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REVIEW ARTICLE
Year : 2020  |  Volume : 16  |  Issue : 7  |  Page : 1555-1559

Immune-related organizing pneumonitis in non-small cell lung cancer receiving PD-1 inhibitor treatment: A case report and literature review


1 Department of Oncology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Lung Cancer Institute, Jinan, China
2 Department of Pathology, The People's Liberation Army, No. 960 Hospital, Jinan, China

Date of Submission14-Jul-2020
Date of Decision13-Oct-2020
Date of Acceptance22-Dec-2020
Date of Web Publication9-Feb-2021

Correspondence Address:
Jun Wang
Department of Oncology, The First Affiliated Hospital of Shandong First Medical University; Shandong Lung Cancer Institute, Jinan
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_971_20

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 > Abstract 


Immune checkpoint blockade with programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) inhibitors has been standard care for metastatic nonsmall cell lung cancer (NSCLC) and after progression using first-line platinum-containing chemotherapy. Although several management guidelines exist for immune checkpoint inhibitor-induced toxicities, uncommon, complicated, and life-threatening immune-related adverse events remain challenging for oncologists. In this report, we presented a male patient with NSCLC who received pembrolizumab during disease progression. He developed interstitial pembrolizumab-induced organizing pneumonia (OP). The patient received 9 months of anti-PD-1 pembrolizumab when he presented with dry cough and fatigue. The patient developed a solitary nodular lung lesion mimicking a newly occurred metastatic lesion in the lung without a significant circulating tumor marker increase. Sputum analysis was negative for acid-fast bacilli and fungi. A computed tomography-guided percutaneous lung biopsy was conducted and showed alveolar fibrous thickness and various lymphocyte infiltration. Immunotherapy-related OP was identified, and he subsequently responded well to corticosteroids. This case describes a clinical situation, where PD-1-induced OP is radiologically similar to NSCLC disease progression in the lungs. Oncologists should be aware of uncommon pulmonary PD-1/PD-L1 inhibitor toxicity. Lung biopsy may help to distinguish immune-related pneumonitis, lung infections, and progressive nodular lesions.

Keywords: immune checkpoint inhibitor, immune-related adverse event, nonsmall cell lung cancer, organizing pneumonia, programmed cell death 1 inhibitor, programmed cell death ligand 1


How to cite this article:
Yin B, Xiao J, Li J, Liu X, Wang J. Immune-related organizing pneumonitis in non-small cell lung cancer receiving PD-1 inhibitor treatment: A case report and literature review. J Can Res Ther 2020;16:1555-9

How to cite this URL:
Yin B, Xiao J, Li J, Liu X, Wang J. Immune-related organizing pneumonitis in non-small cell lung cancer receiving PD-1 inhibitor treatment: A case report and literature review. J Can Res Ther [serial online] 2020 [cited 2021 Apr 15];16:1555-9. Available from: https://www.cancerjournal.net/text.asp?2020/16/7/1555/308776




 > Introduction Top


Immune checkpoint blockade with programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) inhibitors has changed the therapeutic strategy for advanced lung cancer. Anti-PD-1/PD-L1 immunotherapy works by disrupting PD-1 and PD-L1 direct interactions in the tumor microenvironment and reactivates an immune cell antitumor response.[1] In phase III studies, advanced nonsmall cell lung carcinoma (NSCLC) patients benefit from second-line PD-1/PD-L1 therapy in comparison to those treated with second-line docetaxel monotherapy.[2],[3],[4],[5],[6] Currently, immune checkpoint blockade and combination immunotherapy have been the standard care for metastatic NSCLC and progression after first-line platinum-containing chemotherapy.[7],[8]

