A reappraisal of primary gallbladder carcinoma

A 10-year experience with 14 patients with primary carcinoma of the gallbladder encountered in a typical community hospital has been reviewed. Abdominal discomfort in its many manifestations occurred in all patients, with chronic pain of long duration frequently being noted. Six patients were jaundiced. Twelve had documented cholelithiasis. Histologic examination revealed adenocarcinoma in all instances. One patient is alive and well at 3 years; survival of the remaining patients was from 9 days to 25 months. Primary carcinoma of the gallbladder occurs in more than 1% of surgically removed gallbladders. The disease is largely one of elderly persons with chronic calculous cholecystitis. Not only will it be seen with increasing frequency as life expectancy increases, but also it is preventable. Improvement in treatment can thus be initiated by prophylactic removal of diseased gallbladders in otherwise healthy persons. Malignancy may be obscured in those patients presenting with acute cholecystitis eluding surgeon and pathologist alike. These cases, as well as all early malignancies, are diagnosed only by careful histologic examination. Therefore, all gallbladders should be opened and examined by the surgeon in the operating room. Suspicious areas should be evaluated histologically by frozen section so that extension of the operation to include removal of adjacent hepatic parenchyma and performance of an extensive regional lymphadenectomy can be undertaken if cancer is found. By routinely considering every older patient who comes to cholecystectomy as suspect of harboring gallbladder cancer, survival may well be improved.     

Promoter methylation profile in preneoplastic and neoplastic gallbladder lesions

Gallbladder carcinoma (GBC) is a highly malignant neoplasm and represents the leading cause of cancer death in Chilean women. In order to determine the potential role of promoter methylation in gallbladder carcinogenesis, we investigated the frequency of this epigenetic mechanism by methylation-specific polymerase chain reaction (MSP) in 35 chronic cholecystitis (CC, separated according to the presence or absence of metaplasia), 19 early cancers (mucosa or muscularis propia invasion) and 48 advanced carcinomas with invasion of the gallbladder subserosa (25 cases) and serosa (23 cases). We examined 14 genes and observed an increase of multigenic methylation during tumoral progression which was not significantly associated with the patient's age. Four genes (DAPK1, DLC1, TIMP3, and RARbeta2) displayed a progressive increase in their methylation status from CC without metaplasia to advanced carcinoma invading the serosa layer (P 相似文献   

伴有明显间质纤维化的胆囊腺癌19例临床病理分析

背景与目的:胆囊癌的肉眼类型多是息肉型、隆起型或菜花状肿块,组织学类型有高、低分化腺癌,粘液腺癌和未分化癌。而伴有明显间质纤维化的胆囊腺癌较少见,本研究旨在探讨其临床病理特征。方法:应用光镜和免疫组化SP法,对19例伴有明显间质纤维化的胆囊腺癌手术标本切片进行病理学观察,并结合临床资料进行分析。结果:伴有明显间质纤维化的胆囊腺癌临床表现多有长期的胆囊炎、胆囊结石病史,B超检查提示胆囊壁呈不规则增厚或结节状改变。其大体形态不形成癌结节突入胆囊腔,胆囊壁呈局限性增厚,少数病例胆囊壁呈弥漫性不规则增厚。病理组织学特点:腺癌细胞多呈单层排列,较少复层排列,形成大小不等、形态不一、排列不规则的腺样结构;核显示异型性,核分裂像可见,但较少;增生的大量纤维性结缔组织间可伴有以淋巴细胞、浆细胞为主的炎性细胞浸润。免疫表型:强阳性表达CK(AE1/AE3)、CK(AE1)、CK7(OV-TL12/30)、CK8(C51)、CK18(Dc-10)、CK19(RCK108)、EMA(Mc-5);中等阳性表达CEA(COL-1)、CK20(Ks20.4)、MUC-5AC(CLH2);弱阳性表达MUC-2(B306.1);灶性表达CK17(E3)。结论:伴有明显间质纤维化的胆囊腺癌的临床表现、肉眼类型、组织学特点等不同于其它腺癌;其发生可能与慢性胆囊炎有关。     

