—  SPECIALTY CONFERENCE  —

Gastrointestinal Pathology

Case 2 - Ischemic Colitis due to Churg-Strauss Syndrome

John A. Hart
University of Chicago Hospitals
Chicago, IL


Click on each slide thumbnail image for an enlarged view
Clinical History
This 43-year-old male presented with an acute abdomen and underwent an exploratory laparotomy, revealing a colonic perforation. An ileocecectomy was performed. [Case courtesy of Dr. Hong Chen, St. Mary's Hospital, Centralia, IL]


Case 2 - Figure 1 - Low power view demonstrating mucosa ischemia and submucosa edema.
Case 2 - Figure 2 - Medium power view reveal mucosal ischemia and active vasculitis involving small submucosal vessels
Case 2 - Figure 3 - Small artery with active vasculitis, partially occluded by thrombus.


Case 2 - Figure 4 - Higher power view of small vessel as in Figure 3, highlighting the inflammatory cell infiltration of the wall.
Case 2 - Figure 5 - Adjacent small arteries demonstrating the patchy nature of involvement by the vasculitic process.
Case 2 - Figure 6 - High power view showing the extravascular inflammatory cell infiltrates.

Gross and Microscopic Findings
Extensive colonic mucosal necrosis was evident in a patchy distribution, primarily involving the distal portion of the specimen. The appendix and portion of terminal ileum were unremarkable.

Sections revealed extensive recent mucosal necrosis with marked submucosal edema and numerous scattered eosinophils in all bowel layers. Many small subserosal and intramural arteries and veins exhibited intense inflammatory cell infiltration, including a prominent component of eosinophils. Fibrinoid necrosis of vessel walls and luminal occlusion by fibrin thrombi were also often present. No granulomas were identified.

Diagnosis: Ischemic colitis due to active small vessel vasculitis, most likely Churg-Strauss syndrome

Additional Clinical History
The patient had a long history of asthma and sinusitis. A WBC count at the time of surgery revealed 21% eosinophils.

Final Diagnosis: Ischemic colitis due to Churg-Strauss Syndrome

Discussion

Introduction
In the minds of some clinicians gastrointestinal ischemia occurs almost exclusively in elderly patients with severe atherosclerosis and poor cardiac function, develops after an episode of poor hydration (secondary to diarrhea or diuresis), and affects only the so-called "watershed" zones. This mindset has resulted in significant under diagnosis of ischemia by clinicians. The various systemic vasculitides are good examples to illustrate that ischemia can occur in virtually any segment of the gastrointestinal tract (including segments with especially rich vascular supplies) and in a wide variety of patient populations.

Systemic vasculitides have been classified according to several systems, all of which derive from the system originally proposed by Zeek in 1953 [1]. In 1990 the American College of Rheumatology published consensus definitions for the various forms of systemic vasculitis known at that time [2]. Over the next few years it became clear that serologic tests for various anticytoplasmic neutrophil antibodies (ANCAs) would be very helpful in the clear separation of these disorders, and so in 1994 the American College of Rheumatology issued revised consensus criteria taking the new data into account [3]. In this system, which is most widely used currently, the disorders are classified according to the size and type of vessel affected, the pattern of organ dysfunction, and various serologic markers. The histologic features are also regarded as an important element, but the authors stress that a correct diagnosis cannot be assured by biopsy findings alone.

Table 1 - Systemic Vasculitides

Large vessel
Giant cell arteritis
Takayasu arteritis
Polyarteritis rheumatica
Medium vessel
Polyarteritis nodosa
Kawasaki disease
Small vessel - ANCA associated
Wegener's granulomatosis
Churg Strauss syndrome
Microscopic polyangiitis
Small vessel
Henoch-Schönlein purpura
Behçet's syndrome
Thromboangiitis obliterans
Leukocytoclastic vasculitis
Systemic lupus erythematosus
Rheumatoid arthritis

Gastrointestinal Involvement by Systemic Vasculitides [4, 5]
Most of the primary and secondary systemic vasculitides can affect the gastrointestinal tract, although involvement by thromboangiitis obliterans, Kawasaki disease, and the large vessel diseases (Takayasu arteritis, giant cell arteritis and polymyalgia rheumatica) are exceedingly rare. (These forms of vasculitis will not be discussed further in this handout).

