Abstract
Vascular disorders of the gastrointestinal tract range from non-symptomatic lesions to acute life-threatening disorders. Generally, they can be classified as ischemic or bleeding, although this is often a superficial distinction with much overlap. Primary vascular disorders of the gastrointestinal tract are assessed by pathologists at the time of biopsy or surgical resection, as well as at autopsy. Diagnoses requires a multidisciplinary approach, but pathology often plays a particularly important role in suggesting or confirming a diagnosis. Careful attention to pathologic specimens is important, as the distinguishing features of each entity may be subtle and difficult to appreciate. Likewise, patient management may differ significantly among conditions with overlapping diagnostic features. This chapter will provide a concise review of the diagnostic elements to consider in vascular disorders of the gastrointestinal tract, and will discuss practical aspects that should help the pathologist to arrive at the best diagnosis for each case.
Introduction
Vascular disorders of the gastrointestinal (GI) tract range from non-symptomatic lesions to acute life-threatening disorders. Generally, they can be classified as ischemic or bleeding, although this is often a superficial distinction with much overlap. Primary vascular disorders of the GI tract are assessed by pathologists at the time of biopsy or surgical resection, as well as at autopsy. Diagnosis requires a multidisciplinary approach, but pathology often plays a particularly important role in suggesting or confirming a diagnosis. Careful attention to pathology specimens is important, as the distinguishing features of each entity may be subtle and difficult to appreciate. Likewise, patient management may differ significantly among conditions with overlapping diagnostic features. This chapter will provide a concise review of the diagnostic elements to consider in vascular disorders of the GI tract and will discuss practical aspects that should help the pathologist to arrive at the best diagnosis for each case.
Ischemia of the Gastrointestinal Tract
Esophagus
Ischemia of the esophagus is a rare and life-threatening clinical syndrome. The esophagus receives an intricate segmental blood supply that separates it into the upper, middle, and distal esophagus. Compared to the densely vascularized upper and middle parts of the esophagus, the distal esophagus is a slightly more “watershed” area and therefore ischemic injury is more likely to arise in this area.1
Acute esophageal necrosis (AEN), commonly referred to as “black esophagus” or “acute necrotizing esophagitis,” is a multifactorial disorder that leads to diffuse ischemic necrosis of the esophagus and to upper GI bleeding in older, typically male patients (Fact Sheet 6.1). While the pathophysiology is not entirely understood, the disease is likely to be the result of a low flow state, reduced mucosal protective mechanisms, and the damaging effects of gastric acid reflux.2 Multiorgan dysfunction, hypoperfusion, vasculopathy, sepsis, diabetic ketoacidosis, alcohol intoxication, gastric volvulus, traumatic transection of the thoracic aorta, thromboembolic phenomena, and malignancy are documented risk factors for developing AEN.1 Whatever the cause, the result is diffuse esophageal necrosis and tissue death. This is considered a catastrophic condition because it is generally a marker of a more dangerous underlying systemic disease including severe cardiovascular disease, sepsis, and malignancy, any of which independently may lead to death. The reported mortality rates range from 13% to 36%. However, rare cases of esophageal perforation also occur that lead to mediastinitis and rapid clinical deterioration.
Fact Sheet 6.1 Acute Esophageal Necrosis
General
Typically affects older male patients
Upper GI bleeding
Diffuse ischemic necrosis
Rarely esophageal perforation and risk of death
Risk Factors
Multifactorial
Multiorgan dysfunction
Vasculopathy
Hypoperfusion, sepsis, diabetic ketoacidosis
Alcohol intoxication
Gastric volvulus
Traumatic transection of the thoracic aorta
Thromboembolic phenomena
Malignancy
Gross/Endoscopic Features
Circumferential, dark or black necrotic mucosa
Affects distal esophagus and stops at gastroesophageal junction
May extend proximally over a variable length
Duodenal bulb often also involved by erosions, ulcers, and edema (same blood supply)
Histologic Features
Variable necrosis of mucosa, submucosa, and sometimes muscularis propria
+/−Leukocyte infiltration
Abundant necrotic debris
Grossly and endoscopically, the distal esophagus is involved by circumferential, dark or black-appearing necrotic mucosa. Classic “black esophagus” abruptly stops at the gastroesophageal junction, but the changes may extend proximally to involve a variable length of the esophagus.3 Sometimes, the entire esophagus is involved.
