Research progress on combined small cell lung cancer_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

ZHANG Jishen ¹ , JIN Defeng ² ,  WEI Yutao ^2,3

1. School of Clinical Medicine (Affiliated Hospital), Jining Medical University, Jining, 272000, Shandong, P. R. China;
2. Department of Thoracic Surgery, Jining No. 1 People’s Hospital, Jining, 272000, Shandong, P. R. China;
3. Institute of Thoracic Diseases, Jining Medical Science Academy, Jining, 272000, Shandong, P. R. China;

Corresponding author：

WEI Yutao, Email: wytgyh@163.com

Keywords：

Combined small cell lung cancer; small cell lung cancer; lung cancer; pathology; review

DOI：

10.7507/1007-4848.202507042

Video：

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Abstract Full text Figures/Tables Video References Cited by

Combined Small Cell Lung Cancer (C-SCLC) is a relatively rare type of lung cancer, which involves a combination of small cell carcinoma (SCLC) and any type of non-small cell lung cancer (NSCLC) histological components. The incidence of C-SCLC is increasing, with a higher proportion of affected patients being male and having a history of smoking. Currently, the diagnosis of C-SCLC is mainly based on pathology, and the most common pathological types of the coexisting non-small cell carcinoma components are squamous cell carcinoma and adenocarcinoma. Several studies have identified EGFR, TP53, and RB1 gene mutations, as well as high expression of YAP1, are potential biomarkers of C-SCLC. Treatment options for C-SCLC include surgery, chemotherapy, and radiotherapy in combination. For early-stage C-SCLC, surgical resection is the most effective method, while for patients in the middle or late stages who miss the surgical opportunity, chemotherapy and radiotherapy offer the most benefit. Currently, immunotherapy and targeted therapy show certain potential in the treatment of C-SCLC patients.

