Figure 4.219 Granulomatous pattern, Histoplasmosis. Granulomata can be associated with a varied list of differential diagnostic considerations, including infection, medication injury, IBD, and diverticular disease, among many others. This case originated from a patient with an unremarkable history who presented for screening colonoscopy. A small nodule was noted, which histologically consisted of a granuloma with foreign body giant cells.
Figure 4.220 Granulomatous pattern, Histoplasmosis. Higher power of the previous image. The patient originated from Ohio where the thermally dimorphic fungus is seen with regularity. The characteristic yeast forms displayed a uniform 2 to 3 μm size on GMS or PAS/D (not shown). An AFB special study was negative.
Common etiologic considerations of the granulomatous pattern are listed subsequently (Figs. 4.219 and 4.220).
CHECKLIST: Etiologic Considerations for the Granulomatous Pattern
Inflammatory Bowel Disease
Nonspecific Mucosal Injury
Diverticular Disease
Infections
Medications
Sarcoidosis
Vascular Injury
Pneumatosis Cystoides Intestinalis
Autoimmune Diseases (including common variable immunodeficiencies and chronic granulomatous disease)
Cord Colitis Syndrome
Lymphoproliferative Disorders
Granulomata in the colon usually inspire a fair amount of clinical interest, particularly regarding potential underlying diseases. Cases without careful notes will invariably result in at least one of the following clinical inquiries: “Could this finding represent Crohn disease?” “Sarcoidosis?” “Mycobacterium or fungal infection?” Unfortunately, granulomata are entirely nonspecific. The key to navigating the laundry list of considerations is to carefully scrutinize the background mucosa in search of other diagnostic clues, in addition to a thorough clinical chart review; for example, if the background shows active chronic colitis, the differential diagnostic considerations narrow to those agents associated with both granulomata and active chronic mucosal injury, such as IBD, diverticular disease, diversion, infections, medication (such as ipilimumab), or cord colitis syndrome, as detailed in the chronic colitis pattern discussion, this chapter. While granulomata can be seen in either ulcerative colitis or Crohn cases, their morphology and distribution can serve as useful diagnostic clues. Granulomata in ulcerative colitis are more commonly well-delineated structures seen in association with damaged crypts and extruded mucin, whereas granulomata in Crohn disease are more commonly poorly formed collections of epithelioid macrophages. Those cases accompanied by the additional red flags of upper-tract injury, transmural disease, and a patchy progression would favor a diagnosis of classic Crohn disease, and those with red flags of rectal-based, mucosa-restricted, diffuse disease progression would favor classic ulcerative colitis (Figs. 4.221–4.225). Granulomata are seen in up to 26% of diverticular disease-associated colitis cases, the leading etiology in patients with changes restricted to the segment of colon involved by diverticular disease.104 Syphilitic and or LGV infections would be favored if chart review uncovered the red flags of HIV seropositivity in MSM and the histology showed an intense mononuclear infiltrate with copious plasma cells (Fig. 4.226). More common infectious considerations include mycobacterial and fungal infections. Both are assessed with AFB and GMS special stains, or separate submission of tissue for cultures. Microbiologic cultures are preferred, when possible, because of improved sensitivities and the advantages of speciation and determination of drug susceptibility and resistance patterns. Diversion-associated colitis would be a consideration if the granulomata were seen along with florid lymphoid aggregates in the excluded bowel segment of a patient with a history of diversion (Fig. 4.227). Sarcoidosis involving the GIT is seen in less than 1% of sarcoidosis patients and most commonly involves the stomach, followed by the colon.105 The sarcoid granulomata are not uncommonly multifocal and striking, and their polyp or mass like appearance can raise clinical concerns for malignancy.106 Correlation with the clinical history of sarcoidosis or pertinent clinical red flags such as a history of bilateral hilar lymphadenopathy, elevated serum angiotensin converting enzyme levels, and joint, skin, eye, or lung dysfunction can help build a case for sarcoidosis (Figs. 4.228 and 4.229). If the background mucosa shows an ischemic pattern of injury and the granulomata are centered on damaged vessels, a granulomatous vasculitis enters the differential diagnosis; similar findings can be seen in Crohn disease. Granulomata may also serve as clues to an underlying autoimmune disease. If the background mucosa is devoid of plasma cells, consider common variable immunodeficiency (CVID), which is accompanied by granulomata in up to 19% of colonic specimens.107 In the pediatric setting, the granulomatous pattern of injury must invoke the possibility of chronic granulomatous disease (CGD). In a recent study of 87 patients and 15 autopsy cases with established CGD, 65% of colon specimens had pigmented macrophages and 46% had granulomata.108 Granulomata can also be a clue to a hematopoietic malignancy. If atypical lymphoid cells are seen, maintain a low threshold for seeking a formal hematopathology consultation.109 In summary, scrutiny of the background histology and careful chart review can prove exceptionally helpful in ascribing clinical significance to the nonspecific finding of granulomata.
