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
Final Diagnosis: Ischemic colitis due to Churg-Strauss Syndrome
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 . In 1990 the American College of Rheumatology published
consensus definitions for the various forms of systemic vasculitis known at that time . 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 . 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
| Giant cell arteritis|
| Takayasu arteritis|
| Polyarteritis rheumatica|
| Polyarteritis nodosa|
| Kawasaki disease|
|Small vessel - ANCA associated|
| Wegener's granulomatosis|
| Churg Strauss syndrome|
| Microscopic polyangiitis|
| Henoch-Schönlein purpura|
| Behçet's syndrome|
| Thromboangiitis obliterans|
| Leukocytoclastic vasculitis|
| Systemic lupus erythematosus|
| Rheumatoid arthritis|
Gastrointestinal Involvement by Systemic Vasculitides
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.
|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 . 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)
A relationship between ANCA and systemic vasculitis was first demonstrated for Wegener's
granulomatosis . 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 .
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 . 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 
|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 . 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.
This entity, first designated "microscopic polyarteritis" , 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
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
Table 4 - Diagnostic Criteria: Wegener's Granulomatosis 
|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]|
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
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 
|Weight loss > 4 kg (not related to dieting)|
|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
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 . 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 
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
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 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 
|Palpable purpura (not related to thrombocytopenia)|
|Age < 20 years at presentation|
|Bowel ischemia (clinical, radiographic, or pathologic evidence)|
| [Two of four required for diagnosis]|
Enterocolic Lymphocytic Phlebitis
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.
- Zeek PM. Polyarteritis nodosa and other forms of necrotizing vasculitis. N Eng J Med 1953; 248:764-72.
- Hunder GG et al. The AmericanCollege of Rheumatology 1990 criteria for the classification of vasculitis: introduction. Arthritis Rheum 1990; 33:1065-7.
- Jeanette JC et al. Nomenclature of systemic vasculitides: proposal of an international consensus conference. Arthritis Rheum 1994; 37:187-92.
- Muller-Ladner U. Vasculitides of the gastrointestinal tract. Best Practice Res Clin Gastroenterol 2001; 15:59-82.
- Frankel SK et al. Vasculitis: Wegener's granulomatosis, Churg-Strauss syndrome, microscopic polyangiitis, polyarteritis nodosa, and Takayasu arteritis. Crit Care Clinics 2002; 18:1-24.
- Burke AP et al. Localized vasculitis of the gastrointestinal tract. Am J Surg Pathol 1995;19:338-49.
- Van der Woude FJ et al. Autoantibodies against neutrophils and monocytes: tool for diagnosis and marker of disease activity in Wegener's granulomatosis. Lancet 1985; 1:425-9.
- Seo P et al. The antineutophil cytoplasmic antibody-associated vasculitides. Am J Med 2004; 117:39-50.
- Savige J et al. International consensus statement on testing and reporting of antineutrophil cytoplasmic antibodies. Am J Clin Pathol 1999; 111:507-13.
- Savige J et al. Addendum to the international consensus statement on testing and reporting of antineutrophil cytoplasmic antibodies (ANCA). Am J Clin Pathol 2003; 120:312-318.
- Csernok E. Anti-neutrophil cytoplasmic antibodies and pathogenesis of small vessel vasculitides. Autoimmunity Rev 2003; 2:158-64.
- Churg J, Strauss L. Allergic granulomatosis, allergic angiitis, and periarteritis nodosa. Am J Pathol 1951; 27:277-301.
- Solans R et al. Churg-Strauss syndrome: outcome and long-term follow-up of 32 patients. Rheumatology 2001; 40:763-71.
- Lhote F et al. Polyarteritis nodosa, microscopic polyangiitis and Churg-Strauss syndrome. Lancet 1998; 7:238-58.
- Masi AT et al. The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis). Arthritis Rheum 1990; 33: 1094-100.
- Lanham JG et al. Systemic vasculitis with asthma and eosinophilia: a clinical approach to the Churg-Strauss syndrome. Medicine 1984; 63:65-81.
- Davson J et al. The kidney in polyarteritis nodosa. Q J Med 1948; 17:175-202.
- Agard C et al. Microscopic polyangiitis and polyarteritis nodosa: how and when do they start? Arthrit Rheumat 2003; 49:709-15.
- Storesund B et al. Severe intestinal involvement in Wegener's granulomatosis: report of two cases and review of the literature. Br J Rheum 1998; 37:387-90.
- Leavitt RY et al. The American College of Rheumatology 1990 criteria for the classification of Wegener's granulomatosis. Arthritis Rheum 1990; 33:1101-07.
- Lightfoot RW et al. The American College of Rheumatology 1990 criteria for the classification of polyarteritis nodosa. Arthritis Rheum 1990; 33:1088-93.
- Gastrointestinal manifestations of systemic lupus erythematosus. Singapore Med J 2001; 42:380-4.
- Hallegua DS, Wallace DJ. Gastrointestinal manifestations of systemic lupus erythematosus. Curr Opin Rheum 2000; 12:379-85.
- Sultan SM et al. A review of gastrointestinal manifestations of systemic lupus erythematosus. Rheumatology 1999; 38:917-32.
- Marshall SE. Behçet's disease. Best Pract Res Clin Rheum 2004; 18:291-311.
- Chang WL et al. Gastrointestinal manifestations in Henoch-Schönlein purpura: a review of 261 patients. Acta Paediatr 2004; 93:1427-31.
- Mills JA. The American College of Rheumatology 1990 criteria for the classification of Henoch-Schönlein purpura. Arthritis Rheum 1990; 33:1114-21.
- Saraga E, Bouzourenne H. Enterocolic lymphocytic phlebitis: a rare cause of intestinal ischemic necrosis. Series of patients and review of the literature. Am J Surg Pathol 2000; 24:824-9.
- Flaherty MJ et al. Mesenteric inflammatory veno-occlusive disease. A seldom recognized cause of intestinal ischemia. Am J Surg Pathol 1994; 18:779-84.
- Abrahams SC. Case 5 - Gastroduodenal lymphocytic phlebitis. USCAP 2004 G.I. Pathology Specialty Conference Handout. Web address: http://www.uscap.org/newindex.htm?93rd/specgasth5.htm