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2.	Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2024, 74(3): 229-263.
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6.	Men Y, Hui Z, Liang J, et al. Further understanding of an uncommon disease of combined small cell lung cancer: clinical features and prognostic factors of 114 cases. Chin J Cancer Res, 2016, 28(5): 486-494.
7.	Guo Y, Yang L, Liu L, et al. Comparative study of clinicopathological characteristics and prognosis between combined and pure small cell lung cancer (SCLC) after surgical resection. Thorac Cancer, 2020, 11(10): 2782-2792.
8.	Zhu Y, Li S, Wang H, et al. Molecular subtype expression and genomic profiling differ between surgically resected pure and combined small cell lung carcinoma. Hum Pathol, 2023, 141: 118-129.
9.	Wang X, Guo Y, Liu L, et al. YAP1 protein expression has variant prognostic significance in small cell lung cancer (SCLC) stratified by histological subtypes. Lung Cancer, 2021, 160: 166-174.
10.	Li Y, Wang Y, Zhou W, et al. Different clinical characteristics and survival between surgically resected pure and combined small cell lung cancer. Thorac Cancer, 2022, 13(19): 2711-2722.
11.	Tatematsu A, Shimizu J, Murakami Y, et al. Epidermal growth factor receptor mutations in small cell lung cancer. Clin Cancer Res, 2008, 14(19): 6092-6096.
12.	Lu HY, Sun WY, Chen B, et al. Epidermal growth factor receptor mutations in small cell lung cancer patients who received surgical resection in China. Neoplasma, 2012, 59(1): 100-104.
13.	Zhang J, Zhang L, Luo J, et al. Comprehensive genomic profiling of combined small cell lung cancer. Transl Lung Cancer Res, 2021, 10(2): 636-650.
14.	Luo Y, Hui ZG, Yang L, et al. Clinical analysis of 80 patients with combined small-cell lung cancer. Chin J Lung Cancer, 2015, 18(3): 161-166.
15.	Qin J, Lu H. Combined small-cell lung carcinoma. Onco Targets Ther, 2018, 11: 3505-3511.
16.	Zhang C, Yang H, Zhao H, et al. Clinical outcomes of surgically resected combined small cell lung cancer: a two-institutional experience. J Thorac Dis, 2017, 9(1): 151-158.
17.	Wallace AS, Arya M, Frazier SR, et al. Combined small-cell lung carcinoma: an institutional experience. Thorac Cancer, 2014, 5(1): 57-62.
18.	Nicholson SA, Beasley MB, Brambilla E, et al. Small cell lung carcinoma (SCLC): a clinicopathologic study of 100 cases with surgical specimens. Am J Surg Pathol, 2002, 26(9): 1184-1197.
19.	Lu HY, Mao WM, Cheng QY, et al. Mutation status of epidermal growth factor receptor and clinical features of patients with combined small cell lung cancer who received surgical treatment. Oncol Lett, 2012, 3(6): 1288-1292.
20.	Moon SW, Seo JH, Jeon HW, et al. Effect of histological subtype and treatment modalities on T1-2 N0-1 small cell lung cancer: a population-based study. Thorac Cancer, 2019, 10(5): 1229-1240.
21.	Hajmanoochehri F, Mohammadi N, Zohal MA, et al. Epidemiological and clinicopathological characteristics of lung cancer in a teaching hospital in Iran. Asian Pac J Cancer Prev, 2014, 15(6): 2495-2500.
22.	Luo J, Ni J, Zheng H, et al. Clinical analysis of 88 cases with combined small cell carcinoma. Tumor, 2009, 29(2): 156-159.
23.	Mangum MD, Greco FA, Hainsworth JD, et al. Combined small-cell and non-small-cell lung cancer. J Clin Oncol, 1989, 7(5): 607-612.
24.	Ganti A, Loo BW, Bassetti M, et al. Small cell lung cancer, version 2. 2022, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw, 2021, 19(12): 1441-1464.
25.	Verma V, Choi JI, Simone CN. Proton therapy for small cell lung cancer. Transl Lung Cancer Res, 2018, 7(2): 134-140.
26.	Yang CF, Chan DY, Speicher PJ, et al. Role of adjuvant therapy in a population-based cohort of patients with early-stage small-cell lung cancer. J Clin Oncol, 2016, 34(10): 1057-1064.
27.	Lei Y, Feng H, Qiang H, et al. Clinical characteristics and prognostic factors of surgically resected combined small cell lung cancer: a retrospective study. Lung Cancer, 2020, 146: 244-251.
28.	Liu J, Cao Y, Shao T, et al. Exploring the prognostic impact of differences in treatment strategies for SCLC with different histologies and prognostic factors for C-SCLC: a SEER population-based study. Heliyon, 2024, 10(12): e32907.
29.	He J, Xu S, Pan H, et al. Treatments for combined small cell lung cancer patients. Transl Lung Cancer Res, 2020, 9(5): 1785-1794.
30.	Zhao X, McCutcheon JN, Kallakury B, et al. Combined small cell carcinoma of the lung: is it a single entity? J Thorac Oncol, 2018, 13(2): 237-245.
31.	Cai S, Yang W, Luo H, et al. Clinical features and prognostic factors of IV combined small cell lung cancer: a propensity score matching analysis. PLoS One, 2024, 19(11): e313221.
32.	Riely GJ, Wood DE, Ettinger DS, et al. Non-small cell lung cancer, version 4. 2024, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw, 2024, 22(4): 249-274.
33.	Luo J, Wu FY, Li AW, et al. Comparison of vinorelbine, ifosfamide and cisplatin (NIP) and etoposide and cisplatin (EP) for treatment of advanced combined small cell lung cancer (cSCLC) patients: a retrospective study. Asian Pac J Cancer Prev, 2012, 13(9): 4703-4706.
34.	Zhou C, Li YY, Yang DX, et al. Comparison of therapeutic efficacy of different chemotherapeutic regimens on combined small cell lung cancer. Chin J Clin Oncol, 2015, 42(2): 91-95.
35.	Cheng Y, Chen J, Zhang W, et al. Benmelstobart, anlotinib and chemotherapy in extensive-stage small-cell lung cancer: a randomized phase 3 trial. Nat Med, 2024, 30(10): 2967-2976.
36.	Kim SY, Park HS, Chiang AC. Small cell lung cancer: a review. JAMA, 2025, 333(21): 1906-1917.
37.	Horn L, Mansfield AS, Szczesna A, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med, 2018, 379(23): 2220-2229.
38.	Paz-Ares L, Dvorkin M, Chen Y, et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet, 2019, 394(10212): 1929-1939.
39.	Wang Y, Xu J, Han B, et al. The role of prophylactic cranial irradiation in surgically resected combined small cell lung cancer: a retrospective study. J Thorac Dis, 2018, 10(6): 3418-3427.

1. Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2022. CA Cancer J Clin, 2022, 72(1): 7-33.
2. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2024, 74(3): 229-263.
3. Nicholson AG, Tsao MS, Beasley MB, et al. The 2021 WHO classification of lung tumors: impact of advances since 2015. J Thorac Oncol, 2022, 17(3): 362-387.
4. Travis WD, Brambilla E, Burke AP, et al. Introduction to the 2015 World Health Organization classification of tumors of the lung, pleura, thymus, and heart. J Thorac Oncol, 2015, 10(9): 1240-1242.
5. Babakoohi S, Fu P, Yang M, et al. Combined SCLC clinical and pathologic characteristics. Clin Lung Cancer, 2013, 14(2): 113-119.
6. Men Y, Hui Z, Liang J, et al. Further understanding of an uncommon disease of combined small cell lung cancer: clinical features and prognostic factors of 114 cases. Chin J Cancer Res, 2016, 28(5): 486-494.
7. Guo Y, Yang L, Liu L, et al. Comparative study of clinicopathological characteristics and prognosis between combined and pure small cell lung cancer (SCLC) after surgical resection. Thorac Cancer, 2020, 11(10): 2782-2792.
8. Zhu Y, Li S, Wang H, et al. Molecular subtype expression and genomic profiling differ between surgically resected pure and combined small cell lung carcinoma. Hum Pathol, 2023, 141: 118-129.
9. Wang X, Guo Y, Liu L, et al. YAP1 protein expression has variant prognostic significance in small cell lung cancer (SCLC) stratified by histological subtypes. Lung Cancer, 2021, 160: 166-174.
10. Li Y, Wang Y, Zhou W, et al. Different clinical characteristics and survival between surgically resected pure and combined small cell lung cancer. Thorac Cancer, 2022, 13(19): 2711-2722.
11. Tatematsu A, Shimizu J, Murakami Y, et al. Epidermal growth factor receptor mutations in small cell lung cancer. Clin Cancer Res, 2008, 14(19): 6092-6096.
12. Lu HY, Sun WY, Chen B, et al. Epidermal growth factor receptor mutations in small cell lung cancer patients who received surgical resection in China. Neoplasma, 2012, 59(1): 100-104.
13. Zhang J, Zhang L, Luo J, et al. Comprehensive genomic profiling of combined small cell lung cancer. Transl Lung Cancer Res, 2021, 10(2): 636-650.
14. Luo Y, Hui ZG, Yang L, et al. Clinical analysis of 80 patients with combined small-cell lung cancer. Chin J Lung Cancer, 2015, 18(3): 161-166.
15. Qin J, Lu H. Combined small-cell lung carcinoma. Onco Targets Ther, 2018, 11: 3505-3511.
16. Zhang C, Yang H, Zhao H, et al. Clinical outcomes of surgically resected combined small cell lung cancer: a two-institutional experience. J Thorac Dis, 2017, 9(1): 151-158.
17. Wallace AS, Arya M, Frazier SR, et al. Combined small-cell lung carcinoma: an institutional experience. Thorac Cancer, 2014, 5(1): 57-62.
18. Nicholson SA, Beasley MB, Brambilla E, et al. Small cell lung carcinoma (SCLC): a clinicopathologic study of 100 cases with surgical specimens. Am J Surg Pathol, 2002, 26(9): 1184-1197.
19. Lu HY, Mao WM, Cheng QY, et al. Mutation status of epidermal growth factor receptor and clinical features of patients with combined small cell lung cancer who received surgical treatment. Oncol Lett, 2012, 3(6): 1288-1292.
20. Moon SW, Seo JH, Jeon HW, et al. Effect of histological subtype and treatment modalities on T1-2 N0-1 small cell lung cancer: a population-based study. Thorac Cancer, 2019, 10(5): 1229-1240.
