小型單發性及同時多發性肺腺癌之臨床病理、基因表現與手術治療預後的相關性

Clinicopathology and Genetic Profile of Small Solitary and Synchronous Multiple Lung Adenocarcinomas: Implication for Surgical Treatment

林孟暐(Mong-Wei Lin)

指導教授 ： 張逸良

國立臺灣大學/醫學院/病理學研究所/博士(2014年)

https://doi.org/10.6342/NTU.2014.00005

摘要

近幾年來，由於低輻射劑量電腦斷層檢查的普及，臨床上越來越常見到小型肺腺癌病例。這些病患過去因為沒有症狀，往往無法被早期發現。小型肺腺癌包括兩種形態：單一肺腺癌，以及同時多發性肺腺癌。關於這兩類肺腺癌的基因特性，臨床病理特徵，以及與手術治療後預後的相關性等方面，目前仍未有詳細研究。
本研究收納了172位小型單一肺腺癌，及64位小型同時多發性肺腺癌病例。這些病患的肺腺癌腫瘤各別大小均 ≤ 2公分，且均經過手術完全切除。本研究採用石蠟包埋檢體，進行EGFR，p53及KRAS基因定序分析，並將基因分析結果與臨床病理特性，病患預後等相關因子進行統計分析。
在小型單一肺腺癌的病患中，EGFR跟p53基因突變的比率分別為60.5% (104/172)及20.9% (36/172)。EGFR基因突變與腫瘤大小(>1公分)有關聯，而p53基因突變與腫瘤大小(>1公分)及中等度腫瘤分化(moderately differentiated)有相關。這一組病患中，有163位屬肺癌分期第一期，就這些第一期病患進行無病存活率分析(Disease-free survival)，發現四個疾病復發因子：p53 基因突變 (p = 0.039)，腫瘤肋膜表層侵犯(visceral pleural surface invasion, PL2; p = 0.001)，癌症胚胎抗原異常(carcinoembryonic antigen; p < 0.001)，以及中等度腫瘤分化(moderately differentiation; p = 0.002)。共有30位病患有疾病復發的情形，在其中23位腫瘤有EGFR基因突變的病患中，有接受標靶藥物治療的病患五年存活率比僅接受傳統化學治療的病患要好，五年存活率分別各為71.1%與44.4%。
本研究納入的64位小型同時多發性肺腺癌病患，其五年無病存活率(disease-free survival)與總存活率(overall survival)分別為86.1%及95.8%，與第一期肺腺癌存活率相近。這組病人的腫瘤基因分析，EGFR，p53與KRAS基因突變比率分別為64.1% (41/64)，12.5% (8/64)及6.3% (4/64)。利用EGFR/p53/KRAS這三個基因突變進行克隆性分析(clonality assessment)，其中14位病患屬於同源性(same clonality)，30位病患屬於異源性(different clonality)，這些研究結果可進一步支持”field cancerization”理論。多變數無病存活率分析發現兩個與腫瘤復發相關的因子：淋巴結轉移(p = 0.003)與抽煙 (p = 0.011)。手術方式(lobar or sublobar resection)，克隆性分析結果(clonality)，以及腫瘤位置與腫瘤復發均無統計上的顯著相關性。
因此，總結來說，在小型單一肺腺癌病例，p53基因突變與腫瘤復發有顯著關聯，可當作IB期病患是否要接受手術後化學治療的一個參考因子。對於腫瘤復發的病患來說，若EGFR基因有突變，可採用標靶藥物治療，以得到較好的存活率。對於小型同時多發性肺腺癌病患，無論是腫瘤位置或是以EGFR/p53/KRAS基因突變進行克隆性分析的結果如何，對每一個病灶採用肺節切除(segmentectomy)或是肺楔狀切除(wedge resection)進行完整的腫瘤切除後，可以達到很好的長期無病存活率。淋巴結轉移是腫瘤復發的危險因子，因此，病患若手術後發現有淋巴結轉移的情形，應考慮給予術後化學治療。

