Cory A. Roberts, MD
Where in the esophagus are you most likely to find heterotopic gastric mucosa (inlet patch)?
The cervical region is the most common location.
What is the underlying pathophysiology of achalasia?
It is characterized, in part, by nearly complete absence of the myenteric plexus within the esophagus.
What infectious agent and disease present a nearly identical clinical and pathologic scenario as idiopathic achalasia?
Infection with Trypanosoma cruzi causes Chagas’ disease which results in findings similar to achalasia.
In a patient with achalasia, what type of esophageal tumor occurs at an increased rate compared to the general population?
Squamous cell carcinoma.
True/False: An esophageal biopsy report says there are 23 eosinophils per high-power field. This person has eosinophilic esophagitis.
It depends on where in the esophagus the biopsies were obtained. EoE is a clinicopathologic diagnosis whereby there are 15 or more eosinophils per high-power field and an absence of pathologic reflux by pH studies and/or lack of response to high-dose proton pump inhibitors. Biopsies taken from the mid-and proximal esophagus are more specific for EoE. Furthermore, while the pathologist can suggest EoE as a diagnosis, they will typically not have all of the clinical data to make the diagnosis with certainty.
What is the most common type of esophagitis in biopsy specimens and what are the histologic features?
Reflux esophagitis is the most common type and is characterized by epithelial hyperplasia, elongation of the papillae, basal hyperplasia, spongiosis, vascular ectasia within the papillae, and epithelial infiltration by neutrophils and eosinophils. The histology can be identical to eosinophilic esophagitis, hence the reason that EoE is a clinicopathologic diagnosis.
List some risk factors for development of squamous cell carcinoma of the esophagus.
Smoking, alcohol, history of lye stricture, achalasia, previous radiation, Plummer–Vinson’s syndrome, and tylosis.
A 47-year-old man with frequent, long-standing classical reflux symptoms undergoes endoscopy. A 7-cm circumferential segment of columnar appearing mucosa proximal to the gastric folds is seen. A representative biopsy is shown below. What is the diagnosis?
Figure 2-1 See also color plate.
Barrett’s esophagus with high-grade dysplasia. Note the goblet cells on the right and high-grade dysplasia on the left.
In a biopsy of Barrett’s esophagus, at what pH should one use an alcian blue stain to demonstrate the specific mucin seen in the specialized intestinal metaplastic cells?
The alcian blue stain should be at an acidic pH of 2.5.
True/False: In progressive systemic sclerosis (scleroderma), the esophagus is commonly involved.
True. About 80% of patients have some esophageal abnormality. Most of these will also have Raynaud’s phenomenon.
What are the typical histological findings in the esophagus of a patient with progressive systemic sclerosis?
Smooth muscle atrophy, fibrosis, and hyaline thickening with luminal narrowing of small arterioles.
What benign tumor of the esophagus is characterized by bland, granular appearing cells in the subepithelial tissue that are S100 positive by immunohistochemistry?
Granular cell tumor.
What is the most common type of tissue heterotopia in the stomach?
Pancreatic tissue is most common and is usually present in the submucosa of the distal stomach or pylorus.
A 34-year-old male patient with recurrent solid dysphagia but no reflux symptoms undergoes upper endoscopy that demonstrates multiple concentric rings. Biopsies from the mid-esophagus are shown below. What is the diagnosis?
Figure 2-2 See also color plate.
This is the classic description of eosinophilic esophagitis. Typical histologic findings include 15 or more eosinophils per high-power field, spongiotic change (intraepithelial edema), degranulation of eosinophils, and possibly eosinophilic microabscesses and/or a luminal predominance of eosinophils.
What microbial organism is associated with development of extra-nodal marginal zone lymphoma also known as lymphoma of gastric mucosa-associated lymphoid tissue (MALT)?
What stain(s) would you use to highlight Helicobacter pylori in a gastric biopsy tissue section?
