肾上腺髓质内、外嗜铬细胞瘤181例与多发性内分泌肿瘤的临床病理资料分析

目的 分析肾上腺髓质内、外嗜铬细胞瘤与多发性内分泌肿瘤2型( MEN2)的发病变化,探讨它们在临床症状、体征、病理变化方面的异同点和相互关系.方法 运用游程检验、方差分析、t检验、x2检验,对天津医科大学总医院病理科1993-2008年181例肾上腺髓质内、外嗜铬细胞瘤(根据世界卫生组织《内分泌器官肿瘤病理学和遗传学2004年版》分别将其分为良性、恶性倾向、恶性病变3组)及伴MEN2的检出率、构成比、平均诊断年龄、性别比例及临床表现、病理变化进行统计学分析.结果 16年外检总数167 702例,肾上腺疾病、肾上腺髓质内、外嗜铬细胞瘤的例数(外检率)分别是910例(0.54％)、139例(0.08％)、42例(0.03％),其中嗜铬细胞瘤的良性、恶性倾向、恶性3组的例数(构成比)在肾上腺髓质内分别是102例(73.4％)、29例(20.9％)、8例(5.7％),102例良性病变中伴MEN2者共8例(7.8％);在肾上腺髓质外分别是18例(42.8％)、12例(28.6％)、12例(28.6％).16年间肾上腺疾病、肾上腺髓质内、外嗜铬细胞瘤及良性病变伴MEN2的检出率和构成比及嗜铬细胞瘤的良性、恶性倾向、恶性3组的构成比均无变化趋势(P＞0.05),并随病变恶性度的增加逐渐由女性多见转变为男性多见的发病规律.嗜铬细胞瘤患者总平均诊断年龄在髓质内良性组、恶性倾向组分别为42.7和40.1岁,均低于恶性组患者的51.6岁.髓质外良性组、恶性倾向组分别为43.1和45.2岁,均高于恶性组的37.8岁(P＜0.05).恶性病变患者中,髓质内的发病年龄(51.6岁)明显高于髓质外(37.8岁,P＜0.05);伴MEN2患者只见于患肾上腺髓质内良性嗜铬细胞瘤的女性,其平均诊断年龄(38.9岁)低于良性病变(42.7岁),而且甲状腺髓样癌的发生均早于肾上腺髓质内嗜铬细胞瘤.肾上腺髓质内、外嗜铬细胞瘤患者均显示恶性病变伴有高血压症状者的比例较良性、恶性倾向者明显下降(P＜0.05).仅肾上腺髓质内嗜铬细胞瘤发生双侧病变,其中恶性病变( 2/8)的发生率明显高于良性(15.7％)、恶性倾向(6.9％).复发病变在肾上腺髓质内、外嗜铬细胞瘤的比例均随良性(11.8％,0)、恶性倾向(13.8％,25％)、恶性(33.3％,37.5％)的病变恶性度的上升而逐渐增加.肾上腺髓质内、外嗜铬细胞瘤体积平均直径亦随良性(4.2、4.0 cm)、恶性倾向(5.3、5.6 cm)、恶性病变(7.3、6.9 cm)的恶性度上升而逐渐增大(P＜0.05).结论 肾上腺髓质内、外嗜铬细胞瘤良性、恶性倾向、恶性病变3组的临床表现与病理变化密切相关,确切的病变类型和肿瘤性质仍要由病理学检查确定.     

散发性嗜铬细胞瘤患者RET原癌基因突变检测

目的在嗜铬细胞瘤散发患者中进行RET原癌基因突变筛查。方法收集42例病理诊断确诊为嗜铬细胞瘤的患者基因组DNA，其中12例为外周血基因组DNA，30例为嗜铬细胞瘤病理切片组织中提取的基因组DNA。对RET原癌基因第10和第11外显子，采用DNA测序技术进行基因突变筛查。结果在42例中，2例在RET基因的第11外显子存在基因突变。1例634位密码子由TGC突变为TAC，另1例632位密码子由GAG突变为AAG。结论在嗜铬细胞瘤患者中存在RET原癌基因突变携带者，有必要对散发的嗜铬细胞瘤患者进行RET原癌基因的常规突变筛查。     

