Pathology of Pulmonary Alveolar Proteinosis

Updated: Dec 18, 2019
  • Author: Rodolfo Laucirica, MD; Chief Editor: Philip T Cagle, MD  more...
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Pulmonary alveolar proteinosis (PAP) is a rare disease characterized by the accumulation of granular eosinophilic material within alveolar spaces. [1]  PAP has also been referred to as pulmonary alveolar phospholipoproteinosis or alveolar lipoproteinosis, reflecting the abundance of lipids within the granular exudate. PAP has a worldwide distribution and an estimated incidence of 0.2 case per million population. [1]


Etiology and Pathophysiology

Animal and human studies indicate that more than one pathway exists for the different forms of pulmonary alveolar proteinosis (PAP). The congenital form of PAP results from multiple genetic abnormalities. These include defects in genes encoding for surfactan protein B or C, transporter molecules within type II pneumocytes, and the beta chain receptor of granulocyte-macrophage colony-stimulating factor (GM-CSF). [2, 3, 4, 5]

Autoimmune PAP is characterized by the presence of anti-GM-CSF antibodies. This leads to a deficiency or malfunction of GM-CSF, which is an integral component of surfactant homeostasis. [6, 7, 8, 9, 10, 11] Analysis of bronchoalveolar lavage (BAL) fluid suggests that the pathogenesis of autoimmune PAP may also involve abnormal clearance rather than excessive production of pulmonary surfactant. [12, 13]


Clinical Features and Imaging

Pulmonary alveolar proteinosis (PAP) is classified into two main categories: congenital (neonatal) and acquired. Acquired PAP is subdivided into an autoimmune form (previously termed idiopathic/primary) and secondary form (ie, due to an underlying disease). [14] Most cases of PAP are the autoimmune form (90%), [1, 14, 15] followed by secondary (4%), and congenital (1%), with the remaining 5% consisting of undetermined PAP-like disease. [1] Adults between aged 39 and 51 years are most commonly affected, with a 2:1 male-to-female predominence. [1] Infants and children can also be affect. [1]

Secondary PAP is associated with various underlying diseases. These include various infections, hematologic malignancies, inorganic dust exposure (silica, aluminum, or titanium), and immunodeficiency states such as infection with human immunodeficiency virus (HIV) and lung transplantation. [16, 17, 18, 19, 20, 21, 22, 23] Less common causes include Fanconi anemia, lysinuric protein intolerance, and surfactant protein B deficiency. [24, 25, 26]

The onset of clinical disease is usually insidious, with a varying presentation and nonspecific symptoms, which may delay the diagnosis of PAP by months to years. Most patients experience progressive dyspnea and dry cough. [1] White sputum production, weight loss, hemoptysis, and fever have also been described in patients with PAP. [14, 27, 28] Patients with the congenital form of PAP (see Etiology and Pathophysiology) usually present with an acute onset of rapidly progressive respiratory distress immediately after birth. [14]

Chest radiographs demonstrate bilateral and symmetric areas of airspace consolidation that primarily involve the perihilar regions and lower lobes. [6, 29] These areas of consolidation tend to have a vaguely nodular configuration. With high-resolution computed tomography (HRCT) scanning, the characteristic finding is the presence of ground glass opacities associated with interlobular septal thickening, imparting a “crazy paving” appearance to the lung parenchyma. [30, 31]

The diagnosis of PAP can be confirmed by various methods. In patients with autoimmune PAP, measurement of the autoantibody level against granulocyte macrophage colony-stimulating factor (GM-CFS) has been used to identify this disease. Using an enzyme-linked immunosorbent assay (ELISA)–based testing platform, Uchida and colleagues were able determine that a serum level of 5 ug/mL as the optimal cutoff value for distinguishing autoimmune PAP from normal serum. [32] Confirmation of PAP can also be obtained through examination of tissue specimens obtained by one of several methods. Previously, an open biopsy was considered the criterion standard to establish the diagnosis of PAP. However, transbronchial biopsies or cytologic evaluation of bronchoalveolar lavage (BAL) samples are now routinely used to diagnose this disease. [1, 6, 7, 33, 34, 35]


Differential Diagnosis

The differential diagnosis of pulmonary alveolar proteinosis (PAP) includes other diseases associated with intra-alveolar exdudates. These include pulmonary edema, pneumocystis pneumonia, and alveolar mucinosis. Pulmonary edema has a homogeneous appearance and lacks the granularity typical of PAP (see the images below). The exudate of pneumocystis pneumonia has a frothy or foamy appearance due to the negative image of the cyst form of Pneumocystisjiroveci (formally known as carinii).

Pathology of pulmonary alveolar proteinosis. Contr Pathology of pulmonary alveolar proteinosis. Contrast between the granular exudate of pulmonary alveolar proteinosis (PAP) (media file 13885) and the frothy exudate of pneumocystis pneumonia in the transbronchial biopsy (A) (hematoxylin and eosin, x400) and broncheoalveolar lavage (BAL).
Pathology of pulmonary alveolar proteinosis. Contr Pathology of pulmonary alveolar proteinosis. Contrast between the granular exudate of pulmonary alveolar proteinosis (PAP) (media file 13885) and the frothy exudate of pneumocystis pneumonia in the transbronchial biopsy (B) (Papanicolaou, x600). Note the negative images of the cysts impart the foamy characteristic of the exudate.