G.I. biopsies from patients with systemic vasculitides, even those involving small and/or medium-sized vessels, typically reveal only generic ischemic changes, since the diagnostic vascular changes are usually limited to the submucosal, subserosal or mesenteric vessels. Surgical pathologists should be aware that all vessels located within the bowel wall in any part of the G.I. tract are regarded as "small-sized" in the context of the classification of systemic vasculitides. Only the larger mesenteric vessels qualify as "medium-sized", and polyarteritis nodosa is the likely diagnoses when vessels of this caliber are involved.

When involvement of small intramural vessels in the G.I. tract is identified the primary differential (based on the likelihood of G.I. involvement – see Table 2) is between microscopic polyangiitis and Churg-Strauss syndrome, with SLE, rheumatoid arthritis and Wegener's granulomatosis as less likely alternatives. The histologic appearance of the vasculitis in all of these conditions is very similar. The vessels (arterioles, venules and small arteries) exhibit intense inflammatory cell infiltration, often with fibrinoid necrosis of the vessel wall. Fibrin thrombi sometimes produce luminal occlusion. The presence of eosinophils as part of the vasculitic infiltrate or as an extravascular infiltrate in the surrounding tissues strongly favors a diagnosis of Churg-Strauss syndrome. In addition, extravascular granulomas occur only in Churg-Strauss syndrome and Wegener's granulomatosis. In the absence of these features a specific diagnosis cannot be suggested, and clinical correlation is required. Henoch-Schönlein purpura, in contrast, involves only vessels of the smallest caliber (capillaries, arterioles and venules), and has a distinctive leukocytoclastic appearance. Thus, it is unlikely to be confused histologically with the other systemic vasculitides. Small vessel vasculitis can also be seen in Behçet's syndrome, but histologic features of ischemia are usually not prominent. With the exception of the demonstration of IgA in vessel walls by immuno-fluorescence techniques in Henoch-Schönlein purpura, special studies are not useful in the diagnosis of systemic vasculitides involving the G.I. tract.

Table 2
Type of vasculitis Frequency of G.I. Involvement
Polyarteritis nodosa 30 - 50 %
Wegener's granulomatosis 5 - 10%
Microscopic polyangiitis 30 - 56 %
Churg-Strauss syndrome 37-62 %
Behçet's syndrome Up to 30 %
Takayasu's arteritis Up to 15 %
Giant cell arteritis < 1 %
Henoch-Schönlein purpura 50 - 75 %
Systemic lupus erythematosus < 15 %
Rheumatoid arthritis vasculitis Up to 10 %
(Enterocolic lymphocytic phlebitis) ( > 90 %)

Special note must be made of vasculitis isolated to the G.I. tract. In the most common form small arteries are involved, and often exhibit fibrinoid necrosis similar to that seen in polyarteritis nodosa. Evolution to systemic involvement is uncommon. In the largest series of such patients with G.I. involvement the colon, appendix, or gallbladder was most often involved [6]. The cases were thought to represent an isolated form of polyarteritis nodosa, but data regarding ANCA status were not available at the time the paper was published. It is possible that such cases actually represent a limited form of microscopic polyangiitis, based on the size of the vessels that are usually involved. A high titer of pANCA would be confirmatory. Phlebitis limited to a G.I. organ has also been described and has been designated as "enterocolic lymphocytic phlebitis". This entity is discussed in detail at a later point in the handout.

Antineutrophil Cytoplasmic Antibodies (ANCA) [7, 8, 9, 10, 11] A relationship between ANCA and systemic vasculitis was first demonstrated for Wegener's granulomatosis [7]. Subsequently high serum ANCA titers were also found to be common in Churg-Strauss syndrome (CSS) and microscopic polyangiitis (MPA), but not any of the other systemic vasculitides. The vasculitis in all three of these disorders is histologically identical and affects small arteries.

