ALK融合肺腺癌小细胞转化1例并文献复习

ALK fusion small cell transformation of lung adenocarcinoma:A case report and literature review

间变淋巴瘤激酶(anaplastic lymphoma kinase,ALK)融合的肺腺癌患者经ALK-酪氨酸激酶抑制剂(ALK-tyrosine kinase inhibitor,ALK-TKI)治疗后可能会产生耐药,其耐药机制尚未完全明确。遵义医科大学附属医院2021年9月收治1例ALK融合的肺腺癌患者,经ALK-TKI治疗后出现耐药,疾病进展后再次活体组织检查(以下简称“活检”),病理类型转化为小细胞肺癌。该患者为54岁女性,首诊主要症状为咳嗽、咳痰、胸痛4个月。胸部CT检查见右上叶后段-右下叶肿瘤性病变并阻塞性肺炎,右肺下叶转移瘤,纵隔、右肺门淋巴结增多、增大,右肺门软组织增厚;支气管镜检查病理活检明确诊断肺腺癌;二代测序基因检测结果提示棘皮动物微管样蛋白4-间变淋巴瘤激酶(echinoderm microtubule associated protein like 4-anaplastic lymphoma kinase,EML4-ALK)融合伴随肿瘤蛋白53(tumor protein 53,TP53)和视网膜母细胞瘤1(retinoblastoma 1,RB1)基因突变。给予二代ALK-TKI阿来替尼靶向治疗,无进展生存期11个月。随后出现疾病进展,考虑对阿来替尼耐药,改为三代ALK-TKI洛拉替尼靶向治疗1个月无效,疾病快速系统性进展,神经元特异性烯醇化酶(neuron specific enolase,NSE)明显升高,短期内新发胸膜、心包、颅内、肝脏、骨转移。二次活检的结果提示为小细胞肺癌,更改治疗方案为化学治疗联合免疫治疗,症状缓解。ALK-TKI治疗ALK融合的晚期非小细胞肺癌耐药机制复杂,病理类型小细胞转化也是耐药机制之一,发生率极低,伴随TP53和RB1基因突变可能是其向小细胞转化的特征,NSE异常升高是腺癌向小细胞转化有预测作用的血清标志物,耐药后及时进行二次活检,根据不同耐药机制选择后续治疗对疾病全程管理非常重要。

Patients with anaplastic lymphoma kinase(ALK)fusion lung adenocarcinoma may develop drug resistance after treatment with ALK-tyrosine kinase inhibitor(ALK-TKI),and the mechanisms of this resistance are not yet fully defined.The Affiliated Hospital of Zunyi Medical University admitted a patient who was resistant to ALK fusion after ALK-TKI treatment,leading to disease progression and subsequent biopsy indicating a transformation to small cell lung cancer in September 2021.The patient,a 54-year-old female,initially presented with symptoms of cough,sputum production,and chest pain for 4 months.Chest CT showed a neoplastic lesion in the posterior segment of the right upper lobe to right lower lobe with obstructive pneumonia,metastasis in the right lower lobe,increased and enlarged mediastinal and right hilar lymph nodes,and thickening of the right hilar soft tissue.Bronchoscopy and pathological biopsy confirmed the diagnosis of lung adenocarcinoma.The results of next-generation sequencing indicated that echinoderm microtubule associated protein like 4-anaplastic lymphoma kinase(EML4-ALK)fusion is associated with tumor protein 53(TP53)and retinoblastoma 1(RB1)gene mutations.The patient received second-generation ALK-TKI aletinib,achieving a progression-free survival of 11 months before disease progression suggested aletinib resistance.Subsequently,the third-generation ALK-TKI lorlatinib administered for one month without efficacy,resulting in rapid systemic disease progression.The neuron specific enolase(NSE)was significantly increased,and the patient developed new pleural,pericardial,intracranial,liver,and multiple bone metastases occurred in a short period.A second biopsy indicated small cell lung cancer.Modification of treatment regimen to chemotherapy combined with immunotherapy proved effective.The mechanisms of drug resistance of ALK-TKI treatment for advanced non-small cell lung cancer with ALK fusion are complex,and small cell transformation of pathological type is one such mechanism,although rare.Concurrent TP53 and RB1 gene mutations may be characteristic of this transformation.Elevated NSE can serve as a predictive serum marker for adenocarcinoma transforming to small cell carcinoma.Timely re-biopsy and selection of subsequent treatments based on different resistance mechanisms are crucial for comprehensive disease management.