Selective Pathology - Gastrointestinal Pathology Fellowship

Candidates must be board certified or eligible for certification in anatomic pathology or AP/CP.

All application materials, including recommendation letters, must be submitted online, and include the following:

• Completed online House Staff Application
• Current Curriculum Vitae
• Personal Statement
• Transcript from Medical School(s)
• Three Recommendation Letters

Apply Online

Applications are accepted from mid-April to July 31 for positions beginning July 1 two years later. Interviews are conducted starting in July or August and are completed by the end of August of the application year.

Dr. Hong Yu, PGY-3
Mentor: Dr. Shilpa Jain

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Case #1

Case history: A 48-year-old woman with untreated HIV infection presented with multiple hepatic and pulmonary lesions and a cholestatic pattern of liver enzyme elevation (alkaline phosphatase, 285 U/L; peak, 395 U/L; AST, 113 U/L; ALT, 29 U/L). Her serum ferritin level was 2,965 ng/mL.

Pathology: The liver biopsy demonstrated predominantly portal-based mixed inflammation with poorly formed granulomas. Grocott methenamine silver staining identified a rare budding yeast form, whereas periodic acid–Schiff and acid-fast bacillus stains were negative. These findings raised concern for an infectious process.

Follow-up: Bronchoalveolar lavage of the right middle lobe revealed no fungal organisms on direct smear, although Aspergillus fumigatus grew in one of three culture media. No systemic antifungal therapy was administered before or after the procedure.

Case #2

Case history: A 69-year-old woman with biopsy-proven pulmonary sarcoidosis, steatotic liver disease, and persistently elevated liver enzymes (ALT, 96 U/L; AST, 62 U/L) underwent liver biopsy for fibrosis assessment after imaging demonstrated moderate-to-severe hepatic steatosis and a nodular hepatic contour concerning for cirrhosis. Her pulmonary sarcoidosis had been diagnosed in 2011 after chest CT demonstrated bilateral parenchymal infiltrates, pulmonary nodules, and lymphadenopathy. Endobronchial ultrasound-guided transbronchial needle aspiration demonstrated granulomatous inflammation compatible with sarcoidosis. A serum angiotensin-converting enzyme level was not available for review.

Pathology: The liver biopsy showed a solitary, well-formed, non-necrotizing lobular granuloma, compatible with hepatic involvement by the patient’s known sarcoidosis after exclusion of other granulomatous processes. No bile duct-associated granulomas or bile duct injury were identified.

Question

Liver biopsies from six patients demonstrate granulomatous inflammation. For each patient, select the most likely diagnosis from the list below. Each answer may be used once, more than once, or not at all.

A. Primary biliary cholangitis
B. Sarcoidosis
C. Mycobacterial infection
D. Drug-induced liver injury
E. Q fever
F. Cat-scratch disease
G. Foreign-body granulomatous reaction
H. Crohn's disease

1. A 53-year-old woman presents with fatigue, pruritus, and persistently elevated alkaline phosphatase. Antimitochondrial antibody is positive, and serum IgM is elevated. The biopsy shows portal inflammation and poorly formed epithelioid granulomas centered on injured interlobular bile ducts. No necrosis is identified. AFB and GMS stains are negative.
2. A 30-year-old woman with bilateral hilar lymphadenopathy and biopsy-proven pulmonary granulomas has elevated alkaline phosphatase. The liver biopsy contains multiple discrete, compact, well-formed, non-necrotizing granulomas in portal tracts and lobules. The granulomas show minimal surrounding inflammation and are not preferentially associated with bile ducts. AFB and GMS stains are negative.
3. A 47-year-old immunocompromised patient presents with fever, weight loss, pulmonary nodules, and cholestatic liver enzyme abnormalities. The biopsy demonstrates numerous lobular and portal granulomas, some containing central necrosis. Special staining reveals rare acid-fast bacilli.
4. A 64-year-old man develops fever, rash, eosinophilia, and elevated liver enzymes three weeks after beginning allopurinol. The biopsy shows portal and lobular inflammation containing eosinophils and several poorly formed non-necrotizing granulomas. Infectious stains are negative.
5. A 42-year-old veterinarian presents with prolonged fever, headache, and elevated aminotransferases after assisting with livestock deliveries. The liver biopsy shows fibrin-ring granulomas composed of a central lipid vacuole surrounded by a ring of fibrin and epithelioid histiocytes. Serologic testing demonstrates antibodies to Coxiella burnetii.
6. A 35-year-old woman presents with fever and tender regional lymphadenopathy several weeks after a cat scratch. The biopsy demonstrates stellate necrotizing and suppurative granulomas containing central neutrophilic debris. Warthin–Starry staining highlights rare pleomorphic bacilli, and Bartonella henselae serology is positive.

Correct Answers

A. Primary biliary cholangitis
B. Sarcoidosis
C. Mycobacterial or fungal infection
D. Drug-induced liver injury
E. Q fever
F. Cat-scratch disease

Explanation

The differential diagnosis of hepatic granulomas should integrate five major features:

1. Granuloma location
2. Granuloma architecture
3. Presence and type of necrosis
4. Associated histologic findings
5. Clinical history, medications, serologic studies, cultures, and special stains

Primary biliary cholangitis

Granulomas in PBC are usually portal-based, poorly formed, and closely associated with injured interlobular bile ducts. The accompanying chronic nonsuppurative destructive cholangitis, also called a florid duct lesion, is highly characteristic. Supporting clinical findings include a cholestatic biochemical profile, positive antimitochondrial antibody, elevated IgM, and, in AMA-negative cases, PBC-specific antibodies such as anti-gp210 or anti-sp100. Granulomas are most often encountered in early-stage PBC and may be absent in advanced disease.

