Esophageal Varices

Esophageal varices are dilated, tortuous veins within the lamina propria and submucosa that bulge into the esophageal lumen because of portal hypertension and portosystemic shunting. Esophageal varices may develop in any condition that leads to portal hypertension, but they are most often associated with alcoholic cirrhosis. The demographic features of patients with esophageal varices are similar to those of patients with cirrhosis and portal hypertension (see Chapter 50). Worldwide, hepatic schistosomiasis is a common cause of esophageal varices. Varices are typically asymptomatic until they rupture into the esophageal lumen, resulting in hematemesis or melena.

Bleeding varices are most common in the caudal portion of the esophagus; however, a discrete bleeding site is usually difficult to identify pathologically. Varices tend to collapse at the time of autopsy and therefore are best diagnosed endoscopically. In autopsy specimens, eversion and formalin fixation of the esophagus are techniques that can be used to help demonstrate varices. Grossly dilated, tortuous veins may be seen in the distal 3 to 4 cm of the esophagus when they bulge into the lumen (Fig. 10.1, A). Thrombosis may be observed in the dilated veins.

Histologically, dilated submucosal veins are characteristic, and these are usually associated with fresh hemorrhage or organizing thrombi (see Fig. 10.1, B). Surface ulcers or erosions are uncommon. In specimens examined after treatment with sclerotherapy or endoscopic ligation, findings may include thrombosis, ulceration, necrosis, inflammation, and fibrosis.^10,11

Although variceal bleeding is the most important cause of hematemesis in patients with portal hypertension, other causes of upper GI bleeding are implicated in approximately 50% of patients who are seen with hematemesis (Table 10.2; see also Table 10.1).

Esophageal varices often rebleed, and the risk of dying within 6 weeks of an initial bleed is 20% to 30% in patients with cirrhosis-related portal hypertension.¹² Variceal bleeding may precipitate hepatic encephalopathy in cirrhotic patients. Treatment modalities include sclerosis and banding of individual varices, portosystemic shunting, and pharmacologic management of portal hypertension.

Mallory-Weiss Lacerations

Mallory-Weiss lacerations are longitudinal tears of the mucosa located in the region of the gastroesophageal junction. These lesions may bleed profusely.¹³ A clinical history of retching or forceful vomiting is identified in approximately 30% of patients. Mallory-Weiss lacerations develop mainly in patients with chronic alcoholism and typically occur in the third to fifth decades of life. Concomitant aspirin use has been reported in approximately 30% of patients. Other risk factors include upward diaphragmatic movement related to coughing, heavy lifting, pregnancy, and abdominal trauma.¹⁴ Mallory-Weiss laceration is an uncommon complication of upper GI endoscopy, in association with retching and hiatal hernia. In addition, some patients are seen with melena or iron deficiency anemia.

The pathogenesis of Mallory-Weiss lacerations is related to upward movement of the diaphragm and an increase in intraabdominal pressure, which leads to protrusion of the proximal stomach into the thoracic cavity. This is often preceded by nausea, which causes distention of the stomach and reflux of gastric contents into the esophagus. When protrusion of the distended stomach is forceful, longitudinal lacerations may develop. Lacerations are more likely in patients with a hiatus hernia.

Most Mallory-Weiss lacerations are located on the gastric side of the gastroesophageal junction. Only a minority involve the tubular esophagus.¹³ They occur most commonly on the lesser curve of the proximal stomach (Fig. 10.2) but may also occur at the gastroesophageal junction. Histologically, Mallory-Weiss lacerations are characterized by a longitudinal breach of the mucosa that extends into the submucosa, but generally not into the muscularis propria, usually accompanied by hemorrhage, either with or without an acute inflammatory response. Healing Mallory-Weiss lacerations show granulation tissue, fibrosis, epithelial regeneration, and other features of healing ulcers.

Mallory-Weiss lacerations are usually treated supportively. In occasional patients with persistent bleeding, pharmacologic management, balloon tamponade, embolization, and, rarely, surgery may be required to establish hemostasis. Boerhaave syndrome (acute rupture of the esophagus) is a catastrophic event that is sometimes considered to be a complication of Mallory-Weiss lacerations. However, patients with Boerhaave syndrome are not typically seen with severe acute GI bleeding.¹⁵

Esophagitis and Esophageal Ulcers

Esophagitis and esophageal ulcers are most commonly caused by GERD, infection (e.g., herpesvirus, Candida, cytomegalovirus), drugs, chemical or physical injury from ingestion of toxic substances, or foreign objects. Bleeding from esophagitis is usually occult, and patients commonly are seen with anemia. Bleeding from esophageal ulcers varies in severity depending on the cause, but it is most often acute. Signs and symptoms include hematemesis, epigastric pain, and odynophagia. Most patients with acute bleeding are seen in the emergency department,¹⁶ and many of them have significant comorbid conditions.