Although immune checkpoint inhibitors are generally viewed as tolerable medications, 10%–15% of patients will develop grade 3–4 toxicity known as immune-related adverse events (irAEs), including dermatitis, colitis, hepatitis, and pneumonitis.[9] Immune-related toxicities are distinct from chemotherapy or targeted drug-induced adverse events. Among them, pneumonitis is reported in 5% of patients with lung cancer receiving PD-1/PD-L1 therapy, and severe pneumonitis is potentially fatal or life-threatening.[10],[11] Pneumonitis is more frequent in patients treated with anti-PD-1/PD-L1 antibodies compared to anticytotoxic T-lymphocyte-associated protein 4 antibodies.[12],[13] The clinical and radiologic characteristics of pulmonary toxicity are diverse and complicated. Patients with PD-1/PD-L1 inhibitor-related pneumonitis may present clinically with drug cough, dyspnea, fever, and chest pain; but radiologic findings often are nonspecific.[10],[11] As a result, it is tough to predict immune-related pneumonitis. Several management guidelines for immune checkpoint inhibitor-related toxicities have been established. However, uncommon, complicated, and life-threatening immune-related adverse effects remain a challenge for oncologists.[14],[15],[16] Here, we reported a case with NSCLC who received pembrolizumab during disease progression. He developed interstitial pneumonitis with features of pembrolizumab-induced organizing pneumonia (OP), mimicking disease progression.


 > Case Report Top


A 62-year-old Chinese male patient was initially presented with right upper lung cancer at Qilu Hospital, Shandong University in September 2017. Preoperative computed thermotropy (CT) and magnetic resonance imaging demonstrated that he did not have distant metastatic lesions. He subsequently received a right upper lobectomy with mediastinal lymph node dissection and was diagnosed with right upper lobe infiltrating adenocarcinoma, acinar type, with a primary tumor size of 2.0 cm × 1.7 cm × 1.5 cm. Six hilar lymph nodes and one subcarinal lymph node were positive. His final pathological stage was pT1N2M0. Gene mutation analysis showed no somatic mutations in the epidermal growth factor receptor, anaplastic lymphoma kinase, or c-ros oncogene 1. However, a transition mutation in KRAS exon 2 codon 12 was found. He subsequently completed six cycles of adjuvant chemotherapy with pemetrexed and cisplatin from October 2017 to March 2018. In July 2018, the patient complained of right iliac regional pain, and subsequent positron emission tomography-computed tomography (CT) revealed extensive bone metastases in the right iliac acetabulum, sacroiliac joint, right sacrum, and bilateral ilium. The patient was given a first-line treatment of pemetrexed and carboplatin. Unfortunately, the patient's pain did not relieve after two chemotherapy cycles and presented with disease progression with newly occurred mediastinal and retroperitoneal lymph node metastases.