Sarcoidosis

Sarcoid granulomas are typically compact, well-formed, non-necrotizing, and located in portal tracts or lobules. They usually have a sparse lymphocytic cuff and are not specifically centered on damaged bile ducts. Clinical evidence of pulmonary, lymph-node, skin, or other systemic involvement supports the diagnosis. Serum ACE may be elevated but has limited sensitivity and specificity and should not be used alone to establish the diagnosis. Infection must be excluded before diagnosing sarcoidosis, particularly in an immunocompromised patient.

Mycobacterial and fungal infections

Infectious granulomas may be portal or lobular and range from poorly formed histiocytic aggregates to well-developed necrotizing granulomas. Necrotizing granulomas raise concern for mycobacterial and fungal infections, although the presence or pattern of necrosis is not entirely specific. AFB, Fite, GMS, and PAS stains may identify organisms, but negative tissue stains do not exclude infection. Tissue cultures, molecular testing, antigen testing, and clinical findings are often necessary. Immunocompromised patients may have numerous organisms but only poorly formed granulomas because of an impaired immune response.

Drug-induced liver injury

Drug-associated granulomas are usually small, poorly formed, non-necrotizing granulomas located in portal tracts or lobules. Eosinophils, cholestasis, hepatitis, or bile duct injury may accompany them. A detailed medication history is essential, including the timing of recently initiated prescription drugs, over-the-counter medications, supplements, and herbal products. Implicated agents include allopurinol, sulfonamides, nitrofurantoin, hydralazine, carbamazepine, phenytoin, and immune-checkpoint inhibitors. Drug-induced granulomas are a diagnosis of exclusion because their morphology is not specific.

Q fever

Fibrin-ring, or “doughnut,” granulomas contain a central lipid vacuole surrounded by a ring of fibrin and epithelioid histiocytes. They classically suggest Q fever caused by Coxiella burnetii, particularly in patients exposed to livestock or animal-birthing products. However, fibrin-ring granulomas are not specific and may also occur in other infections, drug reactions, autoimmune diseases, and malignancies. Serologic or molecular confirmation is therefore required.

Cat-scratch disease

Bartonella henselae infection may produce stellate, necrotizing, suppurative granulomas with abundant central neutrophilic debris. A history of cat exposure and regional lymphadenopathy provides an important clue. Warthin–Starry staining may demonstrate organisms but has variable sensitivity. Serologic testing or PCR can support the diagnosis. Similar suppurative granulomas can occur with other bacterial and fungal infections, so morphology alone is insufficient.

Additional Considerations

Foreign-body granulomas are centered on exogenous or endogenous material. Polarizable material may be identified under polarized light. Relevant histories include prior surgery, embolization, injection, trauma, or exposure to medications and other foreign substances.

Crohn disease can rarely produce small, non-necrotizing granulomas in portal tracts or lobules. The diagnosis depends on compatible gastrointestinal findings because hepatic granulomas alone are nonspecific.

Lobular microgranulomas are small clusters of Kupffer cells or histiocytes within sinusoids. They are nonspecific and may be encountered in drug reactions, infections, systemic inflammatory disorders, and other hepatic injuries.

Key Diagnostic Approach

When hepatic granulomas are identified, the pathologist should first determine whether they are bile duct-centered, randomly distributed, lobular, portal-based, or associated with foreign material. The granulomas should then be classified as well-formed or poorly formed and as non-necrotizing, necrotizing, suppurative, or fibrin-ring type. Associated bile duct injury, eosinophils, organisms, vasculitis, foreign material, and background liver disease should be documented. Final interpretation requires correlation with immune status, systemic symptoms, travel and animal exposures, medication history, autoimmune serology, microbiologic studies, and imaging findings.

References

1. Czaja AJ, Carpenter HA. Optimizing diagnosis from the medical liver biopsy. Clin Gastroenterol Hepatol. 2007;5(8):898-907. doi:10.1016/j.cgh.2007.05.031

2. Drebber U, Kasper HU, Ratering J, et al. Hepatic granulomas: histological and molecular pathological approach to differential diagnosis-a study of 442 cases. Liver Int. 2008;28(6):828-834. doi:10.1111/j.1478-3231.2008.01695.x

3. Tanaka A, Ma X, Takahashi A, Vierling JM. Primary biliary cholangitis. Lancet. 2024;404(10457):1053-1066. doi:10.1016/S0140-6736(24)01303-5

4. Marazuela M, Moreno A, Yebra M, Cerezo E, Gómez-Gesto C, Vargas JA. Hepatic fibrin-ring granulomas: a clinicopathologic study of 23 patients. Hum Pathol. 1991;22(6):607-613. doi:10.1016/0046-8177(91)90240-P

5. Gaspar R, Andrade P, Silva M, Macedo G. Hepatic granulomas: a 17-year single tertiary centre experience. Histopathology. 2018;73(2):240-246. doi:10.1111/his.13521