ANCAs (either cytoplasmic or perinuclear) are identified by adding the patient's serum to normal peripheral blood neutrophils and detection of antibody binding by indirect immunofluorescence. Recent studies have demonstrated that in patients with systemic vasculitides the autoantigens responsible for ANCA positivity are proteinase 3 (PR3) and myeloperoxidase (MPO), and ELISA tests have been developed to identify them specifically. A high titer of cANCA (anti-PR3+) is highly sensitive (95%) and specific (90%) for active systemic Wegener's granulomatosis (WG). On the other hand, a high titer of pANCA (MPO+) does not distinguish between CSS, MPA or WG, and can also be seen in rheumatoid arthritis, Goodpasture syndrome, SLE and other connective tissue diseases. Also, a negative ANCA does not exclude WG, MPA or CSS, and is common during remission and after immunosuppressive therapy. It appears that ANCAs are directly involved in the vasculitic process, but the pathogenic mechanisms responsible for their formation and destructive effects are not well understood at present [11].

Churg-Strauss Syndrome [4, 5, 8, 12, 13, 14, 15, 16]
In 1951 Churg and Strauss described a type of systemic vasculitis distinct from PAN in 14 patients who presented with asthma, peripheral blood eosinophilia, and fever, and coined the term allergic granulomatosis and angiitis [12]. Histological examination of affected tissues in these patients revealed small vessel vasculitis, extravascular eosinophil infiltration, and extravascular granulomas. The Chapel Hill consensus conference defined Churg-Strauss syndrome (CSS) as an eosinophil-rich and granulomatous inflammation involving the upper respiratory tract and necrotizing vasculitis affecting small to medium-sized vessels (capillaries, venules, arterioles and arteries), associated with asthma and eosinophilia. Recommended diagnostic criteria developed by the American College of Rheumatology in 1990 (before widespread use of serologic tests for ANCA) are listed below in Table 3:

Table 3 - Diagnostic Criteria: Churg-Strauss Syndrome [15]

Bronchial Asthma
Peripheral blood eosinophil count > 10%
Mono- or polyneuropathy
Non-fixed pulmonary infiltrates on chest X-ray
Chronic paranasal sinusitis
Biopsy showing small vessel vasculitis & extravascular eosinophils
 
[four of six required for diagnosis]

Patients with CSS typically first manifest a prodromal phase characterized by allergic rhinitis and nasal polyposis and asthma. This phase may last for up to 30 years. Next the patients experience systemic symptoms related to eosinophilic infiltration of tissue, most often the lung, but sometimes the G.I. tract. Pulmonary involvement can raise the possibility of chronic eosinophilic pneumonia or the hypereosinophilic syndrome. Finally systemic vasculitis develops, and the diagnosis is made. Of course, these three phases do not develop sequentially in every patient [16]. Nonetheless, large case series emphasize that the correct diagnosis is often not made until years after the first symptoms develop. For instance, in one report asthma (which is present in > 95% of CSS patients) was diagnosed at a mean of 9 years prior to the diagnosis of CSS (range 0 to 61 years). Asthma developing relatively late in life (> 35 years) should raise the possibility of CSS. Peripheral neuropathy (mononeuritis multiplex) is another common manifestation of CSS, due to both eosinophilic infiltration of nerves and vasculitis involving epineural arteries. Purpura due to dermal vasculitis is also typical, occurring in about 50% of cases. Cardiac involvement, producing rapid-onset heart failure, is more common in CSS than any of the other ANCA-associated systemic vasculitides.

Laboratory evaluation is helpful in confirming the diagnosis of CSS. Peripheral blood eosinophilia (> 1,500/ml) is almost invariably present, except in patients receiving high dose steroids for their asthma. In addition, a high titer pANCA (anti-MPO) is present in about 50-75% of cases. In <10% of cases cANCA is present. Radiographic examinations, including angiograms, are almost always normal.

