促泌素在肾上腺原发肿瘤中的表达及其临床意义

目的比较促泌素(secretagogin,SCGN)与传统神经内分泌标记物在肾上腺原发肿瘤中的表达差异。方法收集肾上腺原发肿瘤手术标本共37例,其中包括18例皮质腺瘤、3例皮质腺癌、16例嗜铬细胞瘤。同时选取5例正常肾上腺组织,5例肾透明细胞癌作为对照。所有标本均使用SCGN、PGP9.5、CD56、NSE、Syn及CgA进行免疫组织化学SP法染色。结果SCGN在全部5例正常肾上腺皮质均有表达,而在髓质不表达(P<0.01),其中在皮质的表达明显高于PGP9.5和CgA的表达(P均<0.01);全部18例皮质腺瘤均表达SCGN,且明显高于NSE(P<0.05)、PGP9.5和CgA(P均<0.01);肾上腺嗜铬细胞瘤中SCGN的阳性表达率仅为18.8%(3/16),明显低于其它标记物(P均<0.01)。SCGN在皮质腺瘤(18/18)中的表达明显高于嗜铬细胞瘤(3/16)(P<0.01),而PGP9.5和CgA在嗜铬细胞瘤(15/16,16/16)中的表达明显高于皮质腺瘤(3/18,1/18)(P均<0.01);CD56、NSE和Syn在皮质腺瘤、皮质腺癌和嗜铬细胞瘤中均有高表达,但两两组间比较均无统计学差异(P均>0.05)。SCGN在全部5例肾透明细胞癌中均不表达。结论SCGN对肾上腺皮质腺瘤有较高敏感性,其与嗜铬细胞瘤的标记物CgA和PGP9.5联合可在两者的诊断和鉴别诊断中发挥重要作用。     

胃异型增生上皮和胃腺癌神经内分泌分化的检测

目的检测胃异型增生上皮及胃腺癌组织中神经内分泌的表达.方法应用免疫组织化学法检测10例正常胃粘膜、63例癌旁低度异型增生、26例高度异型增生及相应胃腺癌组织中嗜铬粒蛋白A(CgA)、突触素(Syn)和神经元特异性烯醇化酶(NSE)表达结果 CgA、Syn和NSE在癌旁低度异型增生、高度异型增生及相应胃腺癌组织中阳性表达率有显著性差异(P<0.01).结论胃异型增生上皮和胃腺癌伴神经内分泌是一种常见的现象,它反映了胃腺癌发生发展的多步骤过程.     

胎儿胰腺发育中CgA和NSE的表达及其意义

目的检测人胎儿胰腺中CgA和NSE的表达特征,初步探讨胎儿胰腺发育过程弥散神经内分泌系统的形成及其生物学作用.方法用免疫组织化学SP法,检测嗜铬素A(chromograin A,CgA)和神经元特异性烯醇化酶(neuron specific enolase,NSE)在不同胎龄胎儿胰腺组织中的表达.结果CgA在16-38周的胰腺中均有表达,随胎儿发育,CgA阳性细胞分布状态和反应程度均有差异变化;NSE在22-38周胎儿胰腺中表达,集中定位于胰腺的内分泌部细胞.结论CgA和NSE在人胎儿胰腺中的阳性表达,反映出弥散神经内分泌系统在胎儿胰腺中的形成过程;表明胎儿胰岛的形成及其DNES细胞的分泌,有调节胰腺外分泌部发育分化的作用,也提示胰岛DNES细胞通过调节血糖可能对胎儿个体发育具有重要影响.     

肺癌细胞多向分化与异质性的研究

探讨肺癌细胞多向分化与异质性。用光镜、免疫组化方法观察了87例肺癌手术标本组织切片,30例细胞涂片。（1）标本取材块数与病理分型种类多少里显著性正相关。（r=0．407,P＜0．01）;（2）作为单一类型的小细胞癌、鳞癌、腺癌、大细胞癌及类癌仅占27．6％、20％鳞癌、16．7％腺癌、23．3％大细胞癌KER、VIM双表达。66．7％有鳞、腺、神经内分泌三向分化;（3）在混合类型肺癌中,细胞学与组织学分型符合率为56．7％。肺癌细胞类型有明显异质性,其发生分子基础尚待进一步研究。     

