肺腺癌病理类型转化特征及耐药机制分析

doi:10.3877/cma.j.issn.1674-6902.2022.06.003

目的

分析肺腺癌转化为鳞状细胞癌(small cell lung cancer, SCC)和小细胞肺癌(squamous cell carcinoma, SCLC)的可能机制及治疗策略。

方法

选择2017年1月至2022年2月我院收治的肺腺癌转化为SCLC及SCC患者7例为对象，分析临床病理特征及基因检测结果，随访并记录转归及预后。

结果

7例肺腺癌转化前病例1未检测到驱动基因，病例3为ROS1融合，其余为EGFR突变，病例6伴随TP53、BRCA1突变；转化后SCC 5例，SCLC 2例，转化后病例1检测到ALK融合，病例3、5和病例6保持原有突变，其余病例转化后未完善基因检测；7例肺腺癌转化前TKI中位治疗时间14个月(0~74个月)。初诊时，2例SCC SCC-Ag升高，1例SCLC NSE升高；转化后1例SCC SCC-Ag升高，1例SCLC NSE水平升高约4.7倍，2例SCLC Pro-GRP升高约16倍。7例中位转化时间27个月(11~92个月)，SCC 27个月，SCLC 11个月。化疗为基础的综合治疗，一线治疗ORR 100%, DCR 100%，转化后一线治疗中位PFS 7个月，OS为9个月，转化后SCLC与SCC的一线治疗中位PFS分别为7个月和8个月，OS为9个月和8个月；性别、吸烟、初始接受TKI治疗大于12个月、接受三代EGFR-TKI治疗、EGFR突变对转化时间影响无统计学意义(P>0.05)。

结论

病理类型转化是肺腺癌重要的耐药机制之一，SCC-Ag、NSE、Pro-GRP水平升高及TP53突变可能与病理类型转分化有关；转化后一线化疗具有临床意义。

关键词: 肺腺癌, 转化, 小细胞肺癌, 鳞状细胞癌

Objective

To analyze the clinical features of LUAD transformed into SCC or SCLC and explore its possible molecular mechanism and treatment.

Method

The clinical characteristics and genetic tests of 7 LUAD patients transformed into SCC or SCLC were retrospectively analyzed. The 7 patients were followed up by telephone, and the outcome and prognosis of the patients were recorded.

Result

Before the transformation of the 7 LUAD patients, case 1 detected no driver gene, case 3 was ROS1 fusion, and the others were EGFR mutations; case 6 was accompanied by TP53 and BRCA1 mutations. After transformation, 5 cases were SCC and 2 cases were SCLC; case 1 detected ALK fusion, cases 3, 5 and 6 remained original mutations. The rest cases didn′t receive the genetic test after transformation. The median time of taking TKIs was 14 months (0-74 months). At initial diagnosis, SCC-Ag was higher than the upper limit of normal in 2 of the patients transformed into SCC; NSE was higher than the upper limit of normal in 1 of the patients transformed into SCLC. After transformation, SCC-Ag was higher than the upper limit of normal in 1 of the patients transformed into SCC; NSE was about 4.7 times higher than the initial level in 1 of the patients transformed into SCLC; Pro-GRP in 2 SCLC patients was about 16 times higher than the initial level. The median transformation time of 7 LUAD patients was 27 months (11-92 months), the median transformation time of SCC was 27 months, and SCLC was 11 months. All patients received chemotherapy-based comprehensive therapy after transformation. The ORR of first-line therapy was 100%, the DCR was 100%, and the median PFS of first-line therapy was 7 months. the median OS after transformation was 9 months. The median OS of SCLC and SCC after transformation was 9 months and 8 months, respectively; and the median PFS of first-line therapy was 7 months and 8 months, respectively. Gender, smoking, initial TKI treatment for more than 12 months, third-generation TKI treatment, and EGFR mutation had no significant effect on transformation time(P>0.05).

Conclusion

Pathological transformation is one of the important drug resistance mechanisms of LUAD. Elevated levels of SCC-Ag, NSE, Pro-GRP and TP53 mutation may be related to pathological transformation; first-line chemotherapy can still benefit after transformation.

Key words: Lung adenocarcinoma, Transformation, Small cell lung cancer, Squamous cell carcinoma

表1 7例肺腺癌转化前的临床特征及治疗情况

病例	转化前病理类型	驱动基因	伴随突变	TKI治疗时间(月)
1	肺腺癌	无	无	无
2	浸润性腺癌	EGFR-L858R、T790M	无	28
3	低分化腺癌	ROS1	无	12
4	腺癌	不详	不详	12
5	浸润性腺癌伴神经内分泌分化	20INS、EGFR-L858Q	无	14
6	浸润性腺癌	EGFR-19缺失、T790M	TP53、BRCA1	20
7	低分化腺癌，伴鳞癌分化	EGFR-19缺失、T790M双突变，MET扩增	无	74

表1 7例肺腺癌转化前的临床特征及治疗情况

病例	转化前病理类型	驱动基因	伴随突变	TKI治疗时间(月)
1	肺腺癌	无	无	无
2	浸润性腺癌	EGFR-L858R、T790M	无	28
3	低分化腺癌	ROS1	无	12
4	腺癌	不详	不详	12
5	浸润性腺癌伴神经内分泌分化	20INS、EGFR-L858Q	无	14
6	浸润性腺癌	EGFR-19缺失、T790M	TP53、BRCA1	20
7	低分化腺癌，伴鳞癌分化	EGFR-19缺失、T790M双突变，MET扩增	无	74

表2 7例肺腺癌转化后的临床特征及治疗情况

病例	转化用时(月)	后病理类型	转化后基因突变	转化后0S(月)
1	27	鳞癌	ALK	23
2	29	鳞癌	未测	3
3	12	鳞癌	ROS1	－
4	14	鳞癌	不详	8
5	11	小细胞癌	L858Q	14
6	33	小细胞癌	EGFR-19缺失、T790M、EGFR扩增，MCL1扩增、ART突变	9
7	92	鳞癌	未测	1

表2 7例肺腺癌转化后的临床特征及治疗情况

病例	转化用时(月)	后病理类型	转化后基因突变	转化后0S(月)
1	27	鳞癌	ALK	23
2	29	鳞癌	未测	3
3	12	鳞癌	ROS1	－
4	14	鳞癌	不详	8
5	11	小细胞癌	L858Q	14
6	33	小细胞癌	EGFR-19缺失、T790M、EGFR扩增，MCL1扩增、ART突变	9
7	92	鳞癌	未测	1

表3 肺腺癌转化前后的病理特征

病例	初诊CD56	初诊CgA	初诊CK5/6(P63)	转化后CD56	转化后CgA	转化后CK5/6(P63)
1	－	－	－	－	－	+
2	－	－	－	－	－	+
3	－	－	－	－	－	+
4	－	－	－	－	－	+
5	+	－	－	+	－	－
6	/	/	/	+	+	－
7	/	/	散在+	/	/	+

表3 肺腺癌转化前后的病理特征

病例	初诊CD56	初诊CgA	初诊CK5/6(P63)	转化后CD56	转化后CgA	转化后CK5/6(P63)
1	－	－	－	－	－	+
2	－	－	－	－	－	+
3	－	－	－	－	－	+
4	－	－	－	－	－	+
5	+	－	－	+	－	－
6	/	/	/	+	+	－
7	/	/	散在+	/	/	+

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Characteristics and mechanism of pathological transformation of lung adenocarcinoma

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Characteristics and mechanism of pathological transformation of lung adenocarcinoma