核增殖指数MIB-1在肾上腺皮质癌诊断和预后判断中的价值

Study on predictive value of MIB-1 in the diagnosis and prognosis of adrenocortical carcinoma

目的探讨核增殖指数(MIB-1)在肾上腺皮质癌(ACC)诊断和预后判断中的价值。方法回顾性分析2018年6月至2022年8月北京协和医院收治的ACC患者和肾上腺良性病变患者的临床资料。ACC组59例,男25例,女34例,男女比例1:1.4。年龄(46.1±2.1)岁,其中<20岁4例,21~30岁7例,31~40岁11例,41~50岁14例,51~60岁13例,61~70岁8例,>70岁2例。体质量指数(24.3±2.4)kg/m^(2)。收缩压(149.3±5.2)mmHg(1mmHg=0.133kPa),舒张压(93.4±1.7)mmHg。典型库欣综合征表现51例,高血压52例,血糖升高44例,低钾血症16例,雄激素分泌致月经异常和痤疮16例。实验室检查:血糖(7.2±0.3)mmol/L,糖化血红蛋白(8.6±1.4)%,总胆固醇(5.7±0.3)mmol/L,三酰甘油(2.0±0.3)mmol/L。24h尿游离皮质醇(234.4±39.0)μg/24h,其中46例升高。8:00时促肾上腺皮质激素(9.5±4.1)pg/ml,其中48例下降。血游离皮质醇(401.2±17.1)μg/dl,其中42例节律消失。醛固酮升高17例。硫酸脱氢表雄酮(713±159)μg/dl,其中16例升高。神经烯醇化酶(21.2±5.3)ng/ml,其中27例升高。胰岛素样生长因子-1(272.0±42.1)ng/ml,其中26例升高。46例行大、小剂量地塞米松抑制试验均不被抑制。39例肿瘤为功能性。59例术前行腹盆腔增强CT、MRI、B超检查,21例行PET/CT检查。肿瘤位于左侧32例,右侧26例,双侧1例。肿瘤最大径(9.6±1.7)cm,其中≤10cm43例,>10cm16例。伴淋巴结转移5例,远处转移16例,局部侵犯11例。肿瘤临床分期Ⅰ期(T_(1)N_(0)M_(0)期)4例,Ⅰ期(T_(2)N_(0)M_(0)期)27例,Ⅲ期T_(1~2)N_(1)M_(0)期、T_(3)N_(0)M_(0)期23例,Ⅳ期(T_(1~4)N_(0~1)M_(1)期、T_(3)N_(1)M_(0)期、T_(4)N_(0~1)M_(0)期)5例。伴肾上腺中央静脉、肾静脉、下腔静脉瘤栓6例。对照组53例,均为肾上腺皮质良性病变患者,男26例,女27例。年龄(44.3±3.2)岁,典型库欣综合征表现28例,24h尿游离皮质醇(176.4±41.2)μg/24h。27例游离皮质醇节律消失。硫酸脱氢表雄酮正常。23例行大、小剂量地塞米松抑制试验均不被抑制。肿瘤最大径(4.2±2.3)cm。ACC组T_(1)N_(0)M_(0)期患者接受机器人或腹腔镜根治性肾上腺切除术,切除范围包括肿瘤周围淋巴组织;分期≥T_(2)期患者接受开放根治性肾上腺切除术+淋巴结清扫。6例因肿瘤侵犯肾脏,界限不清,行根治性肾上腺切除术联合肾切除术。11例局部种植转移,行立体定向放疗。9例伴肝转移患者,行介入栓塞治疗。3例伴肺转移孤立病灶,行手术切除。4例多发肺转移,行放疗联合米托坦治疗。根据术后病理检查结果,记录ACC组的病理Weiss评分和MIB-1表达情况。分析不同MIB-1表达、临床分期、Weiss评分亚组的预后情况。结果本研究ACC组59例,达到RO切除35例,R1切除19例,R2切除5例。术后病理检查结果显示,肿瘤质量(370±52)g,≤300g42例,>300g17例。对照组MIB-1阳性率为1%~5%,ACC组MIB-1阳性率均>5%,两组比较差异有统计学意义(P<0.01)。对术后病理检查确诊包膜侵犯、包膜破裂、脉管内瘤栓和MIB-1>10%的53例患者,予肿瘤瘤床放疗和米托坦药物治疗,二线选择联合免疫治疗、依托泊苷+顺铂+多柔比星方案化疗等。不同肿瘤分期ACC患者的5年生存率分别Ⅰ期65%,Ⅱ期58%,Ⅲ期38%,IV期<5%。预后分析结果显示,临床分期早(Ⅰ、Ⅱ期)和分期晚(Ⅲ、Ⅳ期)亚组的总生存期分别为3.6年和1.1年(P=0.003),无病生存期分别为25个月和11个月(P=0.011)。R0、R1、R2组的5年生存率分别为61%、31%、17%,差异有统计学意义(P=0.030)。生存曲线显示,ACC组MIB-1>10%亚组和≤10%亚组的5年总生存率分别为17%和32%,差异有统计学意义(P=0.021)。ACC组Weiss评分(7±2)分,其中3~5分组21例,6~9分组38例,两组的5年生存率分别为62%和19%,差异有统计学意义(P=0.017)。结论MIB-1可以作为ACC的一种辅助诊断和预后评估指标,MIB-1高表达有助于ACC的早期诊断和确定治疗策略。

Objective To explore the value of nuclear proliferation index(MIB-1)in the diagnosis and prognosis of adrenal cortical carcinoma(ACC).Methods A retrospective analysis was conducted on the clinical data of ACC patients and patients with benign adrenal lesions admitted to Beijing Union Medical College Hospital from June 2018 to August 2022.There were 59 cases in the ACC group,25 males and 34 females,with a male to female ratio of 1:1.4.Age(46.1±2.1)years old,including 4 cases under 20 years old,7 cases between 21-30 years old,11 cases between 31-40 years old,14 cases between 41-50 years