Ischemic Disease

Intestinal ischemic disease can be divided into two major subsets: nonthrombotic (approximately 60% of cases) and thrombotic (approximately 40% of cases).⁶ Nonthrombotic causes of ischemic disease include decreased mesenteric blood flow secondary to cardiac failure, shock, atherosclerotic vascular disease, disseminated intravascular coagulation, vasculitis, and fibromuscular dysplasia. Thrombotic causes can be divided into arterial embolism, arterial thrombosis, and venous thrombosis. These are a heterogeneous group of disorders usually seen in elderly individuals.⁷ Colonic ischemia, the most common disorder (typically nonthrombotic), has a favorable prognosis. Acute mesenteric ischemia, in contrast, has a poor prognosis, with a survival rate of only 50%.⁶ Histologically, resultant lesions range from epithelial and lymphocytic apoptosis⁸ to mucosal necrosis and transmural infarction of the bowel (Fig. 6.1). Specifics concerning histology and pathology are discussed in Chapter 10.

Bullous Diseases

The majority of primary dermatologic bullous disorders that involve the GI tract occur in conjunction with a skin disorder (excluding dermatitis herpetiformis). These diseases typically involve the upper portion of the esophagus. Patients are seen with symptoms of dysphagia and odynophagia. Histologically, the lesions in esophageal squamous mucosa appear similar to those in the skin. The key distinguishing morphologic features are the level of the plane of separation (vesicle formation), the type of inflammatory infiltrate, and the presence or absence of acantholysis.⁹ Because the bullae rarely remain intact, diagnosis of these lesions on GI biopsy specimens is challenging. The diagnosis is usually made on the basis of appropriate clinical information combined with biopsies of the skin lesions. In the esophagus, lesions often rupture and produce erosions; occasionally, fibrosis and stricture formation are also seen.

Dermatogenic Enteropathy

Many GI symptoms and histologic findings have been described in patients with active psoriasis and eczema. Steatorrhea and malabsorption are not uncommon, and the terms dermatogenic enteropathy and psoriatic enteropathy have been applied to these syndromes.^28,29 Histologically, the duodenal mucosa shows an increase in the numbers of mast cells and eosinophils. A subset of patients have increased numbers of duodenal intraepithelial lymphocytes and antibodies to gliadin (suggestive of latent celiac sprue).³⁰ In addition, the colon may show increased lamina propria cellularity, active inflammation, and occasional gland atrophy in mucosal biopsy specimens from patients who have psoriasis without bowel symptoms.³¹

Acanthosis nigricans consists of numerous brown, hyperpigmented, velvety skin plaques located in the axillae, groin, and flexural areas. The lesion has two major forms—one associated with internal malignancies and the other associated with insulin resistance. Microscopically, dermal lesions are characterized by diffuse hyperkeratosis and papillomatosis. Epithelial hyperplasia of the esophagus also has been described.

When present, this lesion is usually associated with adenocarcinomas of the stomach and colon. At least one report has suggested that it is caused by the production of transforming growth factor-α by tumor cells.³²

Adrenal Gland

Addison disease (primary chronic adrenocortical insufficiency) may cause common GI disturbances such as anorexia, nausea, vomiting, and diarrhea.³⁸ Pheochromocytomas are characterized by hypertension due to high catecholamine levels. Intestinal pseudo-obstruction, megacolon, and even bowel ischemia have also been described and are thought to be secondary to the vasoconstrictive action of excess catecholamine levels.³⁹

Hypothalamus and Pituitary

The hypothalamus and pituitary function as a unit. Disorders of either one infrequently affect the GI tract. Hypopituitarism affects intestinal motility, as does hypothyroidism. Pituitary adenomas are part of the multiple endocrine neoplasia (MEN) syndrome, discussed later in this chapter. Of the hyperpituitary lesions, acromegaly is of interest with respect to GI neoplasia. Acromegaly is characterized by chronic hypersecretion of growth hormone and insulin-like growth factor, usually due to a pituitary adenoma. It is associated with overgrowth of the musculoskeletal system and all organs, including the GI tract. Acromegaly has been shown to increase epithelial cell proliferation in the colon,⁴⁰ and an increased prevalence of colonic adenomas and colonic carcinoma has been observed.⁴¹ An increased risk of gastric carcinoma has also been suggested but is less well established.⁴²

Pancreas

Diseases of the exocrine and endocrine pancreas commonly affect the GI tract. These include pancreatic exocrine insufficiency, diabetes, and hormonal effects of functional pancreatic endocrine neoplasms. Pancreatic exocrine insufficiency typically gives rise to steatorrhea and malabsorption and is discussed further in Chapter 39.

Diabetes can involve significant GI symptoms.⁴³ These result from decreased motility secondary to autonomic nervous system dysfunction. Patients have symptoms such as abdominal pain, bloating, early satiety, nausea, and vomiting. Abdominal bloating appears to correlate best with decreased gastric emptying.⁴⁴ The delayed gastric emptying associated with gastric atony and gastric dilation is called gastroparesis diabeticorum, and an increased risk of bezoar formation is apparent. Patients can also experience periodic intractable diarrhea and crampy abdominal pain. Because of hypomotility, these patients are at risk for bacterial infection and malabsorption. Patients are also at increased risk for Candida infection of the esophagus.⁴⁵ Histologic features are nonspecific. Neuropathic findings with silver stains have been described,⁴⁶ as have periodic acid–Schiff (PAS)-positive vascular deposits in the vessels of the submucosa.⁴⁷

Excess hormonal production from the pancreatic islets of Langerhans can be a result of diffuse hyperplasia (nesidioblastosis) or pancreatic endocrine tumors. Many hormones, such as insulin, glucagon, somatostatin, pancreatic polypeptide, gastrin, adrenocorticotropic hormone, calcitonin, parathormone, and serotonin, can be produced by these lesions. All GI manifestations reflect altered digestive function and motility.⁴⁸

Parathyroid

Both hyperparathyroidism and hypoparathyroidism can cause GI symptoms. GI symptoms occur in half of patients with hyperparathyroidism and may be the presenting symptom in 15% of cases.⁴⁹ These patients typically have abdominal pain, nausea, vomiting, and constipation. Many of these symptoms are thought to be due to hypercalcemia, which results in altered neuronal transmission and neuromuscular excitability.⁵⁰ Hypoparathyroidism can be associated with malabsorption and steatorrhea. The small intestinal mucosa is typically histologically normal, but rare associations with celiac sprue have been reported.⁵¹