GDF-15在子宫内膜样腺癌中的表达及意义

目的通过检测生长分化因子15(growth differentiation factor-15,GDF-15)蛋白在正常子宫内膜组织和子宫内膜样腺癌组织中的表达,探讨其在子宫内膜样腺癌中的临床意义。方法运用组织芯片技术和免疫组织化学法检测30例正常子宫内膜组织和52例子宫内膜样腺癌组织中GDF-15表达情况,采取多种统计学方法对数据进行详细分析比较。结果GDF-15在子宫正常内膜组织和内膜样腺癌中的阳性表达率分别是6.7%(2/30)和69.2%(36/52),差异具有统计学意义(χ2=29.947,P=0.000);GDF-15在子宫内膜样腺癌组织浸润深度达≥1/2肌层组中阳性率是90.0%(18/20),明显高于浸润深度1/2肌层组的阳性表达率56.3%(18/32,χ2=6.581,P=0.010);GDF-15在FIGO分期Ⅲ以上癌组织阳性表达率为100%(11/11),显著高于在Ⅰ-Ⅱ期癌组织中阳性表达率61.0%(25/41,χ2=6.201,P=0.013);GDF-15在出现淋巴结转移的阳性表达率为89.5%(17/19),显著高于无淋巴结转移的阳性表达率57.6%(19/33,χ2=5.759,P=0.016);,年龄、月经状态、肿瘤最大直径、病理学分级均与GDF-15表达无关(全部P0.05)。结论 GDF-15表达上调促进子宫内膜样腺癌发展,检测其表达对子宫内膜样腺癌患者的发展及预后的判断有重要参考价值。     

具有腺和神经内分泌双向分化及伴Paget样扩散的肛门癌合并腺癌1例并文献复习

目的 探讨1例具有腺和神经内分泌双向分化伴Paget样扩散的肛门癌合并腺癌的临床病理特征、组织学起源、诊断及鉴别诊断。方法 应用HE染色、免疫组织化学染色对重庆市中医院收集的1例肛门具有腺和神经内分泌双向分化的癌伴Paget样扩散合并腺癌进行临床病理分析,并进行相关的国内外文献复习,探讨其临床病理特征。结果 手术切除标...     

P63和TTF-1在肺癌组织中的表达及意义

目的研究P63和TTF-1在肺癌各种类型组织中的表达及其意义。方法随机收集原发性肺癌组织标本53例（其中鳞癌16例,腺癌16例,小细胞癌14例,大细胞癌7例,均为中低分化程度癌组织）,采用免疫组织化学S-P法分别检测P63蛋白和TTF-1蛋白在各种类型肺癌组织中的表达并结合二者表达的结果进行分析。结果二者的表达在肺癌细胞中定位于细胞核,呈棕黄色。在肺鳞癌、肺腺癌、肺小细胞癌和肺大细胞癌中,P63的阳性表达率分别为93.8%（15/16）、37.5%（6/16）、21.4%（3/14）、28.6%（2/7）;TTF-1的阳性表达率分别为18.8%（3/16）、75%（12/16）、78.6%（11/14）、0%（0/7）。结论①P63在肺鳞癌中的表达水平较高,可以作为鉴别低分化鳞癌与低分化腺癌,小细胞癌的指标;②TTF-1在低分化腺癌和小细胞癌中的表达水平较高,对于肺癌组织类型和非癌组织的鉴别具有一定意义;③根据P63和TTF-1在肺癌组织的特异性表达,将二者联合起来有助于对低分化鳞癌和低分化腺癌以及低分化鳞癌和小细胞癌的鉴别诊断。     

胃肠道双向分化癌2例临床病理特征及文献复习

目的 探讨胃肠道双向分化癌的临床病理特点、分级及鉴别诊断。方法 回顾性分析2例双向分化癌患者的临床病理资料,并复习相关文献。结果 2例患者均行根治性手术治疗,例1以腺样、巢片状生长伴黏液产生,例2在黏液背景中呈印戒细胞样生长。2例均可见细胞内外黏液,细胞核染色质细腻,且免疫组织化学表达腺和神经内分泌标记,证明其具有双向分化特征。2例病例高级别肿瘤成分均> 75%,分级均为3级。结论 双向分化癌是一种具有双向分化特征的恶性肿瘤,诊断主要依赖组织学形态及免疫组织化学检测。     

伴肠母细胞分化的胃腺癌合并神经内分泌小细胞癌1例并文献复习

目的 探讨伴肠母细胞分化的胃腺癌(gastric adenocarcinoma with enteroblastic differentiation,GAED)合并神经内分泌小细胞癌的临床病理特征、免疫表型及预后.方法 应用HE染色、免疫组织化学染色对我院收集的1例伴肠母细胞分化的胃腺癌合并神经内分泌小细胞癌进行临床病...     

