Gastrointestinal Pathology

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Anatomic pathology of the entire (mouth to anus) gastrointestinal tract. Well, maybe, I'll put mouth into the "oral pathology" category, depending on how I feel.

Electron micrograph of Whipple disease

There is the cigar-shaped bug.

Enterobius vermicularis (pin worm)

On H&E section of the appendix, a worm with a pseudocoelom and lateral alae are identified. What is the most likely organism?

Gastrointestinal stromal tumor of the small bowel

This is a CD117 stain. What is the diagnosis?

Mast cells

This is a CD117 stain in an esophageal leiomyoma. Clearly, the neoplastic cells aren\'t staining. What are those rare wretches who bare the burden of horseradish peroxidase?

CD34

With which vascular marker do GIST cells stain?

Normal colonic mucosa

Ulcerative colitis

Histologically characterized by mucosal-based chronic crypt destructive colitis with continuous involvement from the rectum extending proximally

anti-inflammatory and immunosuppressive drugs; surgery if not responsive

Treatment of ulcerative colitis

Indications for colectomy in ulcerative colitis

fulminant disease (toxic colitis), high-grade dysplasia, DALM, and adenocarcinoma

Chronic, active ulcerative colitis

Endoscopic imagery of _____. Diffuse erythema and granular appearance.

Crohn disease. Strictures are unusual in ulcerative colitis.

Is it Crohn disease or ulcerative colitis that tends to be associated with intestinal strictures?

Crohn disease. Serositis is unusual in ulcerative colitis.

Is it Crohn disease or ulcerative colitis that tends to be associated with serositis?

Crohn disease. Bowel wall thickening is unusual in ulcerative colitis.

Is it Crohn disease or ulcerative colitis that tends to be associated with bowel wall thickening?

Ulcerative colitis

Longitudinal opening usually reveals a bowel wall that is of normal thickness, which opens with ease in the fresh state. Strictures are unusual. The mucosa may be flattened, bloody, and friable.

The two characteristic histologic findings in chronic ulcerative colitis

Crypt architectural distortion and increased mucosal chronic inflammation.

Ulcerative colitis

Marked inflammation, crypt distortion, and crypt abscesses.

Paneth cells are normal in the ascending colon but are considered an indicator of prior mucosal injury and repair in the distal colon.

In which part of the colon are Paneth cells considered an abnormal finding?

Ulcerative colitis

Colon resection. The inflammatory process is confined predominantly to the mucosal surface and has an abrupt interface with the submucosa .

Ulcerative colitis

Colon resection. Diffuse involvement by inflammatory polyps and pseudopolyps with mucosal bridging. *Inflammation is confined to the mucosa.*

Inflammation is more severe distally

Topographic distribution of inflammation severity in ulcerative colitis

p-ANCA

A serologic test that is often positive in ulcerative colitis.

Long-standing ulcerative colitis is associated with an increased risk for dysplasia and adenocarcinoma, even in patients with well-controlled, quiescent disease.

What affect does good clinical control of ulcerative colitis have on the otherwise increased risk of colonic adenocarcinoma in these patients?

Dysplasia can be found in both flat, grossly undetectable, and raised mucosa, termed DALM (dysplasia-associated lesion or mass).

What is a DALM in ulcerative colitis?

Din ulcerative colitis may appear at the crypt base, in contrast to dysplasia in colonic adenomas, which begins at the surface.

What is a difference between the dysplasia seen in ulcerative colitis and the dysplasia seen in colonic adenomas?

Dysplasia-associated lesion or mass (DALM)

Biopsy from a patient with ulcerative colitis. Crypt architectural distortion with nuclear hyperchromatism, enlargement, and irregularity.

High grade DALM

Biopsy from a patient with ulcerative colitis. Pronounced nuclear changes including nuclear pleomorphism, hyperchromasia, and overlap. Architecturally, there is loss of polarity, more crypt crowding complex glands, and glandular distortion

Usually referred for colectomy because there is almost always an underlying invasive malignancy, regardless of the histologic grade

What is the clinical significance of a villiform (non-adenoma-like) DALM in a background of ulcerative colitis?

Crohn disease

Which inflammatory bowel disease can present with fistulas between organs (enterovaginal, enterovesical, and enterocutaneous) may result in the passage of blood, feces, pus, and air from the vagina, urethra, or skin.

Seen in many Crohn disease cases, but rarely in ulcerative colitis

Are anal and perianal fissures and fistulas are features seen in Chron disease or ulcerative colitis?

Crohn enteritis

Endoscopic view of small bowel with longitudinal \"rake\" ulcers with intervening normal mucosa.

