247 terms

Gastrointestinal Pathology

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?
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
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?
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 _____.
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?
When the GIST is negative for c-Kit, what will it still be positive for?
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
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"
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?
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?
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?
Type A gastritis is an autoimmune disease with antibodies directed at the parietal cells, leading to achlorhydria. The achlorhydria leads to increased gastrin secretion, which leads to enterochromaffin cell hyperplasia, which results in carcinoid tumor
What is type A gastritis?
- Somatostatin analogs or antrectomy to decrease the gastrin stimulation of the carcinoid
- Gastrectomy is NOT indicated as these lesions are indolent and treatable by other means
Appropriate treatment for type I gastric carcinoid tumors (those associated with autoimmune gastritis)
Zollinger Ellison syndrome or MEN 1
What two clinical syndromes are associated with type II gastric carcinoid tumors?
- Treat the underlying cause of the hypergastrinemia that is driving the tumorigenic process.
- Usually seen in a background of Zollinger-Ellison syndrome or MEN 1.
Treatment for type II gastric carcinoid tumors
Type 3 gastric carcinoid tumor
This is a sporadic carcinoid in a patient that is otherwise normogastrinemic
Treatment depends on tumor grade
Treatment of type 3 gastric carcinoid tumor.
Duodenal infections in the immunocompromised host that do not elicit much of an inflammatory response
- Cryptosporidium
- Isospora belli
- Microsporidium
- Cryptosporidium
- Isospora belli
- Microsporidium
Duodenal infections in the immunocompromised host that do not elicit much of an inflammatory response
- No. Giardia trophozoites are chlorine resistant.
- Need to filter drinking water in addition to treating it with halide.
Is chlorine treatment of drinking water enough to prevent Giardia infestation?
Can actually be found anywhere in the GI tract (stomach, small bowel, colon, gall bladder, etc)
What part of the GI tract does Cryptosporidium live?
- Strongyloides stercoralis
- This belongs to the nematode family
Rhabditiform larvae is what organism?
Histologic findings of hyper-infective state of Strongyloides stercoralis
- Filariform larvae
- Very dense eosinophilic infiltration with Splendori-Hoeppli phenomenon (ground glass, eosinophilic debris deposited around the blood vessels)
- This is an endoscopic diagnosis: see attached picture of a diaphragm
- All histology shows is a paucicellular fibrosis of the lamina propria
- Due to slow release of NSAIDS
Diaphragm disease of the small bowel
- A systemic autoimmune disorder
- Sensitivity is to gliadin and prolamin fraction of gluten proteins
Pathogenesis of gluten-sensitive enteropathy (celiac sprue)
- GI symptoms do not have to be the presenting symptom
- Neurologic symptoms or infertility can be the presenting symptom
Presenting symptoms of celiac disease (gluten sensitive enteropathy)
Intraepithelial lymphocytes (normal number is 2 lymphocytes to 10 enterocytes); this is a very sensitive finding, but 0% specificity
Lymphocytes in celiac disease
Celiac sprue
If it looks like a lymphocytic colitis, but the biopsy is from the small bowel, it is _____.
Histology alone is not enough to make the diagnosis; this is a clinical diagnosis that is confirmed by serology
What is needed to make a diagnosis of celiac disease?
Currently the most sensitive and specific serologic finding in celiac disease
- Anti-tissue transglutaminase antibody
- Others that are used: anti-gliadin and anti-endomysial antibodies
- Anti-tissue transglutaminase antibody
- Others that are used: anti-gliadin and anti-endomysial antibodies
Currently the most sensitive and specific serologic finding in celiac disease
Which HLA phenotypes are associated with gluten sensitive enteropathy?
- γδ T cells
- Usually CD3+/CD8+
- If CD8 is dropped, the patient is at a very high risk of enteropathy associated T cell lymphoma
Type of intraepithelial lymphocytes normal seen in celiac disease
TCR rearrangement studies
If enteropathy-associated T cell lymphoma is suspected, then what is the appropriate laboratory test to perform on the biopsy material?
- Patients can make fat but cannot make chylomicrons
- As a result, the lipid accumulates in the enterocytes; beware because this picture can happen in a normal patient after a fatty meal
- Can only make this diagnosis in the appropriate clinical setting of low chylomicrons and VLDL and serum lipid
- Much more aggressive neoplasm than typical carcinoid
- The carcinoid cells stain for neuroendocrine markers
- The goblet cells stain for epithelial markers
Compare the natural history of goblet cell carcinoid of the appendix to conventional carcinoid of the appendix.