少突胶质细胞瘤中PTEN基因突变和10q 染色体的杂合性缺失分析

目的 探讨PTEN基因突变和10q染色体的杂合性缺失(LOH)在少突胶质细胞瘤发生和发展中的意义。方法 以55例少突胶质细胞瘤和混合性胶质细胞瘤为研究对象，PCR扩增PTEN基因所有9个外显子，其产物经变性梯度凝胶电泳(DGGE)后，DNA序列分析检测PTEN基因突变。应用不同颜色荧光标记10q微卫星标志物引物，PCR扩增后，其产物在自动测序仪上进行聚丙烯酰胺凝胶电泳，用Gene Scan软件分析LOH。结果 2／55例有PTEN基因突变，1例是PTEN的第9外显子的20号T碱基缺失导致终止密码351易位至347，另1例在139位发生C到A的转换，使得Phe变成Leu。23／55(42％)例出现染色体10q的LOH，其中15／55例位于10q^23.3(D10S541)，其为PTEN基因位点，12／55例10q微卫星标志物位点完全缺失。结论 在少突胶质细胞瘤中PTEN突变较少见，而10q LOH较频繁，尤其在恶性度高的少突胶质细胞瘤中表现明显，提示10q LOH与少突胶质细胞瘤恶性进展有关，且10q上可能存在其他抑癌基因。     

膀胱嗜铬细胞瘤14例临床病理分析

目的：探讨膀胱嗜铬细胞瘤的临床病理学特征、病理诊断以及鉴别诊断。方法：搜集14例膀胱嗜铬细胞瘤患者的临床病理资料,回顾性总结膀胱嗜铬细胞瘤的临床及病理学特征,复习相关文献。结果：14例患者中男性8例、女性6例;年龄14~63岁,平均年龄46.7岁。肿瘤最大径从0.2~8 cm不等,平均最大径2.5 cm。以排尿后头痛、心悸、血压升高为临床主要症状。镜下可见较一致的多边形或圆形上皮样肿瘤细胞,排列成条索、巢团及片状结构,形成典型的zellballen细胞巢,无包膜,在膀胱壁中浸润性生长;肿瘤间质富含薄壁血管,大部分血管呈血窦状、无显著扩张;大部分细胞较一致,散在少数胞体形状不规则、核大深染的瘤细胞,部分胞浆略嗜碱性,核分裂罕见,瘤巢周边见散在梭形细胞。免疫组织化学显示肿瘤细胞CgA、Syn阳性,增殖指数Ki-67阳性1%~10%不等,瘤巢周边梭形细胞S-100阳性;瘤细胞AE1/AE3阴性。9例采用经尿道膀胱肿物切除,其中4例复发。5例采用膀胱部分切除术,其中2例复发。结论：膀胱嗜铬细胞瘤是发生于膀胱的罕见肿瘤,需要依赖组织形态与免疫组织化学特点与其它膀胱肿瘤进行鉴别诊断;单纯肿瘤切除容易局部复发,引起转移的恶性病例少见。     

一个单纯家族性嗜铬细胞瘤家系的VHL基因突变筛查

目的检测一个单纯家族性嗜铬细胞瘤家系的VHL基因突变情况。方法对一个单纯家族性嗜铬细胞瘤家系进行VHL基因突变检测，抽取该家系5例患者及15名血缘亲属外周血基因组DNA，对VHL基因3个外显子进行PCR，产物进行DNA测序。结果该家系5例患者均检测出VHL基因第2外显子上第587位核苷酸A—C突变，该突变导致第125位编码氨基酸由组氨酸（H）转变为脯氨酸（P）。15名家系成员中筛查出7名成员为该突变基因携带者，B超检查发现1例为双侧肾上腺肿瘤，1例为右肾囊肿。该突变为首次报道。结论该嗜铬细胞瘤家系中检测到可能的致病突变，VHL基因检测可早期发现致病基因携带者，建议对单纯家族性嗜铬细胞瘤患者常规进行VHL基因突变筛查。     

