A 47-year-old man who underwent orthotopic heart transplantation one year ago has an x-ray showing a right upper lobe pulmonary nodule. The lung biopsy is shown. The most likely diagnosis is 

A. atypical carcinoid tumor.
B. infection with Candida albicans.
C. Nocardia species opportunistic infection.
D. post-transplant lymphoproliferative disorder (PTLD).
E. pulmonary Cryptococcus infection.

Answer E

The finding of a pulmonary nodule one year after a transplant raises possibilities of infection and lymphoma. Tissue biopsy is necessary to make a diagnosis. The biopsy in this patient shows an encapsulated yeast-like budding fungus without any spores or mycelia. The distinctive appearance of the organism demonstrated by mucicarmine and Gamori's methenamine silver (GMS) stains is diagnostic. The dark, round nucleus is surrounded by a wide border of unstained, gelatinous material. Budding forms are frequently present.

The slide essentially excludes a malignancy as the cause of the abnormal chest x-ray. Nocardia appears as a filamentous organism that is acid fast and can, therefore, be confused with Mycobacterium tuberculosis. Candida is seen as branching septated organisms which do not look like this under the microscope. 

There are 19 different species of the genus cryptococcus but the causative organism in humans is almost always Cryptococcus neoformans. The lung and the central nervous system are the most commonly affected sites in humans. The organism can be seen with hematoxylin-eosin stain and with India ink preparations (spinal fluid). As in this example the appearance of the organisms is enhanced by mucicarmine and GMS stains. The portal of entry is usually respiratory and it has a predilection for the upper halves of the lung fields. Non-immunocompromised patients present with one or several peripheral nodules. Compromised patients can present with a variety of patterns including hilar adenopathy, cavitated lesions, or pleural effusions. Treatment is with antifungal agents, typically Amphotericin B, with careful monitoring of the creatinine, potassium, and hematocrit. The drug dosage is reduced if any toxicity is noted.

Ellis DH, Pfeiffer TJ. Ecology, life cycle, and infectious propagule of Cryptococcus neoformans. Lancet 1990;336:923-5.
Cryptococcus neoformans is a biotrophic smut-like fungus, and the epidemiology of cryptococcosis can mainly be explained by exposure to an infective aerosolised inoculum. For C neoformans var gattii it is postulated that the principal infectious propagule is the basidiospore and that exposure to Eucalyptus camaldulensis, the host tree, is required to initiate infection in man and animals. C neoformans var gattii may have been exported from Australia by infected seeds of E camaldulensis containing dormant dikaryotic mycelium of the fungus. For C neoformans var neoformans both the basidiospore and desiccated encapsulated yeast cells are postulated to act as infectious propagules, the basidiospores showing a seasonal distribution in association with an as yet unidentified host plant, and the encapsulated yeast cells dispersed from accumulations of dried bird (mainly pigeon) droppings which act as a year-round vector.

Perfect JR. Cryptococcosis. Infect Dis Clin North Am 1989;3:77-102.
Cryptococcosis emphasizes the importance of the host-parasite interaction. C. neoformans has developed factors to invade the host but generally requires host immune dysfunction to establish infection. Cryptococcal infection has increased as our immunocompromised pool of patients enlarges. Although many questions regarding management of cryptococcosis remain, it is a well-studied infection with excellent guidelines for diagnosis, treatment, and prognosis