伴破骨样巨细胞胰腺未分化癌的临床病理特征与治疗策略

Clinicopathological characteristics and treatment strategies of undifferentiated carcinoma with osteoclast-like giant cells of pancreas

目的探讨伴破骨样巨细胞胰腺未分化癌(UCOGCP)的临床病理特征与治疗策略。方法采用回顾性描述性研究方法。收集2004年1月至2019年1月北京大学第一医院收治的5例UCOGCP病人的临床病理资料;男1例,女4例;中位年龄为56岁,年龄范围为33~71岁。病人术前行实验室检查、影像学检查及活组织病理学检查。胰头部肿瘤行胰十二指肠切除术,胰体尾部肿瘤行胰体尾+脾切除术,均行标准范围淋巴结清扫。术后辅助治疗方案依据多学科讨论结果个体化制订。观察指标:(1)术前检查结果与治疗情况。(2)术后组织病理学检查情况。(3)随访情况。采用门诊和电话方式进行随访,了解病人肿瘤复发情况。随访时间截至2020年1月。正态分布的计量资料以x±s表示,偏态分布的计量资料以M(范围)表示。计数资料以绝对数表示。结果(1)术前检查结果与治疗情况:5例病人中,1例术前CA19-9升高为65.43 U/mL,4例肿瘤标志物水平均为正常值。5例病人术前增强CT检查结果显示:4例为囊实性肿瘤,1例实性肿瘤边缘延迟强化伴中心坏死。5例病人磁共振成像检查T1序列、T2序列及加权弥散序列均表现为低信号。5例病人影像学检查评估结果显示:3例为可切除肿瘤;1例为局部进展期肿瘤,侵犯结肠、胃及部分小肠且伴门静脉癌栓;1例为胰头肿瘤伴同时性肝左外叶长径为0.4 cm孤立转移灶。PET-CT检查结果示肝左外叶高代谢病灶,术前经内镜超声引导下细针穿刺活组织病理学检查结果示UCOGCP。5例病人均行根治性手术治疗。3例可切除肿瘤病人中,2例行胰十二指肠切除术,1例行胰体尾+脾切除术;1例局部进展期胰体尾部肿瘤病人行胰体尾+脾+横结肠+胃部分切除+门静脉瘤栓取出术;1例胰头部肿瘤伴肝转移病人行胰十二指肠切除+肝左外叶切除术。5例病人中,2例术后行吉西他滨单药辅助化疗,1例行白蛋白结合型紫杉醇+吉西他滨联合化疗,1例行替吉奥单药化疗,1例未行辅助化疗。(2)术后组织病理学检查情况:5例病人中,4例大体标本呈囊实性,1例呈实性伴中心出血坏死。肿瘤长径为5.2 cm(2.0~14.0 cm)。5例病人手术切缘均为阴性。5例病人中,1例伴门静脉侵犯,2例伴脉管侵犯,3例伴神经侵犯,2例伴淋巴结转移(同一例病人可合并多处侵犯和转移)。5例病人中,4例可获取留存石蜡标本,重新行免疫组织化学染色检测,CD68及Vimentin均呈阳性,3例程序性死亡配体-1染色呈阳性,其中2例为5%阳性、1例为25%阳性。术后组织病理学检查结果示大量梭形组织细胞样肉瘤细胞间可见破骨样巨细胞,散在多形癌巨细胞。4例病人肿瘤突变负荷为3.23 Muts/Mb(2.61~21.77 Muts/Mb)。4例病人微卫星不稳定性检测为状态稳定。4例病人行二代基因测序,均携带胰腺导管细胞癌常见的KRAS基因突变,其中合并TP53胚系突变,合并TP53体细胞突变,合并TP53、BLM、CDKN2A体细胞突变,合并ARID1A体细胞突变各1例。(3)随访情况:5例病人均获得随访,随访时间为14~173个月,中位随访时间为46个月。随访期间,4例病人无病生存,1例病人术后第11个月肿瘤局部复发。结论UCOGCP临床罕见,影像学检查常表现为囊实性肿瘤,肿瘤组织程序性死亡配体-1常呈高表达。病人行根治性手术治疗预后良好,即使肿瘤已侵犯邻近脏器或远处转移,病人仍可从扩大根治性手术中获益。

