancy is increased relative to the general population for hepatoblastoma (__x), duodenal carcinoma (__x), ampullary carcinoma (__x), nasopharyngeal adenofibroma (__x), thyroid carcinoma (__x) (specifically, the cribriform morular variant of papillary thyroid carcinoma is strongly associated with APC gene mutations), brain tumors (__x), and pancreatic carcinoma (__x).

In addition to colorectal polyps, ~90% of patients with FAP also develop gastric and duodenal polyps. Other systemic manifestations of FAP include osteomas (80%), congenital hypertrophy of the retinal pigment epithelium (70-80%), desmoid-type fibromatosis (15%), and dental abnormalities. Risk of malignancy is increased relative to the general population for hepatoblastoma (847x), duodenal carcinoma (330x), ampullary carcinoma (123x), nasopharyngeal adenofibroma (25x), thyroid carcinoma (7.6x) (specifically, the cribriform morular variant of papillary thyroid carcinoma is strongly associated with APC gene mutations), brain tumors (7x), and pancreatic carcinoma (4x).

218

What is "attenuated FAP"?

Attenuted FAP is a phenotype with fewer adenomas (<100), more proximal colonic location of polyps, delayed age of onset of carcinoma, and lower overall lifetime risk of carcinoma (69%) as compared to classic FAP. Patients with attenuated FAP also often lack family history of polyposis or extraintestinal manifestations. Attenuated FAP is typically caused by mutations in the most proximal or most distal portions of the APC gene.

219

What is the correction for ionized calcium level in the setting of hypo/hyperalbuminemia?

The equation used to measure corrected calcium in cases of hypo/hyperalbuminemia is: Corrected (Ca) = Measured total (Ca) + (0.8 x [4.5 - (alb)]). Or, 0.8 mg/dL Ca per 1g/dL protein. While this formula often provides a good estimate of the ionized calcium, its use should be avoided in patients with acid-base disturbances, renal insufficiency, liver disease, and neonates.

220

What are causes of secondary hyperparathyroidism?

Renal failure (impaired calcitriol production, hyperphosphatemia). Decreased calcium intake. Calcium malabsorption (vitamin D deficiency, bariatric surgery, celiac disease, pancreatic disease (fat malabsorption)). Renal calcium loss (idiopathic hypercalciuria, loop diuretics). Inhibiton of bone resorption (bisphosphonates, hungry bone syndrome).

221

What are causes of hypocalcemia?

Low PTH (hypoparathyroidism): genetic disorders, post-surgical (thyroidectomy, parathyroidectomy, radical neck dissection), autoimmune, infiltration of the parathyroid gland (granulomatous, iron overload, metastases), radiation-induced destruction of parathyroid glands, hungry bone syndrome, HIV infection. High PTH (secondary hyperparathyroidism in response to hypocalcemia): vitamin D deficiency or resistance, parathyroid hormone resistance, renal disease, loss of calcium from the circulation (hyperphosphatemia, tumor lysis, acute pancreatitis, osteoblastic metastases, acute respiratory alkalosis, sepsis or acute severe illness. Drugs. Disorders of magnesium metabolism.

222

Metabolic acidosis can be categorized by presence or absence of anion gap. List causes from each category.

With increased AG (>12): ketoacidosis (diabetic, starvation, EtOH-associated), lactic acidosis, D-lactic acidosis, ingestions (methanol, ethylene glycol, diethylene glycol, propylene glycol, salicylate, toluene (if early or if kidney function is impaired)), pyroglutamic acid (5-oxoproline), CKD/uremia. With normal AG (<12): diarrhea or other intestinal losses, ureteral diversion, ketoacidosis posttreatment, carbonic anhydrase inhibitors, type 1 (distal) RTA, type 2 (proximal) RTA, type 4 RTA (hypoaldosteronism), toluene ingestion (if late and if renal function is preserved - dut to excretion of sodium and potassium hippurate in the urine), CKD and tubular dysfunction (but relatively preserved GFR).

223

What is hepatorenal syndrome?

HRS is one of many potential causes of AKI in patients with acute or chronic liver disease. Affected patients usually have portal hypertension due to cirrhosis, severe alcoholic hepatitis, or (less often) metastatic tumors, but can also have fulminant hepatic failure from any cause. The HRS represents the end-stage of a sequence of reductions in renal perfusion induced by increasingly severe hepatic injury. It is a diagnosis of exclusion and is associated with a poor prognosis.

224

What is the most common cause of renal failure in the cirrhotic patient?

Spontaneous bacterial peritonitis.

225

Hepatorenal syndrome is the development of progressive renal impairment in patients with severe end-stage liver disease in the absence of another identifiable cause of renal disease. What is seen on renal biopsy?

The renal biopsy is essentially normal in HRS, but an abnormal bx must be interpreted cautiously - many patients with cirrhosis due to hepatitis viruses have an associated GN, and cirrhosis can by itself lead to an IgA-like nephropathy.

226

What is the pathogenesis of hepatorenal syndrome?

Arterial vasodilatation in the splanchnic circulation, which is triggered by portal hypertension, appears to play a central role in the hemodynamic changes and the decline in renal function in cirrhosis. The presumed mechanism is increased production or activity of vasodilators, mainly in the splanchnic circulation, with nitric oxide thought to be most important. As the hepatic disease becomes more severe, there is a progressive rise in cardiac output and fall in systemic vascular resistance; the latter change occurs despite local increases in renal and femoral vascular resistance that result in part from hypotension-induced activation of the renin-angiotensin and sympathetic nervous systems. Thus, the reduction in total vascular resistance results from decreased vascular resistance in the splanchnic circulation. The decline in renal perfusion in this setting is associated with reductions in GFR and sodium excretion and a fall in mean arterial pressure, despite the intense renal vasoconstriction.

