Prevalence of activating K-ras mutations in the evolutionary stages of neoplasia in intraductal papillary mucinous tumors of the pancreas.

OBJECTIVE: The purpose of the study was to determine the prevalence of activating K-ras mutations in the pancreas of patients with intraductal papillary mucinous tumors (IPMT) and to analyze their relation to the degree of site-specific histopathologic abnormality. BACKGROUND: Intraductal papillary mucinous tumors of the pancreas have a biologic behavior that is significantly different from pancreatic ductal adenocarcinoma. Activating K-ras mutations, which may be important events in a multistage process of carcinogenesis, have been reported in IPMT. METHODS: Forty-six different histologic specimens (comprising normal pancreatic ducts, hyperplasia, low-grade dysplasia, high-grade dysplasia-carcinoma in situ, and carcinoma) from 16 patients with IPMT and 9 specimens from patients with pancreatic ductal adenocarcinomas were designated by a pathologist. Genomic DNA was extracted from paraffin-embedded tissue sections after microdissection. The K-ras gene was amplified by polymerase chain reaction and subjected to DNA sequencing. RESULTS: The K-ras mutations were detected in at least one specimen in 13 (81.2%) of 16 patients with IPMT. All mutations were found in codon 12. No codon 13 mutations were detected. The relative frequency of K-ras mutations in the different stages of IPMT was 16.7% in normal epithelium and papillary hyperplasia, 28.6% in low-grade dysplasia, and 57.1% in high-grade dysplasia-carcinoma in situ and invasive carcinoma. The K-ras mutations were detected in 6 (66%) of 9 pancreatic ductal adenocarcinomas. CONCLUSIONS: The K-ras codon 12 point mutations are as frequent in IPMT as in ductal adenocarcinoma. A stepwise increase in the frequency of codon 12 mutations correlated with the stage of neoplastic evolution to cancer. This finding is consistent with an important role of K-ras gene mutations in the transformation from normal epithelium to invasive carcinoma in the majority of patients with IPMT.     

Spectrum of cystic tumors of the pancreas.

The pathologic and clinical classification, as well as the behavior, of cystic tumors of the pancreas has been the subject of controversy. We retrospectively reviewed 50 patients with a diagnosis of cystic tumor of the pancreas observed at The Johns Hopkins Hospital from 1984 to 1991. These tumors were classified into three broad groups: I, cystadenoma; II, cystadenocarcinoma; and III, adenocarcinoma with mucin production or an associated cyst. The three groups did not differ with respect to age or sex. The most common clinical presentation was abdominal pain. Symptoms and signs among the three groups were similar except that patients with cystadenomas were less likely (p less than 0.05) to be jaundiced and more likely (p less than 0.05) to be asymptomatic. Radiologic findings on computerized tomography, cholangiography, and arteriography also overlapped, making precise preoperative determination of tumor type difficult. Operative classification was also often not possible. The resectability rate (Group I, 91%; Group II, 67%; Group III, 53%) and 5-year survival rate (Group I, 90%; Group II, 72%; Group III, 14%) correlated with careful pathologic determination. Cystic tumors of the pancreas represent a spectrum of disease ranging from benign cystadenoma to adenocarcinoma masquerading as cystadenocarcinoma. We recommend resection whenever possible, even when preoperative evaluation suggests benign disease.     

Mucinous cystic tumors of the pancreas

Purpose: This study was conducted to clarify the clinicopathologic characteristics relevant to the specific diagnosis of mucinous cystic tumors of the pancreas. Methods: We retrospectively reviewed the clinical features and histopathologic findings of five patients who underwent curative resection for mucinous cystic tumors of the pancreas at our hospital between 1975 and 2000. Results: All five patients were women, ranging in age from 36 to 69 years, and the tumors were located in the pancreatic body and tail. Histopathologically, three tumors were mucinous cystadenomas and two were mucinous cystadenocarcinomas. All five tumors had ovarian-type stroma, and stromal luteinization was found in the three adenomas. These tumors were classified into two groups according to whether the epithelial lining was endocervical or intestinal. All tumors were spherical and multilocular with a fibrous pseudocapsule. On T1-weighted magnetic resonance images, mucinous cystadenomas with watery mucin showed low signal intensity, but mucinous cystadenocarcinomas with gelatinous mucin or hemorrhagic contents demonstrated high signal intensity. Conclusions: Signal intensity on T1-weighted magnetic resonance images provides highly useful diagnostic information on mucinous cystic tumors of the pancreas. Furthermore, tumors may be classified into two groups according to the type of epithelial lining. Received: December 19, 2001 / Accepted: May 7, 2002 Reprint requests to: T. Hara     