Ampulla of Vater
Somatostatinomas occur predominantly at which anatomic location?
- Diagnosis is psammomatous somatostatinoma
- This tumor has a very high association with NF1
Psammoma bodies in an ampullary mass?
- Ischemic colitis
- Must have diagnosis of of C. difficile infection from the microbiology lab before a surgical pathologist can render a diagnosis of pseudomembranous colitis
Histologic mimic of pseudomembranous colitis
- Ischemic colitis
- Looking at the disruption of the muscularis mucosa is vital to making the diagnosis
Paucicellular lamina propria (ie, not much in the way of inflammatory cells) with disruption of muscularis mucosa
- Irritable bowel syndrome (no pathologic findings)
- Microscopic colitis (ie, lymphocytic colitis or collagenous colitis); > 2 lymphocytes/10 colonic enterocytes- Irritable bowel syndrome (no pathologic findings)
- Microscopic colitis (ie, lymphocytic colitis or collagenous colitis);
Differential diagnosis of diarrhea in middle aged females?
- Normal: collagen IV
- Abnormal (collagenous colitis): I, III, and VI
Normal basement membrane collagen in the colonic basal lamina versus collagen in collagenous colitis?
- Salmonella
- Shigella
- Campylobacter
Which bacteria are associated with acute self-limited colitis?
- Looks just like inflammatory bowel disease
- So, should never call IBD on first biopsy because IBD-like histology could be self-limited colitis. Must repeat the biopsy to see if the histology normalizes.
What other disease process does acute self-limited colitis mimic histologically?
Diagnostic utility of Paneth cell metaplasia
- Paneth cells are normal in the right colon
- If one sees Paneth cells in the left colon is an indication of chronic inflammatory disease
Gross differences between UC and Crohn disease
Carney-Stratakis syndrome
What is the eponym for the syndrome that presents with gastric GIST and paraganglioma?
Results from mutations in the various subunits of the succinate dehydrogenase genes
Carney-Stratakis syndrome genetic pathology
Carney-Stratakis syndrome
Results from mutations in the various subunits of the succinate dehydrogenase genes
Carney triad is not a familial disorder, ie, it does not show any mode of inheritance. The underlying genetic etiology is unknown.
What kind of inheritance does Carney triad demonstrate?
The triad comprises gastric GIST, paraganglioma (like Carney-Stratakis syndrome plus), and pulmonary chondroma
Carney triad. Hint: Carney-Stratakis syndrome pulse pulmonary chondroma
Carney triad
What is the eponymous disease that comprises gastric GIST, paraganglioma (these two are also seen in Carney-Stratakis syndrome), and pulmonary chondroma?
Young women
What patient population is most affected with the GISTs that develop in Carney triad and Carney-Stratakis syndrome?
- Carney triad
- Carney-Stratakis syndrome
What syndromes are associated with epithelioid gastric GISTs, especially in young women?
- Usually epithelioid
- Multinodular
- Mainly located in the antrum
- Lymph node metastases are common, regardless of size and mitotic activity of the primary lesion
What is the typical histology of gastric GISTs seen in Carney triad and Carney-Stratakis syndrome?
- Tends to present in young women
- Tends to present with lymph node metastasis, without regard to size or mitotic activity
- Despite all this, they still have relatively indolent behavior
- Usually has epithelioid or mixed epithelioid-spindled morphology
Describe the unique biological behavior of GISTs seen in Carney-Stratakis syndrome (gastric GISTs with paragangliomas) and Carney triad (Carney-Stratakis syndrome plus pulmonary chondromas)?
- Tends to be multinodular and plexiform
- Often presents with lymph node or abdominal metastases
- Most often negative for mutations in KIT and PDGFRA and are, thus, resistant to therapy with imatinib
Describe the unique histopathology associated with the rare childhood GIST
Childhood GISTs
Which patient demographic tends to have GISTs that are negative for PDGFRA and KIT mutations?
Childhood GISTs
A subset of GISTs in this age group has mutations in SDHB or SDHC (succinate dehydrogenase subunit B or C, respectively) genes, like those seen in Carney-Stratakis syndrome
Gastric GISTs tend to have a better prognosis than intestinal GISTs.