Identification of musashi-1 and ALDH1 as carcinogenesis, progression, and poor-prognosis related biomarkers for gallbladder adenocarcinoma

In this study, we investigated the expressions of Msi-1 and ALDH1 in gallbladder adenocarcinoma (n=100), peritumoral tissues (n=46), adenomatous polyp (n=15), and chronic cholecystitis (n=35) using immunohistochemical method. The percentage of cases with positive Msi-1 and ALDH1 expression were significantly higher in gallbladder adenocarcinoma than that in peritumoral tissues, adenomatous polyp and chronic cholecystitis (ps < 0.01). The expression of Msi-1 and ALDH1 was significantly associated with differentiation, tumor mass, lymph node metastasis and invasion of adenocarcinoma. The expression of Msi-1 and ALDH1 was found to be highly consistent in gallbladder adenocarcinoma (p < 0.01). Univariate Kaplan-Meier analysis showed a negative correlation between Msi-1 (p=0.042) or ALDH1 (p< 0.001) expression with overall survival. The average survival time of patients with both low or no Msi-1 expression and ALDH1 expression was significantly longer than patients with the other three subtypes (p< 0.001). Multivariate Cox regression analysis showed that positive expression of Msi-1 or ALDH1 (p=0.016, p=0.006, respectively) was an independent bad-prognostic predictor in gallbladder adenocarcinoma. Our study suggested that Msi-1 and/or ALDH1 expression might be closely related to the carcinogenesis, progression, clinical biological behaviors, and prognosis of gallbladder adenocarcinoma.     

Significance of intestinal metaplasia for the evolution of cancer in the biliary tract

Of 25 cases of cancer in the intrahepatic bile ducts, 44 cases of cancer in the extrahepatic bile ducts, 30 cases of adenoma in the gallbladder, and 100 cases of infiltrating carcinoma in the gallbladder, several to about 20% of the cases showed Paneth's cell metaplasia and/or enterochromaffin cell metaplasia within the tumor mass or in its surrounding mucosa. These metaplasia were not found in small adenomata of the gallbladder, but they were frequently seen in large adenomata. Goblet cell metaplasia and marked hyperplasia of mucous glands were seen more frequently in the mucosa surrounding cancer than in the mucosa of 500 non-neoplastic gallbladders. Although cancer in the gallbladder occasionally developed on the basis of intestinal metaplasia alone, intestinal metaplasia was not likely to be related to induction of most adenomata, but it was likely to be associated with growth and cancerous change of adenoma.     

酪氨酸激酶B在涎腺腺样囊性癌中的表达及与嗜神经侵袭的关系

目的检测酪氨酸激酶B(TrkB)在涎腺腺样囊性癌(ACC)的表达情况，探讨TrkB与ACC嗜神经侵袭的关系。方法研究对象为28例ACC，3例正常腮腺，3例正常颌下腺，3例正常舌下腺及5例涎腺腺泡细胞癌标本，采用免疫组织化学及图像分析法对组织切片中的TrkB进行检测。结果以病理学表现为标准，28例ACC中的嗜神经侵袭率为46．4％(13／28)，TrkB阳性率为92．8％(26／28)，存在嗜神经现象组中TrkB表达水平明显高于未见嗜神经现象组(P=0．001)。TrkB的表达在正常大涎腺的导管细胞为阳性，而在腺泡细胞癌胞浆内均为阴性。结论TrkB可能作为ACC嗜神经侵袭的生物学标志物。TrkB表达的增高可能是ACC嗜神经侵袭的机理之一。     