MDM2基因和TBX2在子宫内膜样腺癌中的表达及临床意义

目的:探讨MDM2和TBX2基因在正常增殖期子宫内膜、子宫内膜增殖症和子宫内膜样腺癌组织中的表达和临床意义。方法:采用免疫组织化学链菌素亲生物素基因过氧化物酶连接法(SP法)和组织芯片技术检测20例增殖期子宫内膜、41例子宫内膜增生性病变和45例子宫内膜样腺癌中MDM2和TBX2基因的表达情况。结果:MDM2在增殖期子宫内膜和单纯性增生子宫内膜中均无强阳性表达,复杂性增生子宫内膜和子宫内膜样腺癌中MDM2强阳性表达率分别为23.81%和51.11,明显高于增殖期子宫内膜和单纯性增生子宫内膜(P<0.05)。子宫内膜样腺癌中MDM2的强阳性表达率为51.11%(23/45),明显高于复杂性增生子宫内膜和复杂性非典型增生中的子宫内膜(P<0.05)。子宫内膜样腺癌中MDM2强阳性表达与肿瘤分化程度和TNM分期密切相关,Ⅱ、Ⅲ级子宫内膜样腺癌的强阳性表达率明显高于I级(72.41%vs 13.33%,P<0.05),而与淋巴结转移无相关性(P>0.05)。TBX2在增殖期子宫内膜,单纯性增生子宫内膜,复杂性增生子宫内膜,子宫内膜样腺癌中的阳性表达率分别为30%,35%,45%和72.7%。子宫内膜样腺癌中TBX2基因的阳性表达明显高于其它各组(P<0.05)。TBX2与子宫内膜样腺癌分化程度、TNM分期均有相关性(P<0.05),与有无淋巴结转移均无相关性(P>0.05)。结论:MDM2、TBX2基因在复杂性增生宫内膜和子宫内膜样腺癌中表达明显增强,提示两者在子宫内膜样腺癌发生中起到一定作用。     

Subtypes of thymic epithelial cells defined by neuroendocrine markers

The study attempted to define characteristics of thymic epithelial cells within rat thymus based on the expression of neuroendocrine markers. Using an immunohistochemical approach, the following markers were localised: protein gene product 9.5 (PGP 9.5), neuron-specific enolase (NSE) and chromogranin A (ChA). It was shown that cells displaying immunostaining typical for individual markers reside in distinct regions of the thymus and represent subtypes within various populations of thymic epithelial cells. An immunoreactivity for PGP 9.5 was found exclusively in a subtype of cortical epithelial cells, located mostly within the inner zone of the cortex. On the other hand, NSE represented a marker of most epithelial cells located in the medulla. Few such cells which were negative for NSE proved positive for ChA. Among the cells with a strong reaction for NSE some cells also manifested a positive reaction for ChA. While the pattern of neuroendocrine marker distribution may reflect functional properties of thymic epithelial cells which might be different within distinct areas of the thymus, the differential expression of individual markers seems to reflect biological activity of the cells and/or distinct stages of their differentiation.     