Clinical presentation of Crohn disease

Typically characterized by foci of glandular destruction, aphthous erosions, and serpiginous ulcers, as well as transmural inflammation, fibrosis, and granulomas in the small and large bowel.

Crohn enteritis

Aphthous erosions: small, irregular white mucosal erosions with erythematous borders.

Crohn disease typically spares the rectum; ulcerative colitis nearly universally involves the rectum

The rectum, Crohn disease, and ulcerative colitis

Crohn disease

\"Creeping fat\"

Crohn enterocolitis. There are often intervening areas of normal bowel wall. This \"pipe stem\" bowel is not seen in ulcerative colitis.

Area of constricted lumen with a thickened, fibrotic bowel wall (\"pipe stem\" bowel).

Crohn enterocolitis

Small bowel resection. Longitudinal ulcers with intervening normal mucosa.

Crohn disease

Small bowel biopsy. Discrete foci of inflammation often associated with neutrophils within crypts (cryptitis) and adjacent to histologically normal crypts are common.

Crohn enterocolitis

Aphthous erosion: focal mucosal disruption with neutrophils over a lymphoid nodule. Adjacent crypts appear relatively normal.

Crohn enterocolitis

Small bowel biopsy. Poorly formed, non-necrotizing granuloma associated with marked chronic inflammation.

No, NSAID use is

Is Crohn disease the most common cause of focal, acute ileitis?

NSAID use

In addition to Crohn disease, what else can give submucosal fibrosis of the bowel wall?

Histologic hallmark of Crohn disease

Submucosal fibrosis and transmural inflammation, including transmural lymphoid aggregates.

Crohn enterocolitis

Small bowel resection. Marked submucosal fibrosis associated with transmural and subserosal lymphoid aggregates. Fissuring ulceration.

Crohn enterocolitis

Small bowel resection. Greatly thickened bowel wall with distorted mucosa, fissure, submucosal fibrosis, and transmural lymphoid aggregates.

Crohn disease

Which inflammatory bowel disease has discrete foci of inflammation and architectural changes adjacent to histologically normal crypts.

aphthous erosions, distorted, flattened villi, pyloric metaplasia

Terminal ileal involvement in Crohn enterocolitis

Crohn disease

Which inflammatory bowel disease is associated with fissures, sinuses, and fistulas?

Anti-Saccharomyces cerevisiae antibody (ASCA)

Which serologic test is positive in approximately 70% of patients with Crohn disease and usually negative in ulcerative colitis patients?

Medical management of Crohn disease

Standard therapy includes anti-inflammatory drugs, specifically the 5-ASA compounds (sulfasalazine and other salicylates) and steroids.

Monoclonal antibody directed against tumor necrosis factor-α

What is infliximab?

Infliximab (monoclonal antibody directed against TNFα)

What biological therapy is often used in treat acute episodes of Crohn disease, especially fistulas and other complications?

4 to 20 times more than those without Crohn disease

Relative risk of gastrointestinal adenocarcinoma in patients with Crohn disease

Adenocarcinomas may arise in a morphologically normal bowel, in areas of stricture, and within fistula tracts, making diagnosis difficult.

Does the bowel mucosa in Crohn disease have to demonstrate either inflammation or dysplasia before it gives rise to cancer (a sort of inflammation-dysplasia-carcinoma sequence seen in ulcerative colitis)?

Crohn disease

Deceptively bland adenocarcinoma, like the one pictured in this photomicrograph, is typical for which inflammatory bowel disease entity?

75% to 80%

What percentage of GISTs have a gain of function in the c-KIT gene?

Approximately 8%

What percentage of GISTs have mutations that activate a related tyrosine kinase, platelet-derived growth factor receptor α (PDGFRA), instead of a c-KIT activating mutation?

Interstitial cells of Cajal (thought to be the precursors cells in GISTs).

Which cells in the GI tract normally express c-KIT (CD117) and CD34?

Gastrointestinal stromal tumor

On cross-section a whorled texture is evident within the white, fleshy tumor.

Gastrointestinal stromal tumor

The mass in the GI tract that is covered by intact mucosa.

Gastrointestinal stromal tumor

Histologically the submucosal tumor is primarily composed of bundles, or fascicles, of spindle-shaped tumor cells.

About 5%

What proportion of GISTs do no express CD117?

Somewhat less aggressive than GISTs arising in the small intestine

What is the prognosis of gastric GIST in relation to small intestinal GIST?