Overall, GERD-associated ulcers are most common, and they are seen in all age groups, although they are more prevalent after the age of 40 years. Ulcers caused by infections are more likely to occur in immunocompromised patients. However, herpes simplex virus esophagitis has been documented in immunocompetent patients as well. Other causes of esophageal ulcers include Crohn’s disease and use of NSAIDs. Concomitant alcohol use has been reported in a subset of patients with NSAID-induced esophageal ulcers, suggesting that it may have a synergistic effect. Ulcers related to medication injury are common in the elderly, whereas those caused by foreign objects are more common in children. Reflux is less likely to be associated with bleeding than use of NSAIDs, which cause injury by direct mucosal contact.¹⁷ Radiation-induced injury is mediated by vascular compromise. Injury from chemical agents, such as lye, is caused by their corrosive effect on the mucosa.

Ulcers resulting from GERD occur mainly in the distal third of the esophagus. Adjacent mucosal changes typical of reflux, such as squamous hyperplasia with prominent fibrovascular papillae and intraepithelial inflammation (eosinophils, neutrophils, and lymphocytes), are usually present. Herpesvirus inclusions are identified most readily in squamous cells at the edges of herpetic ulcers (Fig. 10.3). In contrast, cytomegalovirus inclusions are most often found in endothelial cells or stromal cells at the ulcer base. Candida should be sought wherever neutrophils accumulate in the surface epithelium, usually in association with superficial desquamation. Morphologic features of radiation injury include dilated and thickened capillaries with deposition of hyaline, prominent endothelial cells, and reactive stroma with atypical stellate fibroblasts. NSAID-induced ulcers are typically large, shallow lesions with a broad base and are most common in the middle esophagus.¹⁷ Pill esophagitis shows superficial epithelial sloughing, keratinocyte necrosis, spongiosis, and intraepithelial eosinophils. Ulcerating malignant neoplasms may also be a source of bleeding, but this is an unusual presentation of esophageal cancer.¹⁸ However, the most common indication for endoscopy in patients with a secondary malignant neoplasm of the esophagus is GI bleeding.¹⁹ Bleeding from NSAID-induced ulcers is usually active and infrequently complicated by strictures. Rarely, esophageal or gastric ulcers perforate or penetrate into contiguous vascular organs, such as the heart and aorta, leading to massive bleeding²⁰ (Fig. 10.4). Ulcers resulting from foreign bodies are particularly prone to this complication.^18,19,21,22

Esophageal Diverticula

Esophageal diverticula are rare and usually asymptomatic. However, patients with diverticula may occasionally present with upper GI tract bleeding. Bleeding may occur in association with an ulcer, entrapped pills, or use of anticoagulants.²³

Gastric Varices

Gastric varices have clinical and pathologic features similar to those of esophageal varices. They most commonly occur on the lesser curve of the proximal stomach, in continuity with esophageal varices.²⁴ Reports vary as to whether gastric varices, compared with esophageal varicies, are less likely²⁴ or equally likely²⁵ to bleed. Bleeding from gastric varices, when it does occur, is usually severe.²⁴

An estimated 350,000 cases of acute gastric ulcers are diagnosed annually. There are many causes of acute gastric (and duodenal) ulceration. Overall, gastric ulcers are more common in men than in women, and they are seen most often in the middle-aged and elderly population.

Peptic ulcers, both acute and chronic (including those located in the duodenum), account for 20% to 50% of cases of upper GI bleeding.²⁶ Risk factors for peptic ulcer disease include Helicobacter pylori infection, NSAIDs, and alcohol.

Stress ulcers are acute gastric ulcers that develop in patients suffering from shock, sepsis, or trauma.²⁷ Stress ulcers have numerous synonyms, such as acute hemorrhagic gastritis. Curling ulcers develop after severe burns. Cushing ulcers develop after severe head trauma. Steroid ulcers develop because of steroid use. Risk factors for stress ulcers include respiratory failure, coagulopathy, recent major surgery, major trauma, severe burns, hepatic or renal disease, sepsis, and hypotension.²⁸

Bleeding from acute gastritis may occur in long-distance runners and is of uncertain pathogenesis.^29,30 Cocaine can cause gastric erosions and bleeding.³¹ Bleeding may also occur when an ulcer erodes into an underlying blood vessel. Dieulafoy lesions (also called caliber-persistent artery) are bleeding ulcers that occur most commonly in the stomach but can also occur in the small and large intestines and, rarely, in the esophagus.³² Dieulafoy lesions are characterized by the presence of a single, unusually large-diameter mural arteriole that penetrates the submucosa (Fig. 10.5, A). These large vessels erode through the mucosa and cause massive bleeding (see Fig. 10.5, B and C). Cameron ulcers are linear ulcers that form in a sliding hiatal hernia; they also can cause gastric bleeding.