A number of stains can be used. Commonly used, inexpensive, and easily performed stains are Giemsa and Diff-Quik. Silver-based stains also work well but are more technically challenging and slightly more expensive. At present, most laboratories use an immunohistochemical stain directed toward the organism as this is the only stain that will typically detect the organism in the lamina propria, will still react with treated organisms that may have an altered morphology (coccus rather than the bacillus), and will also react with Helicobacter heilmannii.
What three forms of hypertrophic gastropathy are characterized by enlarged rugal folds?
Menetrier’s disease, hypertrophic-hypersecretory gastropathy, and gastric gland hyperplasia in Zollinger–Ellison syndrome.
Describe the usual histologic appearance of Menetrier’s disease.
Gastric glandular atrophy with pronounced hyperplasia of the overlying superficial mucus-producing cells.
On upper endoscopy, a yellowish, sessile polypoid lesion is seen in the stomach. The biopsy is shown below.
What is the diagnosis?
Xanthoma or xanthelasma. This benign incidental lesion is characterized by an accumulation of foamy histiocytes within the lamina propria.
True/False: In Menetrier’s disease, the antrum is typically spared and the transition to the other involved areas is abrupt.
What demographic characteristics and clinical presentation are typically seen in Menetrier’s disease?
It is three times as common in men as women, typically ranges in age from the fourth to sixth decade of life, and presents with weight loss, abdominal, pain and occasionally peripheral edema (due to protein-losing enteropathy).
Where in the stomach would you be most likely to find an adenomatous gastric polyp?
True/False: Gastric polyps are frequently a component of familial adenomatous polyposis and Gardener’s syndrome.
True. Gastric polyps of some type (adenomatous, fundic gland, or hyperplastic/regenerative) are present in more than half of the patients. Most commonly, the polyps are of the fundic gland type which may harbor low-grade dysplasia.
Where are gastrinomas typically found in patients with Zollinger–Ellison syndrome?
The majority are in the pancreas or duodenum.
Describe the typical histologic features of “chemical” gastritis.
In “chemical gastritis” or reactive gastropathy, the foveolae are hyperplastic with increased luminal serrations, the antral glands are atrophic, the lamina propria is fibrotic with splayed smooth muscle fibers, and there is an increased number of congested and somewhat ectatic superficial capillaries.
What is the most common site of origin of primary lymphoma in the gastrointestinal tract?
The stomach is the site of origin in about 50% of the cases—usually of the extra-nodal marginal zone type (ie, MALT lymphoma).
What is the most common segment of the gut affected by GISTs?
The stomach accounts for about half of all cases.
What is the typical histology of a Meckel’s diverticulum?
This is a congenital anomaly that results from persistence of the proximal vitelline duct and is usually found within 90 cm of the ileocecal valve on the antimesenteric border. It is usually lined by small intestinal mucosa; however, gastric, duodenal, colonic, or pancreatic mucosa may also be found.
How does a fundic gland polyp differ histologically from a hyperplastic polyp?
Figure 2-4 See also color plate.
As shown here, fundic gland polyps have fundic epithelial-lined microcysts and shortened foveolae. Proton pump inhibitors can also cause dilatation of gastric pits. In this case, there is surface low-grade dysplasia and this patient had a history of familial adenomatous polyposis.
What is the “rule of two’s” as it refers to Meckel’s diverticulum?
Meckel’s diverticulum is typically found within two feet of the ileocecal valve, is two inches long, causes symptoms in 2% of cases, and is found in 2% of the population.
True/False: Hirschsprung’s disease is more common in males than females.
True. Hirschsprung’s disease is characterized by a loss of both the submucosal (Meissner’s) and myenteric (Auerbach’s) plexuses with resultant nerve trunk hyperplasia. The gender incidence varies—males are four times more likely to have a short segment of affected colon, while patients with long segments are more frequently female. In addition, 10% of Hirschsprung’s disease is found in patients with trisomy 21 (Down’s syndrome).
