Departments of Pathology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Am J Surg Pathol. 2012 Sep;36(9):1279-301. doi: 10.1097/PAS.0b013e318262787c.
The literature on the clinicopathologic characteristics of tumoral intraepithelial neoplasms (neoplastic polyps) of the gallbladder (GB) is fairly limited, due in part to the variability in definition and terminology. Most reported adenomas (pyloric gland type and others) were microscopic and thus regarded as clinically inconsequential, whereas papillary in situ carcinomas have been largely considered a type of invasive adenocarcinoma under the heading of "papillary adenocarcinomas." In this study, 123 GB cases that have a well-defined exophytic preinvasive neoplasm measuring ≥1 cm were analyzed. The patients were predominantly female (F/M=2:1) with a mean age of 61 y and a median tumor size of 2.2 cm. Half of the patients presented with pain, and in the other half the neoplasm was detected incidentally. Other neoplasms, most being gastrointestinal tract malignancies, were present in 22% of cases. Gallstones were identified in only 20% of cases. Radiologically, almost half were diagnosed as "cancer," roughly half with polypoid tumor, and in 10% the lesion was missed. Pathologic findings: (1) The predominant configuration was papillary in 43%, tubulopapillary in 31%, tubular in 26%. (2) Each case was assigned a final lineage type on the basis of the predominant pattern (>75% of the lesion) on morphology, and supported with specific immunohistochemical cell lineage markers. The predominant cell lineage could be identified as biliary in 50% (66% of which were MUC1), gastric foveolar in 16% (all were MUC5AC), gastric pyloric in 20% (92% MUC6), intestinal in 8% (100% CK20; 75% CDX2; 50%, MUC2), and oncocytic in 6% (17% HepPar and 17% MUC6); however, 90% of cases had some amount of secondary or unclassifiable pattern and hybrid immunophenotypes. (3) Of the cases that would have qualified as "pyloric gland adenoma," 21/24 (88%) had at least focal high-grade dysplasia and 18% had associated invasive carcinoma. Conversely, 8 of 47 "papillary adenocarcinoma"-type cases displayed some foci of low-grade dysplasia, and 15/47 (32%) had no identifiable invasion. (4) Overall, 55% of the cases had an associated invasive carcinoma (pancreatobiliary type, 58; others, 10). Factors associated significantly with invasion were the extent of high-grade dysplasia, cell type (biliary or foveolar), and papilla formation. Among systematically analyzed invasive carcinomas, tumoral intraepithelial neoplasia was detected in 6.4% (39/606). (5) The 3-year actuarial survival was 90% for cases without invasion and 60% for those associated with invasion. In contrast, those associated with invasion had a far better clinical outcome compared with pancreatobiliary-type GB carcinomas (3-yr survival, 27%), and this survival advantage persisted even with stage-matched comparison. Death occurred in long-term follow-up even in a few noninvasive cases (4/55; median 73.5 mo) emphasizing the importance of long-term follow-up. In conclusion, tumoral preinvasive neoplasms (≥1 cm) in the GB are analogous to their pancreatic and biliary counterparts (biliary intraductal papillary neoplasms, pancreatic intraductal papillary mucinous neoplasms, and intraductal tubulopapillary neoplasms). They show variable cellular lineages, a spectrum of dysplasia, and a mixture of papillary or tubular growth patterns, often with significant overlap, warranting their classification under 1 unified parallel category, intracholecystic papillary-tubular neoplasm. Intracholecystic papillary-tubular neoplasms are relatively indolent neoplasia with significantly better prognosis compared with pancreatobiliary-type GB carcinomas. In contrast, even seemingly innocuous examples such as those referred to as "pyloric gland adenomas" can progress to carcinoma and be associated with invasion and fatal outcome.
胆囊肿瘤上皮内肿瘤（肿瘤性息肉）的临床病理特征的文献相当有限，部分原因是定义和术语的变化。大多数报道的腺瘤（幽门腺型和其他型）都是显微镜下的，因此被认为临床上无关紧要，而原位乳头状癌在很大程度上被认为是“乳头状腺癌”标题下的一种浸润性腺癌。在这项研究中，分析了 123 例有明确的外生性、直径≥1cm 的浸润前肿瘤的胆囊病例。这些患者主要为女性（女性/男性=2:1），平均年龄 61 岁，中位肿瘤大小为 2.2cm。一半的患者有疼痛，另一半则是偶然发现的肿瘤。其他肿瘤，大多数是胃肠道恶性肿瘤，在 22%的病例中存在。只有 20%的病例发现了胆结石。影像学上，近一半被诊断为“癌症”，约一半为息肉样肿瘤，10%的病变漏诊。病理发现：（1）主要形态为乳头状占 43%，管状乳头状占 31%，管状占 26%。（2）根据形态学上主要模式（病变的>75%），对每个病例进行了最终谱系类型的分配，并辅以特定的免疫组织化学细胞谱系标志物。可以确定主要细胞谱系为胆管型占 50%（其中 66%为 MUC1），胃窝状型占 16%（均为 MUC5AC），胃幽门型占 20%（92%为 MUC6），肠型占 8%（100%为 CK20；75%为 CDX2；50%为 MUC2），嗜酸细胞型占 6%（17%为 HepPar 和 17%为 MUC6）；然而，90%的病例有一定数量的次要或无法分类的模式和混合免疫表型。（3）在符合“幽门腺腺瘤”标准的病例中，24 例中有 21 例（88%）至少有局灶性高级别异型增生，18%有伴发浸润性癌。相反，47 例“乳头状腺癌”型病例中有 8 例显示出一些低级别异型增生灶，47 例中有 15%（32%）无明确浸润。（4）总体而言，55%的病例有伴发的浸润性癌（胰胆管型 58 例，其他型 10 例）。与浸润相关的显著因素是高级别异型增生的程度、细胞类型（胆管型或窝状型）和乳头形成。在系统分析的浸润性癌中，在 606 例中检测到肿瘤上皮内肿瘤 6.4%（39 例）。（5）无浸润病例的 3 年生存率为 90%，伴浸润病例的 3 年生存率为 60%。相比之下，与胰胆管型胆囊癌相比，伴浸润的病例有更好的临床预后（3 年生存率为 27%），即使是在匹配分期的比较中，这种生存优势仍然存在。即使在少数非浸润性病例中（55 例中有 4 例；中位随访时间 73.5 个月）也发生了长期随访后的死亡，强调了长期随访的重要性。总之，胆囊的肿瘤前浸润性肿瘤（≥1cm）与其胰腺和胆管对应物（胆管内乳头状瘤、胰腺内乳头状黏液瘤和胆管内管状乳头状瘤）相似。它们显示出不同的细胞谱系、异型增生谱和乳头状或管状生长模式的混合，常伴有明显的重叠，因此需要将其归为 1 个统一的平行类别，即胆囊内乳头状-管状肿瘤。胆囊内乳头状-管状肿瘤是一种相对惰性的肿瘤，与胰胆管型胆囊癌相比，其预后明显更好。相比之下，即使是那些被称为“幽门腺腺瘤”的看似良性的病例也可能进展为癌，并伴有浸润和致命的结局。