Figure 4.221 Granulomatous pattern, Crohn disease. This high-power view of florid granulomata gives few clues to an etiologically specific diagnosis.
Figure 4.222 Granulomatous pattern, Crohn disease; however, on low power we see the granulomata are transmural and accompanied by transmural chronic inflammation and fibrosis. Moreover, active chronic inflammatory injury was seen in the stomach, terminal ileum, and in a patchy distribution throughout the colon, supporting a clinicopathologic diagnosis of Crohn disease. GMS and AFB special stains were negative and infection and medication injury had been clinically excluded.
Figure 4.223 Granulomatous pattern, Crohn disease. More commonly, granulomata in Crohn disease are poorly formed or difficult to spot at low power, as in this case.
Figure 4.224 Granulomatous pattern, Crohn disease. Higher power of previous image. This collection of macrophages blends almost imperceptibly with the neighboring lymphocytes. AFB and GMS stains were noncontributory (the granuloma was exhausted on deeper sections).
Figure 4.225 Granulomatous pattern, ulcerative colitis. Granulomata in ulcerative colitis are usually in association with damaged crypts and extruded mucin, as seen in this case.
Figure 4.226 Granulomatous pattern, syphilitic and or LGV infections. Granulomata can also be seen in the setting of peculiar infections. This rectal biopsy was from a patient clinically confirmed to be co-infected with syphilis and LGV. The background mucosa showed copious plasma cells and a lack of architectural distortion, acute crypt centric damage, and eosinophilia (not shown). Since granulomata are nonspecific findings, careful scrutiny of the background mucosa is essential to uncovering the hidden etiologic agent to ensure proper treatment. AFB and GMS special stains were negative.
Figure 4.227 Granulomatous pattern, diversion-associated colitis. These loose foreign body giant cells and macrophage collections are seen in association with damaged crypts. The patient had an established history of diversion.
Figure 4.228 Granulomatous pattern, sarcoid. This well-formed granuloma with foreign body giant cells originated from a patient with a long-standing history of sarcoidosis. The background mucosa was unremarkable and AFB and GMS special stains were negative for microorganisms. This case was signed out as “colonic mucosa with scattered granulomata, otherwise nondiagnostic findings, compatible with the history of sarcoidosis.”
PEARLS & PITFALLS
Pneumatosis Cystoides Intestinalis
Pneumatosis cystoides intestinalis (PCI) is another diagnostic consideration when macrophage collections are seen. Although PCI does not feature granulomas per se, biopsy or crush artifact can closely resemble granulomata. Deeper sections and correlation with the endoscopic impression can often clarify such suboptimal specimens. Caution must be exercised to avoid misinterpreting the foreign body giant cell collections of PCI as an evidence of Crohn disease.110 See also Pneumatosis Cystoides Intestinalis, Pigments and Extras, this chapter.
Figure 4.229 Granulomatous pattern, sarcoid. Higher power of previous case.
FAQ: What should I do with an isolated granuloma in an otherwise unremarkable biopsy in an otherwise unremarkable patient?
Answer: Despite the aforementioned exhaustive discussion, not uncommonly, a rogue granuloma in the colon simply signifies a rogue granuloma in the colon. Subsequent AFB and GMS special stains along with a careful chart review are obligatory in an effort to uncover additional diagnostic clues. If these searches prove unrevealing, a careful note often helps the clinician understand the limitations of understanding an isolated granuloma.
SAMPLE NOTE: AN ISOLATED GRANULOMA IN THE COLON OF AN OTHERWISE HEALTHY INDIVIDUAL
Colon, Random (biopsy):
• Colonic mucosa with an isolated granuloma, otherwise nondiagnostic findings.
Note: The biopsy shows a single granuloma in otherwise unremarkable colonic mucosa. This injury pattern is etiologically nonspecific and most likely represents an incidental finding given the unremarkable clinical history (favor nonspecific, remote mucosal injury). Negative for histologic features of active or chronic inflammatory disease. AFB and GMS special stains are negative.
SAMPLE NOTE: AN ISOLATED GRANULOMA, BACKGROUND MODERATE ACTIVE CHRONIC MUCOSAL INJURY, AND NO HISTORY PROVIDED
Note: The biopsy shows a single granuloma in a background of moderate active chronic colitis. This injury pattern is etiologically nonspecific and can be seen in the setting of infection (including STI proctocolitis), medication injury, IBD, diverticular disease, sarcoidosis, vasculitides, autoimmune diseases, among others. Clinical correlation required. AFB and GMS special stains are negative.