A 57-year-old woman with known autoimmune gastritis undergoes upper endoscopy demonstrating several small proximal gastric polyps. A biopsy is shown below. What is the diagnosis?
Figure 2-5 See also color plate.
Carcinoid. These patients develop predominantly hyperplastic gastric polyps; however, about 10% will show foci of dysplasia. They also tend to develop low-grade neuroendocrine tumors (carcinoids) and adenocarcinoma. The adenocarcinoma is typically of the intestinal type and appears to arise from the intestinal metaplasia that is the hallmark of atrophic gastritis histology.
What is the main histologic finding in patients with gluten-sensitive enteropathy?
Blunted small bowel villi with an increased number of intraepithelial lymphocytes and lamina propria plasma cells associated with crypt hyperplasia. The Marsh criteria stratify differing degrees of histologic involvement in celiac disease.
What would you expect to see histologically in the small bowel from a patient with disaccharidase deficiency?
Where would you look in a small bowel biopsy for the causative agent of Whipple’s disease?
The Tropheryma whippelii organisms reside in macrophages that are “stuffed” with organisms amidst an expanded lamina propria. These organisms can be confused with mycobacterial organisms. An acid fast stain is useful to differentiate between the two (T. whippelii is acid fast negative); however, an immunohistochemical stain is also available.
The spindle cell tumor shown below had a thin pedicle attaching it to the gastric muscle wall. Histologic evaluation showed the tumor to be positive for immunohistochemical stains for c-kit (CD117) and DOG1. What is the diagnosis?
Gastrointestinal stromal tumor (GIST). Note the abundant mitotic figures in the image.
A 67-year-old man on chronic hemodialysis presents for further evaluation of chronic diarrhea. A small bowel biopsy contains glassy eosinophilic material which stains positively with a Congo red stain. What is the diagnosis?
Gastrointestinal amyloidosis. Thioflavin-T is another stain for amyloid.
What diagnostic technique is necessary to diagnose microvillus inclusion disease on a biopsy specimen?
Electron microscopy. This autosomal recessive condition is characterized by the absence of surface villi and, ultrastructurally, microvillus inclusions are found within the cytoplasm of the enterocytes. Unfortunately, death prior to the age of two is common unless small bowel transplantation occurs.
What is the inheritance pattern of abetalipoproteinemia?
What condition of the large intestine typically occurs in premature infants, can be associated with umbilical artery catheterization, and results in abdominal distention, loss of bowel sounds, bloody stools, and the presence of pneumatosis intestinalis?
Neonatal necrotizing enterocolitis.
In what segment of the small bowel do primary small bowel adenocarcinoma most commonly occur?
A 27-year-old man presents with a 6-week history of bloody diarrhea, tenesmus, and abdominal cramping.
He is otherwise healthy but has noticed a painful, erythematous rash on his shins. Colon biopsies are shown below. What is the most likely diagnosis?
Figure 2-7 See also color plate.
Ulcerative colitis. Note the marked architectural distortion, increased inflammation, and diminished goblet cells.
A 72-year-old woman presents with chronic watery diarrhea. Stool tests and a colonoscopy were normal.
Random colonic biopsies revealed the findings demonstrated in the figure. What is the most likely diagnosis?
Figure 2-8 See also color plate.
Collagenous colitis. Note the markedly thickened subepithelial collagen table. This condition is much more common in elderly women.
What arbitrary thickness must the subepithelial collagen band reach or exceed to qualify for the diagnosis of collagenous colitis?
The normal subepithelial collagen band measures up to 7 microns and, in collagenous colitis, it reaches 10 microns or greater.
What is major abnormality demonstrated in this colon biopsy specimen taken from a 73-year-old woman with watery diarrhea?
Increased intraepithelial lymphocytes. She was subsequently diagnosed with lymphocytic colitis.
What specific race and disease might you expect to find in a patient with an endocrine tumor of the duodenum which is of the delta-cell type?