Microscopic Polyangiitis [4, 5, 8, 14, 17, 18]
This entity, first designated "microscopic polyarteritis" [17], was developed to distinguish a subgroup of patients with apparent polyarteritis nodosa (PAN) in which renal involvement was characterized by segmental necrotizing glomerulitis due to small vessel vasculitis (rather than the multifocal renal infarct that occur in classic PAN patients due to vasculitis involving larger arteries). It later became clear that it was a distinct entity unrelated to PAN, and that the involvement of small vessels (capillaries, venules and arterioles) was indeed the defining feature that separated it from PAN. In addition, a high titer pANCA, MPO+ (or cANCA) is common in microscopic polyangiitis (MPA) and is not present in PAN.

Nephrologists report most cases of MPA, and thus renal involvement (rapidly progressive glomerulonephritis) is present in virtually every patient. Necrotizing glomerulonephritis with crescent formation occurs due to involvement of glomerular capillaries. Necrotizing arteritis involving the small renal arterioles may also be present. Musculoskeletal and cutaneous involvement are also common manifestations at presentation. Peripheral neuropathy and pulmonary involvement may also occur. (A form of MPA restricted to renal involvement has also been described).

Laboratory evaluation reveals evidence of impairment or renal function. As mentioned above, high titer pANCA (65%) or cANCA (35%) is present in about 75% of patients with MPA. The pANCA is usually of anti-MPO type.

Wegener's Granulomatosis [4, 5, 19, 20]
Wegener's granulomatosis is a well-defined primary systemic vasculitis characterized by granulomatous inflammation of the upper and lower respiratory tract and necrotizing vasculitis involving small to medium-sized vessels, often with necrotizing glomerulonephritis (Table 4). Renal involvement is uncommon at presentation, but eventually occurs in 75-85% of patients, and is often progressive and severe. Skin, ocular, and musculoskeletal involvement frequently develops at some point in the natural history of the disease.

Table 4 - Diagnostic Criteria: Wegener's Granulomatosis [20]

Recurrent oro-nasal inflammation
Fixed pulmonary infiltrates, nodules or cavities by chest X-ray
Renal involvement (glomerulonephritis) - microhematuria
Biopsy showing necrotizing vasculitis and (peri)vascular granulomas
 
[two of four required for diagnosis]

Polyarteritis Nodosa [4, 5, 14, 17, 21]
Unlike the small vessel vasculitides (WG, CSS, MPA) constitutional symptoms (weight loss, fever, malaise) are more common and more prominent in polyarteritis nodosa (PAN). In addition, renal involvement in PAN (60-80% of cases) involves cortical ischemia due to medium-sized vessel vasculitis rather than necrotizing glomerulonephritis as occurs in the small vessel vasculitides. Visceral angiography is very useful in confirming a diagnosis of PAN. Microaneurysms and vascular stenoses in medium-sized vessels of the mesentery or renal arteries are diagnostic features for PAN and are not seen in any other of the vasculitides. Importantly, 7-22% of cases of PAN arise due to serum HBsAg antigenemia. Other viral infections (HIV, CMV, parvovirus B19, and HCV) have been reported rarely. Laboratory evaluation is not otherwise helpful in the diagnosis, except that ANCA titers are consistently negative.

In addition to the renal manifestations described above, cutaneous, musculoskeletal, peripheral nerve, and cardiac involvement are common. Involvement of the G.I. tract may be severe and dominate the clinical picture. Orchitis is a diagnostic feature of PAN, and may be a presenting symptom (Table 5).

Table 5 - Diagnostic Criteria: Polyarteritis Nodosa [21]

Weight loss > 4 kg (not related to dieting)
Livedo reticularis
Testicular pain or tenderness (orchitis)
Myalgias or weakness
Mono- or polyneuropathy
Hypertension (diastolic BP > 90 mmHg)
Elevated BUN or creatinine
Serum HBsAg antigenemia
Abnormal angiogram showing microaneurysms or occlusions
Biopsy showing active vasculitis involving medium-sized vessels
 
[Three of ten required for diagnosis]

Systemic Lupus Erythematosus [4, 22, 23, 24]
Systemic lupus erythematosus (SLE) is a systemic autoimmune inflammatory disease in which vasculitis sometimes occurs. The autoimmune nature of SLE is reflected by the presence of ANA and anti-dsDNA and anti-phospholipid antibodies. Gastrointestinal disease is common in SLE, but ischemia due to small vessel vasculitis (either arteritis or venulitis) is very rare [24]. Immune complex deposition in vessel walls may be detected by immunofluorescence. Angiography is not helpful in demonstrating vasculitis in SLE. Mesenteric thrombosis due to the antiphospholipid syndrome is a more common cause of intestinal ischemia, but is also a rare manifestation.

