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Case Reports

Occam's Razor or Hickam's Dictum?

Gupta, Nishant MD*; Aragaki, Alejandro MD*; Wikenheiser-Brokamp, Kathryn A. MD, PhD; Benzaquen, Sadia MD*; Panos, Ralph J. MD, FCCP*

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Journal of Bronchology & Interventional Pulmonology: July 2012 - Volume 19 - Issue 3 - p 216-219
doi: 10.1097/LBR.0b013e31825c6d0d
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The American Thoracic Society criteria for the diagnosis of pulmonary sarcoidosis include (1) the presence of a consistent clinical and radiographic picture; (2) the demonstration of noncaseating granulomas on biopsy; and (3) exclusion of other conditions that can produce granulomatous inflammation, including infections, autoimmune disorders, and inhalational diseases.1

Despite considerable advances in our understanding of sarcoidosis, the exact pathogenesis remains unknown. This uncertainty creates diagnostic dilemmas as non-necrotizing granulomas (the hallmark of sarcoidosis) are not limited to sarcoidosis. The most common conditions that are confused with sarcoidosis are infections, especially mycobacterial and fungal infections. We present a case of a young man with histopathologic evidence of histoplasmosis who subsequently developed sarcoidosis.


A 36-year-old white man presented to his physician with complaints of fever, myalgia, and a painful skin rash on his anterior shins. A chest x-ray revealed bilateral hilar lymphadenopathy, subsequently confirmed by a chest computed tomography (CT). The patient underwent mediastinoscopy, which revealed the presence of granulomas. Fungal cultures from the biopsy were negative, and he was diagnosed with sarcoidosis. He was started on prednisone with resolution of his symptoms. Six months later, he was referred to our institution for management of sarcoidosis. A review of the subcarinal and paratracheal mediastinoscopic lymph node biopsies demonstrated necrotizing granulomas containing a rare budding yeast form morphologically consistent with Histoplasma species (Fig. 1). On the basis of these histopathologic findings, it was considered that his initial illness was due to histoplasmosis. His prednisone was tapered off. Histoplasma serologies and urine histoplasma antigen were negative. On the basis of the negative serologies and the absence of respiratory symptoms, he was not started on antifungal therapy. A chest CT performed 8 weeks after the cessation of steroids revealed mild hilar lymphadenopathy and bilateral upper-zone predominant micronodular opacifications that were unchanged compared with his original scan (Fig. 2).

Mediastinal lymph node biopsies showing granulomas with multinucleated giant cells (arrowhead), necrosis (arrow), and a budding yeast form morphologically consistent with Histoplasma species in a necrotizing granuloma (Grocott methenamine-silver stain, inset is boxed area enlarged). Original magnification ×100 (top), ×400 (middle), ×1000 (bottom).
Initial computed tomography (CT) chest scans show micronodular pattern bilateral upper lobes (A) and mild bilateral hilar adenopathy (B). Follow-up CT scans show marked progression of a bilateral upper lobe micronodular pattern (C) and progression of bilateral hilar adenopathy (D).

Four months later, the patient presented with symptoms of chest heaviness and weight loss. A repeat chest CT showed marked progression of hilar and mediastinal lymphadenopathy. In addition, the upper-zone predominant micronodular opacifications were more prominent (Fig. 2). We performed bronchoscopy with endobronchial ultrasound-guided transbronchial needle aspirations from bilateral hilar, subcarinal, right, and left paratracheal lymph nodes and transbronchial biopsies and bronchoalveolar lavage from the right middle lobe. Transbronchial needle aspirations from all 5 lymph node stations and the transbronchial lung biopsy revealed non-necrotizing granulomas (Fig. 3). Grocott methenamine-silver and acid-fast stains were negative for fungal and mycobacterial organisms. Three weeks later, the patient developed nausea, constipation, increasing fatigue, and was hospitalized with a calcium of 15 mg/dL. He was diagnosed with sarcoidosis and started on prednisone with drastic resolution of symptoms and correction of hypercalcemia. Six weeks after hospitalization, the patient was asymptomatic and bronchoalveolar lavage fungal cultures were negative for histoplasmosis.

Transbronchial lung biopsy specimens show non-necrotizing granulomas with multinucleated giant cells (arrow). No microorganisms were identified by special stains. Original magnification ×100 (A) and ×400 (B).


The etiology of sarcoidosis is not known. Current evidence suggests that the development of sarcoidosis requires a genetic predisposition and 1 or more types of environmental exposure(s).2 These exposures are thought to provide the antigenic stimulus responsible for initiating an exaggerated immune response and development of granulomatous inflammation. Infectious agents, especially mycobacterium species,3,4 and, less commonly, histoplasmosis5 have been proposed as potential exposures responsible for development of sarcoidosis.

Histoplasmosis and sarcoidosis can produce similar clinical manifestations including erythema nodosum, hepatosplenomegaly, arthritis/arthralgias, uveitis/retinitis, and skin/mucosal ulceration.5–7 The radiographic findings of mediastinal adenopathy and pulmonary infiltrates are also similar. The hallmark histopathologic finding of sarcoidosis—non-necrotizing granulomas—can also be seen in both conditions. Although necrosis within a granuloma favors an infectious etiology, sarcoid granulomas can also exhibit varying degrees of necrosis.8

There are reports of histoplasmosis misdiagnosed as sarcoidosis (as happened originally in this case).9,10 Patients with sarcoidosis who are on immunosuppressants are at increased risk for infectious complications including histoplasmosis.11 However, there are few reports describing the diagnosis of sarcoidosis after a diagnosis of histoplasmosis. Wynbrandt and Crouser12 initially diagnosed a 55-year-old man with pulmonary histoplasmosis but subsequently changed the diagnosis to sarcoidosis. His symptoms resolved with steroids. Wheat et al5 described 11 patients with sarcoidosis accompanied by laboratory evidence for histoplasmosis. Eight patients were treated with corticosteroids and responded promptly without progression of histoplasmosis. One patient received a course of amphotericin B without clinical improvement but responded to corticosteroid therapy. On the basis of these findings, the authors proposed that sarcoidosis can evolve after resolution of histoplasmosis and may represent a persistent inflammatory response to fungal antigens.

Our case is unique, because biopsies performed at 2 different times from the same patient demonstrated entirely different histopathologic patterns. Initially, the mediastinal lymph nodes contained necrotizing granulomas and a budding yeast form consistent with histoplasmosis. One year later, mediastinal lymph nodes and lung parenchyma demonstrated non-necrotizing granulomas with no fungal organisms consistent with a diagnosis of sarcoidosis. The fact that our patient had 2 different histopathologic patterns in a relatively short-time frame suggests a potential association between histoplasmosis and the subsequent development of sarcoidosis as suggested by Wheat et al,5 Wynbrandt and Crouser,12 and Reich.13

A limitation to this interpretation of our case, and others,5,12 is that they occurred in the Ohio River valley where histoplasmosis is endemic. It is certainly possible for 1 patient to have 2 disease processes and, in an endemic area, it is possible to have sarcoidosis with underlying evidence of histoplasmosis.


Whether our patient followed Occam razor and developed sarcoidosis as a result of histoplasmosis or whether he followed Hickam dictum and had both diseases cannot be proven. Because of their similar clinical and radiograph presentations, clinicians should maintain a high index of suspicion about both diseases and carefully evaluate the coexistence of these disorders, especially in an endemic area.


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13. Reich JM. Deciphering histoplasmosis, systemic noncaseating granuloma, and sarcoidosis in the literature. Chest. 1998;113:1143

sarcoidosis; histoplasmosis; pulmonary pathology; endobronchial ultrasound

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