Mass lesions, located either in the mucosa or deeper within the gastric wall, may erode the overlying mucosa and cause chronic low-grade bleeding (Fig. 10.6). Fundic gland polyps, gastric adenomas, ectopic pancreas, malignant tumors (e.g., primary gastric adenocarcinomas, lymphomas, endocrine tumors), GI stromal tumors, and metastatic tumors (e.g., melanomas, breast carcinomas) can all cause upper GI bleeding. Gastric bleeding may also be iatrogenic in origin, such as after surgery for obesity.³³

Portal Hypertensive Gastropathy

Portal hypertensive gastropathy occurs in as much as 90% of patients with cirrhosis-related portal hypertension. It is characterized endoscopically by the presence of a mosaic mucosal pattern, with or without petechial hemorrhages, usually of the proximal stomach. Portal hypertensive gastropathy may also occur in patients without cirrhosis. It is usually detected in patients with portal hypertension who are being evaluated for variceal bleeding. Portal hypertensive duodenopathy has been described in 51% of portal hypertensive patients and is an uncommon cause of occult GI bleeding. Endoscopic features include erythema, erosions, ulcers, telangiectases, and duodenal varices.³⁴

Altered gastric blood flow has been implicated in the pathogenesis of portal hypertensive gastropathy. Other postulated mechanisms include nitric oxide production, tumor necrosis factor-α synthesis, and sensitivity to prostaglandin inhibition.³⁵

Portal hypertensive gastropathy occurs most commonly in the fundus and body of the stomach. Histologic features include the presence of numerous ectatic capillaries and venules in otherwise normal mucosa and submucosa. Fibrin thrombi, inflammation, mucosal fibrosis, and fibrohyalinosis are not histologic components of portal hypertensive gastropathy^35–38 (Fig. 10.7, A). There is no association with atrophic gastritis, CREST syndrome (calcinosis, Raynaud phenomenon, esophageal involvement, sclerodactyly, and telangiectases), or bone marrow transplantation (Table 10.3). Portal hypertensive duodenopathy usually occurs in association with gastropathy; it is characterized by capillary congestion, capillary angiogenesis, and edema in the duodenal mucosa (see Fig. 10.7, B through D) but only minimal inflammation.³⁴

Bleeding from portal hypertensive gastropathy is usually chronic and often controllable by medical or surgical management of the underlying cause of the patient’s portal hypertension.

Gastric Antral Vascular Ectasia

Gastric antral vascular ectasia (GAVE) affects mainly women of middle age, frequently causes iron deficiency anemia, and is associated with portal hypertension in about 30% to 40% of cases. It is sometimes associated with achlorhydria, atrophic gastritis, and the CREST syndrome. Autoimmune disorders are present in approximately 62% of patients with GAVE.³⁵ At endoscopy, GAVE is characterized by a linear pattern of mucosal hyperemia on the antral rugae that appears similar to the stripes of a watermelon; hence, the synonym, watermelon stomach.³⁹ This endoscopic appearance tends to be more diffuse in cases of cirrhosis but usually involves only the gastric antrum. The pathogenesis of GAVE is believed to be altered gastric motility.

Histologically, GAVE is characterized by the presence of dilated capillaries in the mucosa and submucosa, often containing microthrombi. Fibromuscular hyperplasia of the intervening lamina propria and focal hyalinosis are characteristic features, along with edema, congestion, and reactive changes of the foveolar epithelium^37,38,40 (Fig. 10.8). Inflammation is typically minimal. Surface erosion is uncommon.

In mucosal biopsies, both portal hypertensive gastropathy and GAVE should be distinguished histologically from chronic radiation gastritis, which also shows ectatic mucosal capillaries. In contrast, radiation injury is characterized by prominent endothelial cells and hyaline thickening of dilated capillaries and small blood vessels, sometimes associated with thrombosis (Fig. 10.9). Features that differentiate portal hypertensive gastropathy and GAVE are summarized in Table 10.3.

Endoscopic mucosal coagulation is the treatment of choice for most patients with GAVE. Antrectomy is reserved for patients with uncontrollable bleeding.