嗜铬细胞瘤组织芯片免疫组化标记的诊断价值分析

目的 探讨肾上腺嗜铬细胞瘤组织芯片免疫组化标记的诊断价值。方法 制备肾上腺组织芯片，含样本163例，其中正常肾上腺15例，肾上腺皮质增生2例，嗜铬细胞瘤41例，肾上腺皮质腺瘤72例，肾上腺皮质癌22例，肾上腺转移癌11例。用免疫组织化学EnVision法检测多种免疫标记的表达情况。结果 肾上腺髓质素(adrenomedullin，ADM)阳性率分别为：正常肾上腺髓质100％(5／5)，嗜铬细胞瘤60．5％(23／38)，肾上腺皮质肿瘤及转移癌呈阴性；CgA：嗜铬细胞瘤阳性率86．8％(33／38)；Syn：嗜铬细胞瘤阳性率73．7％(28／38)，肾上腺皮质癌阳性率28．6％(6／21)，肾上腺皮质腺瘤及转移癌呈阴性；S-100蛋白：嗜铬细胞瘤支持细胞阳性率47.4％(18／38)；MelanA(A103)和inhibin α在嗜铬细胞瘤呈阴性，但肾上腺皮质及皮质肿瘤高表达。结论 在嗜铬细胞瘤的诊断和鉴别诊断中，必须联合应用ADM、CgA、S-100蛋白等多种标记。组织芯片技术为快速原位检测提供了有效的手段。     

恶性颗粒细胞瘤10例临床病理学观察及文献复习

目的 探讨恶性颗粒细胞瘤的临床病理学特征,评价组织学上诊断恶性的标准。方法 对10例恶性颗粒细胞瘤的临床资料和组织学形态进行回顾性分析,并采用免疫组织化学(LSAB法)和电镜检测研究其免疫表型和超微结构。结果男性4例,女性6例,年龄范围为27～73岁(平均46岁)。临床上,9例表现为皮下或深部软组织内无痛性生长的孤立性肿块,其中1例伴有周围神经症状。肿瘤位于下肢3例,乳腺2例,项部2例,胸壁、右颈部和盆腔者各1例。肿瘤直径2～11cm,平均4．8cm。镜下由成巢或成片的多边形细胞组成,胞质呈嗜伊红色颗粒状,与良性性颗粒细胞瘤极为相似,但仔细观察发现,9例显示至少下述形态中的3种：核增大呈空泡状并可见明显的核仁;多形性瘤细胞;核质比增大;瘤细胞趋向梭形;可见核分裂象;凝固性坏死。除经典性形态外,1例尚可见散在的多核性瘤细胞。余1例除局部区域显示核增大呈空泡状并可见明显的核仁外,其余形态均不明显,但临床上却呈恶性经过。9例均强阳性表达S-100蛋白和神经元特异性烯醇化酶(NSE),7例尚表达CD68。电镜观察显示瘤细胞胞质内充满大量退变的复合性溶酶体。随访7例,5例复发,4例转移,2例死于肿瘤。结论 (1)Fangburg-Smith等的组织学恶性标准具有较高的可重复性,但在少数情形下,最终诊断仍需结合肿瘤的生物学行为;(2)提议将核分裂象的标准修订为＞5／50HPF;(3)广泛性局部切除加上必要的区域淋巴结清扫仍是目前最主要的治疗手段,辅助性化疗和(或)放疗并不能明显改善患者的预后;(4)描述一种尚未见报道的多核性瘤细胞形态亚型。     

INSM1在嗜铬细胞瘤/副神经节瘤和肾上腺皮质腺瘤中的表达和病理诊断价值

目的 探讨胰岛素瘤相关蛋白1(insulinoma-associated protein 1, INSM1)在嗜铬细胞瘤/副神经节瘤和肾上腺皮质腺瘤中的表达及其在鉴别诊断中的意义。方法 采用免疫组化EnVision两步法检测INSM1在嗜铬细胞瘤/副神经节瘤和肾上腺皮质腺瘤中的表达。结果 32例嗜铬细胞瘤中31例INSM1阳性(31/32,96.88%),其中高表达20例(20/32,62.50%)。9例肾上腺外副神经节瘤INSM1均阳性,其中高表达8例(8/9,88.89%)。33例肾上腺皮质腺瘤中INSM1均阴性。INSM1在嗜铬细胞瘤/副神经节瘤中的表达显著高于肾上腺皮质腺瘤(P<0.001)。INSM1高表达的嗜铬细胞瘤/副神经节瘤具有更高的Ki67增殖指数(P=0.016),但与患者性别(P=0.190)、年龄(P=0.439)、肿瘤TNM分期(P=0.793)、生长模式(P=0.495)、凝固性坏死(P=0.790)和脉管/包膜侵犯(P=0.790)均无显著相关性。INSM1鉴别嗜铬细胞瘤/副神经节瘤与肾上腺皮质腺瘤的敏感性为97.6%,特异性为100%,ROC曲线下...     