Thyroid

Both hyperthyroidism and hypothyroidism can cause GI symptoms. Hyperthyroidism produces hypermotility of the gut, and hypothyroidism causes hypomotility. Hyperthyroidism can result in rapid gastric emptying, watery diarrhea, and steatorrhea.⁵² No constant structural changes in the mucosa or in the wall of the bowel have been consistently reported. Hypothyroidism can be associated with gastric bezoar formation, ileus, volvulus, constipation, and megacolon.⁵² In patients with marked myxedema, dilation and thickening of the bowel wall with microscopic accumulation of mucopolysaccharide substances in the submucosa, muscularis propria, and serosa have been described.⁵³

Thyroid neoplasms may also produce GI effects. Medullary carcinoma of the thyroid is a tumor of the calcitonin-producing endocrine C cells of the thyroid. Patients may have prominent “explosive” watery diarrhea as the result of ectopic hormone production.⁵⁴ Papillary carcinoma of the thyroid also can be associated with Gardner syndrome.⁵⁵

Multiple Endocrine Neoplasia

The MEN syndromes are a group of autosomal dominant inherited disorders associated with hyperplasia or neoplasms of several endocrine organs. Three main varieties of this syndrome can occur—MEN I, MEN IIa, and MEN IIb (or III). GI manifestations are caused by the products of endocrine proliferations.⁵⁶ Each of these syndromes is associated with a mutant gene locus—MEN I with the MEN1 gene locus, and MEN IIa and IIb with the RET gene locus. MEN I is associated with pancreatic endocrine tumors (often gastrinomas) and with the Zollinger-Ellison syndrome, which is associated with gastric and duodenal disease. MEN IIb may be associated with ganglioneuromatosis, ganglion cell hyperplasia, and hypertrophy of the plexuses of Meissner and Auerbach in the GI tract. Chronic constipation, diarrhea, or both may be associated with MEN IIb.⁵⁷

Thrombotic Disorders

Sickle cell anemia,⁶¹ polycythemia rubra vera,⁶² and other thrombotic disorders⁶³ can produce thrombosis, leading to infarction and hemorrhage of the intestines. Sickle cell anemia causes sickling of red blood cells and hyperviscosity of the blood and typically produces arterial and capillary obstruction.⁶¹ It involves the watershed areas of the distal transverse colon and splenic flexure, which have the lowest oxygen tension. Sickled red blood cells may be found in the vessels. Polycythemia usually leads to venous obstruction of the portal and mesenteric veins. These lesions involve the deeper parts of the bowel wall, including the muscularis propria. Diagnosis is based on the finding of venous thrombi in the mesenteric and mesocolic tissues not in the field of infarction, which occur in conjunction with appropriate clinical history.

Megaloblastic Anemia

Megaloblastic anemias are associated with deficiencies of folic acid and vitamin B₁₂. These anemias are characterized by megaloblastic proliferation of actively growing cells, as is typically described in bone marrow aspirations but is also seen in the epithelial cells of the GI tract. Owing to impaired DNA synthesis, actively dividing cells in the gastric pits, small bowel, and colonic crypts typically show enlarged, immature-appearing nuclei (Fig. 6.2). The nucleus-to-cytoplasm ratio is decreased. The overall numbers of mitotic figures are also reduced. In addition, PAS-negative, Alcian blue–negative cytoplasmic vacuoles have been described in duodenal enterocytes.⁶⁴ Megaloblastic anemia can be caused by pernicious anemia secondary to autoimmune gastritis; therefore, gastric findings of atrophic autoimmune gastritis may also be present.

Leukemia and Lymphoma

Involvement of the GI tract is often noted in patients with leukemia and lymphoma. This can occur directly by tumor (primary or secondary), secondary to complications of disease, or secondary to therapy (see Chapter 31 for details).

Autopsy studies have revealed GI involvement in 50% of patients with leukemia.⁶⁵ In secondary involvement of the GI tract by either leukemia or lymphoma, tumor infiltrates are often multifocal and may be present anywhere from the esophagus to the rectum.⁶⁶ These infiltrates can cause aphthous-type ulcers (typical of leukemic infiltrations) or can result in polypoid, masslike, or large ulcers (typical of lymphomatous involvement).⁶⁷ The larger mass lesions can occasionally cause obstruction or intussusception.⁶⁸ Histologic features are those typical of the particular type of leukemia or lymphoma. Malignant cells are typically found in the mucosal and submucosal tissue. Tissue should be collected for molecular and cytogenetic analysis, because many leukemias and lymphomas include diagnostic and clinically important changes.⁶⁹ Primary lymphomas of the GI tract are often solitary lesions, although diffuse forms do occur (usually in the small bowel).

Secondary effects of tumor overgrowth, or of chemotherapy, resulting in decreased numbers of platelets and inflammatory cells can lead to hemorrhagic lesions of the GI tract and opportunistic infections. In addition, neutropenic colitis, which is a necrotizing inflammatory disorder of the colon that occurs in neutropenic patients, can occur with chemotherapy and, rarely, as a complication of acute leukemia.⁷⁰ Finally, patients who have received a bone marrow transplant may develop graft-versus-host disease, which is characterized by apoptotic destruction of the epithelium throughout the GI tract. It typically manifests with diarrhea. Histologically, it is characterized by apoptosis of the epithelial cells, followed by crypt and gland loss and, ultimately, mucosal erosion and ulceration.⁷¹

Plummer-Vinson Syndrome (Paterson–Brown Kelly Syndrome)

The unusual Plummer-Vinson syndrome has shown a recent decrease in incidence.⁷⁷ It is characterized by iron deficiency (its presumed cause), dysphagia, and esophageal webs.⁷⁸ Dermatologic findings of angular stomatitis, atrophic tongue, and brittle nails are also seen. Long-standing disease is associated with an increased incidence of postcricoid carcinoma. Iron repletion improves all lesions.