Hereditary Hemorrhagic Telangiectasia (Rendu-Osler-Weber Disease)

HHT, also referred to as Rendu-Osler-Weber disease, is an autosomal dominant condition in which telangiectases involve the mucous membranes of the oral cavity, but also any portion of the GI tract, where they may bleed.⁴¹ The disorder affects both sexes equally and occurs in all races. The typical clinical triad consists of telangiectasia and recurrent epistaxis in a patient with a family history of the disorder. The clinical features are variable. About 20% of patients do not reveal a family history of either telangiectasia or recurrent bleeding.⁸ Most patients express at least two of the following four manifestations: epistaxis, telangiectasia, visceral lesions (including GI telangiectasia), and a positive family history.⁴² At least two gene loci (HHT1 and HHT2) have been implicated in HHT. GI bleeding is more likely in patients with HHT1 mutations.⁴¹ Upper GI bleeding is common and can be difficult to distinguish from epistaxis; the two are the most common manifestations of HHT. GI bleeding is often difficult to control. Blood transfusion requirements in excess of 100 units have been reported.

GI tract lesions include telangiectases, arteriovenous malformations (AVMs), and angiodysplasias. Telangiectases, which are the most common lesions, appear grossly as bright red spots on the mucosa. These lesions are composed of a tuft of dilated venules and arterioles that communicate directly with one another, thereby bypassing capillaries (Fig. 10.10). The precise vascular architecture is often difficult to appreciate in routine histologic sections, but evaluation of serial sections may help.⁴³

Telangiectasia may also occur in patients with scleroderma, as part of the CREST syndrome. The morphology of telangiectases associated with scleroderma is similar to that in HHT, and distinction therefore requires clinical and serologic correlation (rheumatoid factor, antinuclear antibody, SCL-70 antibody, and anticentromeric protein antibody). Telangiectases may also develop in patients with chronic renal failure after hemodialysis.⁴⁴

Treatment options for GI hemorrhage associated with HHT include drug therapy with estrogen, danazol, or aminocaproic acid; endoscopic coagulation, cautery, or laser therapy; and surgical resection.

External Mesenteric Venous Compression

The most common cause of mesenteric venous insufficiency is external mesenteric venous compression. This may be related to volvulus, torsion, adhesions, intussusception, or trauma. Because of the normal low intraluminal pressure of veins, these structures are easily occluded externally. If the occlusion is of sufficient duration, thrombosis may occur. Volvulus, torsion, and bowel entrapment may cause closed-loop obstruction, in which the lumen of the bowel is sealed off at the point of compression. As a result, luminal secretions accumulate, which facilitates bacterial proliferation, toxin production, inflammation, and necrosis (Fig. 10.36). Mesenteric venous compression by extraabdominal trauma is rare but has been attributed to a tight seat belt during prolonged plane travel⁷⁴ (Fig. 10.37).

Mesenteric Venous Thrombosis

Mesenteric venous thrombosis usually manifests as progressive, severe abdominal pain of acute onset. It may occur in individuals of any age, but patients tend to be younger than those with arterial insufficiency. Until recently, mesenteric venous thrombosis was most often diagnosed at laparotomy, in resection specimens, or at autopsy. However, improved radiologic techniques, including computed tomographic angiography and magnetic resonance imaging, now enable many cases to be diagnosed radiologically. Thus, increasing numbers of patients are being treated medically with thrombolytic therapy, rather than surgery.⁷⁵ Furthermore, owing to advances in understanding of hypercoagulable states and myeloproliferative disorders, the cause of mesenteric venous thrombosis is known in as many as 80% of cases.

In the absence of external venous compression, an intramural pathologic process, or a localized cause of thrombosis such as an intraabdominal abscess, acute diverticulitis, acute pancreatitis, or venous invasion by tumor (Fig. 10.38), most patients with mesenteric venous thrombosis have an underlying predisposition to thrombosis. Therefore, it is important to investigate these patients clinically for predisposing conditions that may lead to recurrence or have clinical implications for relatives who carry the predisposition to thrombosis. Hypercoagulable states include factor V Leiden mutation, the presence of antiphospholipid antibody, and deficiency of protein C or S (see Box 10.3). Myeloproliferative disorders, such as polycythemia vera, have also been found to be causative. The JAK2 V617F mutation has been detected in some patients with mesenteric venous thrombosis before the development of an overt myeloproliferative disorder.⁷⁶

The gross and microscopic appearances of the affected segment of bowel are similar to those described in cases of mesenteric venous insufficiency. In addition, thrombi are typically found in veins located in the submucosa, adventitia, and mesentery (Fig. 10.39, A), as well as in those distant from areas of necrosis. The splenic, portal, and hepatic veins may be involved in some cases. Typically, arteries are not affected. Blood vessels located proximal to the thrombus are typically engorged and dilated. Mucosal and intramural congestion and hemorrhage, with submucosal edema and extravasation of erythrocytes, are common (see Fig. 10.39, B and C). Ischemic necrosis of the mucosa may be seen on microscopic examination. When the area of thrombosis is localized, it usually begins within large vessels and propagates proximally toward smaller ones. However, if the underlying cause of ischemia is a hypercoagulable state, thrombosis begins in the small-sized vessels and propagates centrally toward the larger ones.⁷³ Patients may present with acute, subacute, or chronic symptoms and sometimes with Budd-Chiari syndrome. However, even in patients with an acute presentation, it is common to detect thrombi at various stages of organization (see Fig. 10.39, D).