When a gastric GIST and an intestinal GIST have similar dimensions and mitotic rates, which of the two tumors behaves more indolently?
- PDGFRA (platelet-derived growth factor α)
- KIT (another receptor tyrosine kinase)
There are two genes associated with adult, non-syndromic GIST. If there is an appropriate mutation in either one of these two genes, then that patient my have response to imatinib. What are those two genes?
- It is a tyrosine kinase inhibitor with a broader spectrum and greater potency of tyrosine kinase inhibition than imatinib
- In addition to KIT and PDGFR, it targets VEGFR1, VEGFR2, FLT3, and RET
- Sunitinib is a more potent KIT inhibitor than imatinib
- Activating mutation in this signaling enzyme can lead to constitutive activation of the MEK/MAPK pathway that cetuximab therapy won't counteract
According to the American Society of Clinical Oncology (ASCO) guidelines, testing for mutation in which gene should precede utilization of anti-EGFR antibody (cetuximab) therapy in metastatic colorectal carcinoma?
BRAF mutation in colorectal carcinoma is a bad actor.
BRAF mutations are an independent indicator of poor prognosis.
BRAF mutated, KRAS wild-type colon cancers
Genetic phenotype of colon cancer that confers resistance to cetuximab (anti-EGFR) therapy.
CpG island methylator phenotype (CIMP)
BRAF mutations are associated with which pro-oncogenic epigenetic phenotype?
Phosphatase and tensin homologue
What does "PTEN" stand for?
Inhibits signaling initiated by PI3Ks
What is the physiologic function of PTEN?
constitutive activation of the PI3K signaling cascade, thereby conferring resistance to EGFR inhibitors
PTEN (phosphatase and tensin homologue) inhibits signaling initiated by PI3Ks. Loss of PTEN function could therefore lead to _____
- V600E (val to glu).
- This mutation is seen in 60% of BRAF mutations
- This substitution is in the activation segment of the protein
What is the most common mutation seen in BRAF in human oncogenesis?
- The big one is hairy cell leukemia
- Papillary thyroid carcinoma, melanoma, and non-small cell lung cancers of various types
Other than colorectal carcinoma, what other cancers have been associated with BRAF mutations?
- It is a member of the EGFR family
- Thus, it is a receptor tyrosine kinase
- Just for giggles, activation of HER2/neu leads to activation of RAS, RAF, MAPK, PI3K, and mTOR
What kind of a protein is HER2/neu?
Gastric adenocarcinoma
Which GI tumor type is often associated with HER2/neu over-expression?
In the small bowel, lymphomas constitute _____ of all malignant neoplasms.
CD117 is positive in melanoma and in a significant minority of plasma cell neoplasms
Potential pitfall in using CD117 in gastrointestinal stroma tumors
CD34 strongly and diffusely stains approximately 70% of GISTs; the percentage of CD34-positive tumors varies by location with 47% of small intestinal GISTs, 96% of rectal GISTs, and 100% of esophageal GISTs showing CD34 expression.
Percentage of GISTs that stain for CD34.
Percentage of GISTs that have c-Kit over-expression.
Percentage of GISTs that have a PDGFRA mutation.
Most often in exon 11, which results in constitutive activation of the Kit receptor, which is thought to promote proliferation and/or decrease apoptosis.
Most common location of activating mutation in kit gene.
Blood bank findings in gastric cancer
Excess free serum A or B antigens may be present free in serum. This may have the effect in vitro of binding anti-A or anti-B reagents, hus giving the false impression that the patient has type O red cells.
What percentage of gastric carcinomas express CK20?
Intraabdominal desmoid tumor
Another name for sclerosing mesenteritis
Sclerosing mesenteritis (intra-abdominal desmoid tumor)
Sections of the mesenteric mass reveal fibrotic bands traversing the mesenteric fat. Many lymphoplasmacytic and eosinophilic inflammatory cells are present.
Sclerosing mesenteritis (intra-abdominal desmoid tumor)
Sections of the mesenteric mass reveal fibrotic bands traversing the mesenteric fat. Many lymphoplasmacytic and eosinophilic inflammatory cells are present.
The fibrotic areas do not extend into the small bowel wall.
An important histologic feature in avoiding inappropriately calling sclerosing mesentery right is a spindle cell malignancy.