MUC5AC、CDX －2、Ki67在胆囊黏膜肠上皮化生及胆囊腺癌中的表达及其意义

目的：观察 MUC5AC、CDX －2、Ki67在胆囊黏膜肠上皮化生及胆囊腺癌中的表达,探讨胆囊黏膜肠上皮化生与胆囊腺癌的关系。方法：收集胆囊黏膜肠上皮化生40例、胆囊腺癌40例,25例胆结石胆囊正常黏膜做对照。采用免疫组化方法检测 MUC5AC、CDX －2、Ki67三种蛋白质在胆结石胆囊正常黏膜、胆囊黏膜肠上皮化生和胆囊腺癌中的表达。结果：MUC5AC 在胆结石胆囊正常黏膜、胆囊黏膜肠上皮化生、胆囊腺癌中的表达率分别为12．00％（3／25）、62．50％（25／40）、20．00％（8／40）。CDX －2在胆结石胆囊正常黏膜、胆囊黏膜肠上皮化生、胆囊腺癌中的表达率分别为0．00％（0／25）、75．00％（30／40）、50．00％（20／40）。Ki67在胆结石胆囊正常黏膜、胆囊黏膜肠上皮化生、胆囊腺癌中的增殖指数分别为0％～2％、3％～15％、25％～95％。三组间比较 MUC5AC 在胆囊黏膜肠上皮化生的阳性表达率明显高于其他两组,差异有统计学意义（P＝0．001）。CDX －2在胆囊黏膜肠上皮化生、胆囊腺癌中的阳性表达率明显高于胆结石胆囊正常黏膜,差异有统计学意义（P ＝0．001）。Ki67在三组间阳性表达率依次升高。结论：胆囊黏膜肠上皮化生可能是胆囊腺癌发生过程中的一个重要阶段,MUC5AC、CDX －2可能参与了这一过程。结合 Ki67标记核增殖指数,可协同判断胆囊黏膜异型增生,为胆囊黏膜异型增生及胆囊腺癌的病理诊断及鉴别诊断提供检测依据。     

胆囊腺肌瘤病20例临床病理分析

目的:探讨胆囊腺肌瘤病的临床病理特点。方法:对817例胆囊切除标本中病理确诊的20例胆囊腺肌瘤病的临床资料进行回顾性分析。结果:20 例胆囊腺肌瘤病临床表 与慢性胆囊炎胆石症类似。病变大体形态:局限型11例(均位于胆囊底部)、节段型7例和弥漫型2例。组织学特征为胆囊黏膜上皮增生、上皮陷于肌层或浆膜下形成数量较多的罗 阿氏窦、以及肌层增生肥厚。结论:胆囊腺肌瘤病是一种好发于成年女性的瘤样病变,此病常与慢性胆囊炎、胆石症并存,临床诊断困难,确诊需依赖病理检查。     

粘附分子E—cadherin在胆囊癌中的表达及其临床意义

研究粘附分子Ｅ－ｃａｄｈｅｒｉｎ在胆囊腺癌中的表达及与胆囊腺新产品分，侵袭，转移和预后的关系。方法应用免疫组织化学方法对５７例原发性胆囊腺癌、３７例慢性胆囊炎石蜡包埋标本进行Ｅ－ｃａｄｈｅｒｉｎ半定量检测。结果分别有４５例胆囊腺癌组织及１１例，慢性 Ｅ－ｃａｄｈｅｒｉｎ呈阴性或不同有达减弱。     

RCAS1 as a tumour progression marker: an independent negative prognostic factor in gallbladder cancer.

Receptor-binding cancer antigen expressed on SiSo cells (RCAS1) induces apoptosis in immune cells bearing the RCAS1 receptor. We sought to determine RCAS1 involvement in the origin and progression of gallbladder cancer, and also implications of RCAS1 for patient survival. RCAS1 expression was examined immunohistochemically in 110 surgically resected gallbladder specimens. The gallbladders represented 20 cases of cholecystitis with no associated pancreaticobiliary maljunction; 23 cases of cholecystitis with pancreaticobiliary maljunction; 14 cases of adenomyomatosis; 7 adenomas; and 46 cancers. High expression of RCAS1 (immunoreactivity in over 25% of cells) was observed in 32 of the 46 cancers (70%), but not in other diseases, including pre-cancerous conditions. RCAS1 immunoreactivity was associated with depth of tumour invasion (P = 0.0180), lymph node metastasis (P = 0.0033), lymphatic involvement (P = 0.0104), venous involvement (P = 0.0224), perineural involvement (P = 0.0351) and stage by the tumour, nodes and metastases (TNM) classification (P = 0.0026). Thus, RCAS1 expression may be a relatively late event in gallbladder carcinogenesis, possibly promoting tumour progression. Cox regression multivariate analysis demonstrated RCAS1 positivity to be an independent negative predictor for survival (P = 0.0337; risk ratio, 12.690; 95% confidence interval, 1.216-132.423). High expression of RCAS1 significantly correlated with tumour progression and predicted poor outcome in gallbladder cancer.     

