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首页 » JAMA » JAMA:局部淋巴结转移与结直肠癌复发关系研究

JAMA:局部淋巴结转移与结直肠癌复发关系研究

来源:中国医学论坛报 2009-03-03 16:23

局部淋巴结转移是结直肠癌复发的重要预测因素,有局部淋巴结转移者的复发率高达50%。然而,即使是不存在局部淋巴结转移的pN0结直肠癌患者,复发率也高达25%。美国托马斯·杰斐逊(Tomas Jefferson)大学瓦尔德曼(Waldman)等的新研究揭开了其中的奥秘:pN0并不代表淋巴结没有肿瘤细胞浸润。事实上,87.5%的pN0结直肠癌患者存在“淋巴结隐匿性转移”,而鸟苷酸环化酶2C(GUCY2C)表达正是判定隐匿性转移存在与否的一个有效指标。

Waldman等提出,将分子学分期与传统的分期方法相结合,一方面可更好地细分pN0患者,检出复发危险较高者,另一方面也有助于指导治疗,有的放矢地给予辅助化疗。该研究发表在2月18日的《美国医学会杂志》(JAMA )上。

近九成pN0患者存在淋巴结隐匿性转移

GUCY2C是一种单次跨膜蛋白受体,其配体为鸟苷蛋白和尿鸟苷蛋白。在结肠癌变的早期阶段,常出现上述配体的表达缺失,这就会导致GUCY2C信号过程紊乱,继而致癌。肠道肿瘤细胞的GUCY2C过表达,反映了在配体被剥夺后的受体超致敏作用,提示GUCY2C是一种特异性分子标志物。

该前瞻性研究共纳入2002年3月至2007年6月的257例0~Ⅱ期pN0结直肠癌患者,通过定量逆转录-聚合酶链反应(RT-PCR)法检测了取自这些患者的2570枚直径≥5 mm新鲜淋巴结(1~33枚/例,中位数为8枚/例)的GUCY2C表达情况。

结果显示,32例(12.5%)pN0结直肠癌患者淋巴结GUCY2C检测为阴性,为pN0 (mol-),据此判定其不存在隐匿性转移;其余225例(87.5%)患者的1枚或更多枚淋巴结被检出GUCY2C阳性,为pN0(mol+),判定其存在隐匿性转移。

rGC由胞外结构域(ECD)、跨膜片段(TM)、激酶同源结构域(KHD)、卷曲-卷曲结构域(CCD)和鸟苷酸环化酶结构域(GC)构成sGC由血红素结构域(HD)、CCD和GC构成

分子学分期让隐匿性转移“无可遁形”

传统的分期方法主要借助组织病理学检测结果,其局限主要体现在:①仅能纳入少数淋巴结进行分析,易遗漏阳性淋巴结;②仅能纳入淋巴结的少量淋巴组织进行分析,易遗漏肿瘤细胞;③组织病理学检查本身的敏感性低,其分辨率最高仅为从200个正常细胞中检出1个肿瘤细胞。

分子学分期则不但可将所有可得到的组织纳入分析,而且敏感性高,即使在100万个正常细胞中有1个肿瘤细胞也可检出。当然,分子学分期需要依赖于疾病特异性分子标志物。在上述研究中,GUCY2C就是pN0结直肠癌复发的特异性分子标志物。当然,上述研究的随访时间还不够长,需要纳入更多研究对象、随访更长时间的研究来更精准地评估GUCY2C定量RT-PCR检测的预后价值。

分子学分期的另一个用处在于指导治疗。辅助化疗对Ⅲ期结直肠癌患者的生存益处已经比较明确,但对于Ⅱ期pN0患者,一些研究提示其有生存益处,另一些却提示没有,原因何在?淋巴结隐匿性转移的存在可能部分回答了该问题。既然pN0(mol+)患者的复发率类似于Ⅲ期pN1患者,那么其从辅助化疗中的获益也可能类似于后者。(章严)

淋巴结GUCY2C表达预示pN0结直肠癌复发危险

研究者对上述患者随访了2~63个月(中位随访时间为24个月),评估不同GUCY2C表达者的疾病复发和死亡情况,并与87例Ⅲ期pN1患者进行了比较。

结果显示,32例pN0(mol-)患者中仅有2例(6.3%)在随访期间复发。值得一提的是,这2例患者接受GUCY2C检测的淋巴结都非常少(分别为1枚和2枚),这也从某种意义上提示任一种分期技术都需要在足够样本量的基础上进行才有可能更精准。

225例pN0(mol+)患者中有47例(20.9%)复发,复发率不但显著高于pN0(mol-)患者(P=0.006),而且已经接近Ⅲ期pN1患者。

多因素分析显示,淋巴结GUCY2C阳性是pN0结直肠癌患者的独立预后因素:pN0(mol+)患者复发较早[校正风险比(HR)为4.66,P=0.04],无病生存率较低(校正HR为3.27,P=0.03)。(生物谷Bioon.com)

生物谷推荐原始出处:

JAMA,301(7):745-752. ,Scott A. Waldman,David S. Weinberg

Association of GUCY2C Expression in Lymph Nodes With Time to Recurrence and Disease-Free Survival in pN0 Colorectal Cancer

Scott A. Waldman, MD, PhD; Terry Hyslop, PhD; Stephanie Schulz, PhD; Alan Barkun, MD; Karl Nielsen, BS; Janis Haaf, RN; Christine Bonaccorso, RN; Yanyan Li, BS; David S. Weinberg, MD, MSc

Context  The established relationship between lymph node metastasis and prognosis in colorectal cancer suggests that recurrence in 25% of patients with lymph nodes free of tumor cells by histopathology (pN0) reflects the presence of occult metastases. Guanylyl cyclase 2C (GUCY2C) is a marker expressed by colorectal tumors that could reveal occult metastases in lymph nodes and better estimate recurrence risk.

Objective  To examine the association of occult lymph node metastases detected by quantifying GUCY2C messenger RNA, using the reverse transcriptase–polymerase chain reaction, with recurrence and survival in patients with colorectal cancer.

Design, Setting, and Participants  Prospective study of 257 patients with pN0 colorectal cancer enrolled between March 2002 and June 2007 at 9 US and Canadian centers (7 academic medical centers and 2 community hospitals) provided 2570 fresh lymph nodes measuring 5 mm or larger for histopathology and GUCY2C messenger RNA analysis. Patients were followed up for a median of 24 months (range, 2-63 months) for disease recurrence or death.

Main Outcome Measures  Time to recurrence (primary outcome) and disease-free survival (secondary outcome) relative to expression of GUCY2C in lymph nodes.

Results  Thirty-two patients (12.5%) had lymph nodes negative for GUCY2C (pN0 [mol–]), and all but 2 remained free of disease during follow-up (recurrence rate, 6.3%; 95% confidence interval [CI], 0.8%-20.8%). Conversely, 225 patients (87.5%) had lymph nodes positive for GUCY2C (pN0 [mol+]), and 47 developed recurrent disease (20.9%; 95% CI, 15.8%-26.8%) (P = .006). Multivariate analyses revealed that GUCY2C in lymph nodes was an independent marker of prognosis. Patients who were pN0 (mol+) exhibited earlier time to recurrence (adjusted hazard ratio, 4.66; 95% CI, 1.11-19.57; P = .04) and reduced disease-free survival (adjusted hazard ratio, 3.27; 95% CI, 1.15-9.29; P = .03).

Conclusion  Expression of GUCY2C in histologically negative lymph nodes appears to be independently associated with time to recurrence and disease-free survival in patients with pN0 colorectal cancer.

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