Incomplete inside-out growth pattern in invasive breast carcinoma: association with lymph vessel invasion and recurrence-free survival

Invasive micropapillary carcinoma (IMPC) is a rare subtype of epithelial tumor of the breast listed in the 2003 World Health Organization histologic classification of tumors of the breast. It is characterized by inside-out micropapillary morphology, frequent lymph vessel invasion (LVI), and lymph node metastasis; however, its etiology remains unknown. This study investigated the incomplete inside-out growth pattern (IGP) in invasive ductal carcinoma, not otherwise specified (NOS), and examined the association between incomplete IGP and clinicopathologic features, including the presence of intratumoral lymph vessels (ILV), LVI, nodal metastasis, and prognosis. Tumor tissues from 166 invasive duct carcinomas NOS and 10 IMPCs were immunostained using an anti-epithelial membrane antigen antibody to detect IGP and with D2-40 antibody to determine the presence of ILV and LVI. Incomplete IGP was detected focally in 88 (53%) of 166 invasive duct carcinomas NOS. Transition areas between IMPC and invasive duct carcinoma NOS also showed prominent incomplete IGP in 9 (90%) of 10 IMPCs. Incomplete IGP in invasive duct carcinomas NOS was associated with larger tumor size, higher frequencies of ILV, LVI, nodal metastasis, and poorer recurrence-free survival by univariate analysis. Incomplete IGP, ILV, and tumor size independently affected LVI by multivariate analysis. These findings indicate that incomplete IGP of tumor cell clusters is not uncommon and is a useful tool for predicting LVI in invasive duct carcinoma NOS of the breast.     

Correlation of vascular endothelial growth factor-D expression and VEGFR-3-positive vessel density with lymph node metastasis in gastric carcinoma

Lymph node metastasis is an important prognostic factor in gastric cancer. Vascular endothelial growth factor-D (VEGF-D) is a lymphangiogenic growth factor that activates VEGF receptor (VEGFR)-3, a receptor expressed in the lymphatic endothelium. We investigated the clinical value of VEGF-D expression and VEGFR-3 positive vessel density in gastric carcinoma with regard to lymphangiogenesis. Immunohistochemical staining was used to determine the expression of VEGF-D and VEGFR- 3 in specimens from 104 cases of resected gastric cancer. VEGF-D expression was observed in 62.5% of the gastric cancers and in 9.6% of the non-neoplastic gastric tissue. The VEGFR-3-positive vessel density was significantly greater in the VEGFD positive group than the negative group. VEGF-D expression was significantly associated with lymph node metastasis, increased serum CEA levels, and the nonsignet ring cell type. The VEGFR-3-positive vessel density was correlated with tumor size, lymphatic invasion, and lymph node metastasis. The VEGF-D expression and high VEGFR-3-positive vessel density were significant poor prognostic factors for relapse-free survival. These results suggest that VEGF-D and VEGFR-3-positive vessel density are potential molecular markers that predict lymphatic involvement in gastric carcinoma.     

Lymphatic vessel densities of lymph node-negative prostate adenocarcinoma in Korea

Although lymphatic vessel density (LVD) is associated with regional lymph node (LN) metastasis in prostate adenocarcinoma, no study is available that examines whether the LVD is correlated with prognostic factors other than LN metastasis in LN-negative prostate adenocarcinoma. The aim of our study was to analyze intratumoral (IT), peritumoral (PT), and nontumoral (NT) LVDs, and to determine if there is a correlation between the LVD and the clinicopathological parameters in the Korean LN-negative prostate adeocarcinoma patients. Lymphatics were detected by immunohistochemical staining using D2-40 antibody on 39 radical prostatectomy specimens. Mean LVDs of IT, PT, and NT compartments were 5.39±4.22, 10.71±4.61, and 2.04±1.34 per 200× field, respectively. The difference in LVD among the compartments was significant (P<0.001). The IT-LVD was significantly lower in patients with larger tumor volume (P=0.029) and higher preoperative prostate-specific antigen level (P=0.008). The PT-LVD showed no significant correlation with the clinicopathological parameters. Our results suggest that IT- and PT-LVDs may increase in LN-negative prostate adenocarcinoma as a result of lymphangiogenesis, but IT lymphatics may decrease due to mechanical compression and destruction caused by proliferating tumor cells. In addition, IT-LVD may be used as a prognostic factor in LN-negative prostate adenocarcinoma.     

Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma.

Tumor growth and metastasis require angiogenesis; and microvessel density, a measure of tumor angiogenesis, correlates with metastasis in breast and lung carcinoma. To determine how microvessel density correlated with metastasis in prostate carcinoma, we counted microvessels within the initial invasive carcinomas of 74 patients (29 with metastasis, 45 without). Microvessels were highlighted by immunostaining endothelial cells for factor VIII-related antigen. Without knowledge of the patient's cancer stage, microvessels were counted in a 200 field (0.739 mm2) in the most active areas of neovascularization. The mean microvessel count in tumors from patients with metastases was 76.8 microvessels per 200 field (median, 66; standard deviation, 44.6). The counts within carcinomas from patients without metastasis were significantly lower, 39.2 (median, 36; standard deviation, 18.6) (P < 0.0001). Microvessel counts increased with increasing Gleason's score (P < 0.0001), but this increase was present predominantly in the poorly differentiated tumors. Although Gleason's score also correlated with metastasis (P = 0.01), multivariate analysis showed that Gleason's score added no additional information to that provided by microvessel count alone. Assay of microvessel density within invasive tumors may prove valuable in selecting patients for aggressive adjuvant therapies in early prostate carcinoma.     

Correlation between local glucose transporter densities and local 3-O-methylglucose transport in rat brain

The present study addresses the question whether local glucose transport kinetics are correlated with local glucose transporter densities in the brain. In 47 brain structures the local rate constants for 3-O-[¹⁴C]methylglucose (3-O-MG) transport, K₁ and k_2, were quantified, and local glucose Glut1 and Glut3 transporter densities were determined by immuno-autoradiographic methods. Statistically significant correlations were found between the rate constants for glucose transport and the transporter densities. The correlations were tighter for Glut1 than for Glut3. Inasmuch as 3-O-MG is transported by the same transporter as glucose, these results indicate that the local densities of glucose transporters determine local glucose transport rates in the brain.     

重组人内皮抑素腺病毒抗肿瘤实验研究

目的肿瘤生长具有血管依赖性。内皮抑素为胶原X羧基末端裂解片段,是重要的内源性血管抑制因子。实验中利用重组人内皮抑素腺病毒(recombinanthumanendostatinadenorirus,Ad-hEndo)在肿瘤局部给药以探索其抗血管基因治疗的可行性。方法以Ad-hEndo感染体外培养肿瘤细胞,观察重组蛋白表达及其对培养的血管内皮细胞的抑制效应;在裸鼠A549肺癌模型中瘤内注射重组病毒,观察肿瘤抑制效应、剂量依从效应和毒副反应。结果不同感染复数的Ad-hEndo感染肿瘤细胞均表达重组内皮抑素蛋白,并能抑制血管内皮细胞的生长。动物实验中Ad-hEndo治疗组肿瘤体积及肺转移结节数明显低于对照组,且转移数与治疗剂量负相关。结论以腺病毒为载体的肿瘤局部血管基因治疗能抑制肿瘤新生血管形成进而有效抑制肿瘤生长和转移,其效应具有剂量依从性。     

Gastric carcinoma with invasive micropapillary pattern and its association with lymph node metastasis

Ushiku T, Matsusaka K, Iwasaki Y, Tateishi Y, Funata N, Seto Y & Fukayama M
(2011) Histopathology  59 , 1081–1089
Gastric carcinoma with invasive micropapillary pattern and its association with lymph node metastasis Aims: This study aimed to characterize the clinicopathological features of invasive micropapillary carcinoma (IMPC) of the stomach. Methods and results: Seventeen cases of gastric IMPC were identified from histological reviews of 1178 consecutive cases. IMPC components occupied 10–90% of the entire tumours. Fifteen tumours showed invasion into the muscularis propria or deeper, whereas two tumours were limited to the submucosa. All 17 cases were associated with tubular or papillary adenocarcinoma. Lymphatic and venous invasion were identified more frequently in cases with IMPC components than in those without (P = 0.0023 and P = 0.0009, respectively). Nodal metastases were identified in 14 of 17 (82%) cases with IMPC components, whereas they were detected in 540 of 1161 (47%) cases with no IMPC components (P = 0.0053). Multivariate analysis demonstrated that the presence of IMPC was an independent predictor of nodal metastasis. Conclusions: Conservative treatments, such as endoscopic resection, should not be used for gastric carcinoma with IMPC components, as these cases are associated with a high propensity for lymphovascular invasion and nodal metastasis.     

