January 2025 Case of the Quarter
Case history:
A 47-year-old female with history of primary biliary cholangitis (PBC)-autoimmune hepatitis (AIH) overlap syndrome status post liver transplantation 8 years ago presented with confusion spells, headaches, jaundice and general malaise. Liver function tests were elevated (total bilirubin 7.2, ALT 217, AST 323, alkaline phosphatase 1351). Liver Doppler ultrasound was concerning for underlying cirrhosis and an MRCP showed moderate narrowing of the biliary anastomosis but no upstream ductal dilatation. The patient underwent EUS guided liver biopsy.
Pathology findings:
The biopsy sample revealed chronic lymphoplasmacytic portal inflammation with focal interface hepatitis and few portal lymphoid aggregates (Fig 1). In addition, there were scattered clusters of foamy histiocytes involving portal areas (Fig 2) and hepatic sinusoids (Fig 3). Focal lymphocytic infiltration of bile ducts and focal portal endothelialitis were also present (Fig 4).
Given these findings, a number of special stains were performed. The GMS stain highlighted abundant fungal yeast forms (Fig 5). The fungal organisms were round to ovoid, predominantly intracellular and approximately 3 microns in diameter with focal narrow-based budding. The fungal forms were also highlighted on PAS stain, and showed negative staining with mucicarmine and Fontana-Masson stains. AFB stain was negative.
Diagnosis: Hepatic involvement by disseminated histoplasmosis.
Follow up:
The findings were interpreted as hepatic involvement by histoplasmosis in addition to sumperimposed minimal acute cellular rejection (RAI = 3). One year prior to this presentation, the patient was admitted to an outside hospital with shock and pancytopenia. At the time, mold blood cultures and bronchoscopy fluid were positive for Histoplasma. The patient was diagnosed with disseminated histoplasmosis, thought to be from exposure to domestic chickens. She was treated with amphotericin B and then transitioned to itraconazole. She did well for about a year, but had a presumed episode of acute cellular rejection and was treated steroids. Following the most recent biopsy, the patient received IV amphotericin B with plan for continued therapy with posaconazole.
Discussion:
Histoplasma spp, more specifically Histoplasma capsulatum, is the most common dimorphic fungus endemic to central and eastern United States and present in soil and animal droppings. Infection occurs through inhalation of airborn micronodia. Histoplasma is phagocytosed by tissue macrophages, where it proliferates and disseminates. In immunocompetent individuals, infection is frequently asymptomatic or subclinical. However, immunosuppressed patients are at increased risk of disseminated infection.
In the setting of solid organ transplantation, the incidence of histoplasmosis is approximately 0.5% and many cases occur during the 1st year after transplant. In a subset of patients, there is history of therapy for acute rejection preceding the diagnosis of histoplasmosis.
The clinical presentation is varied and symptoms can be nonspecific, including fever, malaise, cough, headache, chest pain and myalgia. The most common sites of disseminated disease are the skin and soft tissues as well as bone marrow, liver, GI tract, kidney and central nervous system. Hepatic involvement is reported in approximately 90% of disseminated cases. Cytopenias can occur in up to 80% of patients and, in some cases, hemophagocytic lymphohistiocytosis (HLH) can occur.
The diagnosis of histoplasmosis can be made through positive urine or serum Histoplasma antigen testing, positive cultures and/or presence of the characteristic yeast-like structures demonstrated in tissue samples.
Histologically, liver specimens involved by histoplasmosis show sinusoidal congestion, portal lymphohistiocytic inflammation and variable sinusoidal Kupffer cell hyperplasia. Clusters of histiocytes may be seen, although well-formed granulomas are less common due to deficient T-cell response in this population. The organisms are most commonly seen as intracellular clusters of uniform, narrow-based budding yeasts ranging from 2-5 microns, and are highlighted on GMS and PAS stains. The differential diagnosis of histoplamosis includes similar GMS-positive organisms, such as Candida, Cryptococcus, Blastomyces and Pneumocystis. Candida is typically extracellular and shows varibly sized yeasts with frequent budding. Pneumocystis is mostly extracellular with no budding. Blastomyces are larger (15 microns) with broad-based budding. Cryptococcus are 3-8 microns in size and positive for mucicarmine (encapsulated) and Fontana-Masson stains (unencapsulated).
Patients with disseminated histoplasmosis are treated with IV amphotericin B followed by azole therapy. However, posttransplant histoplasmosis is associated with significant mortality rates and recurrence after treatment can occur in a minority of patients.
Learning points:
- Histoplasma spp is an endemic fungus commonly seen in central and eastern United States. Liver transplant patients may be at increased risk of infection.
- Disseminated histoplasmosis can be difficult to diagnose due to variable clinical presentation. The diagnosis can be established through blood or body fluid cultures, pathology or cytology specimens, as well as serum or urine antigen testing.
- In the liver, histoplasmosis manifests as lymphoplasmacytic and histiocytic infiltrates involving portal tracts and sinusoids. Granulomas as less common in immunocompromised patients. GMS and PAS stains highlight the intracellular organisms.
References:
Abad CLR, Razonable RR. Clinical Characteristics and Outcomes of Endemic Mycoses After Solid Organ Transplantation: A Comprehensive Review. Open Forum Infect Dis. 2024 Jan 22;11(3):ofae036. PMID: 38444820; PMCID: PMC10913849.
Abad CLR, Razonable RR. Donor-derived endemic mycoses after solid organ transplantation: A review of reported cases. Clin Transplant. 2024 Jan;38(1):e15199. doi: 10.1111/ctr.15199. PMID: 37991084.
Assi M, Martin S, Wheat LJ, Hage C, Freifeld A, Avery R, Baddley JW, Vergidis P, Miller R, Andes D, Young JA, Hammoud K, Huprikar S, McKinsey D, Myint T, Garcia-Diaz J, Esguerra E, Kwak EJ, Morris M, Mullane KM, Prakash V, Burdette SD, Sandid M, Dickter J, Ostrander D, Antoun SA, Kaul DR. Histoplasmosis after solid organ transplant. Clin Infect Dis. 2013 Dec;57(11):1542-9. PMID: 24046304; PMCID: PMC3814825.
Lamps LW, Molina CP, West AB, Haggitt RC, Scott MA. The pathologic spectrum of gastrointestinal and hepatic histoplasmosis. Am J Clin Pathol. 2000 Jan;113(1):64-72. PMID: 10631859.
Case contributed by:
Marcela A Salomao, MD, Associate Professor, Mayo Clinic in Arizona, Scottsdale, AZ, USA