Vitamin Disorders

In general, vitamin disorders are not associated with specific GI symptoms or lesions. Exceptions are brown bowel syndrome, which is thought to be caused by a deficiency of vitamin E (discussed later), and pellagra, which is associated with niacin deficiency (discussed in this section). Multiple vitamin deficiencies are often noted in malabsorptive disorders. Vitamins, macronutrients, and minerals are thought to have a protective effect with respect to neoplasia of the GI tract, especially for esophageal^79,80 and gastric⁸¹ malignancies. Deficiency in vitamin K or anticoagulation therapy leads to a decrease in coagulation factors and can result in hemorrhagic lesions throughout the body.⁸² In the GI tract, these range from focal petechial hemorrhages to frank exsanguination. No specific histologic features are associated with these lesions. Similarly, vitamin C deficiency (scurvy) can lead to hemorrhage and delayed wound healing. Deficiencies of folic acid and vitamin B₁₂ are associated with megaloblastic anemia and megaloblastic changes in the epithelial cells of the stomach and small intestine.⁸³ Olestra (a nonabsorbed fat replacement) may decrease the absorption of fat-soluble vitamins.⁸⁴

Abetalipoproteinemia (discussed further in Chapter 9) is an autosomal recessive disorder characterized by a defect in the secretion of plasma lipoproteins that contain apolipoprotein B. Patients have steatorrhea, usually in infancy, with central nervous system symptoms such as disturbance in gait and balance and fatigue.⁹⁰ On peripheral smear, acanthocytes are usually prominent (in 50% of red blood cells). Laboratory findings show an absence of very-low-density lipoproteins, the presence of chylomicrons, and a reduction in triglycerides and other lipids. The defect occurs in a microsomal triglyceride transfer protein required for the secretion of plasma lipoproteins containing apolipoprotein B.⁹¹ Normal intraluminal digestion of lipids occurs, along with transport of triglycerides and monoglycerides and their reesterification in enterocytes. However, lipids cannot be excreted on the basal lateral membrane of the enterocytes into blood and lymphatics. Histologically, this translates into prominent accumulation of fine lipid droplets within the basal aspect of the enterocytes (Fig. 6.3). These can be stained with Oil Red O on frozen-section tissue or seen by electron microscopic examination. The overall architecture of the small bowel is normally well maintained. One pitfall in diagnosis is the similar appearance of lipid droplets identified in normal individuals after a recent lipid-rich meal; therefore, the diagnosis should be made only in fasting patients.

Tangier Disease

Tangier disease is an autosomal recessive disorder characterized by deposition of cholesteryl esters in the reticuloendothelial system, almost complete absence of high-density lipoprotein in the plasma, and aberrant cellular lipid trafficking.⁹² Clinically, patients present with hepatosplenomegaly, enlarged tonsils, peripheral neuropathy, and, occasionally, diarrhea. Laboratory studies reveal low blood levels of high-density lipoprotein and cholesterol (due to lack of apoprotein A) and high levels of triglycerides. Endoscopically, the lesions are described as tiny yellow nodules or orange-brown spots.⁹³ Microscopic examination reveals clusters of foamy histiocytes in the lamina propria (Fig. 6.4). Electron microscopic findings include intracytoplasmic vacuoles unbounded by membranes; these are often confluent in appearance⁹⁴ (see Chapter 9 for details).

Lysosomal Storage Disorders

Lysosomes, which are a major component of the intracellular digestive tract, contain hydrolytic enzymes made in the endoplasmic reticulum. These enzymes break down a variety of complex macromolecules that are either a component of the cell or are taken up by phagocytosis. Lysosomal storage disorders are inherited disorders (usually autosomal recessive) caused by lack of a functional enzyme or defective enzyme lysosome targeting. Substances typically accumulate within cells at the site where most of the degraded material is found; degradation typically occurs at this location.

Storage disorders can be divided based on the biochemical nature of the accumulated metabolite into glycogenoses, sphingolipidoses (lipidoses), mucopolysaccharidoses, mucolipidoses, and others. Most of these diseases have prominent central or peripheral nervous system effects.⁹⁵ Except for Fabry disease, they do not have significant GI effects. Case reports of malabsorption in GM1 gangliosidosis,⁹⁶ diarrhea in Niemann-Pick disease,⁹⁷ and diarrhea and vomiting in Wolman disease have been described.⁹⁸

The importance of these diseases is that depositions can be identified in a variety of cells in the GI tract (Table 6.2), typically in the phagocytic cells (macrophages) in the lamina propria. The histologic appearance typically reveals an accumulation of cells with foamy cytoplasm. The material may be positive for fat stains such as Oil Red O or Sudan black on frozen-section tissue or PAS stain, depending on the particular substance that has accumulated. Electron microscopic examination typically reveals enlarged, unusually shaped lysosomes. Historically, many of these diagnoses have been made on rectal biopsy with histochemical stains and subsequent electron microscopic examination.^99–101 This technique has largely been supplanted by specific enzyme content analysis of circulating lymphocytes or biopsy material. Differentiation among the common mimics of storage disorders is described in the next section.

Common Mimics of Lysosomal Storage Diseases

Common mimics of lysosomal storage diseases are summarized in Table 6.3. These are divided into two general categories—pigmented and nonpigmented. The majority of lesions result from a proliferation of histiocytes with either engulfed infectious organisms or cellular or extracellular material. Pigmented lesions, which are in the differential diagnosis of neuronal ceroid lipofuscinosis, include mela­nosis, pseudomelanosis, brown bowel syndrome, hemosiderosis, and barium granuloma. Nonpigmented lesions are in the differential diagnosis of all of the rest of the lysosomal storage diseases and include xanthoma, muciphages, Whipple disease, Mycobacterium avium-intracellulare complex (MAC) infection, pseudolipomatosis, malakoplakia, granular cell tumors, signet ring adenocarcinoma, and malignant histiocytosis.