Histologically,3, 4 the findings include abundant necrotic debris, a variable degree of necrosis involving mucosa, submucosa, and sometimes even muscularis propria, with or without significant leukocyte infiltration. Because the esophagus and the proximal duodenum share a point of vascular distribution from the branches of the celiac axis, the duodenal bulb is often concurrently involved by erosions, ulcers, and edema.
Stomach
Gastric ischemia is rare because of the rich collateral vasculature of the organ. Several terms may describe gastric ischemia, including gastric infarction or apoplexy, gastric necrosis, moribund stomach, stress ulceration, chronic ischemic gastritis, and gastropathy.5 Causes of gastric ischemia include systemic hypotension, vasculitis, mesenteric stenosis or occlusion, iatrogenic complications (i.e. stray chemoembolization beads), mesenteric vein thrombosis, gastric volvulus, portal hypertension, and vasoconstrictive drug use (i.e. cocaine).6, 7 Other, nonvasculopathic causes such as stress-related mucosal disease, acute pancreatitis, or postoperative complications can also contribute to gastric ischemia.
Endoscopically, the appearances in gastric ischemia are highly variable and depend on the nature of the lesion. Ulcerative gastric lesions in this setting classically have irregular, sloping edges and sclerotic bases, with or without pseudomembranous material.8, 9 Biopsies are rarely taken from them unless there is some unusual clinical or endoscopic feature to suggest malignancy or infection. Biopsies should ideally target the edge of the lesion so as to increase the diagnostic yield.
As for other parts of the GI tract, the histological findings are variable and depend on the length of time and the severity of the ischemia. In general, they parallel the findings in the intestine (see later). Briefly stated, mucosal epithelial reactive changes, mucosal vascular congestion, edema, and withered atrophic glandular epithelium precede more advanced changes such as lamina propria fibrosis/hyalinization, erosion/ulceration, coagulative necrosis, hemorrhage, necroinflammatory (fibrinopurulent) exudates, and/or pseudomembrane formation5 (Figure 6.1A). The findings tend to be nonspecific as regards determining the etiology. However, there may be specific findings to suggest a cause, such as fibrin thrombi, vascular amyloid, tumor thrombi, or iatrogenic materials (i.e. chemoembolization material) (Figure 6.1B) in the wall of the vessels or on the mucosal surfaces.
(A) Gastric mucosa erosion, vascular congestion/hemorrhage, necrosis, and lamina propria hyalinization with a few residual “withering” deep glands.
(B) Gastric ischemia caused by chemoembolization microspheres in a patient with hepatocellular carcinoma treated with transarterial chemoembolization.
Figure 6.1 Gastric ischemia.
Small Intestine and Colon (Ischemic Bowel Disease and/or Ischemic Enteritis/Colitis)
Representing the most common disorders in this chapter, small intestine and colon ischemia and ischemic enteritis/colitis deserve more attention and are divided into two separate sections: (1) etiologies of acute and chronic ischemia and (2) pathology (gross features, microscopic features, and differential diagnosis).
Etiologies: Acute and Chronic Mesenteric Ischemia
Intestinal ischemia manifests as a spectrum of injury ranging from transient self-limited forms involving the mucosa and submucosa to severe acute fulminant ischemia with transmural infarction and bowel death. It affects the colon more commonly than the small bowel. Although there is a variety of causes, the most common underlying etiology is an acute, self-limited compromise in intestinal blood flow. Acute causes are responsible for approximately 60%–70% of cases of intestinal ischemia.10, 11 Among these, mesenteric arterial embolism accounts for 50%, and its frequency as a cause appears to be rising, in part because there is an increasingly aging population.12 Arterial emboli are typically secondary to thrombi dislodged from the thoracic aorta or left heart chambers. The list of differential diagnoses includes (1) occlusive causes: arterial thrombosis, venous thrombosis (including due to hypercoagulable states), tumor thrombi, infection, volvulus, torsion, incarceration, intussusception, and tumor compression; and (2) nonocclusive causes: hypoperfusion due to systemic hypotension, cardiac failure, shock, vasoconstrictive drugs, dehydration, etc. Occasionally, multiple factors may be associated with the development of acute ischemia. For example, patients with a chronic history of atherosclerosis and vasculopathy may be primed for a secondary event (i.e. infection, vasculitis), leading to acute mesenteric ischemia. The goal of surgical treatment in these cases is to restore a pulsatile blood flow and resect any nonviable bowel.13
Chronic mesenteric ischemia is relatively uncommon and occurs in the setting of systemic atherosclerosis with localized involvement of the mesenteric vessels. These patients typically demonstrate chronic abdominal pain, with particularly severe pain after ingesting a meal. Other rare causes include idiopathic myointimal hyperplasia of mesenteric veins, large vessel vasculitis, or celiac axis compression syndrome (Fact Sheet 6.2).