Portal pylephlebitis may develop as a complication of diverticulitis or perforated appendicitis. Patients typically are seen with a high fever that is sometimes accompanied by jaundice. Pylephlebitis is a form of septic (often suppurative) thrombophlebitis of the portal venous system, usually associated with gram-negative enteric aerobes and anaerobes. Some cases of pylephlebitis are believed to arise from areas of mesenteric venous thrombosis that have become secondarily infected.⁷⁷ Pylephlebitis is most often diagnosed on the basis of clinical and radiologic findings but may be encountered by the pathologist on evaluation of resection specimens or at autopsy. It may also be inferred in patients with a hepatic abscess and an appropriate clinical history.

The pathognomonic histologic lesion is an acutely inflamed vein of the mesenteric/portal system, associated with bacteria or fungi and a recent or organizing thrombus. Pylephlebitis identified in a surgical resection specimen from a patient with a ruptured appendix or diverticular disease–associated abscess should alert the pathologist to the possibility of spread of infected emboli to the liver.

Pylephlebitis usually requires aggressive antimicrobial therapy. If left untreated, it may lead to the development of septic emboli. Hepatic abscesses occur in as much as 50% of cases. The mortality rate exceeds 30%.^75,78 Early diagnosis and therapy improve overall outcome.

Idiopathic Myointimal Hyperplasia of Mesenteric Veins

Idiopathic myointimal hyperplasia of mesenteric veins (IMHMV) is a rare condition. It has been reported mainly in young to middle-aged men who are seen with abdominal pain, diarrhea or constipation, and rectal bleeding. The left colon is most often involved. The endoscopic findings of mucosal erythema, ulceration, friability, granularity, and cobblestoning often result in a presumptive endoscopic diagnosis of inflammatory bowel disease. However, mucosal biopsies do not show features of Crohn’s disease or ulcerative colitis but instead show mild ischemic changes. Abnormally thick-walled mucosal capillaries may sometimes be observed. A diagnosis of IMHMV may rarely be suspected on clinical grounds, but it is usually established only on evaluation of a resection specimen. The disorder is localized to the veins of discrete segments of the intestine, most commonly the sigmoid colon, and therefore is not considered a systemic form of “vasculitis.” Resection of the affected segment of bowel is curative. Disease recurrence has not been reported.

The pathognomonic histologic features of IMHMV are seen in the mural blood vessels; they consist of a concentric proliferation of smooth muscle cells in the intima and media of small to medium-sized intramural veins. This causes stenosis, and sometimes occlusion, of the veins but without an associated inflammatory infiltrate (Fig. 10.40). The arteries are normal, but the veins become enlarged and muscular so that they can easily be mistaken for arteries.⁷⁹ In contrast to acute mesenteric venous ischemia, cases of IMHMV do not show mucosal congestion, vascular engorgement, or hemorrhage into the bowel wall. Rather, the mucosa shows dilated capillaries, abnormal small muscular vessels, and vessels with thickened hyaline walls. The epithelium may reveal mucin depletion and mild atrophic changes. Features typical of ischemia may also be present (i.e., loss of surface epithelium, reactive changes in residual crypt epithelium, and hyalinosis of the lamina propria). On the basis of a similarity of the pathologic changes in the mural and extramural veins to those in saphenous veins that have been used in coronary artery bypass surgery, Genta and Haggitt, in the initial description of this entity, postulated that the disorder may be a consequence of arteriovenous fistulization.⁸⁰ Subsequent studies have supported this theory.⁸¹ Small, localized foci of pathologic changes similar to IMHMV have been demonstrated in intestinal specimens resected for unrelated conditions, but they contained surgical anastomoses or other forms of healed (traumatic) injury, in which arteriovenous communications are expected to occur.⁸² An alternative pathogenetic theory suggests that IMHMV represents the end stage of “phlebitis,” because lesions morphologically similar to IMHMV have been observed in cases of lymphocytic, granulomatous, and necrotizing phlebitis.⁸³

Enterocolic (Lymphocytic, Granulomatous, or Necrotizing) Phlebitis

Enterocolic phlebitis is a term that was introduced to encompass a variety of related disorders termed lymphocytic, granulomatous, or necrotizing phlebitis. This name was proposed on the basis that granulomatous phlebitis and necrotizing phlebitis almost always occur in association with lymphocytic phlebitis, and not uncommonly all three forms are present together in the same pathologic specimen.⁸³ Saraga and Bouzourenne included IMHMV within the spectrum of enterocolic phlebitis,⁸³ but in this chapter it is considered separately, primarily because it occurs predominantly in the left colon, whereas enterocolic phlebitis occurs typically in the ileocecal region. In addition, the age and sex distributions of patients with these entities differ (see Table 10.7). Furthermore, whereas foci of IMHMV may be seen in association with enterocolic phlebitis, as well as other unrelated forms of intestinal injury, most clinically evident cases of clinical IMHMV show no evidence of enterocolic phlebitis.⁸²

