Prognostic significance of overexpression of c-Met oncoprotein in cholangiocarcinoma

Background:

Cholangiocarcinoma (CC) is a highly malignant carcinoma. We attempted to clarify the prognostic significance of c-Met overexpression and its association with clinicopathological factors in patients with CC.

Patients and methods:

One hundred and eleven patients with intrahepatic CC (IHCC) and 136 patients with extrahepatic CC (EHCC) who had undergone curative surgery were divided immunohistologically into c-Met^high and c-Met^low groups. Clinicopathological factors and outcomes were compared between the groups. c-Met and epidermal growth factor receptor (EGFR) expression was also examined in 10 CC cell lines.

Results:

The positivity of c-Met was 45.0% in IHCC and 68.4% in EHCC; c-Met^high expression was demonstrated in 11.7% of IHCC and 16.2% of EHCC. c-Met^high expression was significantly correlated with the 5-year survival rate for CC overall (P=0.0046) and for IHCC (P=0.0013), histopathological classification in EHCC, and for EGFR overexpression in both IHCC and EHCC. Coexpression and coactivation of c-Met and EGFR were also observed in CC cell lines. Multivariate analysis revealed that c-Met^high expression was an independent predictor of poor overall and disease-free survival in patients with IHCC.

Conclusions:

c-Met overexpression is associated with EGFR expression and is a poor prognostic factor in CC.     

Clinicopathological and prognostic significance of EGFR, VEGF, and HER2 expression in cholangiocarcinoma

Epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and human epidermal growth factor receptor 2 (HER2) have been considered as potential therapeutic targets in cholangiocarcinoma, but no studies have yet clarified the clinicopathological or prognostic significance of these molecules. Immunohistochemical expression of these molecules was assessed retrospectively in 236 cases of cholangiocarcinoma, as well as associations between the expression of these molecules and clinicopathological factors or clinical outcome. The proportions of positive cases for EGFR, VEGF, and HER2 overexpression were 27.4, 53.8, and 0.9% in intrahepatic cholangiocarcinoma (IHCC), and 19.2, 59.2, and 8.5% in extrahepatic cholangiocarcinoma (EHCC), respectively. Clinicopathologically, EGFR overexpression was associated with macroscopic type (P=0.0120), lymph node metastasis (P=0.0006), tumour stage (P=0.0424), lymphatic vessel invasion (P=0.0371), and perineural invasion (P=0.0459) in EHCC, and VEGF overexpression with intrahepatic metastasis (P=0.0224) in IHCC. Multivariate analysis showed that EGFR expression was a significant prognostic factor (hazard ratio (HR), 2.67; 95% confidence interval (CI), 1.52-4.69; P=0.0006) and also a risk factor for tumour recurrence (HR, 1.89; 95% CI, 1.05-3.39, P=0.0335) in IHCC. These results suggest that EGFR expression is associated with tumour progression and VEGF expression may be involved in haematogenic metastasis in cholangiocarcinoma.     

Pathology and prognosis of gastric carcinoma: well versus poorly differentiated type

BACKGROUND: The most important parameters predicting outcome of patients with gastric carcinoma are the depth of wall invasion and the status of lymph node metastasis, but the prognostic significance of histologic type is unclear. The aim of this study was to clarify the prognostic value of two major histologic types of gastric carcinoma, that is well and poorly differentiated types. METHODS: Histopathologic findings and outcomes of 504 patients with gastric carcinoma were evaluated by well and poorly differentiated types. Well differentiated gastric carcinoma (WGC) included papillary and tubular adenocarcinomas, poorly differentiated medullary carcinoma, and well differentiated mucinous carcinoma; whereas poorly differentiated gastric carcinoma (PGC) included poorly differentiated scirrhous carcinoma, signet ring cell carcinoma, and poorly differentiated mucinous carcinoma. RESULTS: Patients with WGC were characterized by old age, male predominance, tumor location in the lower third of the stomach, small tumor size, and liver metastasis; whereas patients with PGC were distinguished by their tumor location in the middle third of the stomach, serosal invasion, lymph node metastasis, advanced stage, and peritoneal dissemination. The overall 5-year survival rate for patients with WGC was higher than that for patients with PGC (76% vs. 67%; P = 0.058), especially for patients with >/= 10 cm tumors (42% vs. 14%; P = 0.017). The 5-year survival rate for patients with serosa positive but node negative tumors was higher in WGC patients than in PGC patients (83% vs. 59%; P = 0.086); whereas the 5-year survival rate for patients with serosa negative but node positive tumors was lower in WGC patients than in PGC patients (63% vs. 88%; P = 0.008). Multivariate analysis indicated that among pathologic variables of the tumor, histologic type (WGC vs. PGC) was one of the independent prognostic factors. CONCLUSIONS: Histologic type is important for estimating the tumor progression and outcomes of patients with gastric carcinoma. In addition to the depth of wall invasion and status of lymph node metastasis, histologic type, including well or poorly differentiated type, should be evaluated in the management of gastric cancer.     