In October 2018, the patient was referred to No. 960 Hospital, The People's Liberation Army for further lung cancer treatment. An additional immunohistochemistry assay (VENTANA PD-L1 SP142 Assay) showed his tumor had strong PD-L1 expression in 55% of the tumor cells. Therefore, we initiated a second-line anti-PD-1 antibody pembrolizumab (200 mg) immunotherapy. He experienced a clinical improvement without any evidence of disease progression. After nine cycles of pembrolizumab, he was stable according to solid tumor response evaluation criteria (version 1.1 [RECIST1.1]) but developed new dry cough and fatigue symptoms. A chest CT scan indicated a new lesion with a solitary thick-walled cavity in the right lung [Figure 1]a and [Figure 1]b. Metastatic pulmonary lesions were suspected at the time, but immune-related pneumonitis and secondary infection needed to be excluded. HIV, CMV, and EB virus tests were negative. Blood routine analysis, liver function, renal function, and C-reactive protein level (3.2 mg/L) were normal. However, serum carcinoembryonic antigen levels were elevated (CEA; 9.0 μg/L). Sputum analysis and T-SPOT.TB assay was negative for acid-fast bacilli and fungi. Bronchoalveolar lavage (BAL) showed lymphocytosis in 29% of lymphocytes, without any evidence of infection according to microbiological cultures and polymerase chain reaction of the patient's BAL fluid. Sputum culture did not find any causative microorganisms. Accordingly, a CT-guided transcutaneous lung biopsy was conducted to identify whether the lesion was infectious or immunotherapy related. Lung specimen pathology showed alveolar fibrous thickness and various lymphocyte infiltrations [Figure 2]. OP was identified according to Naidoo's criteria that summarized checkpoint inhibitor-associated pneumonitis as five subtypes.[9] No fungi or malignant cells were found. At the time, the patient was thought to have grade 2 immunotherapy-related pneumonitis. The immunotherapy was stopped and he was treated continuously with oral prednisolone (1 mg/kg/day) according to the Society for Immunotherapy of Cancer's guide to managing immunotherapy toxicity.[16] His symptoms improved over 2 weeks, with a significant inflammatory lesion improvement [Figure 1]c. The prednisolone was tapered back to a 0.5 mg/kg/day dose within 1 week. Steroids were not used for more than 4 weeks, and he was not treated with antibiotics.
Figure 1: Immune-related pneumonitis following treatment with a PD-1 inhibitor. (a) After 7 months of pembrolizumab, a chest CT image showed a small ground-glass opacity in the right lung. (b) After 9 cycles of pembrolizumab, a CT scan of the chest indicated an obvious new lesion accompanied by a solitary thick-walled cavity in the right lung. Metastatic pulmonary node was suspected, but immune-related pneumonitis and secondary infections needed to be distinguished. (c) After immunotherapy-related pneumonitis was identified, this patient was treated continuously with oral prednisolone. His symptoms improved over 2 weeks. CT: Computed tomography

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Figure 2: Nodular lung lesion histology by percutaneous lung biopsy. (a) The alveolar fibrous thickness and various lymphocyte infiltrations were found, suggesting pembrolizumab-induced pneumonitis accompanied with OP (H and E, ×100). (b) CD3+ cell immunohistochemical analysis in inflammatory lesions (×400). (c) CD4+ cell staining (×200). (d) CD8+ cell staining (×200). (e) PD-L1 in inflammatory lesion staining (×200). (f) PD-L2 in inflammatory lesion staining (×200). OP: Organizing pneumonia

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 > Discussion Top


Recent advances with checkpoint inhibitors in the cancer immunotherapy field have contributed to a paradigm shift in metastatic NSCLC treatment. Several checkpoint inhibitors have emerged as lung cancer therapy standard care in first- and second-line settings. Systematic host immune system reactivation results in cancer cell rejection but may be potentially harmful to healthy tissues and organs by autoimmune inflammation. The majority of irAEs are manageable, including cutaneous, hepatic, gastrointestinal, and endocrine toxic events. However, some immune-related toxicities that occur in the heart, lungs, liver, and nerve system are potentially fatal and life threatening. Among them, immune-related pulmonary adverse events are reported in 5% of NSCLC patients treated with immune checkpoint inhibitors. Severe pulmonary toxicity and pneumonitis-related death have been reported in cancer patients treated with PD-1/PD-L1 inhibitors, particularly in lung cancer patients. Preexisting pulmonary damage from prior inflammation, radiation, idiopathic pulmonary diseases, chemotherapy, or tyrosine kinase inhibitors, as well as increased tumor burden, may increase developing pneumonitis risk.[10],[11],[17],[18] Recently, a retrospective study showed that if a patient with developed immune-related pneumonitis also had a history of chest radiotherapy, they were more likely to be treated with curative-intent instead of palliative-intent chest radiotherapy.[19] Our previous reports showed that sequential use with different PD-1/PD-L1 inhibitors increased the risk to develop high-grade or steroid-resistant pneumonitis in NSCLC patients.[20] This strategy demonstrated the efficacy in a subset of patients with long progression-free survival or irAE occurrence in the first immune checkpoint inhibitor.[21]