Expression of class III beta-tubulin in neuroendocrine tumours of gastrointestinal tract

Class III b-tubulin is presented as a specific marker for the cells of neuronal origin as well as for the tumours originating from these cells. Its expression is considered one of the earliest events that appear in the cells revealing neuronal differentiation. Using monoclonal antibody TU-20 in an immunohistochemical analysis, we studied the expression of class III b-tubulin in gastrointestinal carcinoid tumours. Paraffin-embedded, formalin-fixed tissue sections from 49 tumour samples obtained from following locations: stomach (4 cases), small intestine (8 cases), appendix (18 cases), rectum (3 cases), pancreas (5 cases), liver metastases (7 cases) and lymph node metastases (4 cases) were used in the study. In 41 of the 49 tumour samples (83.7%), positive staining for class III b-tubulin was detected, while 8 tumour samples (16.3%) were negative. Expression of class III b-tubulin was prominent in all three rectal carcinoids and in three atypical carcinoids located in small intestine. Pancreatic neuroendocrine tumours revealed either weak immunostaining (2 cases), or were negative for this marker (3 cases). The intensity of class III b-tubulin immunolabelling was not related to the degree of tumour differentiation. The results of this study suggest that class III b-tubulin could be a perspective marker for gastrointestinal neuroendocrine tumours. Moreover, the differences in its expression could also elucidate some aspects of histogenetic relationships of neuroendocrine tumours of gastrointestinal tract.     

Neuron-specific enolase in mucosal endocrine cells and carcinoid tumours of the small intestine: A comparative study with neuron-specific enolase immunocytochemistry and silver stains

Summary Endocrine cells of human small intestinal mucosa, small intestinal carcinoids and carcinoid liver metastases were stained with an immunocytochemical technique using an antiserum against neuron-specific enolase (NSE), with the argyrophil technique of Grimelius and with the argentaffin technique of Masson. In the normal mucosa, scattered NSE-immunoreactive cells were seen mainly in the deeper parts of the crypts. These cells, as shown in the same sections, corresponded to the argentaffin and/or argyrophil cells indicating that they were of endocrine type.All intestinal carcinoids (16 cases) displayed NSE immunoreactivity. However, this reaction did not correlate on the cellular level with the silver techniques employed. Thus, many tumour cells were NSE immunoreactive but lacked an argentaffin or argyrophil reaction and vice versa. On the light microscopical level the silver techniques reveal the presence of neurohormonal granules in the tumour cells, while the NSE immunoreactivity appears to disclose neuroendocrine differentiation of the tumour cells irrespective of their hormone and granular content.Out of 13 carcinoid liver metastases, eight displayed strong NSE immunoreactivity, three were weakly stained and two were unreactive. Consecutive or the same tumour sections showed an argentaffin and argyrophil reaction in all carcinoid metastases. Since silver staining provides one type of information and NSE immunocytochemistry another, they provide in combination a good discriminator for neuroendocrine tumours.     

A single-centre experience with octreotide in the treatment of different hypersecretory syndromes in patients with functional gastroenteropancreatic neuroendocrine tumors

The aim of this research was to assess the clinical and biochemical efficacy of the octreotide in the treatment of patients with various functional gastroenteropancreatic neuroendocrine tumors (GEP-NETs). The study included 14 patients treated with octreotide for 6 months. They were diagnosed with VIPoma, glucagonoma, gastrinoma, medullary thyroid carcinoma (solitary and as a part of MEN-II syndrome), pancreatic carcinoids (solitary and as a part of multiple endocrine neoplasia type-1 syndrome-MEN-1 syndrome) and midgut carcinoids. The patients presented with Verner-Morrison, glucagonoma, Zollinger Ellison and carcinoid syndrome respectively. All had a metastatic disease at the time of diagnosis and a positive octreoscan finding. Initially elevated chromogranin A (CgA) levels were detected in 11 (78.6%) and elevated 5-hydroxyindolacetic acid (5-HIAA) levels in 8 (57.1%) patients. Symptomatic efficacy assessments were made by diarrhea reductions during treatment course, and laboratory efficacy was assessed through changes in 5-HIAA and CgA levels. Assessments were made initially and following 6 months of therapy. Median urinary 5-HIAA and the number of stools decreased significantly (p = 0.016 and p = 0.009 respectively, p < 0.05) while CgA levels had the decreasing tendency but not statistically significant (p = 0.14). There was a positive correlation between the 5-HIAA reduction and the decrease in stool number at baseline and during treatment course (p < 0.05). No correlation was observed between 5-HIAA and CgA levels and also there was no correlation between CgA reduction and symptomatic improvement. The results prove octreotide to be effective in reducing symptoms and biochemical markers associated with hypersecretory syndromes of GEP-NETs.     