old,13 cases between 51-60 years old,8 cases between 61-70 years old,and 2 cases over 70 years old.Body mass index(24.3±2.4)kg/m^(2).Systolic blood pressure(149.3±5.2)mmHg(1 mmHg=0.133 kPa)and diastolic blood pressure(93.4±1.7)mmHg.There were 51 cases of typical Cushings syndrome,52 cases of hypertension,44 cases of elevated blood sugar,16 cases of hypokalemia,and 16 cases of menstrual abnormalities and acne caused by androgen secretion.Laboratory examination:Blood glucose(7.2±0.3)mmol/L,glycated hemoglobin(8.6±1.4)%,total cholesterol(5.7±0.3)mmol/L,and triglycerides(2.0±0.3)mmol/L.24-hour urine free cortisol(234.4±39.0)μg/24 h,with 46 cases showing an increase,and at 8am,corticotropin releasing hormone(9.5±4.1)pg/ml,with 48 cases showing a decrease.Blood free cortisol(401.2±17.1)μg/dl,with 42 cases of rhythm disappearance.17 cases showed elevated aldosterone levels.Dehydroepiandrosterone sulfate(713±159)μg/dl,of which 16 cases increased.Neuroenolase(21.2±5.3)ng/ml,of which 27 cases were elevated.Insulin like growth factor-1 was(272.0±42.1)ng/ml,with 26 cases showing an increase.46 routine high-dose and lowdose dexamethasone inhibition tests were not suppressed.39 cases of tumors were functional.59 cases underwent preoperative abdominal and pelvic contrast-enhanced CT,MRI,and B-ultrasound examination,and 21 cases underwent PET/CT examination.The tumors were located in 32 cases on the left,26 cases on the right,and 1 case on both sides.The maximum diameter of the tumor was(9.6±1.7)cm,with 43 cases≤10 cm and 16 cases>10 cm.There were 5 cases with lymph node metastasis,16 cases with distant metastasis,and 11 cases with local invasion.There were 4 cases of tumor ENSAT clinical staging stage Ⅰ(T_(1)N_(0)M_(0) stage),27 cases of stage Ⅱ(T_(2)N_(0)M_(0) stage),23 cases of stage Ⅲ(T_(1-2)N_(1)M_(0) stage,T_(3)N_(0)M_(0) stage),and 5 cases of stage Ⅳ(T_(1-4)N_(0-1)M_(1)stage,T_(3)N_(1)M_(0) stage,T_(4)N_(0-1)M_(0) stage).Six cases were accompanied by tumor thrombi in the central adrenal vein,renal vein,and inferior vena cava.There were 53 cases of benign adrenal tumors,including 26 males and 27 females.Age(44.3±3.2)years old,typical manifestations of Cushings syndrome in 28 cases,24-hour urine free cortisol(176.4±41.2)μg/24 h.27 cases showed disappearance of free cortisol rhythm.Dehydroepiandrosterone sulfate is normal.23 routine high-dose and low-dose dexamethasone inhibition tests were not inhibited.The maximum diameter of the tumor is(4.2±2.3)cm.T_(1)N_(0)M_(0) stage patients undergo robotic or laparoscopic radical adrenalectomy,with the resection range including the surrounding lymphoid tissue of the tumor;Patients with