少突胶质细胞肿瘤染色体1p、19q和10q杂合性缺失与临床预后的关系

目的 探讨少突胶质细胞肿瘤微卫星变异的遗传和分子特性及其与临床预后的关系。方法 26例少突胶质细胞瘤和25例伴有少突胶质细胞瘤成分的胶质母细胞瘤成对的血和肿瘤标本DNA提取后,进行微卫星不稳定性分析染色体1、19q和10q杂合性缺失。结果 54％少突胶质细胞瘤检出1pLOH,58％检出19qLOH,35％检出10q LOH,其中50％间变性少突胶质细胞瘤出现10q LOH。1p／19q LOH相伴存,二者密切相关（P〈0．0001）;40％GBMO检出1pLOH,仅4例1p LOH伴10q LOH;60％检出19q LOH,64％检出10q LOH。结论 1P和19q LOH是少突胶质细胞瘤分子和遗传特性之一,并且与化疗敏感和预后好有关,10qLOH是少突胶质细胞瘤进展标志。1PLOH与长PFS有关,10qLOH与短PFS有关。GBMO分子表型不同于GBM。     

声带早期癌DNA分析及p53、Ki-67和bcl-X的表达

目的　以声带原位癌和早期微小浸润癌为主要研究对象 ,探讨声带从良性到恶性病变各阶段中DNA倍体及基因表达的变化 ,并结合其临床生物学行为 ,深入了解其实质。方法　对 18例声带肿瘤性病变做激光扫描细胞DNA分析并进行随访。对 6 2例声带病变 ,以声带原位癌 (CIS)和早期微小浸润癌 (EMIC)为主 ,与声带浸润性癌、声带息肉分别分为 3组 ,检测p5 3、Ki 6 7和bcl X的基因表达并作各组间对比。 结果　DNA倍体分析表明CIS、EMIC和浸润性癌不同 ,前两者几乎都是二倍体 ,而后者 90 %为异倍体 ;随访结果示CIS、EMIC病人无 1例死于肿瘤 ;还发现DNA二倍体和有DNA凋亡峰的肿瘤患者预后好 ,而肿瘤呈异倍体的患者预后差。免疫表型 :p5 3蛋白在声带肿瘤性病变中表达异常高 ;86 %的CIS、EMIC和 91%的浸润性癌都表达p5 3蛋白 ,阳性指数分别为 2 35和 2 2 6 ,同时此两组的Ki 6 7的阳性平均指数也分别为 2 9%和 2 7% ,与声带息肉差异有显著性 (P <0 0 1)。另一方面 ,bcl X的表达从良性病变到恶性病变呈递减态势 ,以浸润性癌中下降最明显 ,与息肉病变差异有显著性 (P =0 0 0 2 )。结论　声带良性病变、CIS、EMIC及浸润性癌在基因表达和DNA倍体上表现有所不同 ,提示它们各自之间有本质的差别 ,声带原位癌的表现界于良恶     

Genetic Changes in Chromosomes 1p and 17p in Thyroid Cancer Progression

Little is known about the genetic alterations that occur during the progression of thyroid neoplasms. To understand better the biology of thyroid tumors, we investigated several genetic loci in benign and malignant thyroid neoplasms. Forty-one thyroid tumors (6 adenomas, 16 papillary, 14 follicular, and 5 anaplastic carcinomas) were studied. Normal and tumor cells were microdissected from paraffin-embedded tissues. DNA was used for polymerase chain reaction-based loss of heterozygosity (LOH) analysis with the following markers: D1S243 (1p35–36), D1S165 (1p36) and D1S162 (1p32), TP53 (17p13), and INT-2 (11q13). Immunohistochemistry for Ki-67 was performed. The Ki-67 labeling index (LI) was the percentage of positive tumor cells. LOH at 1p was seen in 2 of 5 (40%) informative cases of anaplastic carcinoma (2 of 2 at D1S162 and 1 of 2 at D1S165) and in 2 of 11 (18%) informative cases of follicular carcinoma (2 of 7 at D1S243, 2 of 7 at D1S165, and 1 of 6 at D1S162). One anaplastic (20%) and two follicular carcinomas (14%) had LOH in at least two of the 1p loci analyzed. None of the adenomas and papillary carcinomas had LOH at these loci. LOH at 17p and 11q13 were infrequent. Ki-67 LI was 1.4, 7, 16, and 65% in adenomas, papillary, follicular, and anaplastic carcinomas, respectively. Allelic loss at 1p may occur in aggressive types of thyroid carcinoma and may be a marker of poor prognosis. LOH at 1p may represent a late genetic event in thyroid carcinogenesis. LOH at 17p and 11q13 (MEN gene locus) is uncommon in thyroid neoplasms.     