227

Acute fatty liver of pregnancy is a rare but serious condition - a medical emergency usually complicated by ___. What is the incidence per 10,000 pregnancies? In which trimester does it usually present? What is the treatment?

Acute fatty liver of pregnancy is a rare but serious condition - a medical emergency usually complicated by DIC. It affects about 1 in 10,000 pregnancies but has a 30% case fatality rate. It usually presents in the third trimester. Immediate delivery is the treatment of choice.

228

What is seen histologically in acute fatty liver of pregnancy?

Widespread microvesicular steatosis, accentuated paracentrally (zone 3), with a paucity of inflammatory activity or hepatocellular necrosis. An oil red O stain on frozen tissue highlights microvesicles.

229

Intrahepatic cholestasis of pregnancy presents with mild jaundice and severe pruritis, usually in the third trimester. What is the most characteristic laboratory finding in this condition?

Serum bile acids (chenodeoxycholic acid, deoxycholic acid, and cholic acid) are increased, often to levels 10x the upper limit of normal.

230

What is Whipple disease? What parts of the GI tract does it affect? Race/gender/age? What entities are in the DDx?

AKA intestinal lipodystrophy. It is a rare systemic infection due to Tropheryma whippelii, a gram positive intracellular actinomycete. It usually affects proximal intestine and mesenteric lymph nodes, and usually white males ages 30-49 yo. DDx: histoplasmosis, MAI, mineral oil ingestion.

231

Histologically, how can one tell intestinal Whipple disease apart from MAI?

Whipple disease has wide open lymphatic channels and characteristic large open round spaces due to dissolved lipids in mucosa and submucosa (appears as large fat vacuoles). MAI has a conspicuous absence of dilated lymphatics or large fatty vacuoles.

232

Lymphomatoid granulomatosis most commonly presents as multiple pulmonary nodules. What are other common sites of involvement?

Brain, kidney, liver, and skin.

233

Hepatosplenic T-cell lymphoma. Where are lymphoma cells found? What type of T-cells are they/immunophenotype? %EBV positive?

The lymphoma cells show marked intrasinusoidal infiltration in the spleen, liver, and bone marrow; lymph node involvement is uncommon. The lymphoma cells are cytotoxic T-cells, usually of the delta-gamma receptor type, which express TIA-1 but are usually negative for perforin. The typical phenotype is CD2+, CD3+, CD7+, CD4-, CD5-, CD8- (usually). EBV is negative.

234

What organ system and organ within it is the most common site of extranodal marginal zone lymphoma?

GI tract most common (50% of all cases); within GI tract, stomach is most common (85%).

235

List diseases associated with colonic pseudomembrane formation.

Amoebic colitis. Antibiotic-associated (pseudomembranous) colitis. Chemotherapy-induced colitis. Colitis complicating obstruction. Heavy metal toxicity (gold salt therapy). Hemolytic uremic syndrome. Ischemic colitis. Neutropenic enterocolitis (typhilitis). Shigellosis.

236

What are the 4 phases in the clinical course of acute acetaminophen overdose?

Initially (phase I) there may be mild nausea and abdominal discomfort, which is self-limited and abates over a matter of hours. Later, often days later (usually over 24 hrs), there is progressive liver injury (phase II). This leads to fulminant hepatic failure (phase III), after which there is resolution (phase IV) in the form of complete recovery, liver transplant, or death.

237

What is a Rumack-Matthew nomogram?

It predicts hepatotoxicity/determines the need for NAC therapy/need for ICU admission in acetaminophen overdose (single acute ingestion) by relating serum acetaminophen concentration to time of ingestion. As there are no early symptoms that predict acetaminophen toxicity, poisoning severity following an acute ingestion is quantified by plotting a timed serum acetaminophen concentration on the modified Rumack-Matthew nomogram. Serum concentrations drawn before four hours may not represent peak values (4 hrs is the time it takes for full absorption), and should not be used.

238

Rumack-Matthew nomograms predict hepatotoxicity/determine the need for NAC therapy/need for ICU admission in acetaminophen overdose by relating serum acetaminophen concentration to time of ingestion. How is it interpreted?

The nomogram stratifies patients into probable hepatic toxicity, possible hepatic toxicity, and no hepatic toxicity. NAC is indicated for patients in the first 2 categories. ICU admission is indicated for patients in the first category.

239

Rumack-Matthew nomograms predict hepatotoxicity/determine the need for NAC therapy/need for ICU admission in acetaminophen overdose by relating serum acetaminophen concentration to time of ingestion. Can the nomogram be used if there were repeated supratherapeutic oral ingestions?

The nomogram should only be used after a single acute acetaminophen ingestion; It cannot be used for ingestions that occurred greater than 24 hours prior to presentation, repeated supratherapeutic oral ingestions, or iatrogenic intravenous overdose. Also, serum acetaminophen level should be obtained four or more hours after an ingestion to ensure that a peak level has occurred.

240

In healthy individuals, what is the potentially toxic dose of acetaminophen?

A dose over 150 mg/kg. Also, any single acetaminophen level over 5 ug/mL places the patient at high risk for hepatic necrosis.

241

How does the liver metabolize acetaminophen?