Growth mode and DNA ploidy in mucosal carcinomas of the stomach

Modes of cancer growth and DNA ploidy were studied in 66 patients with mucosal carcinoma of the stomach. The modes of growth were classified into five histologic patterns; elongated tubular (three patients), expansive (18 patients), tubular and solid (14 patients), carcinoma in situ (10 patients) and infiltrative (21 patients). In every patient, all or most lesions with elongated tubular, expansive, and carcinoma in situ growths were located in the pyloric gland area of the stomach, and were less than 4 cm in diameter. Histologically, the adenocarcinomas papillary or well-, or moderately differentiated. Most lesions with an infiltrative growth were located in the intermediate pyloric and fundic glands areas, depressed in gross appearance, and composed of poorly differentiated glandular or signet ring tumor cells. The lesions with a tubular and solid growth were present in the pyloric gland or intermediate area, and were classified as well-, moderately, or poorly differentiated adenocarcinoma. All lesions with an elongated tubular, tubular and solid, and carcinoma in situ growths, and most lesions with an infiltrative growth showed a narrowly restricted DNA distribution (Type I or II), while most lesions with an expansive growth had mostly a widely scattered DNA distribution (Type III), representing a higher malignant potential.     

慢性胆囊炎壁肥厚和慢性胆囊炎后性壁肥厚型腺癌

我们对慢性胆囊炎壁肥厚１４４例和慢性胆囊炎后性壁肥厚型腺癌９例进行了组织病理学分析。病理学所见胆囊壁呈局限性或弥漫性增厚，粘膜面粗糙或结节状改变，镜下见上度增生，异型或上皮脱失，罗阿氏窦下延，深达肌层或穿过肌层并伴有上皮异型增生，最后导致癌变。由于此类腺癌在临床病理学上有一种独特的特点，我们将慢性胆囊炎壁肥厚型视为胆囊癌前病变，肥厚型胆囊炎所致的癌变命名为慢性胆囊炎后性壁肥厚型腺癌。提示慢性胆囊炎伴有壁肥厚＞１．５ｃｍ，且充满胆石者，再在病人年龄和一般情况许可的情况下，是进行外科切除胆囊的指征。     