Mucinous cystic neoplasm of the pancreas with latent malignancy

Mucinous cystic neoplasms of the pancreas are rare. They have traditionally been classified as cystadenoma or cystadenocarcinoma. Over a 5-year period, and three operations, a patient initially diagnosed as having a cystadenoma of the pancreas was subsequently found at the time of definitive total pancreatectomy to have a cystadenocarcinoma. The recent literature suggests that there is not distinction between cystadenoma and cystadenocarcinoma, since these tumors have been shown to contain coexisting areas of malignant and benign epithelium in both types. The authors' experience with this patient demonstrates the necessity for thorough histologic sectioning of these tumors to document the presence of carcinoma, since all of these tumors should be regarded as potentially malignant neoplasms. Surgical therapy for these lesions should be total excision whenever feasible.     

胰腺囊性肿瘤的定性诊断

目的 探讨胰腺囊性肿瘤病人术前症状、实验室检查、影像学特征及针吸活检在判断病变良恶性及对外科治疗的指导作用.方法 回顾性分析北京大学第一医院1994-2008年手术治疗的69例胰腺囊性肿瘤病人的临床资料,对性别、症状与体征、肿瘤部位、大小、肿瘤标记物、肿瘤实性成分、有否钙化及胰管梗阻等可能预测肿瘤恶性行为的风险因素进行统计学分析.结果 经术后病理证实,69例病人包括浆液性肿瘤13例,黏液性囊性肿瘤30例,胰管内乳头状黏液性肿瘤7例,实性假乳头状瘤12例,囊性内分泌肿瘤及其它肿瘤7例.69例中交界性或恶性44例,良性25例.单因素分析病人术前上述指标,显示梗阻性黄疸、血清CA19-9或CEA水平、肿瘤直径大于5 cm、囊性肿瘤实性成分与恶性病理关系密切,敏感性分别为34.1%(15/44)、47.7%(21/44)、88.6%(39/44)和72.7%(32/44),特异性为96%(24/25)、84%(23/25)、68%(17/25)和72%(18/25);多因素分析发现后三者为预测胰腺恶性囊性肿瘤的独立危险因素.9例病人行穿刺细胞学及囊内容物检查淀粉酶及CEA/CA19-9,其中3例明确恶性诊断.33例行术中冰冻病理,其中1例胰腺导管内乳头状黏液性癌切缘阳性改行全胰切除术.结论 综合评估术前无创检查资料,多能判断胰腺囊性肿瘤的良恶性进而指导临床治疗,术前穿刺活检适于良性可能性大并拟随诊观察者;术中行切缘病理检查可指导手术切除范围.     

胰腺囊性肿瘤的诊断与治疗进展

胰腺囊性肿瘤（cystic tumors of the pancreas）是指一类胰管或腺泡组织上皮细胞增生致使分泌物潴留而发生的肿瘤性囊性病变，是一种少见的肿瘤，国内文献报道较少，极易造成误诊、误治。常见的胰腺囊性肿瘤为胰腺囊腺瘤和囊腺癌、胰腺实性假乳头肿瘤和胰腺导管内乳头状黏液性肿瘤。现将上述几种胰腺肿瘤的临床特点分述如下，以提高术前和术中的诊断准确率，确定正确的治疗方案，提高治疗效果。     