The liver handles acetaminophen in 2 main pathways. Most of the drug is conjugated with glucuronide or sulfate to form nontoxic metabolites. A small amount is metabolized by the P450 system into the toxic metabolite N-acetyl-p-benzoquinoneimine (NAPQI). NAPQI is normally detoxified by gluathione, but glutathione reserves are quickly overwhelmed in toxic ingestions. Furthermore, any agent that induces the P450 system increases the proportion of acetaminophen processed to NAPQI, enhancing toxicity. Chronic ethanol use, for example, has this effect.

242

What metabolite is the main cause of hepatotoxicity in acetaminophen overdose?

The toxic metabolite N-acetyl-p-benzoquinoneimine (NAPQI). NAPQI is normally detoxified by gluathione, but glutathione reserves are quickly overwhelmed in toxic ingestions.

243

The toxic metabolite N-acetyl-p-benzoquinoneimine (NAPQI) is the main cause of hepatotoxicity in acetaminophen overdose. What histologic changes does this metabolite cause?

NAPQI induces centrilobular (zone 3) hepatic necrosis with periportal sparing. Its formation within hepatocytes makes the liver the primary target, but other organs may be affected.

244

What is acute hepatic cell crisis/acute sickle hepatic crisis/right upper quadrant syndrome? What is hepatic sequestration crisis?

Acute sickle hepatic crisis presents with acute RUQ pain, jaundice, elevated LFTs (but not to the level seen in viral hepatitis). The pathogenesis is likely related to ischemia caused by sinusoidal obstruction, and histology may show sickle cell thrombi within sinusoidal spaces with engorgement by RBCs. Patients with SCD may acutely sequester large numbers of RBCs in the spleen, the pulmonary vasculature, and less commonly the liver. Patients with hepatic sequestration usually present with RUQ pain, rapidly increasing hepatomegaly, and a falling Hgb/Hct. The pathophysiology is believed to be obstruction of sinusoidal flow by the masses of sickled RBCs, with trapping of RBCs within the liver.

245

In primary effusion lymphoma, HHV8 is positive in ___% of cases, and EBV is positive in ___% of cases.

In primary effusion lymphoma, HHV8 is positive in 100% of cases, and EBV is positive in 70% of cases.

246

Adenoviruses are grouped into over 40 serotypes. Most of the respiratory infections are caused by serotypes __-__, with types __ and __ associated with epidemic outbreaks of respiratory disease. Types __ and __ are associated with hemorrhagic cystitis. Types __ and __ are associated with childhood gastroenteritis.

Adenoviruses are grouped into over 40 serotypes. Most of the respiratory infections are caused by serotypes 1-14, with types 4 and 7 associated with epidemic outbreaks of respiratory disease. Types 11 and 21 are associated with hemorrhagic cystitis. Types 40 and 41 are associated with childhood gastroenteritis.

247

What is the mechanism of arsenic toxicity, and what are clinical manifestations?

Arsenic inhibits the oxidative production of ATP. Thus, initial toxicity is manifested in dividing tissue such as GI mucosa, with nausea, vomiting, bloody diarrhea, and abdominal pain. The marrow is affected, causing cytopenias (with erythrocyte basophilic stippling similar to that seen in lead toxicity). Chronic toxicity results in peripheral neuropathy, nephropathy, skin hyperpigmentation and hyperkeratosis (particularly palms and soles) and transverse Mees lines in the nails.

248

What are the biochemokinetics of mercury toxicity in its metallic/elemental, inorganic, and organic forms?

Pulmonary absorption of mercury vapor (elemental form) is high; however, this form of mercury is only poorly absorbed from the GI tract and across the skin. The kidney is the major site of deposition for mercury derived from inhalation exposure of mercury vapor. A significant fraction of the mercury vapor taken into the lung is eliminated via exhalation; most of the absorbed mercury is eliminated in the feces. GI absorption of inorganic mercury is on the order of 15 percent. The kidney is the major site of deposition for inorganic mercury compounds. Organic mercury compounds such as methylmercury are highly absorbed from the GI tract and later de-alkylated. The kidney, hair, and CNS are major sites of deposition. Organic mercury readily crosses the placenta, causing severe neurologic impairments in the fetus.

249

Digoxin-Like Immunoreactive Substances (DLIS) / Endogenous Digoxin-Like Substances (EDLS) are endogenous or exogenous substances that cross-react with antidigoxin antibodies and falsely elevate serum digoxin concentrations, interfering in interpretation of results for therapeutic digoxin monitoring. In what populations/conditions is it seen?

Elevated DLIS concentrations are encountered in patients with volume-expanded conditions such as uremia, essential hypertension, liver disease, and preeclampsia. They are also seen in neonates, pregnant women, and renal failure.

250

How is procainamide cleared? What is it metabolized to, and how is the metabolite cleared?

Procainamide is cleared predominantly by the liver. Procainamide is metabolized by hepatic acetyltransferase to N-acetylprocainamide (NAPA), which has pharmacologic activity of its own (in making dosing decisions, the sum of procainamide and NAPA is considered). NAPA is cleared predominantly by the kidneys.

251

What genetic factor determines the rate of procainamide metabolism?

Pocainamide (hepatic clearance) is metabolized to N-acetylprocainamide (NAPA) (renal clearance), which is also biologically active. The rate of conversion to NAPA is determined by the concentration of hepatic acetyltransferase, which is genetically determined. So-called fast acetylators, who have genetically high levels of acetyltransferase, have higher levels of NAPA.