Histological type and marker expression of the primary tumour compared with its local recurrence after breast-conserving therapy for ductal carcinoma in situ

We have investigated primary ductal carcinomas in situ (DCIS) of the breast and their local recurrences after breast-conserving therapy (BCT) for histological characteristics and marker expression. Patients who were randomized in the EORTC trial 10853 (wide local excision versus excision plus radiotherapy) and who developed a local recurrence were identified. Histology was reviewed for 116 cases; oestrogen and progesterone receptor status, and HER2/ neu and p53 overexpression were assessed for 71 cases. Comparing the primary DCIS and the invasive or non-invasive recurrence, concordant histology was found in 62%, and identical marker expression in 63%. Although 11% of the recurrences developed at a distance from the primary DCIS, nearly all these showed the same histological and immunohistochemical profile. 5 patients developed well-differentiated DCIS or grade I invasive carcinoma after poorly differentiated DCIS. Although these recurrences occurred in the same quadrant as the primary DCIS, they may be considered as second primary tumours. Only 4 patients developed poorly differentiated DCIS or grade III invasive carcinoma after well differentiated DCIS. We conclude that in most cases the primary DCIS and its local recurrence are related histologically or by marker expression, suggesting that local recurrence usually reflects outgrowth of residual DCIS; progression of well differentiated DCIS towards poorly differentiated DCIS or grade III invasive carcinoma is a non-frequent event.     

Gene mutation of transforming growth factor beta1 type II receptor in hepatocellular carcinoma.

Alteration of transforming growth factor beta1 (TGF-beta1) type II receptor (RII) appears to cause unresponsiveness to TGF-beta1 in tumorigenic cells. Defect in the mononucleotide repeat sequence, i.e., poly A region of TGF-beta1RII gene has been reported to be related to replication error-positive cancer cells. We examined if there is any TGF-beta1RII mutation in a coding microsatellite in hepatocellular carcinoma (HCC). Genomic DNAs were extracted from formalin-fixed, paraffin-embedded liver tissues obtained at surgery or autopsy in 3 normal individuals and 96 patients with hepatitis C virus-induced chronic liver disease; 3 with chronic hepatitis, 20 with liver cirrhosis and 73 with HCC. The DNA was PCR-amplified at 2 segments of TGF-beta1RII: poly A region which includes the (A)10 microsatellite sequence, and poly GT region. PCR products were directly sequenced. DNA from normal and patients with chronic liver disease contained the 10 wild-type adenines but 3 cases with liver cirrhosis in whom there were only 9 adenines within poly A tract. This microdeletion of one A resulted in a frameshift and truncated a predicted length of amino acids. In HCC lesions, the same deletion was noted in 4 cases (25%) of well-differentiated type, 10 (40%) of moderately differentiated type, 18 (53%) of poorly differentiated type. None of the lesions had mutations within the GT region. Our findings indicate that one adenine deletion of poly A microsatellite tract within TGF-beta1RII is frequently detected in patients with HCC, and the mutation may cause the abrogation of the function of TGF-beta1RII gene.     

Poorly differentiated solid type adenocarcinomas in the stomach: a clinicopathologic study of 71 cases.