N-ras 61 oncogene mutations in Hürthle cell tumors

Mutations of ras oncogenes are believed to play an important role in the initiation or progression of human tumors. In thyroid tumors the incidence of ras activation by specific point mutations has been reported to range from 33% in follicular adenomas up to 60% in anaplastic carcinomas. Because of our long-standing interest in Hürthle cell tumors, we began a study of 70 such cases to determine the incidence of ras mutations and their clinical correlates. Analysis of N-ras sequences at codon position 61, with the polymerase chain reaction method and oligonucleotide probe hybridization, showed point mutations of the normal codon CAA* in eight tumor samples. One was a mutation from CAA to AAA, one from CAA to CTA,* and six from CAA to CGA. These mutations would result in amino acid substitutions of lysine, leucine, or arginine for the normal glutamine at position 61 in the N-ras protein. Identical ras mutations in two tumors and some of their surrounding thyroid tissue may indicate that activating ras point mutations are an early event in carcinogenesis. The incidence of mutations was 1 of 24 (4%) of the histologically benign tumors, 5 of 34 (15%) of the intermediate tumors (with vascular or capsular permeation), and 2 of 12 (17%) in the malignant group. Four of these eight patients died of metastatic thyroid disease and four are alive without evidence of recurrence.     

Intraductal papillary mucinous tumors and mucinous cystic tumors of the pancreas: imaging

Most cystic lesions of the pancreas are nonneoplastic and inflammatory in nature. However, approximately 5%–15% of cystic pancreatic masses may be neoplastic. Among the cystic neoplasms are the mucin-producing tumors, both the intraductal papillary mucinous neoplasms and the mucinous cystic neoplasms. Their imaging features on contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI) can assist in the differentiation of these lesions. The imaging findings of both intraductal papillary mucinous neoplasm and mucinous cystic neoplasm are reviewed with attention to CT and MRI.     

MSCT诊断胰腺无功能性囊性神经内分泌肿瘤

目的探讨胰腺无功能性囊性神经内分泌肿瘤(NF-CNETP)的MSCT表现。方法回顾性分析10例经手术病理证实的NF-CNETP的MSCT表现,对照病理进行分析。结果 10例NF-CNETP中,位于胰头5例,胰尾4例,同时位于胰体尾部1例;肿瘤最大径2.5~6.2cm。10例肿瘤均边界清楚,其中9例见完整包膜。平扫肿瘤密度不均匀,实性囊壁呈等或稍低密度,10例中2例可见钙化。增强扫描动脉期9例呈明显环状不均匀强化,1例含壁结节者明显强化,门静脉期均呈持续性强化。肿瘤囊壁动脉期平均CT值为(128.00±62.62)HU,门静脉期为(132.40±44.66)HU。4例胰管轻度扩张。1例胰周淋巴结转移。6例接受能谱CT双能扫描,肿瘤囊壁动脉期及门静脉期的碘浓度值与腹主动脉的碘浓度值进行标准化后分别为0.40±0.16、0.79±0.22。结论 NF-CNETP的MSCT强化方式及包膜显示具有一定特征性,对诊断与鉴别诊断有一定意义。     

Mucinous cystic tumors of the pancreas: clinicopathological features, prognosis, and relationship to other mucinous cystic tumors

The clinicopathological features of 56 patients with mucinous cystic tumors (MCTs) of the pancreas were studied. Particular attention was paid to the prognosis of MCTs and the relationship to their ovarian, hepatic, and retroperitoneal counterparts. To distinguish MCTs from pancreatic intraductal papillary-mucinous tumors, MCTs were defined as tumors lacking communication with the duct system and containing mucin-producing epithelium, usually supported by ovarian-like stroma. All 56 tumors occurred in women (mean age 48.2 years) and were preferentially (93%) located in the body and tail of the pancreas. In accordance with the WHO classification, MCTs were divided into adenomas (n = 22), borderline tumors (n= 12), and noninvasive and invasive carcinomas (n = 22). Survival analysis revealed the extent of invasion to be the most significant prognostic factor (p<0.0001). Malignancy correlated with multilocularity and presence of papillary projections or mural nodules, loss of ovarian-like stroma, and p53 immunoreactivity. Stromal luteinization with expression of tyrosine hydroxylase, calretinin, or alpha inhibin was found in 66% of the cases. We conclude that the biologic behavior of MCTs is predictable on the basis of the extent of invasion. The similarities (i.e. gender, morphology, stromal luteinization) between pancreatic MCT and its ovarian, hepatobiliary, and retroperitoneal counterparts suggest a common pathway for their development.     