Pleural malignant mesothelioma with invasive micropapillary component and its association with pulmonary metastasis

The micropapillary pattern (characterized by papillary structure with tufts lacking a central fibrovascular core) is a predictor of aggressive carcinoma. The purpose of the present study was to review 34 pleural malignant mesotheliomas (21 epithelioid, five sarcomatoid, seven biphasic and one lymphohistiocytoid), with special reference to the presence of invasive micropapillary component. Two invasive micropapillary pattern‐positive tumors were identified. The invasive micropapillary pattern was seen to have a focal distribution in 15–20% of the tumor tissues. The majority of the invasive micropapillary clusters expressed MUC1 along the outer cell surface. Analysis of pleural malignant mesotheliomas with epithelioid features and with or without invasive micropapillary pattern (21 epithelioid and seven biphasic subtypes) indicated pulmonary micrometastases in only the invasive micropapillary‐positive tumors (P < 0.015), and the spread was probably via the lymphatics. Lymphatic involvement (confirmed on immunohistochemistry with D2‐40 antibody) and lymph node metastasis were found in both of the invasive micropapillary‐positive tumor patients, whereas they were noted in only one of 10 (10%, P < 0.046) and three of nine (30%) invasive micropapillary‐negative patients. To the authors’ knowledge this is the first study to indicate the presence of invasive micropapillary component in pleural malignant mesothelioma. This component can predict more aggressive lymphatic spread, similar to that of carcinomas in other organs with micropapillary pattern.     

原发性肝癌合并肺转移的微创治疗

19例、发热16例、术后疼痛17例及局部出血1例,肺部病灶处理过程中出现出血3例、气胸2例、气促1例,经对症治疗后均缓解.患者近期平均生存期(11.5±1.1)个月.结论 微创治疗技术的综合运用是治疗原发性肝癌合并肺转移的有效手段.     

Correlation between local glucose transporter densities and local 3-O-methylglucose transport in rat brain

The present study addresses the question whether local glucose transport kinetics are correlated with local glucose transporter densities in the brain. In 47 brain structures the local rate constants for 3-O-[¹⁴C]methylglucose (3-O-MG) transport, K₁ and k_2, were quantified, and local glucose Glut1 and Glut3 transporter densities were determined by immuno-autoradiographic methods. Statistically significant correlations were found between the rate constants for glucose transport and the transporter densities. The correlations were tighter for Glut1 than for Glut3. Inasmuch as 3-O-MG is transported by the same transporter as glucose, these results indicate that the local densities of glucose transporters determine local glucose transport rates in the brain.     

原发性肝癌合并肺转移的微创治疗

19例、发热16例、术后疼痛17例及局部出血1例,肺部病灶处理过程中出现出血3例、气胸2例、气促1例,经对症治疗后均缓解.患者近期平均生存期(11.5±1.1)个月.结论 微创治疗技术的综合运用是治疗原发性肝癌合并肺转移的有效手段.     

乳腺癌血管生成及组织蛋白酶D表达与转移的关系

目的：探讨乳腺癌组织微血管密度（ｍｉｃｒｏｖｅｓｅｌｄｅｎｓｉｔｙ，ＭＶＤ）及组织蛋白酶Ｄ（ｃａｔｈｅｐｓｉｎＤ，ＣＤ）表达与转移的关系。方法：应用免疫组织化学方法对乳腺癌组织的ＭＶＤ及ＣＤ进行定量和半定量研究。结果：乳腺癌组织ＭＶＤ及ＣＤ表达与淋巴结转移密切相关，腋下淋巴结转移组的ＭＶＤ（１３１．８±３９．８）明显高于腋下淋巴结阴性乳腺癌（ｎｏｄｅｎｅｇａｔｉｖｅｂｒｅａｓｔｃａｎｃｅｒ，ＮＮＢＣ）组的ＭＶＤ（７８．１±２７．１）（Ｐ＜０．００１）；腋下淋巴结转移组ＣＤ高表达者（３３／３６，９１．７％）明显多于ＮＮＢＣ组（１６／３６，４４．４％）（Ｐ＜０．０１）。乳腺癌组织ＭＶＤ与ＣＤ表达关系密切；远处转移及早期死亡者ＭＶＤ较高且ＣＤ表达极强。结论：乳腺癌组织ＭＶＤ的增加及ＣＤ高表达可能协同促进肿瘤转移。富于微血管及ＣＤ高表达的乳腺癌应作为远处转移及早期死亡的高危患者加以重视。     

