A 65-year-old man presented to our hospital with a cough. The patient was a current smoker. High resolution computed tomography (HRCT) revealed a 28 mm mass shadow in the left lower lobe and enlargement of left hilar, mediastinal, and right subclavian lymph nodes (Fig. 1A). EBUS-TBNA biopsy was performed on the subcarinal lymph node. The patient was diagnosed with left lower lobe lung adenocarcinoma with cT3N3M0 and stage IIIB. Cancer cells showed EGFR wild type and were negative for anaplastic lymphoma kinase (ALK). Immunohistochemical expression of PD-L1 in the EBUS-TBNA biopsy was 98% (Fig. 2A and B). The patient had bilateral deep vein thrombosis (DVT) of the lower limbs and pulmonary microembolism, but he did not show exertional dyspnea and status 0 according to the ECOG Performance Status. The tumor shadow was 40 mm in the largest diameter on chest HRCT performed on the day before pembrolizumab treatment (Fig. 1B). Pembrolizumab (200 mg IV over 30 min) was initiated 22 days after the first visit. The patient's pulse oxygenation on room air worsened from SpO2 98%-90% two days after pembrolizumab administration. On chest HRCT, the primary tumor shadow increased in size to 57 mm, with growing of ground glass shadows (Fig. 1C). Serum KL-6 and lactate dehydrogenase (LDH) levels did not increase. Antibiotics were initiated as we suspected bacterial pneumonia; however, respiratory failure worsened on day 6 after pembrolizumab administration. We suspected interstitial lung disease (ILD) caused by pembrolizumab and started steroid pulse therapy. The ground glass shadow around the tumor improved, but the primary tumor increased in size to 80 mm on chest HRCT on day 21 after pembrolizumab administration (Fig. 1D). SpO2 decreased to 93% (supplementary oxygen mask 4L) on day 21 after pembrolizumab administration. Serum tumor markers were elevated, and the lung cancer progressed very rapidly with a complication of disseminated intravascular coagulation (DIC). Pembrolizumab treatment appeared ineffective; thus, we initiated carboplatin and nanoparticle paclitaxel administration. After the unexpected appearance of significant bloody pleural effusion (Fig. 1E and F), the patient died on day 37 after pembrolizumab administration.
Autopsy was performed 8.5 hours after death which confirmed that the primary tumor of the left lung was in the hilar part of the left lower lobe. Sections showed white, firm, and solid tumor masses in the hilar part of S8 and 9 and almost the entirety of left S4 and S5. Marked thickening of the bronchial wall of the hilar region was observed in the left B8-9 and B4-5, but there was no lumen obstruction. The lymphangitic carcinomatosis was remarkable around the tumor mass and was widespread in the entire left lung. Lymphatic metastasis was observed in the left hilar, para-tracheal, mediastinal, and bilateral cervical lymph nodes. Fresh thromboemboli were found in the main pulmonary artery of the right lower lobe, and there were fresh and organized long thrombi in the right or left femoral veins, which were suspected to be the origin of the pulmonary artery thromboembolism. The lung cancer histology was aggressive mucinous adenocarcinoma and the predominant cancer histology was micropapillary pattern. Widespread alveolar spaces were filled up with cancer cells in the left upper and lower lobes. Histological examination demonstrated lymphangitic carcinomatosis, tumor thrombi in the small pulmonary veins. At autopsy, the bleeding source of left bloody pleural effusion could not be identified. It is thought that the strong lung congestion, dissemination of lung cancer that was found throughout the left pleura, and that bleeding tendency due to DIC were involved. We determined the cause of death to be respiratory failure due to widespread infiltration of lung cancer, which was brought about by HPD after pembrolizumab treatment.
We compared the PD-L1 expression rate of the cancer tissue in the subcarinal lymph node, taken by EBUS-TBNA biopsy (Fig. 2A), to the identical lymph node taken at autopsy. It was 98% in the EBUS-TBNA (Fig. 2B) and less than 1% in the autopsy (Fig. 2C). The PD-L1 expression rate was different in the portions of the primary lung cancer at autopsy, with the highest rate at 10% (Fig. 2D) and the lowest <1% (Fig. 2E). The overall expression rate of the primary tumor at autopsy was approximately 1%. A primary tumor specimen before pembrolizumab administration was not available. PD-L1 expression was measured using a prototype immunohistochemistry assay with an anti-PD-L1 22C3 antibody.