A review of 71 cases of solid carcinoma of the stomach selected from 2,738 cases of surgically resected poorly differentiated adenocarcinomas (PDAs) was undertaken. The average age of the patients, which included 47 men and 24 women, was 62 years. The clinicopathologic features of solid carcinomas were similar to those of the differentiated type adenocarcinomas. The solid carcinomas were divided into 42 of the solid alveolar type and 29 of the free-cell type; 32 of the former (76%) had foci of overt differentiated areas, while most of the latter type lacked such foci and had some signet-ring cells. Many tumors of both types had a prominent venous permeation and lymph node metastasis even in the early stage of invasion. The 5-year survival rates were 37% in all cases, 44% in cases with carcinoma with a limited invasion of the submucosa or the muscularis propria, and 27% in carcinoma invading down to the subserosa. These survival rates were poor in comparison with the 110 cases of ordinary PDA (diffuse type of Laurén) selected as controls. These findings suggest that tumors of the solid alveolar type are transformed from the differentiated type of adenocarcinoma, while those of the free-cell type are originally from PDAs. It is also suggested that solid carcinomas did show a high incidence of venous permeation and lymph node metastasis and that the prognosis for of venous permeation and lymph node metastasis and that the prognosis for this type of carcinoma is poor.     

BRAIN METASTASES FROM CARCINOMA OF UTERINE CERVIX

Metastatic spread of cervical carcinoma occurs by local extension and lymphatic dissemination, yet distant metastases do occur in advanced stage. The common sites of distant metastases include liver, lung, and bone. However, brain metastases are uncommon. We had 11 patients with brain metastases from cervical carcinoma in recent decade and retrospectively reviewed these cases to study the mechanisms, diagnosis, treatment, and prognosis. MATERIALS AND METHODS Between January 1990 and…     

鼻咽癌组织中CDK4和p16蛋白的表达

目的：为了观察ＣＤＫ４和p１６蛋白在鼻咽癌组织中的表达状态,探讨其与鼻咽癌的发生 、发展关系。方法：应用Ｓ－Ｐ免疫组化法检测ＣＤＫ４和p１６蛋白在６０例鼻咽癌和２ ０例正常鼻咽部粘膜组织中的表达。结果：６０例鼻咽癌中ＣＤＫ４和p１６蛋白表达率分别为６６．７％和２３．３％。高分化鳞癌p１６蛋白的表达率明显高于低分化鳞癌（Ｐ〈 ０．０１）。２１例淋巴结转移阳性组中p１６蛋白的过度表达与p１６蛋白的低表达可能涉     

残胃癌的多层螺旋CT表现与术后病理对照分析

目的：探讨残胃癌的多层螺旋CT表现以及多层螺旋CT对残胃癌的诊断价值。方法收集经手术病理证实的22例残胃癌的螺旋CT检查结果,分析不同病理类型的残胃癌的螺旋CT表现。结果22例残胃癌均经手术病理证实,其中印戒细胞癌5例,低分化腺癌7例,中分化腺癌7例,高分化腺癌3例。残胃癌的病理类型以低分化腺癌多见,好发于吻合口,CT表现为吻合口及残胃胃壁受侵犯最常见,其次为贲门区胃壁,再次为食管下段及空肠,表现为胃壁增厚,僵硬,形态不规则,不均匀强化。结论多层螺旋CT对残胃癌的定位和定性诊断提供一定依据,CT表现可与病理类型相对应并对外科手术方式及其他临床治疗方案的选择具有一定参考价值。     

Pathological aspects of so called "hilar cholangiocarcinoma"