Table 6.3

Macrophage Infiltrates in the Lamina Propria

Diagnosis	Histology	Histochemical	Immunohistochemical
Pigmented
Melanosis	Dark brown, granular macrophages	PAS and acid-fast positive	CD 68 positive (must bleach pigment)
Pseudomelanosis	Black, subepithelial macrophages	Iron positive	CD 68 positive
Brown bowel syndrome	Brown smooth muscle cells	PAS, acid-fast positive Yellow autofluorescence	N/A
Hemosiderosis/ hemochromatosis	Finely granular, brown to black particles in epithelial cells	Iron positive	N/A
Barium granuloma	Gray, finely granular refractile pigment	PAS negative	N/A
Chronic granulomatous disease	Golden-brown macrophages	Fat stain and PAS positive	N/A
Nonpigmented
Xanthoma	Clear, foamy macrophages	Fat stain positive on unfixed tissue	α1-Antitrypsin, monocyte chemotactic and activating factor positive
Muciphages	Clear, foamy macrophages	d-PAS, Alcian blue positive	CD 68 and lysozyme positive
Pseudolipomatosis	Clear open space with no cell lining	Negative for all stains	Negative for all immunostains
Whipple disease	Pink, foamy macrophages	d-PAS granular positive	FISH for rRNA positive
Mycobacterium avium	Pink, foamy macrophages	Acid-fast or Fite positive d-PAS diffuse positive	CD 68 positive
Malakoplakia	Pink, foamy macrophages with nuclear grooves Michaelis-Gutmann bodies (MGB)	d-PAS positive MGB positive for calcium and iron	CD 68 positive
Granular cell tumor	Pink, granular histiocytic cells	d-PAS positive	S100 positive
Signet ring cell adenocarcinoma	Clear cytoplasm with displaced nucleus	d-PAS-, Alcian blue-, and mucin-positive globules	Cytokeratin positive
Clear cell carcinoid tumor	Clear cells with foamy cytoplasm	d-PAS and mucin negative	Chromogranin positive
Malignant histiocytosis	Granular Langerhans cells with irregular elongate nuclei and nuclear grooves	d-PAS and mucin negative	S100 and CD1a positive

d-PAS, Periodic acid–Schiff with diastase; FISH, Fluorescence in situ hybridization; PAS, periodic acid–Schiff; rRNA, ribosomal ribonucleic acid.

Pigmented Lesions

Melanosis.

Melanosis coli is characterized by pigment deposition in macrophages in the lamina propria. Endoscopically, the bowel mucosa can appear normal or brownish in color, depending on the amount of pigment present. Occasionally, the pigment is so prominent that the mucosa shows multiple foci of tiny white polypoid lesions on a brown background. The white lesions represent normal or hyperplastic lymphoid aggregates that do not contain pigment.¹⁰⁷ Histologically, the pigment in macrophages has a dark brown, granular appearance, and these cells may be located anywhere in the lamina propria (Fig. 6.5, A). It contains polymerized glycolipids, glycoproteins, and melanin (“melanized ceroid”)¹⁰⁸ and is typically associated with anthraquinone laxative use. However, a number of studies have shown an association with increased apoptosis of epithelial cells^108,109 (caused by laxatives as well as chronic colitis,¹¹⁰ chronic granulomatous disease,¹¹¹ and bamboo leaf extract¹¹²) and have suggested that melanosis is a nonspecific marker of increased apoptosis.

Pseudomelanosis.

This is a rare benign condition characterized by the presence of discrete, flat, small, brown-black spots located typically in duodenal mucosa (speckled duodenum) but also reported in gastric mucosa.¹¹³ It occurs in any age group and appears to be associated with upper GI bleeding, chronic renal failure, hypertension, or diabetes mellitus.¹¹⁴ Unlike melanosis coli, it is not associated with use of anthraquinone laxatives. Microscopically, the black pigment is located subepithelially in mucosal macrophages, often at the tips of the villi (see Fig. 6.5, B). Histochemical studies have revealed that the pigment represents a mixture of iron sulfide, hemosiderin, lipomelanin, and ceroid. It is typically negative or only focally positive with iron stains. Electron microscopic studies have revealed the material to be located in lysosomes.

Brown Bowel Syndrome.

This is a rare acquired disorder that is associated with malabsorptive states and vitamin E deficiency. It is characterized by accumulation and deposition of lipofuscin pigment predominantly in the smooth muscle of the bowel, which gives a brown color to the bowel. It occurs most often in the small bowel but can involve the colon or stomach as well. Vitamin E (α-tocopherol) is an antioxidant that prevents peroxidation of unsaturated fatty acids. It is postulated that a deficiency in this vitamin may result in oxidized lipids, which polymerize with polysaccharides to form the brown pigment. Histologically, the pigment is most prominent in the smooth muscle cells of the muscularis mucosae and propria. Some pigmentation of macrophages, nerves, ganglia, and vascular smooth muscle also is usually observed.¹¹⁵ The distribution of the pigment in conjunction with an appropriate clinical history often helps in differentiation of this lesion from those described earlier. The pigment, which stains positive with PAS, acid-fast, and fat stains on unfixed tissues, also shows the typical bright yellow autofluorescence pattern of lipofuscin. Electron microscopic examination usually reveals mitochondrial damage as well as pigment concentrated in the perinuclear Golgi region.¹¹⁶ Clinically, the pigment does not have any direct effect on the bowel, although defects in contractility,¹¹⁷ intussusception,¹¹⁸ and toxic megacolon have been reported.¹¹⁹

Hemosiderosis/Hemochromatosis.

In advanced iron overload disorders such as hemosiderosis or hemochromatosis, iron is deposited in parenchymal cells throughout the body. In the GI tract, deposits are found most commonly in the parietal cells of the stomach, the Brunner glands in the duodenum, and the epithelial cells of the gut.^120,121 Some minor amounts of pigment can also be seen in macrophages. The pigment appears as finely granular, dark brown to black particles. It stains positive with iron stains. The pigment needs to be differentiated from pseudomelanosis duodeni, which is typically larger and located predominantly in macrophages.

Barium Granuloma.

This is a complication of barium examination, typically of the colon. It occurs secondary to extravasation of barium into the wall of the bowel as a result of mucosal injury, overinflation of the rectal balloon, or intrinsic inflammatory disease.¹²² Endoscopically, it may manifest as a polypoid lesion and may mimic an adenoma or carcinoma. Histologically, one sees a granulomatous reaction surrounding gray, finely granular, refractile, PAS-negative material located in the cytoplasm of histiocytes and in the lamina propria (see Fig. 6.5, C). The material is not birefringent. Radiographs of the paraffin block can help reveal the presence of radiopaque material.¹²³

Nonpigmented Lesions

Xanthoma.

This is a fairly common lesion of the GI tract most commonly found in the stomach. The terms xanthoma, xanthelasma, lipid island, and xanthogranulomatous inflammation are used synonymously. Endoscopically, xanthomas appear as small yellow nodules or streaks on the mucosa. They represent an accumulation of lipid and cholesterol within macrophages. Microscopically, one sees a collection of macrophages containing foamy cytoplasm positive for fat stains on unfixed tissue (Fig. 6.6, A). Immunohistochemical stains for α₁-antitrypsin and monocyte chemotactic and activating factor are also typically positive,¹²⁴ whereas cytokeratin and mucin stains are negative. The lesions are typically associated with chronic inflammatory states¹²⁵ but can be seen with malignancies.¹²⁴

Muciphages.