膜联蛋白A1和A2在胆囊良恶性病变组织中的表达水平及其与胆囊腺癌临床病理特征的关系

目的 研究膜联蛋白A1(ANXA1)和膜联蛋白A2(ANXA2)在胆囊腺癌、癌旁组织、胆囊腺瘤性息肉和慢性胆囊炎组织中的表达水平及其与胆囊腺癌临床病理特征之间的关系.方法 选取108例胆囊腺癌、46例癌旁组织、15例胆囊腺瘤性息肉和35例慢性胆囊炎手术切除标本,常规制作石蜡包埋切片.采用免疫组织化学EnVsionTM法检测各组织中ANXA1和ANXA2的表达水平.结果 ANXA1和ANXA2在胆囊腺癌组织中的阳性表达率分别为59.3%和56.5%,其评分值分别为3.2±0.9和3.4±0.8;在癌旁组织中的阳性表达率分别为34.8%和30.4%,其评分值分别为1.1±0.8和1.0±0.8;在胆囊腺瘤性息肉组织中的阳性表达率分别为26.7%和26.7%,其评分值分别为0.9±0.7和0.9±0.8;在慢性胆囊炎组织中的阳性表达率分别为17.1%和20.0%,其评分值分别为0.7±0.9和0.8±0.8.胆囊腺癌组织中ANXA1和ANXA2的阳性表达率及其评分均高于癌旁组织、胆囊腺瘤性息肉组织和慢性胆囊炎组织(均P＜0.05).ANXA1和(或)ANXA2阳性表达的癌旁组织、胆囊腺瘤性息肉和慢性胆囊炎上皮均呈轻至重度不典型增生.高分化腺癌、肿瘤最大径＜2 cm、淋巴结未转移及未侵犯周围组织的胆囊腺癌患者ANXA1和ANXA2的阳性表达率,均明显低于中或低分化腺癌、肿瘤最大径≥2 cm、有淋巴结转移及侵犯周围组织者(均P＜0.05).在胆囊腺癌组织中,ANXA1和ANXA2的表达呈高度一致性(x2=67.84,P＜0.01),其评分值之间呈高度密切正相关(r=0.78,P＜0.01).Kaplan-Meier单因素分析及Cox多因素回归分析结果均显示,ANXA1和ANXA2的表达均不是影响胆囊腺癌预后的重要因素.结论 ANXA1和ANXA2的表达水平可能是反映胆囊腺癌发生、发展及生物学行为的重要生物学指标,但并不能预测胆囊腺癌患者的预后.     

High risk of gallbladder carcinoma in elderly patients with segmental adenomyomatosis of the gallbladder

The clinical significance of adenomyomatosis of the gallbladder remains unclear. This study aimed to clarify the relationship between segmental adenomyomatosis and gallbladder carcinoma, and to elucidate the histogenesis of gallbladder carcinoma associated with segmental adenomyomatosis. A total of 4,560 consecutive patients underwent cholecystectomy. The specimens were examined grossly and histologically. Adenomyomatosis of the gallbladder was divided into segmental, fundal, and diffuse types. Sixty noncancerous gallbladders with segmental adenomyomatosis were examined for epithelial metaplasia. The incidence of gallbladder carcinoma was higher in patients with segmental adenomyomatosis (22/334, 6.6%) than in those without (181/4226, 4.3%; P=0.049). This difference was more marked among patients equal to or older than 60 years of age (15/96,15.6% versus 147/2407, 6.1%, respectively; P<0.001). The other types of adenomyomatosis did not show any significant increases in the incidence of gallbladder carcinoma. In all 22 patients with both segmental adenomyomatosis and carcinoma, the tumors developed only in the fundal mucosa. Epithelial metaplasia was more marked in the fundal mucosa of segmental adenomyomatosis than in the neck mucosa (P=0.003). Segmental adenomyomatosis is a high-risk condition for gallbladder carcinoma, especially in elderly patients. Epithelial metaplasia appears to be related to increased carcinogenesis in the fundal mucosa of segmental adenomyomatosis.     

PDGF-BmRNA在108例胆囊腺癌中的表达及其临床病理意义

[目的1研究胆囊腺癌组织中PDGF-BmRNA的表达及其与临床病理特征的关系。[方法]108例胆囊腺癌、46例癌旁组织、15例腺瘤性息肉和35例慢性胆囊炎组织采用原位杂交法检测PDGF-B mRNA。[结果]胆囊腺癌PDGF—B mRNA表达阳性率（60．2％）明显高于癌旁组织（21．7％）、腺瘤性息肉（20．0％）和慢性胆囊炎（11.4％）（P〈0．01）；胆囊中、低分化腺癌、肿块最大径≥2．0cm、有淋巴结转移和有胆囊外器官侵犯病例PDGF-B mRNA表达阳性率明显高于高分化腺癌、肿块最大径〈2．0cm、无淋巴结转移和无胆囊外器官侵犯病例（P〈0．01）。[结论]胆囊腺癌PDGF—B mRNA表达可能是反映胆囊腺癌发生、进展、生物学行为及预后的重要生物学标志物。     