Cholangiocarcinoma(CC) arising from the large intrahepatic bile ducts and extrahepatic hilar bile ducts share clinicopathological features and have been called hilar and perihilar CC as a group.However,"hilar and perihilar CC" are also used to refer exclusively to the intrahepatic hilar type CC or,more commonly,the extrahepatic hilar CC.Grossly,a major distinction can be made between papillary and non-papillary tumors.Histologically,most hilar CCs are well to moderately differentiated conventional type(biliary) carcinomas.Immunohistochemically,CK7,CK20,CEA and MUC1 are normally expressed,being MUC2 positive in less than 50% of cases.Two main premalignant lesions are known:biliary intraepithelial neoplasia(BilIN) and intraductal papillary neoplasm of the biliary tract(IPNB).IPNB includes the lesions previously named biliary papillomatosis and papillary carcinoma.A series of 29 resected hilar CC from our archives is reviewed.Most(82.8%) were conventional type adenocarcinomas,mostly well to moderately differentiated,although with a broad morphological spectrum;three cases exhibited a poorly differentiated cell component resembling signet ring cells.IPNB was observed in 5(17.2%),four of them with an associated invasive carcinoma.A clear cell type carcinoma,an adenosquamous carcinoma and two gastric foveolar type carcinomas were observed.     

Non-Hodgkin's lymphomas: an ultrastructural study correlating morphology with immunologic cell type.

Ultrastructural studies were performed on 40 B-cell and 14 T-cell lymphomas of non-Hodgkin's type (NHL). Most B-cell lymphomas were comprised of neoplastic cells with morphologic features compatible with a follicular center cell origin. Dendritic reticulum cells and their desmosome-associated processes, characteristic of germinal centers, were observed in all 11 cases of nodular poorly differentiated lymphocytic lymphoma and in one of two cases of nodular "histiocytic" lymphoma, but were not identified in the lymphomas with a diffuse growth pattern. Desmosomes were observed between dendritic reticulum cells and were not found between lymphoid cells. Large neoplastic cells comprising lymphomas of "histiocytic," mixed lymphocytic "histiocytic," and "undifferentiated" types were characterized ultrastructurally and immunologically as lymphoid cells. Malignant lymphomas of well and moderately well differentiated lymphocytic types (7 cases) revealed B-cell markers, and represented a distinct homogenous group of neoplasms, with electron microscopic features most closely resembling follicular cuff lymphocytes. T-cell malignancies included lymphoblastic lymphomas (3 cases), large cell ("histiocytic") lymphomas (4 cases), lymphoepithelioid cell ("Lennert's") lymphomas (2 cases), mycosis fungoides (3 cases) and diffuse poorly differentiated lymphocytic lymphomas (2 cases). A consistent finding in the T-cell proliferations was the presence of small and/or large lymphoid cells with extremely irregular and/or convoluted nuclei, which occurred in varying proportions and with variable degrees of nuclear complexity. The nuclear irregularity evident in the neoplastic T cells was distinguishable from that observed for lymphoid cells of B-cell lymphomas. In comparing the cytoplasmic features of the T- and B-cell neoplasms ultrastructurally, the only distinguishing feature was the presence of well developed granular endoplasmic reticulum with dilated cisternae, i.e., plasmacytoid features, predictive of a B cell origin.     

137例青年人大肠癌临床病理分析

目的 :探讨青年人大肠癌的临床病理特点与预后的关系。方法 :回顾性研究了 13 7例3 5岁以下青年人大肠癌临床病理资料 ,同时与中、老年人大肠癌做了对比分析。结果 :男性 69例 ,女性 68例 ;其中发生在直肠 10 3例 ;溃疡型 76例 ,隆起型 54例 ,浸润型 7例 ;以中分化腺癌多见有 55例 ,依次为黏液腺癌 3 6例 ,高分化腺癌 19例 ,低分化腺癌 15例 ,印戒细胞癌 9例 ,未分化癌 3例。Dukes A期 3 3例 ,B期 41例 ,C期 63例。结论 :青年人大肠癌男女发病率几乎无差异 ,直肠为大肠癌好发部位。黏液腺癌、印戒细胞癌及未分化癌的比例明显高于中老年人 ,提示青年人大肠癌的预后较差。     

Cancers of unknown origin: 311 cases]