stage≥T_(2)underwent open radical adrenalectomy and lymph node dissection.Six cases underwent radical adrenalectomy combined with nephrectomy due to tumor invasion of the kidneys with unclear boundaries.11 cases of local implant metastasis underwent stereotactic radiotherapy.Nine patients with liver metastasis underwent Interventional Embolization treatment.Three cases with isolated lung metastases underwent surgical resection.Four cases of multiple lung metastases were treated with radiotherapy combined with mitotane.According to the postoperative pathological examination results,record the pathological Weiss score and MIB-1.Analyze the correlation between MIB-1 and clinical pathological indicators and prognosis of patients.Results There were 59 cases in the ACC group,35 cases of RO resection,19 cases of R1 resection and 5 cases of R2 resection.The postoperative pathological examination showed an average weight of approximately(371±52)g,with 42 cases having a tumor mass≤300 g and 17 cases having a tumor mass>300 g.The positive rate of MIB-1 in the control group was 1% to 5%,while the positive rate of MIB-1 in the ACC group was greater than 5%,the diference between the two groups was statistically significant(P<0.01).53 patients diagnosed with capsule invasion,capsule rupture,intravascular tumor thrombus,and MIB-1>10% through postoperative pathological examination were treated with tumor bed radiotherapy and mitotan medication,followed by second-line combination immunotherapy and EDP chemotherapy.The 5-year survival rates of ACC patients with different tumor stages were 65% in stage Ⅰ,58% in stage Ⅱ,38% in stage Ⅲ,and less than 5% in stage Ⅳ.The total survival time of the two subgroups with low and high staging was 3.6 years and 1.1 years respectively(P=0.003),while the disease-free survival time of the two groups was 25 months and 11 months,respectively(P=0.O11).RO resection has a better prognosis than Rl and R2 resection,and its five-year survival rate is higher(P=0.03).The 5-year survival rates of RO,R1,and R2 groups were 61%,31%,and 17%,respectively(P=0.030).Survival analysis showed that adrenal cortical cancer patients with MIB-1 greater than 10% had a worse prognosis,with 5-year OS of 17% and 32% for both groups,respectively(P=0.021).The Weiss score of the ACC group was(7±2).There were 21 cases in the Weiss score 3-5 group and 38 cases in the 6-9 group,the 5-year survival rates of the two groups were 62% and 19%,respectively(P=0.017).Conclusions MIB-1 can serve as an auxiliary diagnostic and prognostic indicator,and high expression of MIB-1 can contribute to the early diagnosis and determination of treatment strategies for ACC.