Loss of heterozygosity and DNA ploidy point to a diverging genetic mechanism in the origin of peripheral and central chondrosarcoma.

Chondrosarcomas are malignant cartilaginous tumors arising centrally in bone (central chondrosarcoma), or secondarily within the cartilaginous cap of a hereditary or sporadic exostosis (peripheral chondrosarcoma). Loss of heterozygosity (LOH) was studied by microsatellite analysis at the loci harboring the EXT genes (implicated in hereditary multiple exostoses), the EXT-like genes, and at 9p21, 13q14, 17p13, and chromosome 10. Nineteen of 20 peripheral chondrosarcomas showed LOH at all loci tested, while only 3 of 12 central chondrosarcomas exhibited LOH, restricted to 9p21, 10, 13q14, and 17p13. LOH at 9p21 did not appear to involve the CDKN2A gene, as assessed by SSCP analysis. DNA flow cytometry demonstrated a wide variation in the ploidy status in peripheral chondrosarcomas (DNA indexes, 0.56-2.01), whereas central chondrosarcomas were predominantly peridiploid. Near-haploidy found in peripheral chondrosarcomas could explain part of the high LOH percentages. Ki-67 immunohistochemistry suggested a higher proliferation rate in peripheral chondrosarcomas. Our results indicate that peripheral chondrosarcomas, arising secondarily to an exostosis, may obtain genetic alterations during malignant transformation, with subsequent genetic instability as demonstrated by a high percentage of LOH and a wide variation in ploidy status. In contrast, peridiploidy and a low percentage of LOH in central tumors suggest that a different oncogenic molecular mechanism may be operative.     

软组织肿瘤13q14染色体不稳定性的荧光原位杂交分析

目的探讨软组织肿瘤染色体13q的基因状态及与肿瘤发生和发展的相关性。方法收集40例患者的41个软组织肿瘤,包括多种分化方向的良性肿瘤9例,低度恶性肿瘤9例,恶性肿瘤23例。应用双色荧光原位杂交（FISH）技术检测染色体13q14中分别包含Rb、RFP2、KCNRG和KLF5基因的3个位点RP11-685115、RP11-352N7和RP11-505F3在肿瘤中的改变情况。结果RP11-685115位点杂合性缺失（LOH）8例,扩增1例;RP11-352N7位点LOH4例,扩增1例;RP11-505F3位点LOH3例,扩增3例。3个位点同时出现LOH2例。2例内对照位点RPll-61K9也出现了LOH。1例恶性外周神经鞘瘤出现3个位点的扩增。13q异常在不同来源肿瘤中发生率不同。结论软组织肿瘤存在染色体不稳定性,从而增加染色体杂合性缺失和肿瘤抑制基因失活的几率。13q异常在不同的肿瘤发生模式中起不同的作用。肿瘤抑制基因Rb、RFP2和KCNRG的LOH与软组织肿瘤的发生可能有关。     

Differential expression of human telomerase catalytic subunit mRNA by In situ hybridization in pheochromocytomas

In pheochromocytomas, it is very difficult to predict malignant potential by conventional histology or immunohistochemical and molecular markers. We investigated the expression of human telomerase catalytic component (hTERT) mRNA, hTERT protein, Ki-67 antigen, and p27^kip1 in pheochromocytomas (27 benign, 7 suspected malignant, and 7 malignant), and evaluated the possibility of expressions of these proteins, and hTERT mRNA serve as diagnostic markers for predicting the biological behavior of these tumors. All tumors showed the classical histology and typical immunohistochemical pattern. By in situ hybridization, hTERT mRNA was expressed in 5/7 malignant tumors (defined as the presence of metastasis and/or extensive local invasion) as compared with 3/27 benign tumors. We examined the hTERT by immunohistochemistry to confirm the mRNA. hTERT mRNA expression was correlated with hTERT protein expression. All benign tumors exhibited no immunopositivity or <1% of cells stained for Ki-67 antigen. Six out of seven malignant tumors have shown either hTERT mRNA expression or Ki-67 immunoreactivity While no statistical difference in p27^kip1 expressions was observed among benign, malignant, and suspected malignant tumors, there was a statistical difference between the normal adrenal medulla samples and tumors (p<0.001). Thus, hTERT mRNA detection by in situ hybridization, hTERT expression, and Ki-67 antigen expression are all useful tools for differentiating malignant from benign pheochromocytomas.     

