November 2016

A 58 year-old man with distal tracheal nodule

Ahmed Shehabeldin, MD, Ibrahim Robadi, MD, H. James Williams, M.D.


A 58 year-old man known to have COPD with frequent exacerbations and hospitalizations requiring corticosteroid therapy, type 2 diabetes mellitus, hypertension, and migraines, presented to a health care facility with complaint of recurrent shortness of breath and hemoptysis.  His symptoms were attributed to COPD exacerbation and he was unsuccessfully managed with multiple antibiotic regimens.  A CT scan of his chest showed moderate emphysema with para-septal bullous changes in the upper lobes and bibasilar atelectasis but no definite infiltrates. There were bilateral calcified hilar lymph nodes noted as well as several calcified and non-calcified nodules in bilateral lung fields.  The patient then underwent bronchoscopy during which a distal tracheal nodule was identified and biopsied (see Figures).

Gross and Microscopic Description

The endobronchial biopsies consisted of three tan-red fragments of tissue ranging from 0.2 to 0.3 cm.  H&E stained slides show respiratory type epithelium with squamous metaplasia and underlying epithelioid histiocytes and scattered lymphocytes (Figures 1 - 3).  Grocott methenamine silver (GMS) and periodic acid-Schiff (PAS) stains were also performed (Figures 4 and 5).

Figure 1: H&E 4x Endobronchial biopsy with benign respiratory epithelium and a subepithelial cellular infiltrate.
Figure 2: H&E 10x On higher power, reactive squamous metaplasia is evident. The subepithelial infiltrate shows epithelioid histiocytes without distinct granuloma with a sprinkling of lymphocytes.
Figure 3: H&E 40x In addition to the epithelioid histocytes, encapsulataed organisms are evident some of which appear to have narrow-necked budding.
Figure 4: GMS 40x The silver stain highlights the organisms which in addition to the narrow-necked budding are seen to show marked variabiltiy in size.
Figure 5: PAS 40x The organisms are also well demonstrated on the PAS stain with encapsulation, variable size, and narrow-necked budding.


Which of the following genes/gene families is most likely involved in the pathogenesis of this syndrome ?


Please select an answer above.


Cryptococcus neoformans is an encapsulated round to oval yeast which measures 5-10 µm.  The capsule is composed of polysaccharides including galactose, mannose, xylose, and glucuronic acid in different rearrangements to form glucuronoxylomannan (GXM) and galactoxylomannan (GalXM).2, 6  In addition to the capsule, the organism is characterized by variation in the size of the yeast forms with narrow-necked budding2 (2).


More than 50 species of cryptococcus have been identified, but only C. neoformans, and C. gattii are considered pathologic to humans.  C. neoformans is a typically harmless commensal organism of the airways in the immunocompetent population.  It can result in meningitis, pneumonia, or disseminated infection in HIV positive patients, organ transplant patients, and in patients who are immunocompromised due to other reasons such as corticosteroid therapy 2, 7(as seen in this patient).  However, infections which are confined to the lungs usually occur in patients with no apparent immunosuppression.7


Cryptococcus is primarily transmitted via inhalation of spores from the environment, but not from human to human is rare.8   In the lungs, Cryptococcus neoformans may cause pneumonia, pulmonary nodules, mass lesions, and rarely, pleural effusion.7  Once inhaled, the spores deposit in pulmonary alveoli where they survive the neutral-alkaline pH of the alveoli with the aid of GCS (glucosylceramide synthase).9  The spores are then phagocytized by alveolar macrophages where the environment is acidic, and GCS is no longer required for the survival of the organism.  The capsular polysaccharide glucuronoxylomannan has antiphagocytic properties (decreased recognition of the yeast cells by macrophages) and inhibits leukocyte migration.  A successful immune response consists of a positive skin test, T-helper cells activation, and a reduction of the number of organisms in the tissue.  Tissue destruction in cryptococcal infection is mainly due to tissue distortion secondary to the growing burden of the organism.7


The typical lesion on histopathologic examination consists of clusters of pleomorphic 5-10 um round to oval yeasts surrounded by a clear zone with occasional narrow-necked budding.  Extensive inflammation, fibrosis, and well organized granulomata formation are rare findings. 2, 10

Commonly used stains to identify the organism include:

  • Mucicarmine typically stains the polysaccharide capsule which helps in differentiating cryptococcus from histoplasma, coccidioides, and blastomyces. 
  • Alcian blue also stains the capsule. 
  • Periodic acid schiff and silver-methenamine stain the cell wall. 
  • India ink is used on CSF samples (latex agglutination is more sensitive and specific).

Capsule deficient variants of the organism do not stain with mucicarmine and characteristically elicit granulomatous immune reaction due to the absence of glucuronoxylomannan.  Such variants can be demonstrated by immunofluorescent antibody, and Fontana-Mason silver stain which proves that the yeast produces melanin characteristic of Cryptococcus.10

Definitive diagnosis is made by culturing CSF, sputum, urine, and blood samples.  Other rapid detection methods include latex agglutination, enzyme immunoassay, and lateral flow immunochromatographic assay.  PCR can be used on tissue specimens.11


Pulmonary cryptococcosis usually resolves without treatment in immunocompetent patients.  On the other hand, immunocompromised patients require treatment with antifungal agents.  Amphotericin B with or without flucytosine is the most widely used regimen in such cases.7


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