Immunohistochemical demonstration of pyloric gland-type cells with low-pepsinogen isozyme 1 in preneoplastic and neoplastic tissues of rat stomachs treated with N-methyl-N'-nitro-N-nitrosoguanidine

The appearance of pyloric gland-type cells with a low pepsinogen isozyme 1 (Pg 1) content in the stomach mucosa of F344/Du rats during stomach carcinogenesis was examined by a combination of paradoxical concanavalin A (Con A) staining and immunohistochemical staining for Pg 1. Male F344 rats were given drinking water containing 100 micrograms N-methyl-N'-nitro-N-nitrosoguanidine [(MNNG) CAS: 70-25-7]/ml for 30 weeks and then normal tap water and were killed in week 10, 20, 30, 40, 50, or 70. Untreated rats were killed in week 30 or 70. Serial sections of pyloric mucosa were stained by paradoxical Con A staining and Pg 1 immunostaining. After MNNG treatment, tissues showing changes were classified into normal-looking pyloric mucosa with a low Pg 1 content, mucosa showing atrophic or hyperplastic changes, adenomatous hyperplasia, and adenocarcinoma. From the results of paradoxical Con A staining and Pg 1 immunostaining, the cells in lesions were classified into gastric types (surface mucous cell type and pyloric gland cell type) and intestinal types (intestinal-absorptive cell type and goblet cell type). In this experiment, the cells in lesions were mainly of the gastric cell types. All pyloric glands of control rats in weeks 30 and 70 contained class III mucins and had a high Pg 1 content demonstrated immunohistochemically. After MNNG treatment, class III mucin-positive pyloric glands with a low Pg 1 content in normal-looking pyloric mucosa were found from week 10; subsequently, their number increased with time. Changed mucosa was found from week 20, and the area of cells of the pyloric gland cell type with little or no Pg 1 in changed mucosa was about 30% of the area of cells of the pyloric gland cell type. Adenomatous hyperplasias were found from week 30; adenocarcinomas were found from week 50. Almost all cells of the pyloric gland cell type (greater than 95%) in areas of adenomatous hyperplasia and adenocarcinomas had little or no Pg 1 content. The present results suggested that the appearance of pyloric glands with a low Pg 1 content in normal-looking mucosa might be an immunohistochemically detectable preneoplastic change preceding morphologically detectable preneoplastic changes in stomach carcinogenesis.     

Xanthogranulomatous cholecystitis misdiagnosed as gallbladder carcinoma： retrospective analysis of 10 cases

Objective： To investigate the reasons for misdiagnosing xanthogranulomatous cholecystitis （XGC） as gallbladder carcinoma, and to provide differential points between these two diseases. Methods： Thirty-three patients with the final diagnosis of XGC in our hospital over a period of 10 years （1996-2005） were reviewed, among which 10 （6 males and 4 females） were misdiagnosed as having gallbladder carcinoma either preoperatively or intraoperatively. Results： 10 misdiagnosed cases were examined preoperatively by B-ultrasound （BUS） and computed tomography （CT）. BUS and CT revealed 5 cases of gallbladder carcinoma and 1 of chronic cholecystitis; 2 cases were diagnosed as gallbladder carcinoma on BUS but chronic cholecystitis on CT; other 2 cases were diagnosed as chronic cholecystitis on BUS but as gallbladder carcinoma on CT. Intraoperatively, thickening of the gallbladder wall was found in all of the patients; xanthogranulomatous tissue was found invading into other tissues including gallbladder bed and omentum majus. Intraoperative frozen section investigation was performed on 1 patient revealing that no tumor cell was found. Open cholecystectomy ＋ partial hepatic wedge resection were performed on 3 patients; cholecystectomy ＋ partial hepatic wedge resection ＋ regional lymphadenectomy in the liver duodenum ligament on 6 patients; cholecystectomy ＋ cholecystoenterostomy ＋ colocolic anastomosis after partial resection of transverse colon on 1 patient. Postoperative pathological findings revealed XGC in all these patients. Conclusion： XGC is an uncommon variant of chronic cholecystitis of which clinical and imaging presentations closely resemble gallbladder carcinoma. Thus differentiation is essential by means of intraoperative frozen section investigation to ensure optimal surgical treatment since XGC has its pathological distinctions, which are not that of a precancerous change.     