21. Hajmanoochehri F, Mohammadi N, Zohal MA, et al. Epidemiological and clinicopathological characteristics of lung cancer in a teaching hospital in Iran. Asian Pac J Cancer Prev, 2014, 15(6): 2495-2500.
22. Luo J, Ni J, Zheng H, et al. Clinical analysis of 88 cases with combined small cell carcinoma. Tumor, 2009, 29(2): 156-159.
23. Mangum MD, Greco FA, Hainsworth JD, et al. Combined small-cell and non-small-cell lung cancer. J Clin Oncol, 1989, 7(5): 607-612.
24. Ganti A, Loo BW, Bassetti M, et al. Small cell lung cancer, version 2. 2022, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw, 2021, 19(12): 1441-1464.
25. Verma V, Choi JI, Simone CN. Proton therapy for small cell lung cancer. Transl Lung Cancer Res, 2018, 7(2): 134-140.
26. Yang CF, Chan DY, Speicher PJ, et al. Role of adjuvant therapy in a population-based cohort of patients with early-stage small-cell lung cancer. J Clin Oncol, 2016, 34(10): 1057-1064.
27. Lei Y, Feng H, Qiang H, et al. Clinical characteristics and prognostic factors of surgically resected combined small cell lung cancer: a retrospective study. Lung Cancer, 2020, 146: 244-251.
28. Liu J, Cao Y, Shao T, et al. Exploring the prognostic impact of differences in treatment strategies for SCLC with different histologies and prognostic factors for C-SCLC: a SEER population-based study. Heliyon, 2024, 10(12): e32907.
29. He J, Xu S, Pan H, et al. Treatments for combined small cell lung cancer patients. Transl Lung Cancer Res, 2020, 9(5): 1785-1794.
30. Zhao X, McCutcheon JN, Kallakury B, et al. Combined small cell carcinoma of the lung: is it a single entity? J Thorac Oncol, 2018, 13(2): 237-245.
31. Cai S, Yang W, Luo H, et al. Clinical features and prognostic factors of IV combined small cell lung cancer: a propensity score matching analysis. PLoS One, 2024, 19(11): e313221.
32. Riely GJ, Wood DE, Ettinger DS, et al. Non-small cell lung cancer, version 4. 2024, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw, 2024, 22(4): 249-274.
33. Luo J, Wu FY, Li AW, et al. Comparison of vinorelbine, ifosfamide and cisplatin (NIP) and etoposide and cisplatin (EP) for treatment of advanced combined small cell lung cancer (cSCLC) patients: a retrospective study. Asian Pac J Cancer Prev, 2012, 13(9): 4703-4706.
34. Zhou C, Li YY, Yang DX, et al. Comparison of therapeutic efficacy of different chemotherapeutic regimens on combined small cell lung cancer. Chin J Clin Oncol, 2015, 42(2): 91-95.
35. Cheng Y, Chen J, Zhang W, et al. Benmelstobart, anlotinib and chemotherapy in extensive-stage small-cell lung cancer: a randomized phase 3 trial. Nat Med, 2024, 30(10): 2967-2976.
36. Kim SY, Park HS, Chiang AC. Small cell lung cancer: a review. JAMA, 2025, 333(21): 1906-1917.
37. Horn L, Mansfield AS, Szczesna A, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med, 2018, 379(23): 2220-2229.
38. Paz-Ares L, Dvorkin M, Chen Y, et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet, 2019, 394(10212): 1929-1939.
39. Wang Y, Xu J, Han B, et al. The role of prophylactic cranial irradiation in surgically resected combined small cell lung cancer: a retrospective study. J Thorac Dis, 2018, 10(6): 3418-3427.

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