The term mesenteric inflammatory veno-occlusive disease (MIVOD) has been largely abandoned. It was originally used to describe seven cases, of which four were lymphocytic phlebitis, two necrotizing phlebitis, and one mixed lymphocytic and granulomatous phlebitis. Three of the seven cases also had foci of IMHMV.⁸⁴

Similar to IMHMV, enterocolic phlebitis is a localized process rather than a systemic one, and resection of the affected segment of the intestinal tract is considered curative. Patients with lymphocytic phlebitis are typically middle-aged to elderly and are seen with abdominal pain caused by ischemia of the right colon or terminal ileum or with a right-sided abdominal mass caused by cecal edema or intussusception.^83,85–87

The ischemic features of enterocolic phlebitis are typical of mesenteric venous obstruction, showing engorgement of the veins of the bowel wall, mural hemorrhage, edema, and mucosal necrosis (Fig. 10.41, A). Histologically, the lymphocytic phlebitis form of enterocolic phlebitis is characterized by a diffuse infiltrate of small lymphocytes within the walls of intramural veins, which also forms dense perivenular cuffs (see Fig. 10.41, B and C). The lymphocyte cuffs are typically circumferential. However, in tissue sections distant from areas of ischemia, a crescentic pattern of inflammation may be seen.⁸⁸ The inflammatory infiltrate is composed of CD3+ CD8+ T cells, some of which have cytotoxic characteristics, admixed with smaller numbers of B cells. Some affected veins may be thrombosed (see Fig. 10.41, D).

In enterocolic phlebitis, areas of necrotizing phlebitis (in which the mural infiltrate is composed mainly of neutrophils and is associated with fibrinoid necrosis of the vessel walls) and thrombosis are usually found underlying, or adjacent to, areas of mucosal necrosis (see Fig. 10.41, E). Granulomatous phlebitis, in which the mural infiltrate contains histiocytes and giant cells associated with damage to the walls of veins (see Fig. 10.41, F), may also be seen focally.⁸⁹ Enterocolic phlebitis has also been reported in association with lymphocytic enteritis and colitis.^87,90 A single report of gastroduodenal lymphocytic phlebitis illustrates that this pattern of inflammatory vasculopathy may not be restricted to the distal small bowel and colon.⁹⁰

Polyarteritis Nodosa

In approximately 50% of patients with polyarteritis nodosa, the celiac and mesenteric arteries are involved, and this may result in small intestinal ischemia. The disease process less commonly affects the colon, liver, and pancreas.¹⁰² Histologically, polyarteritis nodosa is characterized by transmural fibrinoid necrosis of arteries, accompanied by a neutrophil infiltrate in the early stages of disease and monocytes, macrophages, and lymphocytes in the later stages (see Fig. 10.32). Pseudoaneurysms are common and are responsible for the characteristic nodularity of the blood vessels, which is implied by the term nodosa. Polyarteritis nodosa is commonly associated with hepatitis B infection and occasionally with hepatitis C.

Kawasaki Disease

Kawasaki disease usually occurs in children younger than 5 years of age and is characterized by the presence of mucocutaneous lymphadenopathy. In the fully developed disorder, patients have fever, skin rash on the palms and soles, cutaneous desquamation, strawberry tongue, and conjunctival congestion.¹⁰³ The necrotizing arteritis associated with this condition shows a predilection for the coronary arteries, which may develop aneurysms, thrombosis, or rupture. Many patients have intestinal involvement, which manifests as abdominal pain, nausea, vomiting, diarrhea, small-bowel bleeding, and ischemic perforation.

Wegener Granulomatosis

Wegener granulomatosis is a granulomatous disease of the respiratory tract that is often accompanied by nasal sinus and renal involvement. It is associated with paucity of immunoglobulin deposition. Ninety percent of patients are ANCA positive. In addition to the characteristic destructive granulomas, necrotizing small-vessel vasculitis (Fig. 10.46) is typically present. Wegener granulomatosis may affect the GI tract, particularly the mesenteric arteries, which can lead to ischemic injury to the intestines.¹⁰⁴ Granulomatous inflammation of the stomach or ileum may cause diagnostic confusion with Crohn’s disease.¹⁰⁵

Churg-Strauss Syndrome

Churg-Strauss syndrome is a form of allergic angiitis characterized by the presence of asthma, peripheral eosinophilia, granulomatous inflammation of the respiratory tract, and eosinophil-rich necrotizing vasculitis (Fig. 10.47) that usually responds to steroid therapy. Approximately 50% of patients experience abdominal pain and bleeding resulting from GI ischemia.¹⁰⁶ This disorder is associated with a paucity of immunoglobulin deposition. Patients are commonly ANCA positive.