Low grade appendiceal mucinous neoplasm

Appendectomy. Enlarged, pseudostratified nuclei, abundant cytoplasmic mucin, and an absence of complex architectural features.

High grade appendiceal mucinous neoplasm

Appendectomy. Micropapillary tufts of epithelial cells that showed loss of cell polarity and ovoid nuclei with open chromatin and conspicuous nucleoli.

- Patients with acellular mucin almost never die of the disease
- About a third fo patients with neoplastic cells in the mucin die of disease

How is the prognosis of appendiceal mucinous neoplasm related to cellularity of the periappendiceal mucin?

Only a very small proportion (about 5%) of patients with extra-appendiceal mucin go on to develop pseudomyxoma peritonei

What percentage of patients with appendiceal mucinous neoplasm that spreads beyond the appendix go on to develop pseudomyxoma peritonei?

Herpes esophagitis

Esophageal biopsy

Reflux esophagitis

Esophageal biopsy. Intercellular edema and balloon cells.

Endoscopic appearance of eosinophilic esophagitis

Mucosal granularity on esophageal endoscopy.

Endoscopic appearance of eosinophilic esophagitis

Typical furrows and rings on esophageal endoscopy.

Eosinophilic esophagitis

Esophageal biopsy

Eosinophilic esophagitis

A form of allergic esophagitis associated with atopic symptoms

Eosinophilic esophagitis

Esophageal biopsy.

CMV esophagitis

Esophageal biopsy.

Fibroblasts and myofibroblasts

These large cells in the base of an esophageal ulcer are most likely _____.

HER2/neu

Synonym for human epidermal growth factor receptor 2

Human epidermal growth factor receptor 2

HER2/neu synonym

Expression correlates with worse prognosis

In gastric and esophageal adenocarcinoma, what prognostic significance does HER2/neu (human epidermal growth factor receptor 2) over expression have?

Granular cell tumor

Peri-esophageal mass in a 72-year-old. On cell block, the lesional cells decorate with antibody directed against CD68.

CD68 is a marker of lysosomes and stains granular cell tumor which has many large granular lysosomes.

CD68 is normally useful in identifying histiocytes. But, antibodies directed against CD68 also stain granular cell tumors. Why?

Lysosomes. They are irregular, disorganized electron dense granules.

EM. What are the ugly electron dense things?

Granular cell tumor

EM of a peri-esophageal mass. These are lysosomes. Which tumor has a lot of these in its cells?

CD34

When the GIST is negative for c-Kit, what will it still be positive for?

Stomach

Most common location of GIST in the GI tract.

The use of a check list in preparing oncological reports.

The one practice significantly associated with increased likelihood of providing complete oncologic pathology information

transmembrane tyrosine kinase receptor that is a member of the epidermal growth factor receptor superfamily

Function of HER2 (aka, ERBB2, HER2/neu)

intestinal and diffuse

Two general histologic classifications of gastric carcinoma (in antrum, body, and fundus)

gastroesophageal reflux

Most common clinical association in gastroesophageal junction carcinomas

- FAP with osteomas and desmoplastic fibromas
- Mnemonic: gardeners are always having to dig hard rocks out of the soil into which they are planting their exophytic, polypoid cauliflowers.

Gardner syndrome

Cowden syndrome

Colon polyps with tricholemmomas and RCC

Peutz Jegher Syndrome

- Hamartomatous polyps of the small bowel (arborizing muscular stroma)
- Oral mucocutaneous hyperpigmentation
- Adenoma malignum (minimal deviation carcinoma) of cervix

Muir-Torre syndrome

Hereditary non-polyposis colon cancer syndrome associated with sebaceous skin lesions and keratoacanthomas.

Muir-Torre syndrome

Hereditary non-polyposis colon cancer syndrome associated with sebaceous skin lesions and keratoacanthomas.

Bronchogenic cyst of esophagus

Esophageal cystic lesion lined by respiratory epithelium (pseudostratified ciliated epithelium)

- Just "esophageal cyst." Pretty obvious, huh?
- Usually just an incidental finding

Esophageal cyst lined by squamous epithelium is called . . .

Histologic buzz word of Leishmania esophagitis

- "Double knot amastigote"
- Causes esophageal ulceration in immunocompetent hosts

- Giemsa stains Leishmania and Histoplasma
- GMS stains only Histoplasma but not Leishmania

Histochemical differentiation between Leishmania and Histoplasmosis in esophagus

Many people get sick at once because of drinking water contamination

Typical clinical scenario for leishmaniasis

Where aorta crosses the esophagus

Most likely location in the esophagus for pill esophagitis

Alendronate and iron

Two pills most commonly associated with pill esophagitis

Takes forty minutes for pill to get from mouth to stomach, so have to be able to keep esophagus straight for that time

Pathophysiology of pill esophagitis

Polarizable foreign material

Distinctive histologic feature of pill esophagitis

It is adenocarcinoma and not squamous cell carcinoma.