Immune-related pneumonitis is viewed as an exclusion diagnosis, and other competing causes for similar clinical presentation should be considered or excluded, including lung infections, as well as specific clinical presentation and lung disease progression [Table 1]. First, opportunistic infections by bacteria, viruses, fungi, or parasites should be considered.[29] It is also necessary to differentiate between pulmonary disease progression and interstitial pneumonia. In particular, in OP and granuloma-forming interstitial pneumonia, sarcoidosis-like granulomas induced by immunotherapy can mimic tumor progression in advanced NSCLC and melanoma.[22],[23],[24],[25],[26],[27] The onset of these lung lesions mimicking disease progression developed within 3 weeks to 24 months after immunotherapy initiation. Once an immune-related pneumonitis diagnosis is made, patients will receive steroid treatment and usually respond favorably. Our case describes pembrolizumab-induced OP, which mimics progressive lung disease. The patient responded well to steroid treatment. Therefore, the clinical and radiographical presentations may be similar to pseudoprogression following immunotherapy with immune checkpoint inhibitors. However, the lung lesion dynamic, as well as the patients' symptoms and signs need to still be monitored. Following the grade 2 immunotherapy-related pneumonitis diagnosis, immunotherapy should be stopped, and steroid therapy should be initiated according to published guidelines. If improvement is not observed, infliximab by intravenous drip, mycophenolate mofetil, or immunoglobulin by intravenous injection should be considered.[14],[15],[16]
Table 1: Reported case summary distinguishing between immune-related pneumonitis and disease progression in the lungs

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Sometimes, patients do not develop immune-related pneumonitis, but present with real disease progression, presenting a complication in clinical practice. For example, interstitial shadows in the lungs can be diagnosed as lymphangitis carcinomatosa instead of interstitial pneumonitis in NSCLC patients treated with pembrolizumab.[28] Thus, it is not easy to distinguish pulmonary disease progression from immune-related pneumonitis to make accurate treatment decisions accordingly. Clinical signs can aid in immune-related pneumonitis diagnosis and help avoid being mistaken for recurrent or metastatic disease. This includes pulmonary parenchyma radiologic findings with or without hilar lymphadenopathy and paratracheal lymphadenopathy, as well as elevated serum tumor marker levels.[30] In a case study reported by Dall'Olio et al., serum CEA was within the normal range when lung nodular lesions occurred with complete brain metastasis response, suggesting immune-related pulmonary toxicity.[25] In our case, the CEA level was slightly elevated, indicating a low likelihood of true disease progression. Finally, transcutaneous lung biopsy or transbronchial lung biopsy histopathology is recommended to confirm immune-related pneumonitis or metastatic disease. Furthermore, it is not unknown whether gene mutations or PD-L1 expression could impact the interstitial pneumonitis occurrence that mimics pulmonary disease progression. Genetic background and PD-L1 expression were not reported in a majority of cases, but our present case carried a KRAS mutant with strong PD-L1 expression. In the future, a variety of potential biomarkers from different sources would be used to predict or monitor immune checkpoint-related pneumonitis and other severe toxicities, including tumor genetic alterations, tumor microenvironment, and host genetic background.[31]

Overall, our case report highlights the importance of attentive surveillance for immune-related adverse events when initiating immune checkpoint inhibitor treatment. The occurrence of immunotherapy-induced OP with a feature of consolidation or other pulmonary lesions should be differentiated from lung disease progression in patients with advanced tumors, particularly in lung cancer patients.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

This work was supported by National Natural Science Foundation of China (Grant No. 81572875), CSCO-MSD Cancer Research Foundation (Grant No. Y-MSD2020-0350), CSCO-PILOT Cancer Research Foundation (Grant No. Y-2019AZMS-0440), and Wu Jieping Medical Foundation for Clinical Scientific Research (Grant No. 320.6750.2020-12-16).

Conflicts of interest

There are no conflicts of interest.



 
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