Perineural spread of basal cell carcinomas treated with Mohs micrographic surgery

BACKGROUND: Perineural spread is a well-documented feature of cutaneous tumors and may portend a more aggressive course. The incidence of perineural invasion in basal cell carcinoma (BCC) is reportedly 1%. The authors sought to determine whether perineural spread occurs more commonly than previously thought. METHODS: The authors prospectively evaluated 434 patients with BCC treated with Mohs surgery, assessing the presence or absence of perineural inflammation and invasion in tumors requiring more than one stage of surgery. They also documented the demographic features, clinical characteristics, histologic subtype, and operative data in each case. RESULTS: Seventy-eight BCCs required more than one stage of Mohs surgery. Perineural inflammation, perineural tumor invasion, or both were present in 29 of the 78 tumors (37%), or 6.7% of all 434 prospectively evaluated cases. Twenty-one of the 78 tumors (26.9%) exhibited perineural inflammation, 3 (3.8%) demonstrated perineural invasion, and 5 (6.4%) exhibited both. Tumors with perineural invasion required 5.3 surgical stages on average for clearance, in contrast to tumors without perineural invasion, which required 2.2 stages. Tumors with perineural inflammation, inflammation plus tumor invasion, and invasion alone were, respectively, 138%, 149%, and 194% greater in area preoperatively than tumors without perineural involvement, and their mean defect areas after Mohs surgery were, respectively, 151%, 121%, and 605% larger than those of tumors without perineural involvement. CONCLUSIONS: The incidence of perineural invasion among cases of BCC appears higher than previously recognized. Tumor aggressiveness appears to correlate with the presence of perineural invasion. Surgery with horizontal frozen-section margin control enables easy detection of perineural involvement and should therefore be strongly considered for the treatment of high risk BCC patients.     

Mitochondrial DNA mutation at the D310 (displacement loop) mononucleotide sequence in the pathogenesis of gallbladder carcinoma.

PURPOSE: Mutations in the mitochondrial DNA (mtDNA) have been observed frequently in human neoplasia, in both coding and noncoding regions. A mononucleotide repeat (poly-C) between 303 and 315 nucleotides (D310) within the regulatory displacement loop has been identified recently as a frequent hot spot of deletion/insertion mutations in tumors. We investigated the frequency and pattern of D310 abnormalities in the pathogenesis of gallbladder carcinoma (GBC). EXPERIMENTAL DESIGN: DNA extracted from neoplastic and nonneoplastic archival gallbladder tissue including 123 tumors, 53 dysplastic areas, and 90 histologically normal epithelia adjacent to GBC, chronic cholecystitis, and 15 normal gallbladders were examined by PCR-based assay for D310 mutations, followed by sequencing in a subset of cases. RESULTS: D310 mutation was a relatively frequent (47 of 123; 38%) abnormality in GBC. A very high frequency of mutations were detected in dysplastic (8 of 14; 57%) and normal-appearing gallbladder epithelia (10 of 22; 46%) accompanying GBC, showing a clonal relationship compared with the corresponding tumors. D310 mutations were also detected in dysplastic (8 of 39; 21%) and normal (17 of 68; 25%) epithelia obtained from chronic cholecystitis. A single case of 15 normal gallbladders showed a D310 abnormality. Overall, deletions (67 of 91; 74%) at D310 were more frequent than insertions. CONCLUSIONS: D310 mutation at the mtDNA displacement loop is a relatively frequent and early event in the sequential pathogenesis of GBC, being detected in normal-appearing epithelium from chronic cholecystitis. Our findings suggest that mtDNA mutations should be additionally investigated in GBC pathogenesis, and D310 mononucleotide abnormalities could be included in a panel of molecular biomarkers for GBC early detection strategy.