PAP is divided into the following three distinct clinical forms based on its etiology: autoimmune, secondary, and congenital [
10]. Autoimmune PAP represents approximately 90 percent of PAP cases and is caused by neutralizing antibodies against GM-CSF. These populations are mostly normal hosts without underlying disease. Secondary PAP has been described in association with a variety of inflammatory and neoplastic diseases of the hematopoietic and immune systems that impair alveolar macrophage function, resulting in surfactant accumulation [
11]. Congenital PAP is seen especially in children, and the radiological and clinical presentation depends on the gene mutations in encoding surfactant protein B or C or the ABCA3 transporter by the absence of GM-CSF receptor [
12].
The association between secondary PAP and hematological disorders, mostly chronic myeloid leukemia, myelodysplastic syndrome, and lymphoma, is well established [
11]. However, there have been only a few published case reports of PAP occurring in association with solid cancers, including five lung cancers, one metastatic pulmonary melanoma, one mesothelioma and one glioblastoma [
2‐
8]. Of the eight cases, detection of GM-CSF autoantibodies was performed in only two lung cancer cases (Table
1); one was a case of autoimmune PAP with subsequent development of lung cancer [
7], and the other was secondary PAP associated with lung cancer [
8]. Liu
et al. [
8] suggested that the existence of some chemical immune inhibitors secreted from the lung cancer cells causing a local inhibitory effect on macrophages probably induced PAP. Furthermore, Athanassiadou
et al. [
13] reported that patients with primary lung cancer have a high number of functionally incompetent macrophages. In autoimmune PAP patients, Inoue
et al. reported that four of 212 cases (1.9 percent) were associated with cancers, including lung cancer, colon cancer, prostatic cancer, and thyroid cancer [
10]. Since the average age at diagnosis of PAP is 40 to 50 years, PAP with cancer may be rare. To the best of our knowledge, PAP with breast cancer has not been previously described. The present case of PAP co-existed with breast cancer, but this case was categorized as autoimmune PAP due to the positive anti-GM-CSF antibody. However, GM-CSF autoantibodies are also present in healthy persons and in immune globulin prepared from plasma obtained from healthy persons [
9]. Certainly, high levels of GM-CSF autoantibodies are specifically associated with autoimmune PAP. Kitamura
et al. reported that the mean level of the autoantibodies in the sera from 24 idiopathic (autoimmune) PAP patients was 180±22μg/mL, but the range was 35 to 430μg/mL [
14]. The anti-GM-CSF antixbody of this patient was increased to 29.57μg/mL, but still less than 35μg/mL. Moreover, PAP decreased one month after breast cancer resection. A previous report found that significant spontaneous resolution of PAP occurred in 7.9 percent (24 of 303 cases) of patients [
15], but the median time from diagnosis to resolution was 20 months. Thus, breast cancer may have been a factor during PAP development in this patient. Morgan
et al. reported that breast cancer cells induced enhancement of osteoblast-stromal cells to increase prostaglandin E2 (PGE2) production, and the release of PGE2 downregulated GM-CSF production
in vitro [
16]. Liu
et al. reported that overexpression of cytokeratin-associated protein (CAPC) in MDA-231 breast cancer cells downregulated nuclear factor κB (NF-κB) activity and its target genes, including GM-CSF,
in vitro [
17]. These findings suggest that the process of breast cancer causes a local inhibitory effect on macrophages.
Table 1
Clinical features of nine patients with solid organ cancer and pulmonary alveolar proteinosis reported in the literature
1/2) | M/24 | Weight loss | Unknown | N.A. | Melanoma | Co-incident |
2/3) | M/64 | Lt. hemiplegia | Unknown | N.A. | Glioblastoma | Cancer first |
3/4) | M/67 | Cough, Sputum | Unknown | N.A. | Lung cancer (SCC) | Co-incident |
4/5) | M/59 | Cough, Dyspnea | Unknown | N.A. | Lung cancer (SCC) | Co-incident |
5/6) | M/45 | Chest pain | Unknown | N.A. | Mesothelioma | PAP first |
6/7) | F/54 | Dyspnea | Autoimmune | Positive | Lung cancer (Adeno) | PAP first |
7/7) | F/59 | Dyspnea | Unknown | N.A. | Lung cancer (Adeno) | Co-incident |
8/8) | M/57 | Cough, Sputum | Secondary | Negative | Lung cancer (SCC) | PAP first |
9/our case | F/48 | Asymptomatic | Autoimmune | Positive | Breast cancer | Co-incident |