These are mucin-rich phagocytes that accumulate as a result of mucosal damage. They are most common in the rectum (as many as 40% of all rectal biopsies contain muciphages)¹²⁶ and are also commonly found in the lamina propria and in the stalk of adenomatous polyps.¹²⁷ Endoscopically, muciphages can appear as polyps or nodules. Histologically, foamy histiocytes containing coarse cytoplasmic vacuoles are present in the superficial lamina propria (see Fig. 6.6, B). Mild fibrosis and architectural distortion may occur in cases associated with a previous injury.¹²⁸ Histochemical stains with d-PAS (PAS with diastase digestion) and Alcian blue at pH 2.5 and with immunohistochemical stains for CD68 and lysozyme are positive in muciphages.

Pseudolipomatosis.

This is a common iatrogenic lesion caused by influx of air into the mucosa secondary to endoscopy-related trauma. It is a benign, transient lesion¹²⁹ that is characterized histologically by clear open spaces in the lamina propria or submucosa, representing trapped gas, without an epithelial or endothelial cell lining¹³⁰ (see Fig. 6.6, C). These clear spaces do not stain with any specific immunohistochemical or histochemical reaction.

Whipple Disease.

This is a systemic infection that is caused by a cultivation-resistant bacterium, Tropheryma whippelii. In the GI tract, it is primarily found in the small bowel; however, it can involve the stomach,¹³¹ esophagus, and colon as well.¹³² Histologically, one sees characteristic abundant, pink-colored, foamy macrophages filling the lamina propria. These macrophages may contain small granules that are positive for d-PAS. Extracellular lipid is often present as well (see Fig. 6.6, D). Electron microscopic examination reveals intracellular and extracellular bacterial rods in various stages of disintegration. These bacteria are also found within IgA-positive plasma cells.¹³³ With the use of fluorescence in situ hybridization (FISH) for ribosomal RNA, the active organism appears to be most prevalent near the tips of intestinal villi in the lamina propria.¹³⁴

Mycobacterium avium-intracellulare Complex Infection.

This is a common pathogen in AIDS that may also be seen in other immunocompromised patients.¹³⁵ It typically affects the small bowel and colon. Endoscopically, the mucosa can appear normal or coarsely granular.¹³⁶ Histologically, abundant, variably sized sheets of foamy macrophages are seen in the lamina propria and cause widening of the villi (see Fig. 6.6, E). Diagnosis is made with acid-fast or Fite stain positivity; numerous elongated organisms are revealed within the macrophages. PAS stain typically reveals a relatively diffuse fibrillary staining pattern in macrophages, as opposed to the granular staining characteristic of Whipple disease. The organisms are typically intact, unlike the various stages of disintegration that are seen in Whipple disease.

Malakoplakia.

This is a rare bacterial infection that affects patients with an underlying macrophage phagolysosome defect (not typically seen in patients with AIDS).¹³⁷ It is usually caused by Escherichia coli or Klebsiella spp.¹³⁸ and is often seen in the urinary tract. However, it can involve any portion of the GI tract. Endoscopically, the mucosa shows numerous soft yellow plaques on the mucosa. Rarely, a mass lesion composed of macrophages may develop as well. Histologically, there is infiltration of the lamina propria by neutrophils and abundant macrophages; the latter often contain nuclear grooves (see Fig. 6.6, F). Michaelis-Gutmann bodies, which are small, pale, intracytoplasmic concretions that stain for calcium and iron, are diagnostic. Macrophages also stain with d-PAS. Electron microscopic examination reveals degenerated bacilli in phagolysosomes, similar to those seen in Whipple disease.¹³⁹

Granular Cell Tumor.

These tumors are believed to be of neurogenic origin and are typically found in the esophagus, but they can occur anywhere in the GI tract.¹⁴⁰ Rare cases have been described in the small bowel and colon.^141,142 They are mostly benign, but malignant tumors have rarely been described. The tumors typically manifest as nodules in patients with nonspecific GI symptoms. Histologically, these tumors include abundant epithelioid or histiocytic cells with distinct pink granular cytoplasm in the lamina propria or submucosa (see Fig. 6.6, G). The cells are positive for d-PAS and are strongly S100 positive. Electron microscopic examination reveals cells filled with giant autophagic vacuoles (lysosomes) that contain myelin-like debris of giant lysosomes.

Signet Ring Cell Adenocarcinoma.

This tumor (described in detail in Chapters 25 and 27) shows an infiltration of malignant cells with clear cytoplasm and an eccentrically placed hyperchromatic nucleus (see Fig. 6.6, H). It is differentiated from other lesions by the presence of highly atypical nuclear features and by positivity with mucin and cytokeratin stains.¹⁴³

Clear Cell Carcinoid Tumor.

A rare case has been reported of a gastric carcinoid composed entirely of clear cells with foamy cytoplasm.¹⁴⁴ Immunopositivity for endocrine markers such as chromogranin A or electron microscopic demonstration of dense core granules helps define the lesion.

Malignant Histiocytosis.

Langerhans cell histiocytosis can involve any portion of the GI tract, either as part of generalized disease or as a separate primary entity. Involved areas may manifest as a polypoid or mass lesion. Histologically, one sees a mucosal infiltrate composed of Langerhans cells that have irregular, elongated nuclei and prominent nuclear grooves and folds. The cytoplasm of the tumor cells is abundant and finely granular. These tumors are usually associated with a prominent eosinophilic infiltrate as well. As with mucosa-associated lymphoid tissue (MALT) lymphoma, invasion and destruction of the epithelium are common.¹⁴⁵ Immunohistochemical stains for S100 and CD1a are intensely positive in tumor cells. Electron microscopic examination reveals Birbeck granules in the cytoplasm of tumor cells.¹⁴⁶

Amyloidosis

Amyloidosis is not a single disease but the product of a variety of diseases. The common feature of these diseases is extracellular deposition of amyloid proteins that stain with Congo red and show apple-green birefringence under polarized light. The proteins have a typical fibrillary appearance on electron microscopy. All amyloid fibrils are protein complexes with a common tertiary molecular structure, referred to as a twisted β-pleated sheet pattern.