Carcinoma of unknown primary site has been defined as a metastatic disease without known primary site (upon clinical, radiological or endoscopic examination) at the initial therapeutic decision. The incidence of such carcinomas is between 1.6 and 15% of all adult's tumors.The goals of this retrospective and monocentric study were 1) the incidence of these carcinoma; 2) the utility to identify the primary site; 3) the efficacy of treatment in terms of survival; and 4) the prognostic factors to optimize strategic choices. Between January 1980 to December 1995, 311 cases were identified; this represents 1.6% of all cases treated in our center. Histological analyses of metastases revealed adenocarcinoma: 164 cases (92 males, 72 females; 29 well differentiated, 11 poorly differentiated and 41 undifferentiated); squamous cell carcinoma: 90 cases (78 males, 12 females); undifferentiated carcinoma: 27 cases (21 males, 6 females); neuro-endocrine tumor: 10 cases; and others: 20 cases. Median age was 61.1 years (30-94). Half of the patients had a PS between 0 and 1. The carcinoma was revealed by only one site of metastases in 35% of the cases (lymph node 72.9%, bone 35.5%, liver 19.4% and lung 16.5%). The primary carcinoma was found in only 6% of the cases. Median survival of all patients was only 9 months. Multivariate analyses by the Cox method show four positive prognostic factors: sex (female), performance status (PS < 2), histological analyses (squamous cell carcinoma), only one site of metastases.     

A clinicopathological study on colonic carcinomas arising from right side colon

This paper discusses the clinicopathological characteristics of colonic carcinomas arising from right side colon. Out of 214 cases of resected colonic carcinomas during the past 13 years, 36 cases of a right side colon carcinoma (in the cecum, in the ascending colon, or in the hepatic flexure) were encountered. Several characteristics have been associated with this type of cancer. They are as follows: 1) in half of these cases an abdominal pain but no anal bleeding, as has been noted in carcinomas of the sigmoid or rectum; 2) in histological type, poorly differentiated adenocarcinomas or mucinous carcinomas in 30.5% of these 36 cases, and associated with a far distant nodal involvement (n3, n4) in advanced carcinomas; and 3) although there was no difference in the 5-year survival rate between a right side colon carcinoma or a colon carcinoma at another site, the prognosis for those given a curative resection for a right side colon carcinoma was poor--only 22% due to hepatic metastases, indicating that colonic carcinomas of the right side has a poor prognosis due to the subsequent risk of highly potential malignancies.     

Immunohistologic evaluation of parathyroid hormone-related protein in human lung cancer and normal tissue with newly developed monoclonal antibody

With a newly developed monoclonal anti-PTHrP antibody, 4B3, the immunohistochemical localization of the parathyroid hormone-related protein (PTHrP) was studied on the formalin-fixed and paraffin-embedded sections of normal human tissues and various subtypes of lung cancer. Among normal epithelial tissues, keratinocytes in squamous epithelia, transitional and bronchial epithelia with squamous metaplasia, meningoepithelial cells, and mammary ductal cells with lactating changes showed positive immunoreactivity. Also, among endocrine tissues, cells in the parathyroid gland, pancreatic islets, adrenal cortex, pituitary gland, and testis were sporadically positive for PTHrP. These distribution patterns suggested that in a physiologic condition, PTHrP was closely related to keratinization and local secretion and/or the metabolism of calcium in specifically differentiated tissues. In lung cancer, however, PTHrP was detected in all cases of well-differentiated and moderately differentiated squamous cell carcinoma and in most cases of small cell carcinoma, irrespective of the patients' serum calcium level. However, PTHrP was not detected in two of five cases of poorly differentiated squamous cell carcinoma and in all cases of adenocarcinoma. Consequently, it was found that PTHrP was commonly produced by squamous cell carcinomas of the differentiated type, and that humoral hypercalcemia of malignancy could be induced when the PTHrP transgressed the homeostatic mechanisms.     