Losses of chromosomes 1p and 3q are early genetic events in the development of sporadic pheochromocytomas

Despite several loss of heterozygosity studies, a comprehensive genomic survey of pheochromocytomas is still lacking. To identify DNA copy number changes which might be important in tumor development and progression and which may have diagnostic utility, we evaluated genetic aberrations in 29 sporadic adrenal and extra-adrenal pheochromocytomas (19 clinically benign tumors and 10 malignant lesions). Comparative genomic hybridization was performed using directly fluorochrome-conjugated DNA extracted from frozen (16) and paraffin-embedded (13) tumor tissues. The most frequently observed changes were losses of chromosomes 1p11-p32 (86%), 3q (52%), 6q (34%), 3p, 17p (31% each), 11q (28%), and gains of chromosomes 9q (38%) and 17q (31%). No amplification was identified and no difference between adrenal and extra-adrenal tumors was detected. Progression to malignant tumors was strongly associated with deletions of chromosome 6q (60% versus 21% in clinically benign lesions, P = 0.0368) and 17p (50% versus 21%). Fluorescence in situ hybridization confirmed the comparative genomic hybridization data of chromosomes 1p, 3q, and 6q, and revealed aneuploidy in some tumors. Our results suggest that the development of pheochromocytomas is associated with specific genomic aberrations, such as losses of 1p, 3q, and 6q and gains of 9q and 17q. In particular, tumor suppressor genes on chromosomes 1p and 3q may be involved in early tumorigenesis, and deletions of chromosomes 6q and 17p in progression to malignancy.     

Genetic alterations on 3p, 11q13, and 18q in nonfamilial and MEN 1-associated pancreatic endocrine tumors.

Pancreatic endocrine tumors occur sporadically and as part of the multiple endocrine neoplasia type 1 (MEN 1) and von Hippel-Lindau (VHL) syndromes. The MEN1 locus on 11q13 and a candidate tumor suppressor locus on 3p are known to be hemi- or homozygously mutated in a subset of these tumors. Chromosome arm 18q harbors the SMAD4/DPC4 tumor suppressor gene that is frequently deleted and inactivated in tumors of the exocrine pancreas. We have analyzed 22 nonfamilial and 16 MEN 1-associated pancreatic endocrine tumors for loss of heterozygosity (LOH) at 3p, 11q13, and 18q. LOH at 3p was revealed in 45% and 36% of tumors from 31 patients with nonfamilial and MEN 1-associated disease, respectively. The corresponding proportions for 11q13 were 55% and 91%, and for 18q 27% and 25%, respectively. A striking relation between LOH at 11q13 and 3p and a malignant phenotype was found for the nonfamilial tumors. None of the six benign tumors (all of them insulinomas) had allelic loss at 3p or 11q13, whereas 92% (P < 0.01) of the malignant tumors (including malignant insulinomas) had such deletions. Besides the 11q13 abnormality, more than half of the MEN 1-associated tumors had additional genetic lesions affecting 3p or 18q. LOH analysis of several tumors from two MEN 1 patients suggested different clonal origin of the lesions. Sequencing of the SMAD4/DPC4 gene did not identify mutations in coding regions or at exon/intron boundaries in tumors with LOH at 18q. The data indicate involvement of tumor suppressor genes on 3p and 18q, in addition to the MEN1 gene at 11q13, in the tumorigenesis of both nonfamilial and MEN 1-associated pancreatic endocrine tumors.     

Gastrointestinal stromal tumors: Clinicopathological study of Chinese cases

In the present study, we reviewed 73 Chinese cases of gastrointestinal stromal tumor (GIST), and analyzed factors in evaluating malignant potential, in particular focusing on Ki-67 index and p53 expression to determine whether these can be used as prognostic indicators in GIST. The p53 positive rate was 50.7% and it was significantly higher in malignant (25/35; 71.43%) than in benign cases (13/38; 34.21%). A Ki-67 labeling index of >10% was also significantly different between malignant (23/35; 65.71%) and benign cases (14/38; 36.84%). In the cases in which the patient died, 15/21 and 14/21 cases showed expression of p53 and Ki-67, respectively; both had a higher expression than in surviving cases. Comparing the cases positive for both Ki-67 and p53 with those positive for Ki-67 or p53 alone, and those negative for both Ki-67 and p53, the latter demonstrated the best prognosis. The study also indicated that the malignant potential of GIST is correlated with the mitotic index (> or =1/10 high-power fields; HPF), tumor size (> or =5 cm), high cellularity, tumor invasive growth, tumor location, tumor hemorrhage and tumor necrosis.     