Pathologic Features

Microscopically, amyloid deposits are extracellular and have a classic waxy, homogeneous appearance (Fig. 6.7, A). Pink hyaline amyloid may contain small, slitlike spaces caused by cracking during tissue processing. Histochemical stains for Congo red (the most specific), toluidine blue, crystal violet, fluorochrome, and thioflavine are usually positive with all types of amyloid (see Fig. 6.7, B). Amyloid also stains positive with the PAS reaction and negative with lipid and mineral stains. In general, AA amyloid seems to localize to capillaries, small arterioles, and the mucosa. AL amyloid is often found in the muscularis propria and in medium-sized to large vessels. Aβ2M amyloid is found mainly in the muscularis propria and in small arterioles and venules, forming subendothelial nodular lesions.¹⁶⁰ AL and AA forms also can be distinguished by pretreatment with potassium permanganate. This pretreatment abolishes the Congo red affinity of the AA fibrils but not that of the AL fibrils.¹⁶¹ Immunohistochemical stains with antibodies to amyloid A, immunoglobulins λ and κ light chain amyloid fibril proteins, β₂-microglobulin, and transthyretin characterize the majority of amyloid deposits.¹⁶² Electron microscopy reveals an interlocking meshwork of fibrils that measure 7.5 to 10 nm in diameter with variable length.

Amyloidosis should be differentiated from arteriosclerosis in blood vessels and from collagen in the lamina propria, submucosa, and muscularis (in systemic sclerosis). Congo red stains can help with this differential diagnosis in that neither arteriosclerosis nor collagen stains with Congo red. One study suggested that Congo red stain may not be sensitive enough in patients with early amyloidosis in minute amounts.¹⁶³

GI biopsy is a procedure commonly used to diagnosis amyloidosis. Rectal biopsies have a sensitivity of 85%, compared with a sensitivity of 54% for fat biopsies.¹⁴⁷ In the rectum, amyloid deposits are most commonly seen in small arterioles and veins in the submucosa; therefore, a deep suction biopsy is usually required for adequate evaluation. Some studies have suggested that gastric or small bowel biopsies have a sensitivity as high as 100% for the diagnosis of amyloidosis.^156,164

Familial Mediterranean Fever (Familial Paroxysmal Polyserositis, Recurring Polyserositis)

Familial Mediterranean fever is an inherited autosomal recessive disorder seen almost exclusively in Sephardic Jews, Arabs, Armenians, and people of Turkish descent. It is characterized by recurring and self-limited attacks of fevers and serosal inflammation involving the peritoneal, synovial, and pleural membranes. This disease typically begins in childhood or adolescence and recurs at irregular intervals throughout life.¹⁶⁵ GI involvement consists of acute inflammation limited to the serosal surfaces of the bowel (peritonitis). Repeated episodes can result in the formation of peritoneal adhesions that may cause obstruction. Systemic amyloidosis may also occur in untreated patients. The AA amyloid type is believed to develop as a consequence of recurrent inflammation. Furthermore, amyloid deposits in the lamina propria and the submucosal vessels may occur without symptoms. The disease is often treated with colchicine.

Decidualization of the Peritoneum

Ectopic decidualization of the peritoneum is a rare lesion. It can yield macroscopic nodules (peritoneal deciduosis or deciduosis peritonei) that mimic peritoneal carcinomatosis.¹⁷⁶ Grossly, multiple light-tan peritoneal masses or nodules typically are identified at the time of caesarean section. Microscopically, plump pink (decidualized) cells are present between the mesothelial cells and muscularis propria (Fig. 6.8). This is a physiologic reaction with an excellent prognosis and spontaneous resolution after delivery.

Endometriosis is a condition characterized by the presence of endometrial glands or stroma outside of the uterus. It can involve any portion of the GI tract. The most common sites of involvement are organs in the pelvis such as the rectosigmoid colon, appendix, and small bowel. The GI tract is involved in 12% to 37% of cases.¹⁷⁷ Intestinal endometriosis is usually asymptomatic. However, when symptomatic, it typically causes obstructive symptoms as a result of adhesions. Complete obstruction of the bowel lumen occurs in fewer than 1% of cases.¹⁷⁷ Other atypical presentations include diarrhea and GI bleeding. Symptoms are often temporally associated with the onset of menses.

Pathologic Features

Endometriosis may be solitary or multifocal, and it may manifest as a mass lesion or with volvulus, intussusception, luminal narrowing, or adhesions. Endometrial glands or stroma are usually present on the serosal surface but may involve any layer of the bowel wall. On a cut surface, the endometriosis often appears sclerotic with punctate hemorrhagic or brown areas. Microscopically, this disorder is characterized by the presence of endometrial-type glands or stroma (smaller, slightly elongated cells that are packed together, often with intermingled red blood cells) and hemosiderin-laden macrophages (Fig. 6.9). At least two of these three findings should be present for a diagnosis of endometriosis to be established with certainty. In addition, fibrosis and prominent smooth muscle proliferation may surround foci of endometriosis. Fresh hemorrhage may occur. Immunohistochemical staining for estrogen receptors is usually positive in both the glands and stromal cells.¹⁷⁸

Scleroderma

Scleroderma (progressive systemic sclerosis) is a systemic disease of unknown cause characterized by inflammation, fibrosis, upregulated collagen production, and vasculitis. GI involvement is common and is typically characterized by hypomotility (see Chapter 7 for details). Scleroderma can be part of the CREST syndrome (calcinosis, Raynaud phenomenon, esophageal involvement, sclerodactyly, and telangiectases). Scleroderma most commonly involves the esophagus; manometric abnormalities are seen in up to 90% of patients.¹⁸¹ However, abnormalities of the entire GI tract may also be observed. Colonic dysfunction has been reported in up to 20% of patients.¹⁸²

In the esophagus, lower esophageal sphincter pressure is reduced and gastric emptying of the stomach is delayed.¹⁸³ Both of these factors increase the incidence of GERD, erosive esophagitis, and stricture formation. The small and large intestine may also be involved. Typical features include scattered wide-mouthed diverticula,¹⁸⁴ pseudo-obstruction,¹⁸⁵ and intestinal perforation.¹⁸⁶

Pathologically, scleroderma is characterized by smooth muscle atrophy and its replacement by collagenized fibrous tissue (Fig. 6.10). The lesion most commonly affects the inner circular muscle layer but can involve the entire muscularis propria on occasion. Fibrous tissue is highlighted by the trichrome stain, which reveals atrophy and loss of muscle tissue. Fibrosis may also involve the submucosa to a variable degree.¹⁸⁷ Muscular atrophy results in atony and dilation and produces wide-mouthed pseudodiverticula that can be identified radiographically. In addition, the small vessels of the bowel may show a proliferative endarteritis and mucinous changes of the media.¹⁸⁸ Rarely, ischemic ulcers can occur as a result.