Fact Sheet 6.2 Causes of Acute and Chronic Intestinal Ischemia
Acute Intestinal Ischemia
Mesenteric arterial embolism (50% of cases)
Often from thrombi in thoracic aorta or left heart
Occlusive causes
Arterial thrombosis
Venous thrombosis
Tumor thrombi
Infection
Volvulus
Torsion
Incarceration
Intussusception
Tumor compression
Nonocclusive causes
Hypoperfusion due to systemic hypotension, cardiac failure, shock, vasoconstrictive drugs, dehydration
Chronic Mesenteric Ischemia
Usually caused by systemic atherosclerosis with mesenteric vessel involvement
Rare causes
Idiopathic myointimal hyperplasia of mesenteric veins
Large-vessel vasculitis
Celiac axis compression syndrome
Pathology: Gross and Microscopic
The superior mesenteric artery supplies blood to the entire small intestine and the first portion of the colon (cecum, right colon, and first two-thirds of the transverse colon). The inferior mesenteric artery supplies the remaining colon. As such, ischemic pathology of the intestines reflects the territory supplied by the affected vessels. Intestinal segments at the end of their respective arterial supplies are particularly susceptible to ischemic changes. These “watershed areas” include the splenic flexure, where the superior and inferior mesenteric arterial circulations end, and, to a lesser extent, the sigmoid colon and rectum, where inferior mesenteric, pudendal, and iliac arterial circulations terminate (Practice Points 6.1).
Grossly, acute arterial ischemia of the bowel demonstrates edema in its early stages. Subsequently, the mucosa acquires a red-brown/mottled appearance as necrosis develops. The edges of the ischemic tissue are typically sharply demarcated from adjacent viable tissue, and easy to discern (Figure 6.2A and B). In its most severe state, the acutely ischemic bowel develops transmural necrosis and infarction. Gross perforation accompanies these changes in a subset of cases. In mesenteric venous thrombosis, arterial supply continues to flow in the early stage, which leads to a less abrupt transition between the affected segment and the normal bowel segment. However, the ultimate result is similar to that produced by acute arterial obstruction, because impaired venous drainage eventually prevents entry of oxygenated arterial blood.
(A) Segment of small bowel resected for ischemia. Note that the serosal aspect shows intense congestion and hemorrhage.
(B) The mucosal aspect of the ischemic small bowel shows a hemorrhagic appearance of the injured mucosa, as well as sharply demarcated borders between ischemic and normal tissue.
Figure 6.2 Small intestine ischemia.
The histological changes of intestinal ischemia (arterial) are essentially the same as those that occur throughout the GI tract (Fact Sheet 6.3).14, 15 The early histological changes can include any combination of the following: capillary dilatation, mucosal edema, lamina propria hemorrhage, lamina propria hyalinization, and superficial mucosal necrosis (Figure 6.3A and B). Bacterial superinfection and enterotoxin release may cause pseudomembrane formation that resembles Clostridioides difficile–associated pseudomembranous colitis. If sufficiently severe, full-thickness mural necrosis occurs (Figure 6.4A and B).
