Bilateral lung cancer showing various responses to immune checkpoint inhibitors: A case report

Abstract

Background

Combination immune checkpoint inhibitor (ICI) therapy has become the mainstay in cancer treatment, and the various antitumor effects of ICIs are being observed. Synchronous multiple primary lung cancers (SMPLCs), which simultaneously involve tumors of different histologies, are often encountered in clinical settings. In standard lung cancer treatment, an anticancer drug, usually a platinum‐based drug, is administered, and this first treatment provides some antitumor effect. Thus, the initial administration of platinum‐based anticancer agent may mask the detection of SMPLCs. The following case represents different antitumor effects on two different primary lung lesions during treatment with ICIs.

Case presentation

A 72‐year‐old man was referred to our hospital for an abnormal chest shadow, and computed tomography showed masses in the left lower and right upper lungs. Transbronchial lung biopsy from the left lung tumor revealed an adenocarcinoma. Following the administration of pembrolizumab (200 mg/body over 3 weeks) as monotherapy, the tumor in the left lung rapidly reduced in size. However, the tumor in the right upper lung continued to grow. Finally, his disease was diagnosed as SMPLCs of adenocarcinoma and small cell lung cancer.

Conclusion

Bilateral lung lesions considered to be intrapulmonary metastases have completely different responses to ICI treatment. It is necessary to consider a diagnosis of SMPLCs if lesions with different responses to antitumor therapy are observed.

1. INTRODUCTION

Diagnoses of synchronous multiple primary lung cancer (SMPLC) are increasing due to the aging population and improvement in diagnostic methods. ¹ , ² However, the diagnosis of SMPLC still has many obstacles, especially in distinguishing it from lung cancer metastasis.

Recently, many immune checkpoint inhibitors (ICIs) have become available in addition to nivolumab for lung cancer treatment. The response to ICIs is different from that to conventional chemotherapy; therefore, its antitumor effect needs to be observed further. SMPLC requires to be differentiated from multiple primary lung cancer. Here, we describe a case of SMPLC with different morphological patterns (adenocarcinoma and small cell lung cancer [SCLC]), treated with pembrolizumab monotherapy.

2. CASE

A 72‐year‐old man visited our hospital with abnormal lung shadow (Figure 1A) and shortness of breath. He had a 20‐year history of a giant bulla in the right upper lung with a smoking history of 50 pack‐years. His shortness of breath and weight loss had been exacerbated over several months, and computed tomography (CT) showed masses in the left lower and right upper lung (Figure 1B,C). The carcinoembryonic antigen level was in the normal range, but neuron‐specific enolase and pro‐GRP levels were slightly high (36.9 ng/mL and 55.2 pg/mL, respectively). The possibility of SMPLCs was discussed at ground rounds. For small cell lung cancer, the mediastinal lymph nodes were not swollen and could not be diagnosed with EBUS. Transbronchial lung biopsy had been performed only for the left tumor because of the high risk of pneumothorax in the right upper lung. It was pathologically diagnosed as adenocarcinoma without any driver gene mutation (Figure 2). Thus, we decided to consider treatment for adenocarcinoma. It was not possible to determine if either of the bilateral giant tumors was the primary tumor. Enhanced‐CT shows swollen bilateral hilum and subbronchial lymph node (#7) swelling, and although it is unclear which is the primary, we consider it as contralateral lymphadenopathy. Finally, we established the clinical stage as T4N3M1a stage IVA. Programmed death‐ligand 1 (PD‐L1) immunostaining showed high expression (tumor proportion score: 100%) (Figure 2). Following the treatment guideline, pembrolizumab (200 mg/body over 3 weeks) monotherapy was administered starting December 16, 2017.

FIGURE 1.

Imaging findings at first consultation: A, Chest radiograph, posterior to anterior view, showing multiple bilateral nodules. B,C, CT showed masses in the left lower and right upper lung

FIGURE 2.

Transbronchial lung biopsy staining: A, Hemato & Eosin staining; B, TTF‐1; C, Napsin A; D, PD‐L1(22C3). The adenocarcinoma was diagnosed based on the adenocarcinoma morphology of A, H & E staining and B,C, TTF‐1 and NapsinA positivity. D, In the same site staining of PD‐L1, TPS was 100% and the result was strongly positive

After pembrolizumab administration, the tumor on the left side rapidly reduced in size. However, the tumor in the right upper lung continued to grow, and the fluid inside the bulla in the upper right lung had increased within mon month (Figure 3A,B). Initially, we administered antibiotics for intrabulla infection pf COPD for a week. Considering the acute exacerbation caused by COPD, we administered steroids. Even if it is pseudoprogression, it is a treatment considering the expectation of volume reduction by steroid administration. However, the size of the right tumor progressed, and pleural effusion developed only for right side. Pleural effusion drainage was performed, and cytological examination of the pleural effusion showed malignant cells characteristic of SCLC. Although the tumor in the left lung had completely disappeared, the patient's general condition deteriorated rapidly, and he died on March 8, 2018.

