Final Diagnosis -- Bone marrow involved by disseminated histoplasmosis




Histoplasma capsulatum is the most prevalent endemic mycosis in North America and is particularly common in the Ohio and Mississippi River valleys. The fungus is also endemic to parts of South America, Europe and Africa. Histoplasma capsulatum is a thermally dimorphic fungus, meaning that, at environmental temperatures, it grows in the form of hyphae that produce spores but at body temperatures is present as yeast forms. The infection is acquired via inhalation of soil that contains bird or bat feces (1-2).

Histoplasma are engulfed by macrophages, multiply within the cell and are released upon lysis. Clinical manifestations range from benign, self-limited infection, to acute, chronic, progressive, disseminated, and mediastinal infections. Infections are typically controlled, within 2-3 weeks, by helper T cells, such that patients with acquired immune deficiency syndrome (AIDS) are susceptible to more severe infection. Macrophages carry the organisms to hilar and mediastinal lymph nodes, followed by dissemination to other sites. In immunodeficiency, clusters of macrophages filled with the yeast forms can be seen in liver, spleen, lungs, intestine, adrenals and meninges (1-2).

Most H. capsulatum infections are transmitted via a small inocula of organisms in an immunocompetent patient, allowing the infection to be self-limited, involving a relatively small area of the lungs. Most of such infections are asymptomatic. Some cases present with headache, fever and cough but still require no therapy (2-3). Disseminated infection, on the other hand, is associated with symptoms of weight loss, fever, and weakness and can progress slowly over years, depending on the immune status of the host. A retrospective study of 111 patients with systemic histoplasmosis at Mayo Clinic showed that 41% were immunocompetent, however (4).

Histiocytes produce epithelioid granulomas in the lungs, which may eventually undergo coagulative necrosis and may coalesce. In chronic infection, granulomas typically involve the apices of lungs, with thickening and retraction of the pleura, as well as hilar lymph nodes.

Because of their similar pathogenesis, staining of sections with Grocott's methenamine silver (GMS) and periodic acid-Schiff (PAS) stains that highlight yeast forms is important in distinguishing H. capsulatum from M. tuberculosis infection, which can be highlighted with an acid fast (AFB) stain(1, 2, 5, 6). The Histoplasma yeast cell is round to oval, uniform in size and approximately 1-4 microns in diameter, with a central basophilic body, refractile capsule and perinuclear cleared zone or halo. Budding is rarely seen. The organisms can sometimes appear in aggregates with a "cluster of grapes" appearance (1, 7, 8). Several common fungi can cause granulomatous inflammation in the lung and can be differentiated from Histoplasma and from each other based on their morphologic features. These include Blastomyces (round, budding yeast with thick cell wall, basophilic protoplasm and multiple nuclei), Cryptococcus (round, budding yeast, variable in size, with fragmentation and a pale thin cell wall), and Coccidioides (spherules and endospores without budding forms, thick wall) (8, 9). A small percentage of cases of Pneumocystis, which are similar in size to Histoplasma, may also elicit a granulomatous response, but are round rather than oval, often crescent or sickle-shaped, without budding (10).


  1. Cotran, R, Kumar, V, and Collins, T. Robbins Pathologic Basis of Disease. 6th Ed. Philadelphia, PA: W.B. Saunders, 1999.
  2. Rubin, R and Strayer DS. Rubin's Pathology: Clinicopathologic Foundations of Medicine. 5th Ed. Baltimore, MD: Lippinocott Williams & Wilkins, 2008.
  3. Knox, KS and Hage, CA. Histoplasmosis. Proc Am Thorac Soc. 2010;7(3):169-72.
  4. Assi, MA, Sandid, MS, Baddour, LM, Roberts, GD, and Walker, RC. Systemic histoplasmosis: a 15-year retrospective institutional review of 111 patients. Medicine (Baltimore). 2007;86(3):162-9.
  5. Mukhopadhyay, S. Role of histology in the diagnosis of infectious causes of granulomatous lung disease. Curr Opin Pulm Med. 2011;17(3):189-96.
  6. Connor, DH, Chandler, FW, Schwartz, DA, Manz, HJ and Lack, EE. Pathology of Infectious Disease. Stamford, CT: Appleton and Lange, 1997.
  7. Foucar, K, Reichard, K and Czuchlewski, D. Bone Marrow Pathology. 3rd Ed. ASCP, 2010.
  8. Katzenstein, AA. Katzenstein and Askin's Surgical Pathology of Non-Neoplastic Lung Disease. 4th Ed. Philadelphia, PA: W.B. Saunders, 2006.
  9. Larone, DH. Medically Important Fungi: Guide to Identification. 4th Ed. Washington DC: ASM Press, 2002.
  10. Mukhopadhyay, S, and Gal, AA. Granulomatous lung disease: An Approach to the differential Diagnosis. Arch Pathol Lab Med. 2010; 134: 667-690.

Contributed by Rebecca Leeman-Neill, MD, PhD and Christine Garcia Roth, MD

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