Gross and Microscopic Findings

Gross findings

The lungs of patients with pulmonary alveolar proteinosis (PAP) are heavy with a firm consistency. The cut surface oozes yellow fluid due to the marked accumulation of lipid.

Microscopic findings

The characteristic finding in tissue sections is the presence of eosinophilic granular material within the alveolar spaces. The overall lung architecture is preserved, and a mild chronic inflammatory infiltrate within the pulmonary interstitium may be present (see the images below).

Pathology of pulmonary alveolar proteinosis. Alveo Pathology of pulmonary alveolar proteinosis. Alveoli are filled with an eosinophilic granular material. Note the preservation of the normal lung architecture (hematoxylin and eosin, x200).
Pathology of pulmonary alveolar proteinosis. High Pathology of pulmonary alveolar proteinosis. High magnification illustrating the granular material and alveolar macrophages surrounded by intact alveolar septal tissue with minimal reaction (hematoxylin and eosin, x400).

This material is strongly periodic-acid-Shiff positive and diastase-resistant (DPAS) (see the image below).

Pathology of pulmonary alveolar proteinosis. Intra Pathology of pulmonary alveolar proteinosis. Intra-alveolar material is strongly periodic acid-Schiff (PAS) positive (diastase [D]-PAS, x200).

The diagnosis of PAP can also be established by cytologic evaluation of bronchoavleolar lavage (BAL) specimens.

Pathology of pulmonary alveolar proteinosis. Cytol Pathology of pulmonary alveolar proteinosis. Cytologic appearance of intra-alveolar granular material from a bronchoalveolar lavage sample (diastase-periodic acid-Schiff [DPAS], x400).

In addition, another finding reported in BAL samples from patients with PAP is the presence of dense globules that have well-defined borders (see the image below). [36, 37]

Pathology of pulmonary alveolar proteinosis. Bronc Pathology of pulmonary alveolar proteinosis. Bronchoalveolar lavage sample depicting dense globules with sharp borders seen in patients with pulmonary alveolar proteinosis (PAP) (Papanicolaou, x400).

Quantitative analysis of these globules has shown that the presence of 18 or more in BAL samples is a highly sensitive and specific marker for PAP. [38] These globules are believed to represent the multilaminated structures characteristic of PAP that are visible by electron microscopy. [37]


Treatment and Prognosis

The most widely accepted and effective treatment for PAP is therapeutic whole-lung lavage(WLL). [1, 6, 7, 39] This form of therapy is instituted when significant dyspnea limits activity and progressive deterioration of arterial oxygenation. [40, 41]  Bronchoscopic serial lobar lavages have also been used to treat patients with PAP. [42]

The patient’s respiratory function improves due to the removal of proteinaceous material and local anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies. This helps restore the migration and phagocytic functions of alveolar macrophages. [43, 44] Although a significant number of patients exhibit clinical, radiologic, and functional improvement after a single treatment, most require repeat lavage at intervals between 6 and 15 months. [45, 46] Patients receiving whole-lung lavage have shown a significant improvement in their 5-year survival rate compared to those who do not receive this form of therapy. [1, 45] For patients with secondary PAP, in addition to whole-lung lavage, treatment of the underlying condition should also be instituted. [6, 7]

The administration of exogenous GM-CSF or suppression of ant-GM-CSF antibodies has been used to treat those patients with autoimmune PAP. The goal of this treatment is to relieve the deficiency of functional GM-CSF, and this can be administered simultaneously or as an alternate to whole-lung lavage. [47, 48, 49, 50] Although predictors of response to treatment with GM-CSF have yet to be established, those patients with pretreatment variables such as longer time from diagnosis, high vital capacity, normal serum lactate dehydrogenase level, and higher plasma surfactant-protein-B level appear to respond better to GM-CSF. [50]

Novel forms of therapy are being explored for those patients who do not respond to GM-CSF or whole-lung lavage. Plasmapharesis, rituximab, trypsin, chymotrypsin, ambroxol, immunoglobulin G, and antibiotics have been investigated. [51, 52, 53, 54, 55, 56] For refractory PAP, rituximab, plasmapheresis, and lung transplantation may be therapeutic considerations. [6]

Attempts have also been made to use stem cells to treat some forms of PAP. Lachmann et al have investigated the use of induced pluripotent stem cells derived from monocytes and macrophages to treat patients with the hereditary form of PAP. [57]

As a means to monitor disease progression, research has evaluated several ancillary tests, including high molecular weight human MUC-1 mucin and serum KL-6. Both of these makers are increased in most patients with PAP. Based on the work of Bonella et al, it appears that serum KL-6 levels are a strong predictor of disease progression in patients with PAP. [58]