African-American patients with von Recklinghausen’s disease have an increased incidence of delta-cell type endocrine tumors of the duodenum. Delta cells produce somatostatin.
An 80-year-old male presents with bloody diarrhea and severe left-sided abdominal pain. On sigmoidoscopy, patchy areas of ulceration and inflammation extending from the splenic flexure to about 15 cm distally are noted. A representative biopsy specimen is shown below. What is the diagnosis?
Figure 2-11 See also color plate.
This is a classic presentation and histology of ischemic colitis. The histology is characterized by abrupt transition of normal mucosa to inflamed, ulcerated mucosa with hyalinization of the lamina propria, surface epithelial degeneration/sloughing with more preservation of the basal aspect of the crypts, and rare fibrin thrombi.
A tumor is resected from the ileum and your friendly pathologist tells you that, grossly, the tumor is well circumscribed, nodular, and has a distinctly yellow cut surface. What type of tumor do you suspect this is?
This is the classic appearance of a carcinoid tumor.
What autosomal dominant condition is found in people of Mennonite descent in Canada, is associated with diarrhea and dehydration in childhood, and can be deadly?
Torkelson syndrome. These patients sometimes show evidence of common variable immunodeficiency. Histologically, the changes are nonspecific and include blunting of the villi, edema, and focal acute inflammation.
What is acrodermatitis enteropathica?
This is an autosomal recessive condition that is found in children, usually responds to administration of zinc sulfate, and shows ultrastructural rodlike fibrillar inclusions within Paneth cells.
A recently hospitalized man presents to your office complaining of persistent, voluminous, nonbloody diarrhea. Colonoscopy is normal. A representative random colon biopsy is shown in the figure. What is your diagnosis?
This is the classic low-power appearance of pseudomembranous colitis. The biopsy shows the characteristic eosinophilic fibrinous surface debris with a “mushroom” or volcanic eruption appearance. Interestingly, stool tests were negative in this patient.
What pinworm would you expect to find either as an incidental finding in the appendix or, less commonly, associated with acute appendicitis?
Enterobius vermicularis. This organism is found in about 3% of appendectomy specimens in the United States.
A patient undergoes appendectomy for acute appendicitis. Histologic sections of the appendix show multinucleated giant cells which are called Warthin–Finkeldey cells. What viral illness do you suspect?
Warthin–Finkeldey cells occur in the prodromal stage of measles infection in the appendix. The patient will likely develop a typical measles rash in the near future.
What is the difference between acquired and congenital diverticula?
Either acquired (pseudo-)diverticula lack a muscularis propria or they are greatly attenuated, whereas congenital diverticula, such as a Meckel’s diverticulum, are true diverticula as they contain all three layers of the intestinal wall.
What is the term given to describe the presence of numerous submucosal gas-filled cysts which create polypoid projections in the mucosa of the bowel?
Pneumatosis cystoides intestinalis. In children, it is associated with necrotizing enterocolitis and in adults, there is usually an associated gastrointestinal disorder or chronic obstructive pulmonary disease.
What is diagnosis in this biopsy from a 60-year-old woman with diarrhea? Colonoscopy was notable for a subtle brownish discoloration mainly to the right side of the colon. The pigmented material in the biopsy is iron stain negative.
Figure 2-13 See also color plate.
What is the general descriptive term under which the specific diagnoses lymphocytic and collagenous colitis reside?
Describe the microscopic features you would expect to see in a biopsy of solitary rectal ulcer syndrome (mucosal prolapse syndrome).
In spite of the name “solitary,” about one out of ten cases is not solitary at all but rather is multiple. The crypts are dilated with irregular branching which can impart a villiform appearance. The goblet cells are often mucin depleted and the lamina propria exhibits fibrosis, vascular congestion and there is often vertical streaking of smooth muscle bundles in the superficial lamina propria.
Behcet’s syndrome in the colon is characterized by what histologic/endoscopic findings?
It is characterized by ulcers occurring in various parts of the large intestine with an associated “lymphocytic vasculitis” of the submucosal veins. This can result in a colitis which may mimic Crohn’s disease.
