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A 50-year-old man presented with a persistent cough refractory to antibiotic therapy. Chest x-ray revealed a 5.0 cm mass lesion with central cavitation. A PPD was negative. Biopsy attempts were non-diagnostic, and the mass was eventually resected given a high clinical and radiographic suspicion of malignancy. The lobectomy specimen revealed a cavitary mass with a mixed fibrotic and gelatinous cut surface.
Archive Case and Diagnosis:
This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2007, Case 23 and is a pulmonary cryptococcosis.
Criteria for Diagnosis and Comments:
Pulmonary infection by Cryptococcus neoformans may produce a wide variety of histologic changes. In this case, the infection has resulted in the formation of a mass lesion with a somewhat variable histologic appearance. Depending on the section received, this process may consist of an infiltrate of large histiocytic cells with central nuclei and clear, slightly vacuolated cytoplasm. Variable numbers of admixed giant cells and lymphocytes are present in these areas. In some areas, the histiocytes have lightly eosinophilic cytoplasm. Other sections show fibrotic regions with proliferations of relatively bland spindled cells with eosinophilic cytoplasm. Careful examination of these areas will reveal admixed vacuolated areas and sparse admixed histiocytes. Most slides will also show areas of necrosis, but classic well-formed necrotizing granulomas are generally absent. Close examination of the clear cells, vacuolated areas and necrotic zones reveals slightly basophilic, refractile fungal organisms roughly 4-6 microns in diameter, which may exhibit narrow-based budding. The surrounding clear spaces are secondary to the associated mucoid capsule. The yeasts may be highlighted by fungal stains such as GMS and are also positive with Fontana-Masson. Positive staining with mucicarmine, which highlights the mucoid capsule, is relatively pathognomonic.
Pulmonary cryptococcosis may occur in both immunocompetent and immunocompromised hosts, but is more frequent in the latter. The causative organism, Cryptococcus neoformans, is found worldwide and is typically associated with soil contaminated with pigeon droppings. Infection results from inhalation of the spores. Patients may be asymptomatic or have vague respiratory symptoms. Meningitis may also be present, particularly in the immunocompromised host, but all patients with pulmonary disease should be evaluated for this possibility. Radiographically, the infection may result in single or multiple mass lesions which may cavitate or it may produce airspace consolidation as seen with pneumonia.
In addition to the sheet like infiltrates of histiocytes with clear cytoplasm (“muciphagic” pattern) and the fibrohistiocytic pattern seen in this case, cryptococcal infections may produce a variety of other histologic patterns. These include well-formed necrotizing granulomas similar to those classically seen in mycobacterial infections and other fungal diseases, a “mucoid pneumonia” pattern in which numerous organisms fill the alveolar spaces suspended in mucin with minimal tissue reaction, and a particularly deceptive “intravascular” pattern in which the organisms are present only within vascular spaces. Rare slides in this case exhibit the mucoid pneumonia pattern at the periphery of the mass lesion.
Cryptococcal infections are most problematic diagnostically when either the diffuse histiocytic/muciphagic pattern or the fibrohistiocytic pattern is present as a mass lesion. When numerous clear histiocytes are present in a diffuse pattern, the infection may be confused with clear cell tumor of the lung or clear cell carcinomas, particularly metastatic renal cell carcinoma. Giant cells may be present in the muciphagic pattern of cryptococcus, which are an important histologic clue, and the cytoplasm is typically more vacuolated than is seen in true neoplastic processes. Organisms may be sparse in the muciphagic pattern but can usually be located on the H&E sections in most cases. When the fibrohistiocytic pattern of cryptococcus is present, inflammatory myofibroblastic tumor (formerly inflammatory pseudotumor) may be a consideration. Hopefully, awareness of the histologic patterns of cryptococcal infection will lead to a search for organisms, thus avoiding a misdiagnosis. In problematic cases immunohistochemical studies should easily eliminate a neoplastic process. Renal cell carcinoma should be positive for pan-cytokeratin or EMA, while the histiocytes in cryptococcal infections are negative. Clear cell tumor of the lung is a rare neoplasm composed of cells currently thought to be derived from perivascular epithelioid cells. The tumor cells are positive for HMB-45 which distinguishes them from histiocytic infiltrates. Inflammatory myofibroblastic tumor is composed of spindled cells admixed with varying numbers of inflammatory cells and foamy histiocytes. Immunohistochemical findings are somewhat variable but the spindled cells are typically positive for actin and half of cases will express ALK1 protein. Microorganism stains are more important than immunohistochemical stains in distinguishing cryptococcosis from inflammatory myofibroblastic tumor, however.
Other inflammatory lesions may also enter the differential diagnosis. Pulmonary malakoplakia is typically seen in immunocompromised individuals and also presents as a mass lesion comprised of histiocytic cells. The histiocytes of malakoplakia normally have eosinophilic rather than clear cytoplasm and intra-cytoplasmic Michaelis-Gutmann bodies may be identified. In the lung, malakoplakia is typically associated with Rhodococcus equi infections. Similarly, atypical mycobacterial infections may form so-called mycobacterial pseudotumors composed of histiocytes with varying degrees of associated fibrosis. Acid-fast stains reveal numerous organisms packed within the histiocytes.
Finally, it is important to distinguish Cryptococcus from other fungal organisms. As stated previously, the thick mucicarmine positive capsule of Cryptococcus is essentially pathognomonic. Rarely, faint mucicarmine staining may be encountered in Blastomycosis dermatitidis, but these organisms are larger (average 15µm, range up to 30µm) and exhibit broad based budding. Rare, capsule deficient forms of Cryptococcus have been reported, which may be extremely difficult to distinguish from Histoplasma capsulatum, and generally require confirmation by culture for definitive diagnosis.