November 2021 – Cytopathology and Pulmonary Pathology

Pulmonary alveolar proteinosis (PAP)

PAP is caused by the accumulation of lipoproteinaceous substance in the alveoli due to abnormal surfactant production or lack of surfactant clearing. While the etiology of the disease is not perfectly elucidated, the majority of cases are believed to be caused by autoimmune impairment of granulocyte-macrophage colony stimulating factor (GM-CSF), which allows for normal function and maturation of macrophages that would normally clear surfactant. The presence of anti-GM-CSF antibodies in both the serum and the exudate can be indicative of this autoimmunogenic etiology.

Presentation of PAP typically occurs in the third to sixth decade of life and is predominately seen in men. Symptoms are largely nonspecific, with progressive dyspnea being the most common, followed by cough that may or may not be productive. Patients may also experience other symptoms that include, but are not limited to, fatigue, weight loss, and fever. While imaging can show the characteristic “crazy paving” pattern in up to 85% of cases, it is important to note that this is not a specific finding and can be seen in other disease states like pulmonary edema and PCP pneumonia. 

The diagnostic workup for PAP is generally initiated by a BAL. The appearance of the milky-appearing exudate alone may be helpful in diagnosing the disease in the appropriate clinical context. The cytologic evaluation can also make the diagnosis, with the presence of amorphous, PAS(+) material that is diastase resistant in a paucicellular background, as represented in the above images. A biopsy can, of course, be diagnostic and reveals alveoli diffusely filled with eosinophilic material. Exclusion of co-infections (e.g., Nocardia) is imperative. 

With regard to the differential diagnosis, in PCP pneumonia we would anticipate seeing foamy exudate with distinct “dot-like” structures, which would be PAS(-) and GMS(+). Amyloidosis would also be PAS(-) and would show its characteristic green birefringence under cross-polarized light with Congo red staining. 

The classic treatment is a “therapeutic BAL” that can result in almost instantaneous resolution of symptoms. Looking forward, however, are studies in which the supplementation of GM-CSF may be an effective treatment option, as it can supplement the ineffective or deficient GM-CSF in the affected patients. And, of course, given the autoimmune correlation in the majority of cases, more common treatments such as monoclonal antibodies and immunosuppressants may also be considered. 

References

1. Kumar A, Abdelmalak B, Inoue Y, Culver DA. Pulmonary alveolar proteinosis in adults: pathophysiology and clinical approach. Lancet Respir Med. 2018 Jul;6(7):554-565. doi: 10.1016/S2213-2600(18)30043-2. Epub 2018 Feb 1. PMID: 29397349.