Fact Sheet 6.3 Histology of Intestinal Ischemia
Acute Intestinal Ischemia (Arterial)
Capillary dilatation
Mucosal edema
Lamina propria hemorrhage/hyalinization
Superficial mucosal necrosis
+/− Pseudomembrane formation
Full-thickness mural necrosis if severe
Mesenteric Venous Thrombosis
Histology similar to arterial (above)
Transmural congestion and hemorrhage may be more intense
Thrombosed mesenteric veins may be primary or secondary; organization of thrombus favors primary
Chronic Ischemia
Mucosal ulceration and reepithelialization may lead to subacute/chronic changes
Crypt architectural distortion
Paneth cell metaplasia
Pseudopyloric metaplasia
Ulceration
+/− Strictures may occur
(A) Small intestinal mucosa with early ischemic changes including superficial congestion, erosion, and reactive epithelial changes.
(B) Colonic mucosa with early ischemic changes including lamina propria hyalinization and early “withering” crypts.
Figure 6.3 Early ischemic changes.
(A) Small bowel shows entirely necrotic mucosa.
(B) Segment of small bowel with full-thickness ischemic necrosis, entirely denuded mucosa, and perforation.
Figure 6.4 Small intestine ischemic necrosis.
The histopathological changes in mesenteric venous thrombosis are similar, except that there is sometimes more intense transmural congestion and hemorrhage (Figure 6.5A and B). However, even when thrombosed mesenteric veins are present, it is not always a foregone conclusion that they represent the primary event rather than a secondary effect. Evidence of organization of the blood clot indicates a thrombus of some duration (Figure 6.5C), which favors mesenteric venous thrombosis over an artifact or a postmortem clot.
(A) Low- magnification view in a case of ischemic necrosis caused by mesenteric vein thrombosis. Marked vascular congestion and hemorrhage obscures the architectural details, a finding that is more typical of venous obstruction than of arterial obstruction.
(B) Higher magnification shows marked vascular congestion, hemorrhage and the remaining small “withered” crypts.
(C) Organizing thrombus in a mesenteric vein, which is different from a postmortem/postsurgical blood clot.
(D) Cholesterol embolus from atherosclerotic plaques in a mesenteric artery, a cause of small bowel ischemia.
Figure 6.5 Small intestine ischemic necrosis.
In specimens resected for ischemia, the pathologist should examine sections of the attached fat or mesentery closely to identify any vessels with thrombi or emboli. Sometimes, there is a cholesterol embolus (Figure 6.5D), indicating clearly the cause of the acute ischemic episode.
Chronic ischemia in patients with repeated vasculo-occlusive episodes can lead to chronic injury suggestive of chronic colitis. This causes mucosal ulceration and re-epithelialization, often patchy, which can lead to the subacute/chronic histological changes. These include crypt architectural distortion, Paneth cell metaplasia, pseudopyloric metaplasia, and ulceration of variable depth (Figure 6.6). Finally, strictures may form in the area of scarring.14 In fact, the distinction between inflammatory bowel disease (IBD) and chronic ischemia can be difficult.
Unusual Patterns of Colonic Ischemia
Mass-forming ischemic colitis is a well-known but recently characterized pattern of ischemia. Characteristically, there is a high preoperative index of suspicion for tumor based on radiological demonstration of a mass lesion.16, 17 These lesions occur typically in elderly patients and have a predilection for the right colon, particularly the cecum (Figure 6.7A), although there are descriptions of lesions in the rectum.17 On gross examination, clues that suggest an ischemic etiology include mural/subserosal edema, stricture formation, scarring, and abnormal mesenteric vessels. Similarly, focal polypoid areas have been seen in focal ischemia secondary to atheroemboli, mimicking polyps on endoscopy18 (Figure 6.7B and C). Patients have shown no subsequent risk for carcinoma and the lesions sometimes remit with treatment. The differential diagnosis of this type of ischemia includes other mass lesions.
(A) A mass lesion of the cecum endoscopically mimics a malignant process.
(B) Biopsies of the cecal mass lesion reveal diffuse mucosal necrosis with surface necroinflammatory exudate.
(C) Higher magnification demonstrates mucosal necrosis, surface necroinflammatory exudate, and residual degenerated “withering” crypts.
Figure 6.7 “Mass-forming” variant of ischemic colitis.