结直肠癌肝转移与门静脉血K-ras基因突变的关系

目的 检测结直肠癌患者门静脉血液、原发癌组织及肝转移灶中K-ras基因突变,探讨K-ras突变与结直肠癌肝转移的关系.方法 采用实时荧光定量聚合酶链反应(PCR)技术和基因测序技术检测48例结直肠癌患者门静脉血液、原发肿瘤组织、相应的癌旁肠黏膜以及8例肝转移灶组织中K-ras基因突变.结果 48例结直肠癌组织中17例(35.4%)发现K-ras基因突变,48例癌旁黏膜中4例(8.3%)发现K-ras基因突变,明显低于癌组织的基因突变率(P＜0.05).48例结直肠癌患者中16例(33.3%)门静脉血中发现K-ras基因突变,与癌组织的基因突变率差异无统计学意义(P＞0.05).有肝转移患者门静脉血中K-ras基因突变率(7/10,70.0%)明显高于无肝转移者(9/38,23.7%,P＜0.05).16例门静脉血存在K-ras基因突变者,其相应的肿瘤组织中均发现K-ras突变.而结直肠癌组织中无K-ras基因突变者,患者门静脉血及癌旁黏膜无基因突变.8例同时性肝转移患者中5例门静脉血发现K-ras基因突变,且其相应的肝转移灶组织也发现相同的K-ras突变.2例异时性肝转移患者门静脉血检测到K-ras基因突变,手术时无肝转移,但分别于术后第6个月和第9个月经CT检查证实有肝转移.原发肿瘤组织K-ras基因突变类型与门静脉血、肝脏转移灶的K-ras基因突变一致,即K-ras基因12密码子GGT突变为GAT或GTT.结论 结直肠原发癌组织和患者门静脉血有K-ras基因的突变,预示着肿瘤可能有肝脏转移.

Abstract：

Objective To detect mutations of K-ras oncogene in portal vein blood of patients with colorectal cancer, and to find out the relationship between mutated K-ras oncogene and liver metastases in colorectal cancer. Methods Forty-eight patients with colorectal cancer were screened for the mutations of K-ras oncogene in tissue samples from their tumors, portal vein blood, proximally adjacent mucosa and 8metastatic liver biopsies by real-time fluorescence quantitative polymerase chain reaction (PCR) and DNA sequencing. The results were analyzed with their clinical data. Results Sixteen of the 48 patients with colorectal cancer had K-ras point mutations at codon 12 in their portal vein blood, and 17 of 48 patients had K-ras mutations in their primary tumors, but only 4 of 48 patients had K-ras mutations in proximally adjacent mucosa. There was no significant difference in rate of K-ras mutation between tumor tissues and portal vein blood (P ＞ 0. 05 ), but significant difference was found between the tumor tissue and the proximally adjacent mucosa ( P ＜0. 05 ). The rate of K-ras mutations in portal vein blood of colorectal cancer with liver metastases (70. 0% ) was higher than that of without liver metastases (23.7%). Sixteen cases of mutated K-ras in portal vein blood showed mutations in tumor tissues. Patients without mutated K-ras in tumor tissue had no mutations in their portal vein blood and proximally adjacent mucosa. In 5 of 8 patients with simultaneous liver metastasis, mutated K-ras oncogenes were detected in portal vein blood, and the type of K-ras mutation detected in the tumor tissue was accord with that in metastatic liver biopsies. Two patients with mutated K-ras detected in their portal vein blood had no liver metastases during perioperation, but liver metastases were diagnosed by CT at the postoperative month 6 and 9 respectively. The main types of K-ras mutations at codon 12 included GGT to GAT and GGT to GTT. No one had point mutation at codon 13. Conclusion Mutated K-ras detected in both cancer tissue and portal vein blood may indicate livermetastases from colorectal cancer.     