What is the most common polyp in children?
Juvenile or retention polyp; however, in spite of the name “juvenile,” more than 30% of cases are diagnosed in adults. The most common site of occurrence is in the rectum.
True/False: Arteriovenous malformations in the large intestine are most commonly found in the rectum.
False. The vast majority are in the cecum and ascending colon.
What type of polyp is depicted below?
Figure 2-14 See also color plate.
This is a tubular adenoma characterized by hyperchromatic epithelium due to goblet cell depletion, nuclear enlargement, and nuclear pseudostratification. There is mild architectural disarray but no villous component.
What is the risk of malignant transformation in the rectal polyp shown in the photomicrograph below?
Figure 2-15 See also color plate.
None. This is a benign, nonneoplastic hyperplastic polyp as evidenced by the surface and crypt epithelium with serrated glandular lumina, abundant mucin, crypts without basal flattening or branching, and lack of crypt dilatation or hyperserration.
Name three histologic features that help determine the presence of so-called pseudoinvasion of the stalk in an adenomatous polyp as opposed to true malignant invasion?
1. The glands are surrounded by a loose lamina propria stroma not a desmoplastic tissue response.
2. There are associated hemosiderin-laden macrophages.
3. The glands in the stalk are identical to those that are more superficially located.
A polypectomy of a 1.5-cm pedunculated polyp demonstrates adenomatous changes with evidence of adenocarcinoma. Your pathologist tells you that there is lymphatic space invasion by the tumor (as shown below). What other features do you need to know about in order to arrive at an appropriate decision regarding the need for further therapy and/or surveillance for this patient?
Figure 2-16 See also color plate.
The presence of lymphatic invasion, distance to the margin (need at least 1 mm), and grade (high-grade worse prognosis) of the tumor are the three factors one must know in order to decide if there is need for a resection or if the polypectomy is curative.
Describe the inheritance pattern in Peutz–Jeghers syndrome.
Autosomal dominant. It is characterized by multiple hamartomatous polyps of the gastrointestinal tract and abnormal pigmentation of mucosa and skin.
What is the malignant potential of the hamartomatous gastrointestinal polyps seen in Peutz–Jeghers syndrome?
While these patients face a higher risk for development of a carcinoma, it is not related to the polyps but to an increased rate of malignancy in other organs such as the breast or pancreas.
What is the name of the syndrome characterized by the combination of adenomatous polyposis of the colon and associated tumors of the central nervous system, typically gliomas?
This polyp was found in the proximal ascending colon of a 63-year-old man and measured 1.1 cm. The endoscopist was initially not sure if it was a polyp or just a prominent fold. What is the diagnosis?
Figure 2-17 See also color plate.
Sessile serrated adenoma referred to by some as sessile serrated polyp. Note the preservation of goblet cells even at the base of the crypts and the prominent flattening or splaying of the base of the crypts. This example also demonstrates herniation through the muscularis mucosae which is sometimes seen in these polyps.
What is the name of the syndrome composed of colorectal carcinoma with multiple sebaceous tumors and keratoacanthomas?
The Muir–Torre syndrome.
What are the components and inheritance of Cowden’s syndrome?
It is characterized by the presence of oral mucosal papillomas, trichilemmomas of the face, and acral hyperkeratosis. Approximately one-third of the patients have intestinal polyposis. Inheritance is autosomal dominant.
What is the Cronkhite–Canada syndrome?
This syndrome is characterized by the presence of numerous gastrointestinal polyps and abnormalities of the nails termed onychodystrophy.
Where is the allele called DCC (deleted in colon cancer) located?
On chromosome 18q where it encodes for a molecule in the cell adhesion molecule family. The expression of this protein is absent or markedly reduced in almost 75% of colon cancers.
In some patients with a genetic predisposition to development of adenocarcinoma of the colon, there is an abnormality of the DNA on chromosome 2. What is the abnormality?