Another uncommon pattern of colonic ischemia is isolated cecal necrosis. Patients with this condition are typically elderly and vasculopathic. Common associations are chronic heart disease, chronic kidney disease, and use of dialysis. In a subset of patients, there is no obvious predisposing condition.19 Isolated cecal necrosis may mimic acute appendicitis clinically, with right lower quadrant pain as the predominant symptom. Pathologically, there may be no vascular disease. There is, as the name implies, isolated cecal necrosis/infarction of variable severity and size. This condition often requires right hemicolectomy because of its unpredictable nature, particularly its notable ability to recur at the anastomosis.20 It is remarkable for its rarity but should be considered in all cases of right lower quadrant abdominal pain.21
Differential Diagnosis of Ischemic Bowel Disease and/or Ischemic Enteritis/Colitis
Ischemia in the GI tract can present as several patterns that mimic other diseases, including infectious or pseudomembranous colitis, radiation colitis, and IBD (Practice Points 6.2). The less common patterns of ischemia such as mass-forming ischemic colitis can mimic other colonic mass or polypoid lesions, and isolated cecal necrosis can mimic drug-induced injury or clinically acute appendicitis.22 All of these diagnoses are important to recognize because their respective treatments differ significantly. Sometimes, distinction is possible only following careful clinicopathological correlation.
Practice Points 6.2 Differential Diagnosis of Intestinal Ischemia
Infectious colitis
Pseudomembranous colitis
Radiation colitis
Inflammatory bowel disease
Mass or polypoid lesions versus mass-forming ischemic changes
Infectious enteritis/colitis can closely mimic ischemic bowel disease histologically in its acute state. In particular, enterohemorrhagic Escherichia coli and Klebsiella oxytoca are commonly implicated bacteria whose effects can mimic ischemia. They may cause lamina propria hyalinization, necrosis, and degenerative epithelial changes. Classically, the histology of infectious disorders includes a more severe neutrophilic infiltrate. However, this is not always the case in practice. Therefore, clinical exclusion of infectious enteritis/colitis is advisable in all cases of possible acute intestinal ischemia. The early findings of ischemia can be nonspecific and a diagnosis may be difficult to establish, particularly on biopsy specimens.23
Radiation and medication, particularly chemotherapy, also induce mucosal changes that can mimic primary ischemic disorders (see also Chapters 3 and 5). Clearly, clinical history is of the utmost importance for these diagnoses. Radiation damage may have additional histological characteristics, such as endothelial cytological atypia, vascular changes, and bowel wall fibrosis, which are often difficult to appreciate in a small biopsy specimen.
Pathology can be very impactful in the clinical workup of chronic ischemia versus IBD, as patients tend to present similarly (periodic abdominal pain, bloody diarrhea, and/or recent weight loss) and may have similar endoscopic/gross findings (see Chapter 22).24 IBD can also occur in older vasculopathic patients or young patients with hereditary thrombophilia, complicating the diagnostic picture. Careful histological examination is paramount when attempting to establish the correct diagnosis and to guide treatment at a critical juncture. Histological features that suggest Crohn’s disease rather than ischemia include granulomas and, in resections, transmural lymphoid aggregates away from areas of ulceration. In addition, ischemic enteritis/colitis often demonstrates a relative lack of acute inflammation in comparison with other colitides.25 The pathologist should also pay attention to the anatomical pattern of disease. Ischemia tends to affect specific regions of the intestines (see earlier) such as the watershed area of the splenic flexure, rectum or cecum. In addition, ischemia tends to demonstrate sharp transitional borders with normal intestine. Numerous sections of background bowel should be submitted from resection specimens to evaluate for any predisposing conditions. Some studies explore the use of monoclonal antibodies for distinguishing between causes of colitis, including ischemia,26 but the mainstay in routine practice remains careful gross and histological evaluation.
Vascular Abnormalities of the Gastrointestinal Tract
Angiodysplasia
Angiodysplasia is a major cause of GI bleeding, predominantly lower GI but also upper. Angiodysplasias, synonymous with vascular ectasia, are acquired throughout life and their frequency increases with advancing age. This distinguishes them from telangiectasias, which are congenital. Angiodysplasia of the upper GI tract occurs most often in the stomach and duodenum and if the affected patients undergo colonoscopy, concomitant lower GI lesions are present in one-third of instances. Small bowel angiodysplasia accounts for 30%–40% of cases of GI bleeding of obscure origin (the most common cause of bleeding in this cohort). Lesions in the large bowel occur on the right side more often than on the left.27 This lesion is probably responsible for approximately 6% of cases of lower GI bleeding and 1.2%–8% of cases of hemorrhage from the upper GI tract.28–30
Histological diagnosis is difficult, as the majority of angiodysplasias are located submucosally. They are typically not present in biopsy material, and collapse and go unrecognized in resection specimens. Their histological appearance is characterized by clusters of abnormally dilated, tortuous vessels in the submucosa (veins and arteries) and overlying mucosa (capillaries)31 (Figure 6.8A and B). Angiodysplasia should not be confused with Dieulafoy’s lesion (persistent caliber artery), which is typically seen on the lesser curvature of the stomach and is a submucosal artery that retains a large caliber, causing distortion/erosion of the overlying mucosa. There is discussion of this entity later in the chapter.
