PMC6927588_01
The change of pathological morphology. (A) Jun 2013, postoperative specimens: moderately differentiated adenocarcinoma. (B) Aug 2015, resistant to gefitinib: moderately differentiated adenocarcinoma. (C) Jan 2016, resistant to AZD9291: poorly differentiated carcinoma. (D) Oct 2016, lesion A resistant to EC/IO, SCLC. (E) Oct 2016, lesion B resistant to EC/IO, LADC. (F) April 2017, enlarged lesion of right lung after apatinib, NSCLC.
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Pathological findings were as follows, the tumor was 4.5cmx3cmx3.2cm, moderately differentiated adenocarcinoma (Figure 1A), 6th and 11th hilar mediastinal lymph nodes metastasis and EGFR exon 21 L858R mutant.  The result showed adenocarcinoma (Figure 1B) with EGFR L858R and T790M mutant. Pathology (29th Jan 2016) showed poorly differentiated carcinoma, SCLC according to immunohistochemistry (Napsin A -, TTF 1 +, Syn +) (Figures 1C and 3A). Interestingly, the result showed that one was SCLC (IHC: Napsin A-, TTF-1+, Syn-, CD 56+) (Figures 1D and 3B), and the other was lung adenocarcinoma (IHC: Napsin A+, TTF-1+) (Figures 1E and 3C). NSCLC (Figure 1F). NSE was 18.93ng/mL (Figure 4). 
Four times CT-guide needle biopsy. (A) Jan 2016, CT-guided needle biopsy in the enlarged lesion in his right lung. (B) Oct 2016, CT-guided needle biopsy in lesion A after resistant to IO. (C) Oct 2016, CT-guided needle biopsy in lesion B after resistant to IO. (D) Apr 2017, CT-guided needle biopsy in the enlarged lesion of right lung after apatinib.
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We conducted a CT-guided needle aspiration in the enlarged lesion in his right lung (Figure 2A).  We conducted a CT-guided needle biopsy in two different sites (Figure 2B and C). We conducted a CT-guided needle puncture in the enlarged lesion of the right lung (Figure 2D).
The change of Immunohistochemistry. (A) Jan 2016, resistant to AZD9291, indicated SCLC (IHC: NapsinA-, TTF1+, Syn+). (B) Oct 2016, lesion A after resistant to IO, indicated SCLC (IHC: NapsinA-,TTF-1+, Syn-, CD56+). (C) Oct 2016, lesion B after reistance to IO, indicated adenocarcinoma (IHC: NapsinA+,TTF-1+).
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Pathology (29th Jan 2016) showed poorly differentiated carcinoma, SCLC according to immunohistochemistry (Napsin A -, TTF 1 +, Syn +) (Figures 1C and 3A). Interestingly, the result showed that one was SCLC (IHC: Napsin A-, TTF-1+, Syn-, CD 56+) (Figures 1D and 3B), and the other was lung adenocarcinoma (IHC: Napsin A+, TTF-1+) (Figures 1E and 3C).
Fluctuation of serum NSE and pro-GRP. (A) The fluctuation of serum NSE (12.26 ng/mL at baseline, 38.48 ng/mL, at the time of resistant to AZD9291,45.35 ng/mL at time of resistant to EC after 4 cycles, 17.71 ng/mL at time of response to IO after 2 cycles, 52.9 ng/mL at time of resistant to IO after 4 cycles, 18.17 ng/mL at time of response to abraxane after 4 cycles, 25.09 ng/mL at time of resistant to abraxane after 4 cycles,18.93 ng/mL at time of treatment of apatinib after 6 weeks). (B) The fluctuation of serum pro-GRP (22.35 pg/mL at time of response to IO after 2 cycle, 27.94 pg/mL at time of resistant to IO after 4 cycles, 21.05 pg/mL at time of response to abraxane after 4 cycles, 17.79 pg/mL at time of resistant to abraxane after 4 cycles, 18.94 pg/mL at time of treatment of apatinib after 6 weeks).
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NSE was elevated (38.48ng/mL, normal value range: 0-20ng/mL) (Figure 4). NSE was elevated to 45.35ng/mL (Figure 4). NSE was decreased to the normal range (18.17ng/mL) (Figure 4). NSE was increased to 52.90ng/mL (Figure 4).  NSE was returned to the normal value (18.17ng/mL) (Figure 4). NSE was raised to 25.09ng/mL (Figure 4). NSCLC (Figure 1F). NSE was 18.93ng/mL (Figure 4). 
The change of chest CT after different regimens. (A) PR after 2 cycles of EC (right lower lobe, from 6.71 to 3.1 cm). (B) PD after 4 cycles of EC (right lower lobe, from 2.9 to 3.9 cm). (C) PR after 2 cycles of IO (left upper lobe, from 2.72 to 1.65 cm). (D) PD after 4 cycles of IO (left upper lobe, from 1.9 to 3.1cm). (E) PR after 2 cycles of Abraxane (right lower lobe, from 5.41 to 0.4 cm). (F) PD after 4 cycles of Abraxane (right upper lobe,from 2.8 to 4.0 cm). (G) Shrunken lesion of left lung after Apatinib (left lower lobe,from 3.47 to 2.34 cm). (H) Enlarged lesion at right lung after Apatinib (right upper lobe,from 3.74 to 5.73 cm).
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Response evaluation was PR (after 2 cycles) (Figure 5A). The response evaluation of 4 cycles was PD (Figure 5B). We replaced the EC regimen to irinotecan combined with oxaliplatin (IO),and got PR after 2 cycles (Figure 5C). The disease was progressed after 4 cycles on 19th Oct 2018 (Figure 5D). Abraxane was administered to the subjects after the IO regimen failed and obtained an inspiring efficacy, most lesions exhibited shrinkage (Figure 5E). Chest CT showed disease progression again (Figure 5F). Amusingly, one month later, nearly all lesions were shrunk (Figure 5G), while one solitary lesion at the right lung was enlarged (Figure 5H).
Multiple treatment regimens.. Abbreviations: TP, docetaxel combined with cisplatin. AP, pemetrexed combination with cisplatin. EC, Etoposide combined with carboplatin. IO, irinotecan combined with oxaliplatin. BSC, best support care. ADC, adenocarcinoma. SCLC, small- cell lung cancer.
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He died of respiratory failure on 11th July 2017 (Figure 6).