252

Ingested lipid are internalized by small bowel enterocytes and packaged into chylomicrons, which have a low density due to a large ___ component. The chylomicron is the lipoprotein that transports lipid from enterocytes to other somatic cells, particularly hepatocytes, into which they are endocytosed via apolipoprotein ___.

Ingested lipid are internalized by small bowel enterocytes and packaged into chylomicrons, which have a low density due to a large triglyceride component. The chylomicron is the lipoprotein that transports lipid from enterocytes to other somatic cells, particularly hepatocytes, into which they are endocytosed via apolipoprotein E.

253

In the liver, cholesterol and triglyceride undergo additional metabolism before being packaged, for secretion into the blood, into (class of lipoprotein), which has a low density due to a large triglyceride component, and is the vehicle for transport of triglyceride to somatic cells.

In the liver, cholesterol and triglyceride undergo additional metabolism before being packaged, for secretion into the blood, into VLDL, which has a low density due to a large triglyceride component, and is the vehicle for transport of triglyceride to somatic cells.

254

The liver produces a class of lipoproteins called HDL that contain a small amount of lipid, mainly phospholipid and cholesterol, the enzyme licithin cholesterol acyl transferase (LCAT), and apolipoproteins, especially apolipoprotein ___. What is the function of HDL?

The liver produces a class of lipoproteins called HDL that contain a small amount of lipid, mainly phospholipid and cholesterol, the enzyme lecithin cholesterol acyl transferase (LCAT), and apolipoproteins, especially apolipoprotein A-1. The function of HDL is to scavenge cholesterol from the periphery and returning it to the liver.

255

A negative ANCA assay does not rule out a vasculitis. On the other hand, elevated ANCA titers (often p-ANCA and generally low titer levels) have also been reported in many inflammatory conditions such as ___. ANCA positivity is seen in __% of patients with UC and PSC, and in __% of patients with Crohn's disease.

A negative ANCA assay does not rule out a vasculitis. On the other hand, elevated ANCA titers (often p-ANCA and generally low titer levels) have also been reported in many inflammatory conditions such as RA, SLE, Sjogren's syndrome, scleroderma and antiphospholipid syndrome. ANCA positivity is seen in 60-80% of patients with UC and PSC, and in 10-30% of patients with Crohn's disease. Elevated ANCA titers can also be found in some healthy individuals.

256

For HAV, HBV, HCV, HEV, and HGV, what are the modes of transmission, incubation periods, % that produce chronicity?

HAV: fecal-oral, 15-30 days, 0%. HBV: parenteral, 15-150 days, 10%. HCV: parenteral, 30-150 days, 50%. HEV: fecal-oral, 15-42 days, <1%. HGV: parenteral, unknown, unknown.

257

What is the most common viral hepatitis in the US?

HAV.

258

HEV has a __% fatality rate in pregnancy.

HEV has a 20-30% fatality rate in pregnancy.

259

What is HBeAg?

HBeAg indicates active viral replication. In the hepatocyte, the genome of HBV can be present in 2 forms: as replicating virus or integrated into the host genome as a non-replicating form. HBeAg is only produced when the virus is in replicating form; thus, it can be used as a surrogate for HBV DNA production. Antibody against HBeAg (anti-HBe) is found when HBe becomes negative. The presence of anti-HBe does not imply resolved infection or immunity.

260

What is HBeAg-negative chronic hepatitis B?

The HBV genome can undergo mutation, altering clinical features, with one such mutation taking the form of so-called HBeAg-negative chronic hep B. This is characterized by circulating HBV DNA, fluctuating aminotransferases, and a tendency towards fulminant hepatitis with liver failure. This form of hep B results from mutations in the C region of the genome (encodes HBcAg and HBeAg), the most common mutation leading to a premature stop codon that impairs synthesis of HBeAg.

261

__% of people infected with HCV will develop chronic infection. __% of those with chronic HCV will develop cirrhosis. Those with cirrhosis due to HCV have a __% chance of developing HCC.

55-85% of people infected with HCV will develop chronic infection. 10-15% of those with chronic HCV will develop cirrhosis. Those with cirrhosis due to HCV have a 5% chance of developing HCC.

262

What are some extrahepatic manifestations of HCV infection?

Hematologic diseases such as essential mixed cryoglobulinemia, lymphoma, and aplastic anemia. Renal disease, particularly membranoproliferative glomerulonephritis. Autoimmune disorders such as thyroiditis and the presence of autoantibodies. Dermatologic conditions such as porphyria cutanea tarda and lichen planus. Diabetes mellitus.

263

The most characteristic histologic lesion of yellow fever is in what organ?

Liver. There is extensive midzonal necrosis, Councilman bodies, microvesicular fatty metamorphosis, and absence of an inflammatory component.

264

Acute pancreatitis is associated with elevated TG (chylomicrons or VLDL), particularly when greater than ___ mmol/L.

Acute pancreatitis is associated with elevated TG (chylomicrons or VLDL), particularly when greater than 5-10 mmol/L.

265

What are some secondary causes of a predominant hypercholesterolemia?

Hypothyroidism, DM, nephrotic syndrome, cholestasis, cyclosporine, thiazide diuretics, or loop diuretics.

266

What are some secondary causes of a predominant hypertriglyceridemia?

Heavy alcohol consumption, obesity, DM, hepatitis, pregnancy, renal failure, beta blockers, isotretinion, corticosteroids, nephrotic syndrome, and gout.

267

What are Alzheimer type II astrocytes?