Biomarkers and molecular imaging in gastroenteropancreatic neuroendocrine tumors

Neuroendocrine gastrointestinal and pancreatic tumors (GEP-NETs) are a heterogenous group of cancers with various clinical expressions. All tumors produce and secret various amines and peptides, which can be used as tissue and circulating markers. Chromogranin A (CgA) is a general tumor marker stored in secretory granules within the tumor cell and released upon stimulation. CgA is the best general tumor marker at the moment, expressed in 80-90% in all patients with GEP-NETs. CgA and NSE are used as tissue markers for the delineation of the neuroendocrine features of the tumors, but recently also the proliferation marker Ki-67 has been included in the standard procedure for evaluation of the proliferation. GEP-NETs are classified into well differentiated neuroendocrine tumors (Ki-67<2%), well-differentiated neuroendocrine carcinoma (Ki-67 2-20%), poorly differentiated neuroendocrine carcinoma (Ki-67>20%). The molecular imaging of NETs is based on the ability of these tumor cells to express somatostatin receptors as well as the APUD features. Octreoscan has been applied for imaging and staging of the disease for more than 2 decades and will nowadays be replaced by 68Ga-DOTA-Octreotate, with higher specificity and sensitivity. 18Fluoro-DOPA and 11C-5HTP are specific tracers for NETs with high specificity and selectivity. A new potential biomarker is auto-antibodies to paraneoplastic antigen MA2, which might indicate early recurrence of carcinoids after surgery with a curative intent. Circulating tumor cells (CTC) have been applied in GEP-NETs quite recently. There is still an unmet need for new markers.     

Gastrointestinal carcinoid tumours. Histogenetic, histochemical, immunohistochemical, clinical and therapeutic aspects

The increased knowledge of the pathobiology of gastrointestinal carcinoid (neuroendocrine) tumours and the improved therapeutic possibilities have brought a demand for more precise diagnosis. Although the carcinoid tumours can often be tentatively recognized in routinely processed microscopic slides, their more accurate identification requires additional diagnostic procedures. General neuroendocrine markers such as the argyrophil reaction of Grimelius and immunohistochemistry with application of antibodies against chromogranin A and of neuron-specific enolase are discriminatory staining methods which are used to reveal the neuroendocrine origin of almost all highly differentiated carcinoid tumours of the gastrointestinal tract. Mid-gut carcinoids, which predominate among these tumours almost unexceptionally contain serotonin. This biogenic amine can be demonstrated by the argentaffin reaction of Masson, serotonin immunoreactively or by formalin-induced fluorescence. The characteristic staining pattern of mid-gut carcinoids is almost invariably preserved in the metastatic deposits and consequently the staining methods for identifying serotonin can also be used on metastases to reveal a primary mid-gut carcinoid. The enterochromaffin-like (ECL) cell carcinoids of the body and fundic area of the stomach often seen in association with pernicious anaemia are argyrophil with the Sevier-Munger silver stain. Other neuroendocrine tumours, viz. antral, duodenal and rectal carcinoids should be studied by a battery of relevant peptide hormone antisera for adequate diagnosis. During the last decade new peptide hormones have been found in circulation in patients with carcinoid tumours, but serotonin and urinary 5-HIAA are still the most important markers for carcinoids of the mid-gut origin. Other clinically useful tumour markers are chromogranin A + B, pancreatic polypeptide, human chorionic gonadotropin alpha and beta subunits. For localizing procedures, angiography is the most reliable investigative method for primary tumours in the gut, whereas CT-scan and ultrasound investigations are good for detection of liver metastases. During the last five years, the therapy for malignant carcinoid tumours has been considerably improved. Chemotherapy has only revealed objective response rates in about 10-30% of the patients giving median survivals from start of therapy of about 10 months. Recently treatment with alpha interferons and the new somatostatin analogue octreotide have given objective responses in 50-75% of patients with malignant mid-gut carcinoid tumours. These patients have now a median survival from start of therapy of 70 months when treated with alpha interferons. In the future new therapies will come into use such as monoclonal antibodies and perhaps also agents blocking different growth factors.     