Dermatomyositis and Polymyositis

Dermatomyositis and polymyositis are inflammatory myopathies that primarily involve skeletal muscle. Skin involvement occurs also in dermatomyositis. These disorders may be associated with motor dysfunction of the GI tract.¹⁸⁹ The striated muscle of the cervical esophagus is most frequently affected when delayed esophageal emptying is common.¹⁹⁰ Histologic changes include chronic inflammation, edema, and muscle atrophy. Features can mimic scleroderma, but fibrosis is not prominent in these disorders.

Systemic Lupus Erythematosus

SLE is a systemic multisystem autoimmune disease that affects the GI tract in approximately 20% of patients. The development of vasculitis can lead to ischemia¹⁹¹ and perforation of the GI tract. SLE also has been associated with malabsorption, protein-losing enteropathy,¹⁹² and amyloidosis.¹⁹³

Mixed Connective Tissue Disease

Mixed connective tissue disease has features of scleroderma, SLE, and polymyositis. GI abnormalities are common.¹⁹⁴ GI features are similar to those of scleroderma, with motility dysfunction¹⁹⁵ and vasculitis being the most common complications.

Rheumatoid Arthritis

GI involvement occurs in 25% of patients with long-standing rheumatoid arthritis.¹⁹⁶ Notably, this occurs in the form of a necrotizing vasculitis that affects small to medium-sized arteries, similar to polyarteritis nodosa. The condition is usually asymptomatic. However, hemorrhage or even perforation may occur.¹⁹⁷ GI lesions may also be seen in association with long-term use of NSAIDs, and in rare cases, long-standing inflammation can lead to amyloidosis.

Reactive Arthritis

The term reactive arthritis refers to a group of inflammatory disorders associated with arthritis (spondyloarthropathy). It includes psoriatic arthritis, Reiter syndrome, ankylosing spondylitis, and arthritis associated with IBD. Most affected individuals (70%)¹⁹⁸ have chronic active colitis. Interestingly, clinical remission is always associated with normal gut histology.¹⁹⁹

Sjögren Syndrome

Sjögren syndrome is a clinicopathologic entity characterized by dry eyes and mouth secondary to immune-mediated destruction of the lacrimal and salivary glands. Patients with Sjögren syndrome may develop immune-mediated destruction of the pharyngeal and esophageal glands with fissuring and ulceration of the pharynx and esophagus. Esophageal webs have been observed in up to 10% of patients. Atrophic gastritis, atrophy, and chronic inflammation of the esophageal glands have been noted as well.²⁰⁰ Histologically, the salivary glands of the esophagus show a periductal and perivascular lymphocytic inflammatory infiltrate that can occasionally be quite marked.

Hereditary Connective Tissue Disorders

Hereditary connective tissue disorders, such as Ehlers-Danlos syndrome and pseudoxanthoma elasticum, result from a defect in collagen synthesis or structure. These defects result in thinning of the bowel wall and vascular structures²⁰¹; patients are at increased risk for GI hemorrhage and perforation.²⁰² Patients with Ehlers-Danlos syndrome also have diaphragmatic hernias and GI diverticula. Upper GI tract hemorrhage occurs in 13% of patients with pseudoxanthoma elasticum.²⁰³ In these cases, submucosal, yellowish, nodular lesions, similar to xanthoma-like skin lesions, may be seen.²⁰⁴ Histologic examination typically reveals superficial mucosal hemorrhage, erosion, and elastic tissue degeneration of small and medium-sized arteries with calcified plaque formation.

Hemolytic-Uremic Syndrome

HUS is an acute onset of microangiopathic hemolytic anemia, thrombocytopenia, and renal dysfunction. Cases associated with E. coli infection often manifest with a GI prodrome that is difficult to differentiate histologically from an acute colitis.²⁰⁶ Presentations mimicking intestinal intussusception²⁰⁷ and ulcerative colitis have also been described.²⁰⁸ During HUS, an associated colitis is seen in most patients, and there is a 1% to 2% incidence of colonic perforation.²⁰⁹ Marked mucosal and submucosal edema and hemorrhage of the colon can occur, but inflammation usually is not significant (Fig. 6.11). Microvascular angiopathy with endothelial cell damage and overt thrombosis may also be observed.²¹⁰

Chronic Renal Failure

A variety of GI lesions may develop in patients with chronic renal failure. These are mainly associated with uremia, long-term hemodialysis, or kidney transplantation.

Urinary Conduits

Three basic types of urinary diversion have been used in the treatment of congenital or malignant disorders—ureterosigmoidostomy, ileal neobladder, and antirefluxing colonic conduits.

Ureterosigmoidostomy, whereby the ureter is implanted into the sigmoid colon, is associated with a greatly increased risk for colonic neoplasia at or near the site of anastomosis.²²² Hence, this type of diversion is no longer popular. Adenocarcinomas typically arise 15 to 25 years after surgery and are histologically identical to typical colon adenocarcinomas. Endoscopic surveillance biopsies are recommended to screen for epithelial dysplasia.²²³ In addition to dysplasia, one may see inflammatory polyps, edema, crypt branching, and Paneth cell metaplasia.^222,224

Creation of an ileal neobladder (Kock or Charleston pouch) is now the most common procedure performed in patients who require some form of urinary diversion. These pouches are created from a portion of ileum that is separated from the fecal stream, and risk of malignancy has not been associated with these procedures. However, mucosal biopsy of these pouches may reveal histologic changes over time. Early changes (over the first year) include shortening of villi with loss of microvilli and decreased numbers of goblet cells.²²⁵ Late changes (after 4 years) consist of marked flattening of the epithelium with epithelial stratification, similar to urothelium.²²⁶ Dysplasia has not been described.