Experimental liver metastasis: Standards for local cell implantation to study isolated tumor growth in mice

Experimental hepatic metastasis of colorectal tumors is frequently studied by local intrahepatic tumor cell implantation. However, although a variety of factors of the implantation procedure may markedly influence tumor growth characteristics, standards are not defined yet. Herein, we studied the effect of different modes of cell implantation on tumor growth and angiogenesis by in vivo fluorescence microscopy and histology seven days after grafting colorectal CT26.WT tumor cells into the left liver lobe of syngeneic BALB/c mice. We demonstrate that (i) radial growth of cells implanted within the central area of the lobe is inhibited by a regularly observed fissura which crosses at midline the surface of the lobe; (ii) cells suspended during implantation in RPMI show an uncontrolled overwhelming growth 40-fold of those suspended in PBS; (iii) cell implantation in 100 μl and 20 μl suspension medium is significantly more complicated by rupture of the liver capsule, uncontrolled intraparenchymal cell spread and recoil of the cells through the injection canal compared to cells suspended in 10 μl; (iv) the frequency of metastasis within the injection canal and at the puncture site is significantly reduced using 32G compared to 27G or 29G needles; (v) occlusion of the puncture site by acrylic glue or electric coagulation completely abolishes peritoneal tumor spread compared to no treatment or gentle compression by cotton gauze. We conclude that a standardized growth of isolated metastases is best achieved by implanting CT26.WT cells in a 10 μ l PBS blister subcapsularly into the paramedian area of the lower surface of the left liver lobe, using a 32-gauge needle and closing the puncture site with acrylic glue.     

甲状腺滤泡状癌微淋巴管密度与淋巴结转移的关系

目的: 应用新型淋巴管内皮标记物D2-40分析甲状腺滤泡状癌及周围组织微淋巴管密度(MLVD)与淋巴结转移之间的关系.方法: 应用免疫组织化学Envision法检测35例甲状腺滤泡状癌和20例结节性甲状腺肿中D2-40和CD34的表达, 分别计数MLVD和微血管密度(MVD), 分析MLVD与甲状腺滤泡状癌淋巴结转移之间的关系, 同时与病变中MVD行对比观察.结果: 甲状腺滤泡状癌周围结缔组织及被膜中的MLVD和MVD与淋巴结转移有密切关系;MLVD和MVD越高淋巴结转移率越高.同时甲状腺淋巴管内的癌栓与淋巴结转移也显著相关(P<0.01).结论: 甲状腺滤泡状癌的淋巴结转移与微淋巴管及微血管的形成有密切关系, 抑制淋巴管生成, 这可能是未来甲状腺肿瘤治疗的一重要方向.     

Lack of vessel wall elastolysis in human invasive pulmonary aspergillosis.

In experimental studies, the apparent ability of Aspergillus fumigatus isolates to produce elastase in agar plates correlates with their ability to cause invasive pulmonary aspergillosis in mice pretreated with cortisone. Thus, elastase production may govern the pathogenicity of particular isolates. If this is so, then disruption of the elastic layers within blood vessel walls in invasive aspergillosis would be expected. To test this hypothesis, tissue blocks were prepared from nine patients with invasive pulmonary aspergillosis. Separate but immediately adjacent histological sections were stained by the Grocott and periodic acid-Schiff methods for fungal hyphae and by the elastic van Gieson technique for elastic tissue. Comparison of those segments of vessel walls infiltrated by hyphae with those not infiltrated by hyphae showed no overall loss of elastic tissue. Material from five of the cases was also stained with an unconventional combination of histochemical stains, allowing accurate identification of both fungal hyphae and elastic laminae in the same histological sections. The results showed no more disruption of elastic laminae than would be expected from simple physical displacement of elastic laminae. We conclude that if elastolysis contributes at all to invasion of vessel walls by aspergilli, then it seems to be very localized and/or transient.     