Characterizing genetically stable and unstable gastric cancers by microsatellites and array comparative genomic hybridization

Gastric cancer (GCA) displays a variety of genomic aberrations, including DNA copy number alterations, microsatellite instability (MSI), and loss of heterozygosity (LOH). The main aim of the present work was to determine the copy number aberrations in tumors with and without MSI or LOH. Fifteen fresh-frozen GCA samples, 11 of the intestinal and 4 of the diffuse type, were grouped by microsatellite analysis into high-level MSI (MSI-H, n = 2), LOH (n = 5), and microsatellite stable, LOH not detected (MSS/LOH-N, n = 8) tumors. The DNA samples were subsequently analyzed by array comparative genomic hybridization with 16,000 cDNA clones. As expected, the LOH tumors showed more copy number changes; however, the frequency of small-size amplifications was similar across all tumor groups. In addition, the cDNA arrays detected two apparently single-gene amplicons, at 11q13 (CCND1) and 12p12.1 (K-RAS), the presence of which were confirmed using oligonucleotide arrays. A novel amplicon at 5q13.2 was found only in diffuse-type tumors, which were otherwise genetically stable. The results suggest that DNA copy number changes may also occur in gastric cancers that show genomic stability in microsatellite analysis.     

Differential expression of the calcium sensing receptor and combined loss of chromosomes 1q and 11q in parathyroid carcinoma

Malignant transformation of parathyroid tumours is rare. Nevertheless, this small subset of malignant tumours often creates diagnostic and therapeutic problems. In this work, the morphological characteristics of 26 primary parathyroid carcinomas and seven metastases have been studied. Furthermore, immunohistochemical expression profiles for the calcium sensing receptor (CASR), cyclin D1 (CCND1), and Ki-67 were determined for parathyroid carcinomas and compared with adenomas and hyperplasias using a tissue microarray. Loss of heterozygosity (LOH) of the chromosome 1q region containing the HRPT2 gene and chromosome 11q (MEN1) was determined in the carcinomas. In contrast to the adenomas and hyperplasias, 31% of carcinomas demonstrated down-regulation of CASR. A significant correlation was found between CASR expression and the Ki-67 proliferation index. Chromosome 1q and chromosome 11q LOH were found in 12 of 22 (55%) and 11 of 22 (50%) carcinomas tested, respectively. Combined 1q and 11q LOH was seen in 8 of 22 (36%) carcinomas, in contrast to the low percentage of LOH reported in both regions in adenomas. In conclusion, this study demonstrates that combined 1q and 11q LOH in parathyroid tumours is suggestive of malignant behaviour. Strong down-regulation of the CASR protein is seen in a proportion of parathyroid carcinomas with a high proliferation index.     

肠隐窝异常病灶2,3,5,11,17和18号染色体部分位点的杂合子丢失

目的;探讨肠隐窝异常病灶（ACF）作为结直肠癌最早期癌前形态变化的分子基础。方法：微解剖分离提取34例ACF和35例癌组织的基因组DNA,全自动DNA测序仪毛细管凝胶电泳检测ACF和癌组织在2,3,5,11,17和18号染色体上9个微卫星位点的杂合子丢失（LOH）。结果：ACF LOH的发生频率（41．18％）低于癌组织（68．57％）（P＜0．05）,且两者的LOH发生频率在18q12、5q12、3p21、17q21、17q11、11p13和2p16位点LOH有相似的谱形。在18q12、5q12、3p21、17q21和17q11位点发生频率较高,在11p13和2p16位点较低。ACF在18q21和5q21位点LOH明显低于癌组织（P＜0．05）。癌组织LOH与肿瘤的部位、大体类型、组织学类型和Dukes分期均无关。LOH呈阳性的ACF,其同来源的癌组织多见于左半结肠,大体以隆起型为主。结论：（1）ACF作为结直肠癌黏膜癌前早期的形态改变有其分子遗传学证据;（2）进一步证实结直肠癌的发生发展是多基因受累、多步骤的复杂过程。