S-100 protein in human lung neuroendocrine neoplasms. Immunohistochemical study of 14 cases and review of the literature

A group of lung neuroendocrine (NE) neoplasms are investigated in view of the possible presence of S-100 protein immunoreactivity in their cells. The selected tumours were classified according to Gould et al. (1983a) and Mosca et al. (1985). They comprise 5 carcinoids, 3 neuroendocrine carcinomas of the well-differentiated type, or peripheral carcinoids, 5 neuroendocrine carcinomas of the intermediate cell type, or intermediate-cell, poorly differentiated carcinomas, 3 neuroendocrine carcinomas of the microcytoma type, or small cell carcinomas-SCC and a nodal metastasis of microcytoma. All but 2 tumours were immunoreactive for neuron specific enolase (NSE). Few S-100 immunoreactive cells were detected in 4 out of 5 carcinoids, in 1 out of 3 peripheral carcinoids, in 4 out of 5 poorly differentiated carcinomas and in the 3 microcytomas examined. No S-100 positive cells were found in the SCC's nodal metastasis. The S-100 immunolabelled cells can be interpreted as dendritic reticulum cells migrating through the tumours. However, in one case of typical carcinoid, abundant S-100 positive cells were detected: their stellate morphology and their intimate relation with neoplastic cells suggest that they are part of the neoplasia as a sort of satellite cell.     

Quantitative comparison of growth-associated protein GAP-43, neuron-specific enolase, and protein gene product 9.5 as neuronal markers in mature human intestine.

This study was performed to compare GAP-43, PGP 9.5, synaptophysin, and NSE as neuronal markers in the human intestine. GAP-43-immunoreactive nerve fibers were abundant in all layers of the ileum and colon. GAP-43 partially co-localized partially with every neuropeptide (VIP, substance P, galanin, enkephalin) studied. All neuropeptide-immunoreactive fibers also showed GAP-43 reactivity. By blind visual estimation, the numbers of GAP-43-immunoreactive fibers in the lamina propria were greater than those of PGP 9.5, synaptophysin, or NSE. In the muscle layer, visual estimation indicated that the density of GAP-43-immunoreactive fiber profiles was slightly greater than that of the others. The number and intensity of GAP-43-, PGP 9.5-, and NSE-immunoreactive fibers were estimated in sections of normal human colon and ileum using computerized morphometry. In the colon, the numbers of GAP-43-immunoreactive nerve profiles per unit area and their size and intensity were significantly greater than the values for PGP and NSE. A similar trend was observed in the ileum. Neuronal somata lacked or showed only weak GAP-43 immunoreactivity, variable PGP 9.5 immunoreactivity, no synaptophysin immunoreactivity, and moderate to strong NSE immunoreactivity. We conclude that GAP-43 is the superior marker of nerve fibers in the human intestine, whereas NSE is the marker of choice for neuronal somata. (J Histochem Cytochem 47:1405-1415, 1999)     

Phenotypic variations and dynamic topography of transformed cells in an experimental model of diethylstilbestrol-induced renal tumour in male Syrian hamster

This work explores the phenotypic changes affecting transformed cells in an experimental model of diethylstilbestrol (DES)-induced renal tumours in male Syrian hamster. This estrogen-induced neoplasm presents an important cytological pleomorphism and its origin remains largely controversial. In order to characterize phenotypic variations during tumour progression, the occurrence of seven lineage markers was analysed by a morphometric approach in kidney sections of DES-exposed hamsters (6–;11 months). S100 protein, neuron-specific enolase (NSE) and vimentin are expressed by a large percentage of malignant cells during tumour development. Glial fibrillary acidic protein (GFAP), protein gene product 9.5 (PGP 9.5) and desmin are mostly evidenced in advanced neoplasm whereas Leu 7 always presents a focal expression. As evidenced by double-label immunofluorescence, the coexpression of three important neuroectodermal lineage markers (S100, NSE and PGP 9.5) in earliest tumour buds points to a peripheral nerve sheath origin for this neoplasm thus confirming previously published data. For each marker, the fluctuations of expression levels during tumour progression as well as the spatial heterogeneity of distribution suggest variable phenotypic differentiation of transformed cell populations. This observation is largely corroborated by double-label immunofluorescence showing coexpression modification of several markers during tumour progression. This points to a complex dynamic and spatial self-organization of different phenotypes within neoplasms. Altogether, these results support the concept that DES-induced kidney tumours are not made of unstructured cell populations but represent adaptive complex dynamic biosystems.