What is the most common type of esophageal cancer in the West?

- SCC has individual cells and tongues of invasive cells
- SCC has higher ratio of epithelium to stroma than does regenerative epithelium

Distinguish SCC of the carcinoma vs regenerative epithelium

- Carcinoma that extends for > 2 cm from the point of deepest invasion
- Has a very high rate of nodal metastasis, despite low T stage (superficial invasion); this has been a board question

Some factoids about superficial squamous cell carcinoma of the esophagus

- Sometimes impossible, so must call it "indeterminate for dysplasia, please treat ulcer and rebiopsy."
- NEVER get Ki-67 because it will always be high in both
- On K34 or pancytokeratin stain, the tongues of regenerative epithelium will be to the same depth, without any cells straying past the basal lamina

How to distinguish florid regenerative squamous epithelium from invasive SCC?

- All depends on ratio of lymphocytes to eosinophils. If much more lymphocytes, then the diagnosis is reflux esophagitis.
- Opposite ratio for eosinophilic esophagitis.

Reflux esophagitis versus eosinophilic esophagitis

20 eosinophils/hpf

Magic number for eosinophilic esophagitis

- Most likely, the patient has eosinophilic esophagitis.
- Eosinophilic esophagitis is notoriously patchy.

If a patient has three biopsies of the esophagus and two of them show >20 eosinophils/hpf and the third shows only reflux esophagitis, does the patient have GERD or eosinophilic esophagitis?

- Regenerative atypia looks similar from cell to cell and gland to gland.
- Barrett esophagus with dysplasia varies in its appearance from cell to cell and gland to gland.

In the esophagus, how to differentiate between regenerative epithelial atypia and dysplastic Barrett esophagus?

Barrett esophagus with low grade dysplasia

- Cytologic and structural atypia that reaches the surface
- Cell to cell variability with mild loss of polarity
- Goblet cells start to disappear in areas of dysplasia

- Architectural complexity
- Loss of nuclear polarity
- Enlarged nuclea

3 histologic hallmarks of high-grade dysplasia in Barrett esophagus

Because of the constant injury associated with Barrett esophagus, the muscularis mucosa begins to split apart. But, it doesn't matter because surgical resection is the indication for both. This splitting up of the muscularis mucosa is a unique feature of the esophagus; the muscularis mucosa is a useful hallmark of invasion in all other parts of the GI tract.

Why is it hard to tell the difference between Barrett esophagus with high grade dysplasia versus adenocarcinoma?

The typical patient seen with eosinophilic esophagitis is a young boy with atopy and esophagitis-like symptoms.

Typical patient with eosinophilic esophagitis?

No because eosinophilic esophagitis is notoriously patchy.

If a pathologist is given a clinical history of an adult female (ie, not the classic demographic associated with eosinophilic esophagitis) with atopy and esophagitis symptoms, and that pathologist does not see eosinophils on the esophageal biopsy, is it safe to conclude that this patient does not have eosinophilic esophagitis?

Over the last 20 years, the incidence is actual decreasing.

During the last 20 years, is the incidence of H. pylori increasing or decreasing?

Histologic hallmark of GI small B cell lymphoma

Lymphoepithelial lesion

Proton pump inhibitor effect

Hyperplasia of the pink parietal cells caused by PPI because the parietal cells want secrete more acid.

Type A gastritis

Is carcinoid tumor associated with type A or type B gastritis?

Type A gastritis is immune mediated (anti-parietal and anti-intrinsic factor antibodies). This leads to lack of acid secretion (because parietal cells are taken out be the immune system), which in turn leads to increased gastrin in the serum

Describe type A gastritis.

The increased gastrin is due to hyperplasia of the enterochromaffin cells in the stomach, which leads to increased risk of carcinoid tumors.

How does type A gastritis lead to a higher risk of gastric carcinoid.

Only a minority are associated with H. pylori.

Is gastric carcinoid associated with Helicobacter pylori infection?

- Anti-parietal cell and ant-intrinsic factor antibodies.
- Not really related to H. pylori.

Etiology of type A gastritis.

Females are more commonly affected than males (as is true for most autoimmune disease)

Gender predilection of type A gastritis

- Adult: H. pylori
- Children: CMV infection

Infectious associations of Ménétrier disease

Foveolar hyperplasia due to antibody attaching to TGFα receptor, blocking them. This leads to lack of development of chief cells and parietal cells. So there is the paradoxical low gastrin with low acid.