65 years old
Mean age of diagnosis for sclerosing mesenteritis
Molecular pathology of desmoid tumor (intestinal fibromatosis)
Associated with mutations in APC gene, therefore leads to alteration of beta-catenin pathway.
Clostridium difficile-associated pseudomembranous colitis
Classic mushroom- or volcano-shaped pseudomembrane on the surface of the mucosa
Collagenous colitis
Patients with this type of microscopic colitis present with a history of chronic diarrhea. Most are middle-aged to elderly women.
Collagenous colitis
This high-power view shows surface damage with increased intraepithelial lymphocytes and irregular subsurface collagen deposition. Note that there is a superficial plasmacytosis and eosinophils seem to cluster around the collagen bundles
Collagenous colitis
This trichrome-stained section shows the irregular subsurface collagen entrapping a small capillary and inflammatory cells.
Ranitidine and ticlopidine (like clopidogrel, it is an adenosine diphosphate (ADP) receptor inhibitor)
Two drugs that are thought to cause lymphocytic colitis
Mycophenolate mofetil (CellCept)
Which drug is associated with dilated and distorted crypts lined by regenerative epithelium. Note the rather empty lamina propria and the eosinophil-rich debris within the
Ischemic colitis
Hyalinized, smudgy-appearing lamina propria with markedly regenerative crypt epithelium. Note that there is very little inflammation yet the surface is sloughing.
A deficiency of short-chain fatty acids
What is thought to be the cause of diversion colitis?
Short-chain fatty acids, which are usually derived from fermentation of dietary starches by normal colonic bacterial flora.
What is the main source of energy for colonocytes?
Diversion colitis
This diverted segment of colon contains strikingly enlarged lymphoid aggregates with germinal centers as well as occasional crypt abscesses and surface erosions. One could easily misdiagnosis this as chronic inflammatory bowel disease without the appropriate history that these biopsies came from a diverted segment.
Grossly, an infiltrative process that starts in the mesentery and involves the bowel walls. Cystic and spongy cut surface on resection.
Mesenteric mass. The histologic sections demonstrate a cytologically bland, somewhat haphazard aggregation of vessels that are invested with smooth muscle. The stroma between the vessels contains fat, nerve fibers, and occasional lymphoid aggregate.
What is an IHC antibody that is useful in determining lymphatic endothelial differentiation?
Mesothelioma and cerebellar hemangioblastoma
In addition to staining lymphatic endothelium, what else does D2-40 stain?
Lymphangioma has thin walled vessels while angiomyolipoma has thick walled vessels.
Both lymphangiomas and angiomyolipomas have the triad of vessels, fat, and smooth muscle. What is a better histologic difference between the two?
Discovered on GIST-1. A recent tissue microarray study examined 447 GISTs and found that DOG1 stained 87% of GISTs, whereas c-kit stained 74% of GISTs.
DOG1 is an gene associated with GIST. But, DOG1 is also an acronym that stands for what?
Aberrant nuclear staining for this protein, which is involved in the Wnt and E-cadherin signaling signaling cascades, is useful in the diagnosis of gastrointestinal stromal tumors.
This s a 92-kDa protein that binds to the cytoplasmic tail of E-cadherin. It acts in the nucleus to stimulate cell proliferation and is degraded by complexing with the adenomatous polyposis coli gene.
When it is mutated, it is ineffectively degraded and results in unchecked proliferative activity that plays a role in a subset of neoplasms. When there are alterations in is degradation, it accumulates to a sufficient extent to be detected in the nuclei of tumor cells immunohistochemically, a feature that can be exploited in the differential diagnosis of selected neoplasms.
Beta-catenin and the APC tumor suppressor pathway.
Mutation of the APC tumor-suppressor gene initiates the majority of colorectal cancers through the adenoma-carcinoma sequence. One consequence of this inactivation is constitutive activation of [beta]-catenin/Tcf-mediated transcription.
The utility of beta-catenin in distinguishing between tubular adenoma versus dysplasia-associated lesions or masses.
Because beta catenin is over express in situations associated with APC dysfunction (like in the tubular adenoma, adenoma-carcinoma sequence), beta catenin should theoretically be over expressed in tubular adenomas. However, because DALM is associated with p53 mutations, beta-catenin over-expression is not seen in these lesions.
Nuclear expression of this protein is found in nearly all mesenteric fibromatoses but not in gastrointestinal stromal tumor or sclerosing mesenteritis.