Acute hepatic encephalopathy, whether acquired or in Wilson disease, shows Alzheimer type II astrocytes. These astrocytes have enlarged nuclei with clear marginated chromatin, eccentric nucleolus, and scant cytoplasm. They may be found in the deep cerebral cortex, basal ganglia, thalamus, dentate nucleus of the cerebellum and brain stem. They are not associated with Alzheimer's disease.

268

Alzheimer type II astrocytes are astrocytes that have enlarged nuclei with clear marginated chromatin, eccentric nucleolus, and scant cytoplasm. They may be found in the deep cerebral cortex, basal ganglia, thalamus, dentate nucleus of the cerebellum and brain stem. They are not associated with Alzheimer's disease. In what disorders/conditions are they seen?

Acute hepatic encephalopathy, whether acquired or in Wilson disease.

269

List causes of hypoglycemia.

Insulinoma. Nesidioblastosis. ILGF-like hormone secreting tumors (sarcomas, HCC). Advanced malignancy. Anti-insulin receptor antibodies. Autoimmune insulin syndrome. Post-gastric surgery. Drug induced (insulin, sulfonylureas, alcohol, quinine, salicylates, haloperidol, beta blockers, quinolones, pentamidine, ACE inhibitors, IGF-1). Critical illness such as hepatic/renal/cardiac failure, sepsis, inanition (def: an exhausted condition resulting from lack of food and water or a defect in assimilation; starvation). Hormone deficiency (cortisol, glucagon and epinephrine in insulin-deficient DM). Inborn errors of metabolism (glycogen storage disease, hereditary fructose intolerance, galactosemia, carnitine deficiency). Starvation. Accidental, surreptitious, or malicious hypoglycemia.

270

What is the clinical utility of anti-mitochondrial antibody?

AMA is detected in 85% of patients with primary biliary cirrhosis.

271

What is the clinical utility of anti-smooth muscle antibody?

Lupoid (autoimmune) hepatitis is characterized by titers of greater than 1:80. ASMA are specifically directed at F-actin.

272

What is the clinical utility of anti-endomysial antibody?

Endomysin is present in the reticular investment of muscle fibers. Anti-endomysial antibodies are IgA antibodies. They are highly sensitive and specific for celiac sprue and dermatitis herpetiformis. Antibody titers respond to a gluten-free diet.

273

What is the clinical utility of anti-parietal cell antibodies?

80% sensitive for pernicious anemia, but only 70% specific. Presence of the APCA does not correlate with B12 malabsorption.

274

What is the clinical utility of anti-intrinsic factor antibodies?

50-75% sensitive for adult pernicious anemia, but 90% sensitive for pediatric pernicious anemia. There are 2 types: type I, blocking Ab, reacts only with unbound IF, and is extremely specific; type II, binding Ab, reacts with unbound and bound IF, and is both less specific and less sensitive than type I.

275

Anti-mitochondrial antibodies are associated with primary biliary cirrhosis. What are they directed at specifically?

Anti-mitochondrial antibodies are directed against a mitochondrial antigen from the inner mitochondrial membrane, called M2, which is thought to be dihydrolipoamide acetyltransferase, a component of the pyruvate dehydrogenase enzyme complex.

276

Anti-M2 mitochondrial antibodies are found in about __% of patients with primary biliary cirrhosis. What is the specificity?

Anti-M2 mitochondrial antibodies are found in about 90% of patients with primary biliary cirrhosis. They are highly (95-99%) specific.

277

Antibodies to mitochondrial antigens M1 to M9 are associated with various diseases. List.

M1, M2, and M7 are on inner mitochondrial membranes, while M3, M4, M5, M6, M8, and M9 are on outer mitochondrial membranes. Anti-M1: syphilis. Anti-M2, anti-M4, anti-M8, anti-M9: primary biliary cirrhosis (anti-M2 is a specific marker for the diagnosis of PBC). Anti-M3: phenopyrazon-induced pseudolupus syndrome. Anti-M5: undefined collagen diseases. Anti-M6: iproniazid-induced hepatitis. Anti-M7: cardiomyopathy.

278

Anti-liver kidney microsomal type 1 antibody is associated with what condition?

LKM-1 autoantibodies are found in autoimmune hepatitis. Note: Anti-microsomal antibodies (or anti-thyroid microsomal antibodies) are different (a group of anti-thyroid antibodies, which were renamed after the identification of their target antigen, TPO; they have high specificity and sensitivity for Hashimoto disease).

279

p-ANCA is less specific than c-ANCA but still has clinical utility, since it is seen in a small number of disorders. List.

Primary sclerosing cholangitis. Ulcerative colitis. Microscopic polyangiitis. Also, RA and Churg-Strauss syndrome.

280

Other than active sarcoidosis, what are other causes of elevated ACE?

Primary biliary cirrhosis, Gaucher disease, and leprosy. All of these have in common the formation of granulomas; however, most other granulomatous diseases are not associated with an elevated ACE.

281

What diseases are associated with the following HLA types: HLA-DR2, HLA-DR3, HLA-DR4, HLA-B27?

HLA-DR2: multiple sclerosis, narcolepsy, protective for IDDM. HLA-DR3: SLE, Sjogren syndrome, myasthenia gravis, Graves disease (The DR3-DQ2 linkage is associated with IDDM, dermatitis herpetiformis, and celiac disease). HLA-DR4: IDDM, RA, pemphigus vulgaris. HLA-B27: ankylosing spondylitis and other "reactive" arthritidies.