胰腺囊实性肿瘤的临床病理特点及免疫组化研究

对 4例胰腺囊实性肿瘤的临床资料、组织病理和免疫组化结果进行分析。 4例均为女性 ,年龄1 4～ 2 4 (平均 1 9)岁 ;临床表现以腹部肿块为主。病理组织学示瘤细胞大小形态一致 ,圆形椭圆形 ,核异型性不明显 ,核分裂少见 ;以瘤细胞围绕纤维血管轴心呈假乳头排列为特征。免疫组化示 4例瘤细胞弥漫性a1 -AT ( ) ,vimentin( ) ;2例局灶NSE( ) ;4例局灶ER ( ) ,PR ( ) ;4例CgA (- ) ,Syn(- )。提示胰腺囊实性肿瘤多发生于青年女性 ,是一种低度恶性肿瘤 ,手术切除治愈率高。     

Non-functional or silent endocrine tumors of the pancreas. Apropos of a case of cystic form

The authors report a new case of silent cystic pancreatic endocrine tumour discovered by chance on abdominal ultrasonography. This tumour was treated surgically by simple enucleation-resection. On the basis of the histological appearance and the absence of metastases, this tumour was considered to be benign, but only the long-term course will confirm the diagnosis.     

Mucinous cystic neoplasm of the pancreas. Estimation of grade of malignancy with imaging techniques and its surgical implications

The results of diagnostic imaging procedures, macroscopic and microscopic findings and clinical follow up data of 20 mucinous cystic neoplasms of the pancreas were retrospectively reviewed to determine the grade of malignancy and its surgical implications. The largest mean diameter was 8.9 cm for 10 malignant cases, 5.0 cm for two premalignant cases, and 3.1 cm for eight benign tumours. Ultrasonography or computed tomography or both, corresponded well with macroscopy. The 10 malignant and two premalignant lesions had intracystic mural nodules or extracystic solid components, while the eight benign specimens had neither nodules nor solid portions. Structural complexity seen on ultrasonography or computed tomography, which reflected the irregularity in size and shape of the cysts, internal septa, walls, and solid components, was severe in the 10 malignant and two borderline tumours and mild or moderate in the eight benign lesions. Angiography showed that five of the nine malignant tumours were hypervascular, while the two premalignant and four benign lesions were all avascular. Five of 10 patients with malignant tumours died of local recurrence or remote hematogenous metastases, and one with malignant disease was still alive with liver metastases at the time of writing. We propose that a careful preoperative estimate of the malignant potential of such cysts should be made based on the size of the tumour, the presence of mural nodules and solid areas, and the structural complexity on ultrasonography or computed tomography, as well as the amount of vascularity seen on angiography. Attention should be paid at follow up to the presence of local recurrence and haematogenous metastases in cases of malignant disease.     

K-ras mutations detection in paraaortic lymph nodes and its prognostic value after the surgical treatment of pancreas cancer

Survival after surgery of pancreas carcinoma is still poor. Despite an apparently curative resection, tumor rapidly recur. Thus, the arsenal of diagnostic means should be enriched by sensitive methods to detect the minimal residual disease. The frequency of micrometastases in corresponding paraortic lymph nodes after an apparently curative operation was detected using routine histological, immunohistological and polymerase chain reaction for mutated K-ras methods. Tumor tissue was used for the control. 3 cases out of 69 revealed a positive tumor histological reaction, and 5--immunohistological staining. K-ras mutations are detected in 42 (61%) patients, 12 (17%) of those revealed a positive tumor reaction. Only one patient of a control group showed K-ras mutation. All K-ras positive patients revealed a poor survival prognosis and had a tumor relapse after resection.     

Immunodetection of proliferating cell nuclear antigen assesses the growth fraction and predicts malignancy in endocrine tumors of the pancreas.

Thirty-five endocrine tumors of the pancreas, 17 functioning and 18 nonfunctioning, were immunohistochemically studied for the expression of proliferating cell nuclear antigen (PCNA) using 19A2 and PC10 monoclonal antibodies. The proportion of PCNA-reactive cells (PCNA index) ranged from 0.2 to 27% in functioning tumors and from 0.1% to 55% in nonfunctioning tumors. PCNA index showed a statistically significant correlation with mitotic and Ki67 indexes. The median values of PCNA index identified three groups of patients: group A (PCNA < or = 2%), including 13 functioning and six nonfunctioning tumors; group B (PCNA between 2 and 5%), including three functioning and three nonfunctioning tumors; group C (PCNA > 5%), including one functioning and nine nonfunctioning tumors. All group A tumors were confined to the pancreas. In group B, the functioning tumors were limited to the pancreas, and the nonfunctioning tumors extended to extrapancreatic tissues. All group C patients had extrapancreatic extension of the disease. At follow-up, a PCNA index higher than 5% correlated to a decreased mean survival. Our data suggest that PCNA index is a reliable tool to assess the growth fraction, discern local from advanced diseases, and predict malignancy in pancreatic endocrine tumors.     