胃癌淋巴管E钙黏蛋白、β连环素的表达与癌转移的关系

目的:探讨胃癌淋巴管E钙黏蛋白、β连环素的表达与癌转移的相关性。方法:胃癌标本32例,正常胃组织标本2例。通过免疫组织化学方法,用淋巴管内皮透明质酸受体-1(LYVE-1)标记定位,观察胃癌淋巴管E钙黏蛋白和β连环素的表达。结果:LYVE-1在淋巴管阳性表达,正常组织淋巴管E钙黏蛋白、β连环素表达阴性。胃癌组织淋巴管的E钙黏蛋白表达阴性。β连环素在淋巴管的表达,低分化组表达率为56.5%,与高分化癌淋巴管的表达率(43.3%)有明显差异;有淋巴结转移组表达率58.5%,和无转移癌表达率(43.3%)也有明显差异。结论:E钙黏蛋白/β连环素复合物在介导肿瘤细胞进入淋巴管中起一定的作用,β连环素弱阳性表达与癌的转移有正相关性。     

Hematopoietic growth factors in cancer patients with invasive fungal infections

Hematopoietic growth factors have been used in prophylaxis and treatment of neutropenic febrile episodes. Granulocyte colony-stimulating factor (G-CSF) and granulocyte macrophage colony-stimulating factor (GM-CSF) are the most common growth factors in clinical use. Both successfully shorten the duration of neutropenia following myelosuppressive or myeloablative chemotherapy. The influence of G-CSF and GM-CSF on documented infections and mortality from infections is less obvious. There is no clear evidence that treatment with growth factors reduces the incidence of fungal infections. Since mortality is not affected, considerations of morbidity and cost effectiveness currently dominate the indication for use of growth factors. At current costs, their use is indicated in prophylaxis when the likelihood of developing neutropenic febrile episodes following chemotherapy is 40% or more.     

Pure invasive micropapillary carcinoma of the esophagogastric junction with lymph nodes and liver metastasis

Invasive micropapillary carcinoma (IMPC), an aggressive variant of adenocarcinoma, is associated with a poor prognosis. Although IMPC has been reported to occur in various organs, pure IMPC has only been reported in the breast, pancreas and colon. There are no reports of IMPC of the esophagogastric junction (EGJ). According to previous reports on gastric IMPC, IMPC occupied, at most, 90 % of the whole tumor. IMPC is reported to occur least frequently in the gastric cardia. We herein report a rare case of pure IMPC of the EGJ. A 71‐year‐old male patient presented with epigastric distress. Gastric endoscopy demonstrated an irregularly‐elevated lesion of 50 mm in diameter at the EGJ. The patient underwent proximal gastrectomy, resection of the regional lymph nodes and a punch biopsy of the liver. A histopathological examination revealed that almost all of the regions, including the lymph nodes and the sites of liver metastasis, contained IMPC and that a minute region (<1 % of the whole cancer) contained tubular or papillary adenocarcinoma. The further accumulation of pure IMPC cases like the present case would help to elucidate its pathogenesis.     

淋巴结转移密度与乳腺浸润性导管癌预后的关系

目的探讨淋巴结转移密度与手术治疗乳腺浸润性导管癌患者预后的关系。方法回顾性分析113例乳腺浸润性导管癌的临床资料,按淋巴结转移密度分为ND40组、ND=0组和ND≤40组,采用Kaplan-Meier法和Cox比例风险模型,比较临床病理特征及淋巴结转移密度评价手术治疗乳腺浸润性导管癌患者5年无瘤生存率和总生存率的价值。结果 ND40组、ND=0组和ND≤40组5年无瘤生存率及总生存率,差异有统计学意义(P均0.05)。在Ⅲ期乳腺癌患者中,淋巴结转移密度提供良好的分层意义,ND40组Ⅲ期乳腺癌与Ⅳ期乳腺癌预后无差异(P=0.453)。单因素分析显示,脉管癌栓、淋巴结转移密度、TNM分期、雌、孕激素受体状态及p N分期均与患者的5年无瘤生存率和总生存率有关(P均0.05)。多因素分析显示,组织学分级及淋巴结转移密度是影响患者5年无瘤生存率的独立因素(P均0.05);淋巴结转移密度是影响患者5年总生存率的独立因素(P0.05)。结论淋巴结转移密度是手术治疗乳腺浸润性导管癌患者预后的独立因素,提示其可作为乳腺癌预后的参考标准,ND40组提示预后不良。