Autoimmune Pulmonary Alveolar Proteinosis with Suspected Exacerbation after Osimertinib Administration for Lung Cancer

Abstract

A 46-year-old woman with lung cancer who received chemotherapy was admitted to our hospital for lower-lobe bilateral ground-glass opacity (GGO). GGO developed after the lung cancer diagnosis, deteriorated after the initiation of osimertinib, and incompletely decreased after interrupting osimertinib; therefore, flexible bronchoscopy was performed. Transbronchial lung biopsy histology and anti-granulocyte/macrophage colony-stimulating factor autoantibody positivity revealed autoimmune pulmonary alveolar proteinosis (aPAP) that did not require treatment. This rare case of aPAP comorbid with lung cancer suggested that using PAP findings to differentiate from drug-induced lung injury or lymphangitis is difficult and that osimertinib was suspected to exacerbate aPAP.

Introduction

Pulmonary alveolar proteinosis (PAP) is a devastating lung disease characterized by the abnormal accumulation of pulmonary surfactant within pulmonary alveoli (1-3). Approximately 90% of cases have an autoimmune aetiology, characterized by a high level of anti-granulocyte/macrophage colony-stimulating factor (GM-CSF) autoantibody (1), and secondary PAP is mainly due to haematological disease, immunodeficiency, the inhalation of inorganic dust, or certain infections (2,3). Cases of PAP associated with primary lung cancer have rarely been reported (4,5); furthermore, tyrosine kinase inhibitors (TKIs) for lung cancer have never been reported to cause deterioration of PAP.

We herein report a case of autoimmune PAP (aPAP) exacerbated by TKIs after a lung cancer diagnosis.

Case Report

A 46-year-old woman visited our hospital with a 5-month history of cough and a fever. She had a medical history of gastroesophageal reflux. Chest computed tomography (CT) revealed a nodule in the right lower lobe and a moderate amount of right pleural fluid (Fig. 1A). Cytologic findings of the pleural fluid and histopathological findings of a transbronchial lung biopsy (TBLB) revealed combined adenocarcinoma and squamous cell carcinoma [positive epidermal growth factor receptor (EGFR) exon 19 deletion mutation]. Therefore, she was diagnosed with lung cancer (T4N3M1a, stage IVA).

Figure 1.

Chest computed tomography showed a nodule in the right lower lobe and left pleural fluid with air in the pleural space due to chest drain tube insertion at the first visit to our hospital (A). Bilateral ground-glass opacities (GGOs) developed in the lower lobe after the diagnosis of lung cancer (B). The GGO area increased after osimertinib was initiated (C). The GGO remained at the time of bronchoscopy (D).

Repeat CT showed new bilateral ground-glass opacities (GGOs) in the lower lobe (Fig. 1B). These GGOs were considered to be the result of carcinomatous lymphangitis; thus, osimertinib treatment was initiated. After six weeks, the patient was suspected of having osimertinib-related drug-induced pneumonitis, as the GGO worsened while her lung cancer ameliorated (Fig. 1C). Osimertinib was therefore interrupted, and 20 mg of prednisolone was initiated, tapered, and then stopped for 3 months. Consequently, the GGO decreased but remained.

Chest CT after second- and third-line chemotherapy (one cycle of carboplatin and albumin-bound-paclitaxel and four cycles of carboplatin and tegafur/gimeracil/oteracil potassium) showed growing lung cancer and remnant bilateral GGO (Fig. 1D). Therefore, the patient was admitted to our hospital for the further investigation of her GGO.

A vital sign examination revealed a low-grade fever of 37.4°C, and a physical examination revealed no abnormalities on admission. Her laboratory findings showed a white blood cell count of 3,660 cells/μL, C-reactive protein of 0.75 mg/dL, lactate dehydrogenase of 207 U/L, and serum Krebs von den Lungen-6 of 1,814 U/L (normal range: ＜500 U/mL). Serum tumour marker assays revealed the following: 3.1 ng/mL carcinoembryonic antigen, 58.7 U/mL sialyl Lewis-x antigen, 5.9 ng/mL cytokeratin 19 fragment, and 1.3 ng/mL squamous cell carcinoma antigen. Flexible bronchoscopy was performed, and the appearance of bronchoalveolar lavage fluid was milky-like on a gross examination. A histological examination of a TBLB performed at the anterior and lateral basal segmental bronchi revealed eosinophilic material and cholesterol crafts filling the alveolar space, showing slight periodic acid-Schiff (PAS) positivity and strong surfactant apoprotein A positivity (Fig. 2). Her serum GM-CSF autoantibody level (SRL, Tokyo, Japan) was 43.0 U/mL (normal range ＜1.7 U/mL). Accordingly, she was diagnosed with aPAP.

Figure 2.

The histological examination of a transbronchial lung biopsy specimen revealed (A) eosinophilic material and cholesterol crafts filling the alveolar space (Hematoxylin and Eosin staining, ×40), which showed slight positivity for periodic acid-Schiff staining (B) and strong positivity for surfactant apoprotein A staining (C). B: Periodic acid-Schiff staining, ×40, C: Surfactant apoprotein A staining, ×40

The patient's aPAP did not require treatment. She was administered four cycles of docetaxel and ramucirumab for lung cancer. Her lung tumour decreased, and her aPAP did not deteriorate.

We obtained informed consent from the patient for the publication of this case.