282

Why is the specificity of IgA anti-transglutaminase antibodies for celiac sprue low in the setting of chronic liver disease?

There is a high incidence of IgA anti-transglutaminase antibodies in patients with chronic liver diseases (particularly among those with autoimmune liver diseases).

283

Anti-transglutaminase antibodies, anti-endomysial antibodies, and antigliadin antibodies vary with exposure to gluten, but none correlate with mucosal recovery in celiac disease. What test of mucosal absorption, and what serum analyte does correlate with mucosal recovery?

Tests of mucosal absorption, such as the D-xylose absorption test, may be useful. Transthyretin (a rapidly responsive indicator of nutritional status) correlates very well with mucosal recovery.

284

What auto-antibodies are associated with atrophic gastritis (pernicious anemia), and how are they detected?

Anti-parietal cell and anti-IF. IIF on cryostat sections of rat stomach/liver/kidney.

285

What auto-antibodies are associated with ulcerative colitis, and how are they detected?

pANCA. IIF on ethanol-fixed neutrophils.

286

What auto-antibodies are associated with celiac disease, and how are they detected?

Anti-gliadin, anti-endomysial, ,and anti-transglutaminase. ELISA; IIF on cryostat sections of rat stomach/liver/kidney.

287

What auto-antibodies are associated with autoimmune hepatitis, and how are they detected?

Anti-smooth muscle. IIF on cryostat sections of rat stomach/liver/kidney.

288

What auto-antibodies are associated with primary biliary cirrhosis, and how are they detected?

Anti-mitochondrial. IIF on cryostat sections of rat stomach/liver/kidney.

289

What auto-antibodies are associated with IDDM, and how are they detected?

Anti-islet cell, anti-glutamic acid decarboxylase (GAD), anti-insulin receptor. IIF on cryostat sections of pancreas; ELISA; bioassay.

290

Scleroderma (progressive systemic sclerosis) is associated with obliterative vasculopathy, dermal sclerosis, epidermal atrophy, tenosynovitis, esophageal sclerosis, interstitial lung disease, pulmonary hypertension, telangiectasia, calcinosis, and renal hypertension. What auto-antibodies are associated with scleroderma, and how are they detected?

ANA, anti-nucleolar, anti-Scl-70 (anti-topoisomeraseI). IIF on C. luciliae or HEp-2 cells; ELISA.

291

Although rare, appendiceal endocrine tumors are the most common neoplasm of the appendix, and are the second most frequently occuring digestive endocrine tumor. AETs are separated into 2 groups: classic appendiceal endocrine tumors and goblet cell carcinoids. Describe each group: presentation, incidence, location of tumor in the appendix, histologic appearance, treatment.

Most classic AETs are diagnosed incidentally during appendectomy. They are associated with, but not related to, acute appendicitis b/c most tumors are located at the tip of the appendix (60-75%) and do not induce obstruction. M:F = 1:2. Histologically, classic AETs have uniform tumor cells arranged in rounded, solid nests, with some peripheral palisading infiltrating the appendiceal wall. Treatment is local resection for tumors

292

Autoimmune/lymphoplasmacytic/sclerosing pancreatitis is associated with elevation of serum IgG4 in ___% of cases.

Autoimmune/lymphoplasmacytic/sclerosing pancreatitis is associated with elevation of serum IgG4 in more than 70% of cases.

293

Although somatostatin is a normal product of endocrine cells in both the pancreas and duodenum, somatostatin-producing neuroendocrine tumors arising in these 2 sites tend to behave differently. How?

Pancreatic: usually in the head of the pancreas; are not associated with NF-1; contain fewer psammoma bodies; have poorer prognosis; more commonly have the somatostatinoma syndromes. Duodenal: 6 times more common than pancreatic; functional ones are distinctly unusual in the duodenum; duodenum and periampullary location is more common in patients with NF-1; psammoma bodies are seen in over half of sporadic tumors and all of the NF-1 associated ones.

294

Duodenal somatostatin-producing neuroendocrine tumor with psammoma bodies. What syndrome is it associated with?

NF-1.

295

The main differential diagnosis of pseudomembranous colitis includes ischemic colitis and severe inflammatory bowel disease. Extensive, confluent mucosal necrosis can be present in all three entities and, when present, can make differentiating between the three impossible. What are histologic features that may help to distinguish these 3 entities?

Ulcerative colitis often exhibits contiguous involvement of the colon and involves the rectum whereas C. difficile colitis can be discontiguous and may spare the rectum. In the setting of ischemia, secondary infections may complicate the picture. The presence of pseudomembranes and inflammation with submucosal extension can be seen in both C. difficile colitis and ischemic colitis. In the later stages of ischemic colitis, fibrosis of the lamina propria and hemosiderin-laden macrophages are important diagnostic clues that are not present in pseudomembranous colitis

296

Echinococcal or hydatid cysts have a characteristic cyst wall seen microscopically. Describe.

The cyst wall is composed of a laminated membrane lined by a germinal layer. The laminated layer is no more than 1 mm thick and acellular. The germinal layer is 10-25 um thick and contains nuclei but may be too degenerated to be seen clearly. Scolices develop from the germinal layer. They contain calcareous bodies which can be seen free floating in the degenerated cyst contents.

297

H. pylori infection is a major etiologic factor of gastric carcinoma, especially the intestinal type of adenocarcinoma. So why do the majority of individuals infected with H. pylori not develop cancer?