应用cDNA微阵列基因芯片筛选胃低分化腺癌相关基因的研究

背景与目的：胃低分化腺癌癌变的分子机制至今不清楚,关键是未找到与胃低分化腺癌密切相关的基因.本研究拟建立胃低分化腺癌基因表达谱,筛选差异表达基因,进一步分析差异表达基因与胃癌发生、发展关系.方法：用含10 000个已知基因的cDNA微阵列分析胃低分化腺癌和癌旁正常胃黏膜基因表达谱的变化,免疫组化研究差异表达基因与胃癌的关系.结果：二倍以上的差异表达基因212个,其中在胃低分化腺中表达上调169个,表达下调43个.S-P免疫组化结果显示：EMS1蛋白表达定位于胞质,呈黄色至棕黄色;EMS1蛋白在20例正常胃黏膜阳性表达率为20%（4/20）,在146 例胃癌中阳性表达率为89.72% （131/146）;EMS1蛋白在胃癌中的表达高于正常胃黏膜（P＜0.001）.结论：发现EMS1与胃癌有关,为进一步寻找胃癌相关基因提供了重要的研究线索.     

Sex hormone dependency and endocrine therapy in diffuse carcinoma of the stomach

In order to investigate the hormone dependency of gastric cancer, the presence of estrogen receptor (E.R.) in surgically resected carcinomatous tissues was studied. E.R. assay was performed by dextran coated charcoal method. We have found 10% E.R. positive cases in gastric cancer (4/40). These 4 patients were all female, and showed Borrmann 3 or 4 type macroscopically. The histological types of these cases were signet-ring cell carcinoma or poorly differentiated adenocarcinoma. Furthermore, experimental studies suggest that the growth of signet-ring cell carcinoma transplanted on nude mice depends on sex hormone. Based on these observations, the clinical trial of chemo-endocrine therapy after gastrectomy for female patients with diffuse carcinoma of the stomach has been performed in our hospital since 1980. The therapy consists of Mitomycin-C plus subsequent Tegafur, with or without Tamoxifen 20 mg/day given orally, twice a day starting 2 weeks after surgery. The results are as follows: The cumulative 3-year survival rate in 21 cases receiving chemo-endocrine therapy (TAM+) after gastrectomy revealed higher (43.3%) than that (5.6%) in 23 cases receiving chemotherapy alone (TAM-). Furthermore, 2 and 3 years survival rates of TAM + in curatively resected cases (8 cases) were both 100% including 2 recurrent cases. In TAM- 10 cases, 2 and 3 years survival rate showed 68.4% and 16.3% respectively with statistically significance (p less than 0.01). Chemo-endocrine therapy for non-curatively resected and recurrent cases were also effective. This result suggests that the chemo-endocrine therapy after gastrectomy may be a new hopeful adjuvant in female patients with diffuse carcinoma of the stomach.     

鼻烟癌细胞流式细胞光度分析

Fifty cases of nasopharyngeal carcinoma were analysed by flow cytometry for DNA index (DI) and cytokinetics in order to study their relation with histopathology and prognosis. The results showed that DI values ranged from 0.96 to 1.96 with an average of 1.58; aneuploid frequency was 94% (47/50 cases); higher %S+G2M or PI was found; the 5 year survival rate was 26.47%. Cross comparison of these data indicated that 1. vesicular nuclear cell carcinoma was different from the poorly differentiated squamous cell carcinoma as to DI and aneuploid frequency, supporting the former as an independent clinico-pathological type; 2. DI, aneuploid frequency, cytokinetics and prognosis were not significantly different in the pale even nuclear and dark granular nuclear patterns of poorly differentiated squamous cells carcinoma and 3. there were higher %S+G2M values in all the three groups (vesicular, pale even and dark granular nuclear patterns).     

Diffusely infiltrating primary colorectal carcinoma of linitis plastica and lymphangiosis types.

A review of 2369 cases of resected primary colorectal carcinoma identified 15 cases of diffusely infiltrating colorectal carcinoma. Depending on the histologic pattern and extent, these cases were classified as linitis plastica (LP) type (seven cases) or lymphangiosis (LA) type (eight cases). The LP type consisted of poorly differentiated adenocarcinoma or signet ring cell carcinoma; it showed an annularly thickened and rigid bowel wall. The LA type consisted of moderately differentiated adenocarcinoma. The colon wall of the LA type was hemilaterally thickened at the mesenteric side. The prognosis was extremely poor for both types. The LP type mainly had peritoneal dissemination (70%), but the LA type frequently had distant metastasis (88%). Early diagnosis and curative operation are important for both types; however, the LA type also requires therapy for distant metastasis.