Antirefluxing colonic conduits, using a segment of colon that is isolated from the fecal stream, appear to be associated with a lower degree of retrograde reflux and therefore a decreased incidence of pyelonephritis.

Sarcoidosis

Sarcoidosis rarely involves the GI tract. The stomach is the most common site of sarcoidosis,²³² although involvement of the entire GI tract has been reported. It occurs in middle-aged patients and is usually associated with pulmonary disease, although the GI tract may rarely be the first site of involvement. Sarcoidosis is characterized by an abnormal immune response and the formation of multiple noncaseating granulomas. This condition is also associated with high serum angiotensin-converting enzyme activity. ²³³ The cause is unknown. In patients with sarcoidosis, a high frequency of humoral autoimmunity (increased incidence of antibodies to H⁺,K⁺-ATPase, gliadin, and endomysium) is seen.²³⁴ However, there does not appear to be an increased incidence of pernicious anemia or celiac disease.

The pathology of sarcoidosis is variable. The mucosa may show no abnormalities, or it may be severely involved, with a linitis plastica–like appearance of the stomach.²³⁵ Ulceration and bleeding have been reported. Microscopically, the hallmark of sarcoidosis is the presence of noncaseating granulomas. These granulomas are composed of epithelioid histiocytes, with or without giant cells, and are often associated with a rim of lymphocytes at the periphery (Fig. 6.13). They may be present in any layer of the bowel wall and may be associated with tissue damage.

The importance of sarcoidosis lies in its differential diagnosis with other causes of granulomas (which are numerous) and with Crohn’s disease. Often, the cause can be ascertained only with an appropriate clinical history. Sarcoidosis is less common than Crohn’s disease in the GI tract and is more often seen in black patients. Mycobacterial infections (especially in patients with associated pulmonary disease) should also be considered. Acid-fast stains may be performed on the granulomas in suspected cases, and the purified protein derivative skin test may also help to distinguish between the two diseases. Essentially, a diagnosis of sarcoidosis can be established only after other diseases have been excluded.

Mastocytosis

Both systemic mastocytosis and urticaria pigmentosa (the skin form of mast cell disease) may have GI involvement by disease or by an increase in the number of mast cells. In systemic mastocytosis, 70% to 80% of patients have GI symptoms when a careful history is obtained.²³⁶ Abnormalities include diarrhea, peptic ulcer pain, GI bleeding, nondyspeptic abdominal pain, urgency, and fecal incontinence.²³⁷ A proportion of patients also have gastric acid hypersecretion caused by hyperhistaminemia. This condition can lead to ulcer disease and may even mimic the Zollinger-Ellison syndrome. Gastric erosions, duodenal ulceration or varices secondary to hepatic fibrosis, and portal hypertension can cause GI hemorrhage.²³⁶

The stomach and duodenum are most commonly involved.²³⁸ A variety of changes can be seen, including focal urticaria-like mucosal lesions, edematous thickening of the mucosal folds, gastric erosions, and peptic-type ulcerations.

Histologically, mastocytosis is characterized by an abnormal proliferation of tissue mast cells. The mast cell infiltrate is usually seen throughout the GI tract but predominantly in the mucosa and submucosa (Fig. 6.14, A). It is often associated with other inflammatory cells such as eosinophils (see Fig. 6.14, B). The infiltrate can be very dense. Associated and mild mucosal villous blunting may be seen. Secondary changes due to gastric acid hypersecretion, such as erosions, may be seen as well. Mast cells can be stained with chloroacetate esterase stains, with the Giemsa stain, and with immunohistochemical stains for CD117 (see Fig. 6.14, C) or for mast cell tryptase. Patients with urticaria pigmentosa may also show increased numbers of mast cells in biopsies of the stomach and duodenum, although mast cell numbers do not correlate with elevated skin mast cell counts in this condition.²³⁹

Several studies have suggested that increased mast cells are present in patients with irritable bowel syndrome and diarrhea. The term mastocytic enterocolitis has been recommended. These studies suggest that the presence of more than 20 mast cells per high-power field (normal, 13 to 15 ± 3 per high-power field) indicates a pathologically increased mast cell number.^240,241

Neoplastic Disease

Neoplastic diseases from other sites may involve the GI tract through tumor invasion of the GI tract or indirectly through paraneoplastic syndromes.

Tumors can invade the GI tract either by direct extension or by metastasis. As many as 20% of extraintestinal tumors metastasize to the bowel.^242,243 The most common neoplasms that directly involve the small or large intestine are carcinomas from the pancreas, prostate, urinary bladder, and female genital tract and ovarian tumors through peritoneal seeding. Peritoneal seeding typically involves the serosal surface. Tumors that metastasize relatively frequently to the intestines are melanoma and carcinoma of the breast and lung. Primary carcinoma of the digestive tract may also metastasize to other parts of the GI tract, particularly the diffuse linitis plastica variant of gastric carcinoma.²⁴⁴ Metastatic breast carcinoma, particularly the lobular type, can mimic primary signet ring cell carcinoma and may even have a linitis plastica appearance²⁴⁵ (Fig. 6.15). Immunohistochemical stains for estrogen and progesterone receptors, gross cystic fluid protein, and CK5/6 are often positive in breast carcinoma, whereas CK20, DAS-1, MUC5AC, and MUC6 are often positive in gastric carcinoma.²⁴⁶ Epithelial malignancies that metastasize to the GI tract are typically differentiated from primary tumors of the GI tract by the lack of epithelial dysplasia or other (adenoma) precursor lesions adjacent to the tumor and by the finding of prominent lymphatic invasion by metastatic lesions. Metastases are often multicentric as well. Furthermore, colonic tumors are usually CK7 negative and CK20 positive, whereas gastric or other foregut tumors are often CK7 positive and CK20 variable.²⁴⁷

Paraneoplastic syndromes may develop secondary to release of hormones or antibodies from tumor cells. Typical examples include the watery diarrhea syndrome seen with bronchial carcinoid tumors and oat cell carcinoma of the lung. The syndrome is caused by the release of serotonin, which causes hypermotility of the gut.²⁴⁸ Oat cell carcinoma can also lead to gastroparesis secondary to antibody (anti-Hu) production by the tumor.²⁴⁹ Another example is Zollinger-Ellison syndrome caused by excessive gastrin production from gastrinomas; patients often present with multiple duodenal ulcers secondary to gastrin-induced acid hypersecretion.²⁵⁰