Gastric Antral Vascular Ectasia
Gastric antral vascular ectasia (GAVE) is a clinicopathological condition. It occurs typically in middle-aged women who have autoimmune or connective tissue disease and present with iron deficiency anemia. Perhaps the most specific feature of this entity is the endoscopic appearance of parallel erythematous linear mucosal lesions in the antrum, from which the eponym “watermelon stomach” is derived (Figure 6.9A). Histologically, there are several non-specific features, including increased superficial ectatic vessels, fibrin thrombi, and fibromuscular hyperplasia (Figure 6.9B). Of these, fibrin microthrombi are the most specific. However, all of these features may also be seen in gastric hyperplastic polyps and in portal hypertensive gastropathy32. In fact, there is a certain degree of overlap between this condition and portal hypertensive gastropathy (with up to 40% of patients with GAVE having cirrhosis)33, 34. If possible, GAVE should be distinguished from portal hypertensive gastropathy because the treatment differs (Fact Sheets 6.4 and 6.5).
Portal Hypertensive Gastroenteropathy (Varices, Portal Gastropathy, Portal Enteropathy/Colopathy)
Portal hypertension is a common vascular abnormality, and evidence of its presence can manifest in many different forms along the length of the GI tract. Chronic portal hypertension leads to the build-up of blood and dilatation of submucosal vessels in the esophagus (varices), stomach (portal hypertensive gastropathy) and small and large bowels (portal hypertensive enteropathy/colopathy).
Esophageal varices are a common complication of portal hypertension due to build-up of blood via the left gastric vein, the principal drainage site of lower esophageal blood. For this reason, esophageal varices are nearly always in the lower esophagus. Rates of up to 90% among cirrhotic patients have been reported. The second most common cause of esophageal varices is schistosomiasis.35 In addition, varices are the cause of 10%–30% of all upper GI bleeding.36, 37
Grossly, varices are engorged submucosal vessels that protrude into the lumen. They can be difficult to appreciate on surgical resections or at autopsy if they have not previously bled, because there is no active blood flow and the vessels become flattened. Histologically, there is an increase in the number of submucosal vessels, and these appear dilated and/or congested with blood.
Portal hypertensive gastropathy is a clinicopathologic entity that lies on the same spectrum as GAVE. There is no correlation between its severity and portal pressure measurement, or the type of liver disease. It is a relatively uncommon cause of upper GI bleed, but more severe cases can lead to chronic bleeding and iron deficiency anemia.38, 39 Endoscopically, a “mosaic” or “snake-skin” like pattern is apparent involving the body and fundus, and only rarely the antrum. Severe cases show discrete pinpoint red marks likened to a scarlatina rash.39, 40 Biopsies are rarely taken, because of the possibility of inducing bleeding. The histological appearance is that of dilated superficial vessels in the mucosa/submucosa, with or without reactive epithelial changes akin to reactive gastropathy (Figure 6.10A). The distinction from GAVE should only be made following clinical and endoscopic correlation. While GAVE can be seen in portal hypertensive patients, it is not unique to this population. Indeed, the hemodynamics of venous drainage of the antrum is different from the rest of the stomach, no doubt contributing to the relatively low frequency of antral involvement by portal hypertensive gastropathy.40 GAVE tends to demonstrate a comparatively increased number of dilated vessels and microthrombi. Cases that show characteristics of both portal hypertensive gastropathy and “watermelon stomach” should be classified as hypertensive gastropathy, as this is probably the unifying entity (Fact Sheets 6.4 and 6.5).