Only certain types of H. pylori are carcinogenic and need environmental and host factors to result in carcinoma.

298

True or false. Herpetic hepatitis occurs only in reactivation disseminated disease, not as a primary manifestation.

True.

299

Enterobius vermicularis (pinworm). After being laid, how soon do the eggs become infective, and for how long do they remain infective?

The eggs become infective after 4-6 hrs, and remain infective for up to a week in cool moist conditions. The eggs can be infective by ingestion or inhalation.

300

What is the CK7 and CK20 staining for hepatocellular carcinomas?

Negative for both. Only 16% are CK7 positive, and only 8% are CK20 positive.

301

Is the EML4-ALK fusion unique to non-small cell lung cancer?

No. This fusion has been detected, at lower frequency, in breast and colorectal adenocarcinomas, although its role in the pathogenesis of these tumors is unknown.

302

What are the mutation rates of MSH2, MSH6, MLH1, PMS2, and EPCAM in Lynch syndrome?

MSH2 - 40%. MSH6 - 7-10%. MLH1 - 50%. PMS2 - less than 5%. EPCAM - 1-3%.

303

What is the typical IHC staining pattern for MSH2, MSH6, MLH1, and PMS2 with gene mutation/silencing of EPCAM?

MSH2-, MSH6-, MLH1+, PMS2+.

304

For sporadic colorectal cancers with BRAF V600E, is having MSI-high or microsatellite stable associated with a worse prognosis?

Microsatellite stable CRC with BRAF V600E has a worse prognosis than MSI-high CRC with BRAF V600E.

305

Sporadic and syndromic fundic gland polyps are histologically and immunohistochemically indistinguishable, but have different genetic and molecular backgrounds. Describe.

Sporadic FGPs show a very high frequency of activating mutations in the beta-catenin gene, whereas syndrome FGPs occur through an inherited germline mutation in the APC gene coupled with additional somatic mutations, leading to complete inactivation of both copies of the APC tumor suppressor gene. But when low-grade dysplasia is present in either sporadic or syndromic FGPs, truncating mutations in the APC gene occur in both settings.

306

The ductal system of the pancreas is subdivided into what 5 parts?

Centroacinar cells, intercalated ducts, intralobular ducts, interlobular ducts (large and small), and main ducts.

307

The ductal system of the pancreas is subdivided into 5 parts: Centroacinar cells, intercalated ducts, intralobular ducts, interlobular ducts (large and small), and main ducts. What are the centroacinar cells?

Small, relatively inconspicuous, flat to cuboidal cells with pale or lightly eosinophilic cytoplasm and central oval nuclei. Centroacinar cells are located in the middle of the acini, where they partially border the acinar lumina along with the acinar cells, to which they are joined by tight junctions. The lumen surrounded by acinar and centroacinar cells drains into the intercalated ducts.

308

Germline mutations in the UGT1A1, DPYD, GSTP1, XPD, and MGMT genes can affect therapy for ___ cancer.

Germline mutations in the UGT1A1, DPYD, GSTP1, XPD, and MGMT genes can affect therapy for colon cancer.

309

What is precore mutant hepatitis B virus?

A precore mutant is a variety of hepatitis B virus that does not produce hepatitis B virus e antigen (HBeAg). The G1764A and A1762T mutations are usually responsible for the decreased preCore (PC) mRNA synthesis. The G1896A mutation is the most prevalent and produces a translation stop codon at amino acid position 28 in the HBeAg sequence, with inhibition of HBeAg synthesis. Precore and core mutant HBV is associated with fulminant hepatitis and increased risk of HCC.

310

Mutations in KIT or PDGFRA can be seen in GISTs and are mutually exclusive. KIT mutation is present in 80% of GISTs, PDGFRA mutation is seen in 8% of GISTs, and 10-15% are wild type. What exons are the mutations seen in?

KIT mutations are present in exon 11 (juxtamembrane domain) > exon 9 (extracellular domain) > exon 13 (TK1 domain/ATP-binding) = exon 17 (TK2 domain/activation loop). PDGFRA mutations are present in exon 18 (TK2 domain /activation loop) > exon 12 (juxtamembrane domain) > exon 14 (TK1/ATP-binding) domain.

311

In GISTs, KIT mutations are present in exon 11 (juxtamembrane domain) > exon 9 (extracellular domain) > exon 13 (TK1 domain) = exon 17 (TK2 domain), and PDGFRA mutations are present in exon 18 (TK2 domain) > exon 12 (juxtamembrane domain) > exon 14 (TK1) domain. What are the frequencies of these mutations?

KIT mutations are present in exon 11 (juxtamembrane domain) - 67%, exon 9 (extracellular domain) - 10%, exon 13 (TK1 domain/ATP-binding) - 1%, exon 17 (TK2 domain/activation loop) - 1%. PDGFRA mutations are present in exon 18 (TK2 domain/activation loop) - 5%, exon 12 (juxtamembrane domain) - 2%, exon 14 (TK1/ATP-binding) domain - 1%.

312

In drug therapy for GISTs, why do KIT exon 9 mutants tend to show primary resistance to imatinib?

The KIT exon 9 mutated tumors respond better to higher doses of imatinib than needed for exon 11 mutated tumors.

313

In GISTs, KIT mutations are present in exon 11 (juxtamembrane domain) - 67%, exon 9 (extracellular domain) - 10%, exon 13 (TK1 domain/ATP-binding) - 1%, exon 17 (TK2 domain/activation loop) - 1%. When secondary resistance mutations develop after treatment with imatinib, which exons are the mutations seen in?