Rheumatoid Arthritis [4]
A small vessel vasculitis complicates the course of rheumatoid arthritis in about 20% of patients. Involvement of the gastrointestinal tract can be difficult to distinguish from drug induced injury (eg., NSAIDs). The vasculitis generally is not as intensely inflammatory as in the other systemic vasculitides.

Behçet's Syndrome [4, 25]
This primary systemic vasculitis can involve small arteries and veins in any organ, but oral and genital and ocular involvement are most characteristic. The etiology is unknown, but currently it is thought that an infectious agent (viral or bacterial) provokes an uncontrolled inflammatory response in a genetically predisposed host. The genetic component of this disease is highlighted by the narrowly restricted geographic distribution of cases (along the silk route from the Mediterranean and East Asia) and the association with the HLA-B51 locus. Recurrent genital and oral aphthous ulceration involvement, the sine qua non of Behçet's disease, may precede other systemic manifestations by decades. Cigarette smoking may suppress mouth ulcers, and relapse after cessation of smoking has been documented (similar to ulcerative colitis). Chronic relapsing ocular involvement, which occurs in 30-70% of patients, may manifest as uveitis, retinitis, scleritis, keratitis, or posterior uveitis. Pathergy, defined as hypersensitivity of the skin following minor trauma, is common in Middle Eastern patients but rare in other patient groups. It can be demonstrating by pricking the skin with a sterile needle, and is considered present if a sterile erythematous papule develops within 48 hours. The vasculitis is usually of small vessels, particularly venules, and is also characterized by perivascular mononuclear cell infiltrates. In the G.I. tract focal ulceration, fistulas and strictures may develop, mimicking the appearance of Crohn's disease. Moreover, some reports mention the presence of granulomas, although there is considerable controversy regarding this point. Interestingly, histologic features typical of ischemia are usually not mentioned in pathologic descriptions of Behçet's syndrome.

Henoch-Schönlein Purpura [4, 26, 27]
Henoch-Schönlein purpura is the most common systemic vasculitis of children. The hallmark of the disease is a non-thrombocytopenic purpura. Streptococcal pharyngitis precedes the diagnosis in 30% of patients. Renal involvement in the form of acute glomerulonephritis is also common. Gastrointestinal involvement is also a diagnostic feature (Table 6). The vasculitis exclusively involves small vessels and is related to the deposition of immune complexes containing IgA in vessel walls. Neutrophils are evident in the vessel walls, sometimes with deposition of fibrin.

Table 6 - Diagnostic Criteria: Henoch-Schönlein Purpura [27]

Palpable purpura (not related to thrombocytopenia)
Age < 20 years at presentation
Bowel ischemia (clinical, radiographic, or pathologic evidence)
Leukocytoclastic vasculitis
 
[Two of four required for diagnosis]

Enterocolic Lymphocytic Phlebitis [6, 28, 29, 30]
This is the only type of vasculitis limited strictly to venous channels, and in almost all reported patients has affected only a single organ, usually within the G.I. tract. Only about forty cases have been described in the literature. Most cases involve the colon or small bowel, but localization within the stomach and duodenum, gallbladder, liver, and mesentery, have also been documented. The pathogenesis of this disorder is unknown, although several authors have raised the possibility of a drug hypersensitivity reaction. This entity has not been discussed in the rheumatologic literature and no information is available regarding ASCA status in these patients.

Histologic examination reveals intense, predominantly mononuclear cell infiltrates within the walls of small and medium-sized venous channels, with complete sparing of all arterial vessels. A perivenular infiltrate is usually also present, and granulomas are present in a minority of cases. The affected organ usually exhibits ischemic changes secondary to the venous damage.

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