Discussion

We encountered a rare case of the development of aPAP with lung cancer. Her PAP was difficult to diagnose because it mimicked drug-induced pneumonitis and carcinomatous lymphangitis. In particular, the GGO area increased after osimertinib treatment, and her condition improved after discontinuation, which was suspected to be caused by drug-induced pneumonitis before a bronchoscopy was performed. However, drug-related deterioration was not the definitive diagnosis but rather a tentative diagnosis, and the cause of GGO was ultimately determined to be aPAP based on a bronchoscopic examination. Chemotherapy other than osimertinib did not cause GGO deterioration; therefore, PAP might be exacerbated by TKIs. However, it is possible that these findings reflected the natural course of aPAP, and the diagnosis of aPAP exacerbation due to osimertinib was tentative; we may therefore consider the administration of TKI with careful observation after several courses of cytotoxic chemotherapy, as a TKI was thought to be effective in this case since the patient was positive for the EGFR mutation, exacerbation of aPAP may not be as serious as drug-related pneumonitis, and aPAP can be treated with whole-lung lavage. Accordingly, lung cancer patients who receive TKIs should be carefully observed for the development of not only drug-induced pneumonia but also aPAP, as TKIs may carry a risk of aPAP exacerbation.

Inhibiting phagocytosis and catabolism by alveolar macrophages may lead to a deterioration in the aPAP disease state with corticosteroids, immunosuppressants, and chemotherapy (6,7). Imatinib and dasatinib for chronic myeloid leukaemia can cause aPAP (7). TKI modulates GM-CSF signalling in monocyte-macrophage lineage cells, which might have exacerbated aPAP (7). Therefore, the administration of the TKI osimertinib can exacerbate PAP. Chemotherapy other than TKIs, such as busulfan, may also stimulate surfactant production by pneumocytes II and impair the macrophage function (8,9), although our patient did not show exacerbated aPAP with alternative chemotherapy administration. However, cases of PAP associated with primary lung cancer have rarely been reported, and the characteristics of these cases remain unclear (4,5). Therefore, we reviewed 10 cases of PAP with lung cancer combined.

We collected 10 previous case reports of PAP with lung cancer combined from the PubMed and the Japan Medical Abstracts Society databases using the keywords “pulmonary alveolar proteinosis lung cancer” (Table) (4,5,10-16). The search was limited to English and Japanese languages only. Among 11 patients, including our patient, the median age was 59 (interquartile range 52-65) years old, and there were 6 men. Only our patient developed PAP after the lung cancer diagnosis; other cases were diagnosed before or simultaneously with lung cancer development. Five cases involved adenocarcinoma, and four cases were squamous cell carcinoma. Only one case involved small-cell carcinoma, and there were no cases with adenocarcinoma and squamous cell carcinoma combined other than in our patient. Seven patients underwent surgery for lung cancer. Our patient and the patient in case 10 received chemotherapy (cisplatin and pemetrexed), and the case 10 patient did not experience chemotherapy-induced aPAP exacerbation. Regarding treatment for PAP, four patients underwent lung lavage, and one patient required extracorporeal membrane oxygenation. Serum GM-CSF autoantibody positivity was reported in four of five cases. PAP in patients with lung cancer was mainly autoimmune; however, the classification of PAP in many patients was unclear because the serum GM-CSF autoantibody levels were not measured.

Table.

Literature Review of Cases of Combined Lung Cancer and Pulmonary Alveolar Proteinosis.

Case	Reference	Year	Age, Sex	Symptoms	Preceding diseases	Histology	Therapy for lung cancer	Therapy for PAP	Anti GM-CSF antibody
1	8	1999	67, M	Cough, sputum, dyspnoea, fever	Simultaneous	SCC	Lobectomy	Lung lavage	N.A.
2	9	2004	59, M	Cough, dyspnoea, fever	Simultaneous	SCC	Lobectomy	Lung lavage +ECMO	N.A.
3	10	2007	54, F	Dyspnoea	PAP	Adeno	Lobectomy	No treatment	Positive
4	10	2007	59, F	Dyspnoea	Simultaneous	Adeno	No treatment	No treatment	N.A.
5	11	2009	66, M	None	PAP	SCC	Lobectomy	Lung lavage	N.A.
6	12	2014	57, M	Cough, sputum	PAP	SCC	Lobectomy	No treatment	Negative
7	13	2015	78, F	None	PAP	Adeno	No treatment	Lung lavage	Positive
8	3	2016	50, M	Cough, dyspnoea	PAP	SCLC	No treatment	Lung lavage	N.A.
9	14	2017	64, F	None	Simultaneous	Adeno	Lobectomy	No treatment	Positive
10	4	2018	47, M	Cough, fever	Simultaneous	Adeno	Wedge resection with mediastinal lymph node sample +chemotherapy	No treatment	N.A.
11	Our case	2022	46, F	Cough, fever	Lung cancer	Adeno+SCC	chemotherapy	No treatment	Positive

PAP: pulmonary alveolar proteinosis, GM-CSF: granulocyte/macrophage colony-stimulating factor, Adeno: adenocarcinoma, SCC: squamous cell carcinoma, SCLC: small cell lung carcinoma

In conclusion, we should perform careful observation for GGOs while administering chemotherapy to patients with lung cancer and PAP. In addition, when lung cancer patients receive TKIs, they should be carefully observed for the development of not only drug-induced pneumonia but also aPAP.

The authors state that they have no Conflict of Interest (COI).