FIGURE 3.

CT findings treatment course: A, Pre‐treatment; B, Post‐treatment. A, In pre‐treatment, tumors are found in both lungs (upper right lobe, lower left lobe). B, In post‐treatment, the left lower lung tumor disappeared, but the right upper lung tumor grew and effusion was found in the bulla

Pathological autopsy was performed 1 day after his death. The tumor in the left lung had completely disappeared, while that in the right upper lung showed characteristics of SCLC. Multiple lesions having the same small cell‐like characteristics were also found in the liver (Figure 4). Finally, he was diagnosed as having SMPLCs, with adenocarcinoma in the left lower lung and SCLC in the right upper lung.

FIGURE 4.

Autopsy: A, Right upper lung tumor; B, Left lower lung tumor; C, Liver metastasis. A, At autopsy, small cell lung cancer was observed in the upper right lung tumor, but the left tumor had completely disappeared. Small cell lung cancer was also observed from the metastasis to the liver

3. DISCUSSION

SMPLCs are rare, with reported incidence rates of approximately 0.2% to 20%. ³ , ⁴ , ⁵ When different primary lesions are present in the same organ, they are often mistaken as metastases. Many SMPLCs have been reported in combination with Non‐small cell lung cancer. ⁶ The combination of SCLC and adenocarcinoma is a relatively rare cases. ⁷ , ⁸ , ⁹

Our patient had a high initial NSE value of 36.9 ng/mL (<16.3 ng/mL), and the differentiation of small cell lung cancer at the time of pretreatment diagnosis should have been done more carefully. A higher NSE value is noted in extensive disease than in limited disease (LD); moreover, the chances of LD were considered relatively high from the time of diagnosis. ¹⁰ , ¹¹ However, there was no mediastinal lymphadenopathy typical of SCLC, and one should reflect on the point that a biopsy of the right tumor lesion was not performed.

The course of treatment was the exact opposite of the tumor control obtained with immunotherapy of NSCLC. SCLC‐specific aggressive progression, due to rapid disease progression, was performed following the treatment. Assessing SMPLC with SCLC may be considered more important during the time of diagnosis than during the treatment process.

Presently, ICIs and chemotherapy combination treatment can be used as primary treatment for advanced non‐SCLC (NSCLC). ¹² Considering the fact that the patient was treated before the approval of combination therapy, pembrolizumab monotherapy was administered as the primary treatment. ¹³

If chemotherapy in combination with ICIs had been administered to this patient as first‐line treatment, it may have had an antitumor effect. However, this effect may have been temporary. Regardless of the treatment method, if the tumors respond differently in the course of treatment, tissue biopsy should be attempted, despite the risks. But SCLC has a rapid progression and a poor prognosis, it is considered that chemotherapy + atezorizumab combination is recommended for NSCLC and SCLC double cancer.

ICIs have been reported to have good results in treating SCLC, including pembrolizumab monotherapy in PD‐L1‐positive patients, ¹⁴ and have already changed the clinical treatment of SCLC. ¹⁵ If the patient had been exactly diagnosed as SMPLCs before treatment, CBDCA + ETP + atezolizumab, which is now available but not was available at the time of diagnosis, would have been the treatment option. It is probable that the resulting antitumor effect would have been superior to that obtained with ICI monotherapy. However, only 30% to 40% of SCLC cases are PD‐L1‐positive. In this case, the SCLC was treated with pembrolizumab, but no antitumor effect was observed. PD‐L1 immunohistochemistry was performed later using an autopsy sample, which was negative. From the negative result, it is considered that there was no expression.

Although chemotherapy combined with ICIs has become the mainstay treatment for NSCLC, elderly patients with high expression of PD‐L1 or who cannot tolerate combination therapy due to renal dysfunction may receive ICI monotherapy. Under single‐agent immunotherapy, it is necessary to consider the diagnosis of SMPLC if lesions with various responses to antitumor therapy are observed.

CONFLICT OF INTEREST

The authors have no conflicts of interest to declare.

AUTHOR CONTRIBUTIONS

All authors had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Conceptualization, H.K.; Writing ‐ Original draft, H.K.; Data curation, T.I.; Investigation, R.I.; Visualization, R.I.; Supervision, T.S.; Validation, T.S.; Data curation, H.I.; Conceptualization, Y.H.; Data curation, Y.H.; Methodology, Y.H.; Project administration, Y.H.; Supervision, Y.H.; Writing ‐ Review and Editing, Y.H.

ETHICS STATEMENT

The son of the patient provided consent for the use of the medical information of this case for research and publication on July 7, 2019.

Kodama H, Ibe T, Inoue R, Shimada T, Ishii H, Hamamoto Y. Bilateral lung cancer showing various responses to immune checkpoint inhibitors: A case report. Cancer Reports. 2020;3:e1272. 10.1002/cnr2.1272

DATA AVAILABILITY STATEMENT

The patient data used in the current case report are available from the corresponding author on reasonable request.