Molecular pathology of Ménétrier disease.

- FAP (the APC gene)
- Up to 42% of fundic gland polyps in FAP have dysplasia

Multiple fundic gland polyps seen in what disease?

- PPIs have increased the incidence of fundic gland polyps
- Most of these sporadic fundic gland polyps have a mutation in β-catenin

Medicine associated with sporadic fundic gland polyps?

STK gene on chr19

Gene that is mutated in patients with Peutz Jegher polyp

Mnemonic PASS Boards
- Pancreas
- Adenoma malignum of the cervix
- Sex cord stromal tumors
- Sertoli tumors
- Breast

Extra-GI malignancies associated with Peutz Jegher syndrome

Extra-GI malignancies associated with Peutz Jegher syndrome

Which genetic syndrome is associated with the following malignancies?
- Pancreas
- Adenoma malignum of the cervix
- Sex cord stromal tumors
- Sertoli tumors
- Breast

CD34

Both inflammatory fibroid polyp and GIST stain for the IHC marker _____.

Most benign GIST respect muscularis mucosa and have favorable histology; inflammatory fibroid polyp bursts through the muscularis, but still has favorable histology. Malignant GIST can burst through the muscularis mucosa; however, it will have cytologic features of malignancy. These cytologic features are absent in the inflammatory fibroid polyp.

Histologic difference between inflammatory fibroid polyp and GIST in regards to the muscularis mucosa

Histologic difference between inflammatory fibroid polyp and GIST in regards to the muscularis mucosa

Most benign GIST respect muscularis mucosa and have favorable histology; inflammatory fibroid polyp bursts through the muscularis, but still has favorable histology. Malignant GIST can burst through the muscularis mucosa; however, it will have cytologic features of malignancy. These cytologic features are absent in the inflammatory fibroid polyp.

Meckel diverticulum "rule of two"

- 2% of population has a Meckel diverticulum (anti-mesenteric border)
- 2 feet proximal to the cecum
- Usually 2 inches long

- 2% of population has a Meckel diverticulum (anti-mesenteric border)
- 2 feet proximal to the cecum
- Usually 2 inches long

Meckel diverticulum "rule of two"

GIST

Perinuclear halo in a spindle cell lesion of the GI tract is typical for which neoplasm?

- 4% of patients with Meckel diverticulum will have complications.
- These complications present in the first decade of life. Heuristically, this makes sense, since it is a congenital disease.

What percentage of patients with Meckel diverticulum present with complications?

Gastric (60%)

What is the most common heterotopia in Meckel diverticulum?

H. pylori gastritis

85% of patients with active duodenitis have _____.

No H. pylori has ever been reported in a biopsy of the duodenum.

What is the sensitivity of Helicobacter pylori IHC in finding the organism in a biopsy of the duodenum that shows active duodenitis?

- Hyperplastic polyps of the gastric epithelium occur in milieu that favors dysplasia
- Because of this, if a patient is diagnosed with a hyperplastic polyp on histology, that patient should undergo immediate repeat endoscopy with multiple random biopsies of the gastric mucosa in order to rule out dysplasia

Proper clinical management of a gastric hyperplastic polyp?

- 0% because H. pylori hates intestinal goblet cells, whether in the intestine or the stomach.
- However, 80%-85% of patients with active duodenitis will have H. pylori gastritis (type B gastritis).

In a biopsy of the duodenum that shows active duodenitis, what percent of patients will have a positive H. pylori immunostain in their duodenal biopsy?

- Giardia lamblia
- Whipple disease
- Cryptosporidium parvum
- Strongyloides stercoralis

Infectious diseases in small bowel biopsies that do not illicit an inflammatory response?

5%

What is the prevalence of Giardia lamblia enteritis in the US?

- PCR on the biopsy specimen.
- Repeat PAS-D can show light staining of the dead organisms, leading to a potential false positive result in a patient who has actually received adequate treatment

What is the appropriate laboratory test for follow up of Whipple disease after antibiotic treatment?

MAC

Whipple disease organisms have bright staining on PAS-D. Light staining on PAS-D should raise the suspicion for ____ infection, since these organisms can pick up some PAS (leading to a light staining).

Otherwise healthy, immunocompetent, middle aged, white male.

Typical clinical history for Whipple disease?

Type I carcinoid are associated with chronic atrophic gastritis (type A gastritis)

Background pathology associated with type I carcinoid tumors of the stomach?

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