Henoch-Schönlein Purpura

In Henoch-Schönlein purpura, immunoglobulin A–predominant immune complexes are deposited within small-sized blood vessels that exhibit leukocytoclastic angiitis. The process affects small vessels of the skin, kidneys, joints, and, in 75% of cases, the GI tract. Children in the age range of 4 to 7 years are most often affected, and the condition usually develops after an upper respiratory tract infection. GI involvement results in ischemia with abdominal pain, bleeding, and intramural hemorrhage, which is the GI counterpart of the palpable purpura commonly observed in skin.¹⁰⁷ Histologic features include hemorrhage and edema in the mucosa, submucosa, and bowel wall, accompanied by leukocytoclastic vasculitis. Serologic tests for ANCA are typically negative.

Leukocytoclastic Vasculitis

Although the term leukocytoclastic vasculitis is sometimes used to describe a specific disease entity, it simply refers to a pattern of small-vessel inflammation characterized by leukocyte fragmentation and fibrinoid necrosis of arterioles, capillaries, and venules (Fig. 10.48). This pattern of injury may be seen in a variety of vasculitides. The term is also occasionally used synonymously with hypersensitivity vasculitis, which is a disorder of adults associated with skin rash and leukocytoclastic vasculitis. GI involvement in these cases is usually mild and limited.¹⁰⁸ Hypersensitivity vasculitis bears morphologic similarity to Henoch-Schönlein purpura; however, there is some evidence that they are, in fact, two distinct entities.¹⁰⁹

Cryoglobulinemic Vasculitis

Cryoglobulinemic vasculitis refers to a type of small-vessel immune complex vasculitis occurs in patients with hepatitis C and cryoglobulinemia. The skin and kidneys are more commonly involved than the intestines, but intestinal ischemic injury has occasionally been reported.¹¹⁰

Systemic Lupus Erythematosus and Other Immune Complex Diseases

Approximately 50% of patients with SLE show GI involvement by small-vessel immune complex vasculitis. The clinical manifestations are variable. Patients may experience nausea, vomiting, abdominal pain, diarrhea, malabsorption, pancreatitis, protein-losing enteropathy, and segmental ischemic necrosis of the intestines.¹¹¹ GI involvement is seen in only approximately 10% of patients with rheumatoid arthritis. Symptoms include abdominal pain, nausea, and vomiting. Ischemic injury may lead to bowel necrosis and perforation.¹¹² Resection specimens may show small-vessel vasculitis with hemorrhage and edema in the mucosa, submucosa, and bowel wall, as well as varying degrees of tissue necrosis (Fig. 10.49).

Behçet Disease

Behçet disease, which is a vasculitis of unknown etiology, is linked to the presence of human leukocyte antigen (HLA) B51. It is most common in countries situated along the ancient Silk Road, particularly Turkey, but also occurs elsewhere, especially in Japan.¹¹³ Clinical features, which usually develop in the third or fourth decade of life, are diverse and include oral and genital ulceration, retinitis and uveitis, erythema nodosum and other skin disorders, and arthritis.

GI involvement develops in 3% to 26% of patients and is most common in the terminal ileum and right colon, where it may mimic Crohn’s disease or ulcerative colitis.¹¹⁴ In resection specimens, small-vessel phlebitis, either with or without arteritis, is seen in the submucosa, often with ulceration. Ulcers have been reported to be associated with lymphoid follicles and Peyer patches¹¹⁵ (aphthous lesions); although small, they have a tendency to penetrate deeply within the bowel wall and cause perforation. Large vessels are less commonly involved than small ones, and their involvement may lead to ischemia or infarction.. The vascular inflammation in the GI tract may be predominantly lymphocytic¹¹⁶ or predominantly neutrophilic,¹¹⁷ possibly reflecting different stages of the disease or a response to immunosuppressive therapy.

GI involvement in Behçet disease often necessitates resection of the affected segment of bowel. However, disease recurrence is common, and further intervention is required in approximately 50% of cases. The differential diagnosis of GI Behçet disease includes Crohn’s disease, ulcerative colitis, and chronic ischemic enterocolitis, but the diagnosis is usually made on the basis of both the clinical and the serologic features.