What are the four proteins that immunohistochemical stains can and should be used to evaluate for in a mismatch repair positive tumor?
MLH1, MSH2, MSH6, and PMS2.
According to recent recommendations, which patients with colorectal carcinomas should be screened for microsatellite instability or mismatch repair gene status?
Recently, recommendations have changed and suggest that all patients under age 70 with a new colorectal carcinoma diagnosis should be screened regardless of family history, tumor location, or histology as studies have shown a significant number of hereditary nonpolyposis colorectal cancer (HNPCC) patients will be missed if only traditional screening tools are used.
What does it mean if a tumor is found to be positive for all four mismatch repair immunohistochemical stains (MLH1, MSH2, MSH6, and PMS2)?
It means there is no evidence of a replication error positive tumor (also known as a mismatch repair positive tumor) and, therefore, no evidence of HNPCC (aka Lynch) syndrome. Positive stain results are normal. The absence of staining means there is a defect in that particular gene as evidenced by the lack of expression of that protein and indicates there is evidence of a mismatch repair positive tumor, thus a need to further investigate and determine if the cause is Lynch syndrome or a sporadic error that is not inherited or heritable.
If a tumor is found to be MLH1 negative, what is a logical next step?
Evaluate the tumor for BRAF1 to determine if the loss of MLH1 is a sporadic event or a sign of HNPCC.
Where in the colon do most carcinomas in the Lynch syndrome occur?
They are typically right sided.
How does the prognosis of Lynch syndrome colonic carcinomas compare to traditional colorectal tumors?
It is better.
Describe the typical clinical features of sessile serrated adenomas.
They are typically right sided but can occur anywhere in the colon. They tend to be larger, leading some authorities to say that any polyp with serrated architecture that is larger than 5 mm and located to the right of the splenic flexure should be considered a sessile serrated adenoma (SSA). They are often ill defined endoscopically, sometimes appearing simply as prominent folds and making determination of the precise size and extent difficult.
Describe the typical histologic features of sessile serrated adenomas.
They have serrated gland lumina (often hyperserrated), dilatation of the involved crypts, persistence of goblet cells at the bottom of the crypts, and flattening of the crypts at the base along the muscularis mucosae creating the image of an upside down letter T or an L or backward L. Additionally, they often have increased superficial mitoses and so-called dysplastic goblet cells.
What is the name of the carcinogenic pathway that sessile serrated adenomas follow?
The serrated pathway. They have the ability to progress to malignancy more quickly than the traditional adenoma to carcinoma sequence of classic or traditional colorectal carcinoma.
What is a dysplasia-associated lesion or mass (DALM)?
This is an endoscopically visible area of histologically confirmed dysplasia in a patient with chronic inflammatory bowel disease. One cannot reliably distinguish DALM from a sporadic adenoma not related to inflammatory bowel disease histologically. The same histologic appearance, if submitted as part of surveillance in a setting where there was no visible lesion, would be called flat low-grade dysplasia. The endoscopic appearance is critical in all dysplastic lesions in chronic inflammatory bowel disease.
What is the predominant histologic finding indicative of acute graft versus host disease in mucosal biopsies of the gastrointestinal tract?
Apoptosis of individual crypt cells. Apoptosis refers to individual cell necrosis characterized by dark fragments of what was the nucleus (so-called “nuclear dust”). There is typically not a significant mononuclear cell infiltrate accompanying this, so close microscopic examination is necessary.
• • • SUGGESTED READINGS • • •
Odze RD, Goldblum JR, eds. Surgical Pathology of the GI Tract, Liver, Biliary Tract, and Pancreas. 2nd ed. Philadelphia: Saunders Elsevier; 2009.
Fenoglio-Preiser CM, Noffsinger AE, Stemmermann GN, Lantz PE, Isaacson PG. Gastrointestinal Pathology: An Atlas and Text. Wolters Kluwer Health/Lippincott Williams & Wilkins; 2007.