Objective To investigate the clinicopathological characteristics and treatment strategies of undifferentiated carcinoma with osteoclast-like giant cells of pancreas(UCOGCP).Methods The retrospective and descriptive study was conducted.The clinicopathological data of 5 patients with UCOGCP who were admitted to Peking University First Hospital from January 2004 to January 2019 were collected.There were 1 male and 4 females,aged from 33 to 71 years,with a median age of 56 years.Patients underwent preoperative laboratory test,imaging and histopatho-logical examinations.Patients with pancreatic head tumors underwent pancreaticoduodenectomy,and those with tumors in the body or tail of pancreas underwent distal pancreatectomy combined with splenectomy.All patients underwent standard lymph node dissection.Postoperative adjuvant therapy was individually decided by a multidisciplinary team.Observation indicators:(1)preopera-tive examination and treatment;(2)postoperative histopathological situations;(3)follow-up.Follow-up using outpatient examination and telephone interview was performed to detect tumor recurrence of patients up to January 2020.Measurement data with normal distribution were represented as Mean±SD.Measurement data with skewed distribution were described as M(range).Count data were described as absolute numbers.Results(1)Preoperative examination and treatment:of the 5 UCOGCP patients,CA19-9 was elevated as 65.43 U/mL in only 1 patient preoperatively,while the CA19-9 was normal in other 4 patients.Four patients showed a solid cystic mass on preoperative contrast-enhanced computed tomography(CT)scan,and 1 patient showed a delayed peripheral enhancement of the solid tumor with central necrosis.The magnetic resonance imaging(MRI)scan showed hypointense signals on T1,T2 and weighted diffusion sequences in all 5 patients.Three of the 5 patients were resectable according to imaging data,1 patient had locally advanced tumor,infiltrating the transverse colon,stomach,and partial small intestine,with the portal vein thrombus,and 1 patient had pancreatic head tumor with a liver metastatic lesion of 0.4 cm diameter which was detected on position emission tomography CT and was diagnosed as UCOGCP by endoscopic ultrasound-guided fine-needle aspiration biopsy.All patients underwent radical resection.Of the 3 patients with resectable tumors,2 patients underwent pancreaticoduo-denectomy and 1 patient underwent distal pancreatectomy combined with splenectomy.One patient with locally advanced tumor in the body and tail of pancreas underwent distal pancreatectomy+transverse colostomy+partial gastrectomy+portal vein thrombectomy,and 1 patient with pancreatic head tumor and liver metastasis underwent pancreatoduodenectomy combined with left lateral hepatectomy.Of the 5 patients,2 received postoperative adjuvant chemotherapy with single-agent gemcitabine,1 received albumin-paclitaxel+gemcitabine combination chemotherapy,1 received S1 as single agent chemotherapy,and 1 did not receive adjuvant chemotherapy.(2)Postoperative histopathological situations:of the 5 patients,4 cases showed a cystic solid appearance of gross specimens,and 1 case had a solid appearance with central hemorrhagic necrosis.The tumor diameter was 5.2 cm(range,2.0‒14.0 cm).All the 5 patients achieved negative margins.Of the 5 patients,there was 1 case with portal vein invasion,2 cases with vascular invasion,3 cases with perineural invasion,and 2 cases with regional lymph node metastasis.One patient may had multiple tumor invasion and metastasis.Four of 5 patients had paraffin specimens available for immuno-histochemical staining.Four patients were positive for both CD68 and vimentin stains,while 3 patients were positive for programmed death ligand-1(PD-L1),including 2 samples with 5%positive cells and 1 sample with 25%positive cells.Postoperative pathological examination showed a large number of spindle histiocytoid sarcoma cells scattered with osteoclast like giant cells and pleomorphic carcinoma giant cells.The tumor mutation burden in the 4 patients was 3.23 Muts/Mb(range,2.61‒21.77 Muts/Mb).Microsatellite status was stable in 4 patients.The next generation sequencing of 4 patients showed that all patients had KRAS mutation which was the most frequently mutation in pancreatic ductal adenocarcinoma.Of the 4 patients,1 case had germline pathogenic mutation in TP53,1case had somatic mutation in TP53,1 case had somatic mutation in TP53,BLM,CDKN2A,and 1 case had somatic mutation in ARID1A.(3)Follow-up:5 patients were followed up for 14‒173 months,with a median follow-up time of 46 months.During the follow-up,4 patients achieved disease-free survival and 1 patient had local recurrence at postoperative 11 months.Conclusions UCOGCP is a rare variant of pancreatic tumor that exhibits a cystic solid mass in imaging examinations.High expression of PD-L1 is common in UCOGCP.The prognosis for UCOGCP is favorable following radical surgery.Patients may benefit from extended radical surgery even if the tumor has locally progression or distant metastasis.