關鍵字

早期肺癌 ； 肺腺癌 ； 同時多發性肺癌 ； epidermal growth factor receptor ； KRAS ； p53

並列摘要

As a result of improved lung cancer detection in asymptomatic patients, small solitary and synchronous multiple adenocarcinomas are found more frequently than in the past. However, the genetic profile, treatment, and prognosis of these two kinds of patients remain unclear. For treatment decisions and prognostic applications, we evaluated the correlation of epidermal growth factor receptor (EGFR)/p53 mutations with clinicopathologic characteristics and tumor relapse in 172 surgically resected solitary lung adenocarcinomas ≤ 2 cm in maximal dimension. We also evaluated the presence of EGFR, p53, and KRAS somatic mutations in 64 synchronous multiple lung adenocarcinomas ≤ 2 cm in maximal dimension. Mutational analysis was performed on DNA extracted from paraffin-embedded tumors.
EGFR and p53 mutations were identified in 104 (104/172, 60.5%) and 36 (36/172, 20.9%) small solitary lung adenocarcinomas, respectively. EGFR/p53 mutations were associated with tumor size > 1cm, whereas p53 mutations were frequently observed in moderately differentiated tumors. Disease-free survival analysis showed that p53 mutation (p = 0.039), visceral pleural surface invasion (p = 0.001), carcinoembryonic antigen (p < 0.001), and tumor differentiation (p = 0.002) were significantly correlated with tumor relapse in patients with stage I disease. The 5-year survival rate was higher in relapsed patients with EGFR-mutated tumors who were treated with tyrosine kinase inhibitor (TKI) than in those who were not treated with TKI (71.1% versus 44.4%).
The 5-year disease-free survival of the 64 small synchronous multiple lung adenocarcinoma patients was 86.1%, and the overall survival of these patients was 95.8%. EGFR, p53, and KRAS mutations were detected in 41 (41/64, 64.1%), 8 (8/64, 12.5%), and 4 (4/64, 6.3%) patients, respectively. The high frequency of genetic mutations resulted in high discrimination rate of tumor clonality (68.8%; 44/64) in the study group. Fourteen (14/64, 31.8%) patients were assessed as having the same clonality, whereas 30 (30/64, 68.2%) patients had different clonality, which further supported the concept of field cancerization. Multivariate analysis showed lymph node metastasis (p = 0.003) and smoking (p = 0.011) were significantly correlated with tumor relapse. Surgical method, clonality and tumor location were not correlated with tumor relapse in small synchronous multiple lung adenocarcinomas.
In small solitary lung adenocarcinoma patients, p53 mutation was significantly correlated with tumor progression, and our findings may provide a rationale for the selective use of adjuvant chemotherapy in stage IB lung adenocarcinoma patients with p53 mutations. EGFR mutation was a predictor of EGFR TKI response in relapsed patients. On the other hands, no matter whether the small synchronous multiple lung adenocarcinomas are different or same clonal, sublobar resection of each lesion can achieve long-term disease-free survival and is the treatment of choice. Patients with lymph node metastasis are at risk of relapse and adjuvant chemotherapy is indicated.

並列關鍵字

early stage lung cancer ； epidermal growth factor receptor ； KRAS ； lung adenocarcinoma ； p53 ； synchronous multiple lung cancers

參考文獻

1. Hoffman PC, Mauer AM, Vokes EE. Lung cancer. Lancet. 2000;355:479-85.

2. Yoshimi I, Ohshima A, Ajiki W, et al. A comparison of trends in the incidence rate of lung cancer by histological type in the Osaka Cancer Registry, Japan and in the surveillance, epidemiology and end results program, USA. Jpn J Clin Oncol. 2003;33:98-104.

3. Shigematsu H, Lin L, Takahashi T, et al. Clinical and Biological Features Associated With Epidermal Growth Factor Receptor Gene Mutations in Lung Cancers. J Natl Cancer Inst. 2005;97:339-46.

4. Olayioye MA, Neve RM, Lane HA, Hynes NE. The ErbB signaling network: receptor heterodimerization in development & cancer. EMBO J. 2000;19:3159-67.

5. Chang YL, Wu CT, Lin SC, et al. Clonality and prognostic implications of p53 and epidermal growth factor receptor somatic aberrations in multiple primary lung cancers. Clin Cancer Res. 2007;13:52-8.