Exons 13 and 14 (TK1 domain/ATP-binding) and exons 17 and 18 (TK2 domain/activation loop). They are usually single nucleotide substitutions and occur on the same allele as the original mutation.

314

In GISTs treated with imatinib, are secondary resistance mutations more likely to occur with tumors that had a primary exon 11 or exon 9 mutation?

Exon 11.

315

10%-15% of GISTs lack KIT and PDGFRA mutations = wild-type GISTs. Among these WT GISTs, a small subset is associated with succinate dehydrogenase (SDH) deficiency, known as SDH-deficient GISTs. In addition, GISTs that occur in Carney triad (SDH deficient but not mutated) and Carney-Stratakis syndrome (mutations in SDH subunit B, C, or D) represent specific examples of SDH-deficient GISTs. What are some unique features of SDH-deficient GISTs that differ from the more common GISTs?

SDH-deficient GISTs locate exclusively in the stomach, showing predilection for children and young adults with female preponderance. They have a distinct morphology - epithelioid and multinodular/plexiform. Nearly all are KIT and DOG-1 positive. Accepted GIST risk factors do not apply. The tumor generally pursues an indolent course despite lymph node and distant metastases and exhibits primary resistance to imatinib therapy in most cases. Loss of succinate dehydrogenase subunit B expression and overexpression of insulin-like growth factor 1 receptor (IGF1R) are common features of SDH-deficient GISTs.

316

What is Crail syndrome?

The condition of young-onset colonic polyposis and brain tumors originally termed Turcot's syndrome has been reclassified into 2 conditions depending on the underlying genetic condition. Brain tumors, typically medulloblastomas, in association with FAP-related colonic polyposis, is now termed Crail's syndrome. Lynch syndrome (HNPCC) in association with glioblastomas are properly classified as Turcot's syndrome.

317

What is MUTYH-associated polyposis AKA MYH-associated polyposis AKA MAP?

A condition caused by biallelic pathogenic germline variants in MUTYH characterized by a greatly increased lifetime risk of colorectal cancer (43% to almost 100% in the absence of timely surveillance). Although typically associated with ten to a few hundred colonic adenomatous polyps that are evident at a mean age of about 50 years, colonic cancer develops in some individuals in the absence of polyposis. The colonic phenotype is similar to AFAP but the terminology "FAP/AFAP caused by MYH mutations" is not correct. Extracolonic manifestations include duodenal adenomas/carcinomas, ovarian CA, bladder CA, skin CA.

318

What are the molecular characteristics of MUTYH-associated polyposis AKA MYH-associated polyposis AKA MAP?

A molecular hallmark of carcinomas caused by MUTYH deficiency is the presence of a specific somatic KRAS pathogenic variant (c.34G>T in codon 12) which is found in 64% of MAP colorectal cancers. The majority of CRCs in persons with MAP are microsatellite stable. The normal gene product of the MUTYH gene, the MUTYH protein, is an A/G-specific adenine DNA glycosylase that plays a major role in DNA damage repair. Two common pathogenic allelic variants, c.536A>G (p.Tyr179Cys) in exon 7 and c.1187G>A (p.Gly396Asp) in exon 13, are missense variants carried by approximately 1%-2% of the general population; they account for at least 90% of all MUTYH pathogenic variants in northern European populations, and one or both of these founder pathogenic variants are identified in up to 70% of persons with MAP.

319

With bi-allelic MMR gene mutations (such as with mismatch repair cancer syndrome AKA constitutional mismatch repair deficiency syndrome) what would you expect to see for MMR IHC and MSI PCR?

IHC would be uninterpretable, since both tumor and normal may lack protein expression. In MMRCS, PCR of brain tumors may not show MSI; MSI more likely to be seen in the Lynch syndrome‐associated tumors. Most report that PCR of normal tissue does not show MSI.

320

Mutations in what genes cause Menkes disease and Wilson disease?

Menkes disease: ATP7A (Copper-transporting ATPase 1). Wilson disease: ATP7B (Copper-transporting ATPase 2).

321

What are the 2 types of islets of Langerhans?

Compact islets and diffuse islets. 90% of the islets in the pancreas are compact islets. They are sharply circumscribed nests usually measuring 75-225 um, and found mostly in the body and tail of the pancreas. The cytoplasm is pale and amphophilic. Diffuse islets are essentially restricted to the posteroinferior head of the pancreas derived from the embryonic ventral lobe, and may measure up to 450 um. The diffuse islets have a trabecular appearance, with winding cords of cuboidal and columnar cells intermingled among acini. The cytoplasm is basophilic, the nuclei are somewhat hyperchromatic, and there may be more prominent nucleoli than in the compact islets.

322

The 2 types of islets of Langerhans are the compact islets and diffuse islets. 90% of the islets in the pancreas are compact islets, which are found mostly in the body and tail of the pancreas. The diffuse islets are essentially restricted to the posteroinferior head of the pancreas derived from the embryonic ventral lobe. What is the difference in proportion of cell types between the compact and diffuse islets?

Compact islets: 60-70% beta cells (insulin), 15-20% alpha cells (glucagon), delta cells (somatostatin) less numerous, PP (pancreatic polypeptide) cells rare. Diffuse islets: 70% PP cells, 20% beta cells, 5% alpha cells, 5% delta cells. The difference in proportion of cell types between the compact and diffuse islets reflects their different embryologic origins. The relative proportion of the different peptide-producing cells will also vary with age.