Solid and cystic tumors of the pancreas: A report of two cases

Two patients operated on for solid and cystic tumors of the pancreas are presented. One of them had a history of a benign cerebral tumor (astrocytoma) for which a ventriculo-peritoneal shunt had been done 3 years previously. The operations performed were a type-I regional pancreatectomy in one patient and a Whipple's procedure in the other. The patients were discharged well without complications and no recurrence has been detected 1 year after the operation     

Mucinous cystic neoplasm of the pancreas or intraductal papillary-mucinous tumour of the pancreas.

OBJECTIVE: To compare clinicopathological findings in patients with mucinous cystic neoplasms and intraductal papillary-mucinous tumours. DESIGN: Retrospective study. SETTING: University department of surgery, Japan. SUBJECTS: 21 patients with mucinous cystic neoplasms (group 1) and 48 with intraductal papillary-mucinous tumours (group 2). RESULTS: The mean age was younger in group 1 (53(3.4) years) than in group 2 (65(1) years, p < 0.0001). The male:female ratio was smaller in group 1 than in group 2, being 0.17 (3/18) and 1.4 (28/20), respectively, (p = 0.0007). The main sites of the lesions were also significantly different: in group 1 four (19%) were located in the head and 17 in the body or tail, while 32 (67%) were in the head of the pancreas and 16 (33%) in the body or tail in group 2 (p = 0.0007). A unique endoscopic finding, excretion of mucin from the patulous orifice of the papilla, was present in two (9%) of the 21 mucinous cystic tumours and in 21 (45%) of the 47 intraductal papillary-mucinous tumours examined (p = 0.006). Metachronous or synchronous malignant diseases were found in the pancreas or other organs in one (5%) of the 21 patients with mucinous cystic neoplasm and in 13 (27%) of the 48 with intraductal papillary-mucinous tumours (p = 0.03). The three- and five-year survival rates of 11 patients with mucinous cystadenocarcinoma were 45% and 27%, while those of 15 with intraductal papillary-mucinous carcinoma were 85% and 42%. CONCLUSIONS: These findings suggest that mucinous cystic neoplasm and intraductal papillary-mucinous tumours are different clinicopathological entities. Aggressive surgery with peripancreatic lymph node dissection is recommended, particularly for mucinous cystadenocarcinoma, and postoperative follow-up with attention given to the presence of other malignancy is necessary as well as to local recurrence and haematogenous spread.     

Infrequent RAS oncogene mutations in human prostate cancer.

The RAS gene family includes three functional genes, H-RAS, K-RAS, and N-RAS, which have been most widely studied in human tumors. Point mutations most commonly occurring at codons 12, 13, or 61 of these genes allow the RAS protooncogene to be converted to a RAS oncogene. A variety of human tumors have been studied for RAS mutations to date, however, conflicting data has been reported regarding prostate cancer. Cell line studies and two American studies of clinical material have found a low incidence of RAS mutation in prostate cancer. The few mutations found were predominantly in the H-RAS gene. Conversely, a recent study of Japanese occult autopsy specimens found an approximate 25% incidence of K-RAS mutations. In this current study, DNA was extracted from 24 archival paraffin-embedded, formalin-fixed radical prostatectomy specimens. Twenty-one of the 24 cases had pathologic stage C disease, and paraffin blocks were selected having the most concentrated area of neoplasm. Twelve, seven, and five cases demonstrated moderate, well and poorly differentiated histologic grade respectively. Polymerase chain reaction (PCR) was used to amplify the K-RAS, N-RAS, and H-RAS 12, 13, 61 codons of these specimens and mutations were detected with mutation-specific oligonucleotide probe hybridization of southern and slot blots. No definite point mutations were detected. PCR's and hybridizations were performed three separate times by three investigators to confirm these results. PCR-generated mutation-specific positive controls and known negative controls were used and found to be important to interpret oligonucleotide hybridization assays. RAS gene mutations appear to be infrequent in clinical prostate carcinomas in American males.