In 2009, Cheon and colleagues proposed an algorithm to distinguish Behçet disease from Crohn’s disease. The basis of the algorithm lay in categorizing the typical (not pathognomonic) Behçet ulcer as fewer than five oval, deep, discrete ileocecal ulcers.¹¹⁸ With this definition, patients were classified as “definite BD” if they had concurrent systemic Behçet disease, “probable intestinal BD” if they had an oral ulcer only, or “suspected BD” if they had neither systemic BD nor an oral ulcer. All other ulcers were considered atypical and nondiagnostic in the absence of systemic Behçet disease, although they were categorized as probable intestinal BD if there was a concurrent history of systemic Behçet disease. This algorithm produced greater than 95% sensitivity and greater than 80% specificity in detecting definite, probable, or suspected BD. Although the algorithm has not been validated by another series, there appears to be some value in the recognition that Behçet disease is most often associated with well-defined, discrete, oval, deep ulcers that usually number less than five.

Buerger Disease

Buerger disease, also termed thromboangiitis obliterans, is a vasculitic disorder that affects mainly men younger than 50 years of age who have a long history of cigarette smoking. The disorder results in impairment of the vascular supply to the lower extremities, which causes claudication and rubor, but occasionally the small mesenteric vessels are involved with acute inflammation and thrombosis, resulting in intestinal ischemia.¹¹⁹ The thrombi tend to be inflammatory, but the vessel walls usually escape the effects of severe injury. Typically, the internal elastic lamina remains intact.

Malignant Atrophic Papulosis (Kohlmeier-Degos Disease)

Malignant atrophic papulosis is a rare type of occlusive arteriopathy that occurs in patients of any age and affects both sexes. The epidemiology of this disorder is unclear. However, familial clustering has been reported, with a young male predisposition.¹²⁰ Atrophic papulosis may exist as a purely cutaneous, benign form or as a systemic, “malignant” form that affects the GI tract and central nervous system. Cutaneous red or pink papules are typically found on the trunk, arms, and legs and commonly precede systemic manifestations. Patients may also be seen with abdominal pain and features of peritonitis or with manifestations of central nervous system involvement.¹²¹ Endoscopic findings include infarcts and ulcers.

Malignant atrophic papulosis may involve any region of the GI tract. However, the small bowel is most commonly involved. Lesions are characterized by progressive sclerosis of small and medium-sized arteries with zonal tissue infarction. Serosal white plaques with red borders may be seen grossly.¹²² Characteristic histologic features include intimal hypercellularity with endothelial cell proliferation of small and medium-sized submucosal arteries and superimposed arterial thrombosis, but typically with only minimal or no inflammation. Vascular changes are associated with progressive intestinal necrosis, which may be full-thickness. The GI manifestations may be similar to other types of vasculitis, particularly SLE, a disease of which malignant atrophic papulosis has been considered a variant.¹²²

In patients with systemic involvement, the most common cause of death is intestinal perforation and peritonitis as a consequence of infarction.¹²² Enterocutaneous fistulas have also been reported. In addition to surgical management, medical therapy includes anticoagulants, antiplatelet drugs, and immunosuppressive agents.

Segmental Arterial Mediolysis

Segmental arterial mediolysis (SAM) is discussed here although it is not a true vasculitis. SAM is a rare lesion that was initially described in 1976 as segmental mediolytic arteritis and is best characterized as a noninflammatory, nonatherosclerotic arteriopathy that predominantly affects the abdominal arteries.¹²³ In a review of 27 patients,¹²⁴ Inada and colleagues supported the observations of Slavin¹²³ of partial or total mediolysis of large muscular arteries of the abdomen, most commonly the middle colic artery. In this review, SAM occurred in patients who ranged from 44 to 88 years of age, with a male predisposition, although cases have been reported in younger patients.¹²⁵ The most common presenting symptom was intraabdominal bleeding. On angiography, lesions may mimic the nodular appearance of PAN.

In addition to the middle colic artery, other involved abdominal arteries may include the gastric, gastroepiploic, inferior pancreaticoduodenal and hepatic¹²⁶ arteries. Reportedly, SAM may also affect cerebral, coronary, and pulmonary arteries.¹²⁷ Pathologically, these arteries undergo total or partial mediolysis, medial degeneration, and eventually aneurysm formation, hemorrhage, and rupture.

Patients require surgical intervention and may worsen with immunosuppressive therapy, rendering distinction from PAN important¹²⁸ Rarely, SAM may complicate PAN.¹²⁹

Localized Vasculitis of the GI Tract

In a small subset of patients, vasculitis occurs in the GI tract without systemic involvement. Reports have described patients with isolated GI tract involvement by necrotizing vasculitis,^130–132 emphasizing that vasculitis is not always systemic. These patients commonly undergo surgical intervention with variable outcomes, generally more favorable with involvement of the gallbladder, pancreas, and appendix.¹³²