乳腺基底样浸润性小叶癌临床病理分析

目的 探讨乳腺基底样浸润性小叶癌(ILC)的临床病理特点、临床进展及预后.方法 对4例乳腺基底样ILC进行病理形态学观察,并采用MaxVision法进行免疫组织化学E-cadherin、p120 catenin、雌激素受体(ER)、孕激素受体(PR)、HER2、CK5/6、表皮生长因子受体(EGFR)、p63、p53、Ki-67染色,对其进行随访和分析并回顾相关文献.结果 4例乳腺基底样ILC,1例为混合型,3例为多形型.免疫组织化学染色肿瘤细胞3例E-cadherin阴性,1例少部分胞膜阳性;p120 catenin 均为胞质阳性,l例少部分除细胞质阳性外有少部分细胞膜阳性;ER、PR及HER2均呈“三阴性”;CK5/6和EGFR均呈不同程度阳性;p63 2例阳性;p53阳性或弱阳性;Ki-67阳性指数为30％ ～ 75％.2例有腋窝和锁骨下淋巴结转移,3例获得随访,其中2例发生胸壁转移,1例同时发生肝转移和腹部转移.结论 乳腺基底样ILC癌细胞异型性大、核级高、核分裂象多,免疫表型ER、PR及HER2“三阴性”,CK5/6和EGFR阳性,符合基底样亚型,易发生邻近部位和远处组织或器宫转移,对化疗反应差,预后较差.     

细支气管腺瘤15例临床病理分析

目的 探讨细支气管腺瘤(bronchiolar adenoma,BA)临床病理特征、诊断及鉴别诊断。方法 采用免疫组化EnVision法检测15例BA标本中TTF-1、Napsin A、CK7、CEA、CK5/6、p40、p63、Ki-67的表达,应用NGS法检测EGFR、TP53等基因突变,并复习相关文献。结果 BA主要发生于中老年人(35～78岁),2例有吸烟史,缺乏特异的临床表现。影像学多表现为密度混杂磨玻璃样结节,多呈灰白色实性结节,最大直径0.3～2.0 cm,平均0.75 cm。镜下结构以乳头样或平坦型腺泡为主,部分富含黏液,细胞成分温和,腔面由纤毛细胞、柱状细胞、立方细胞和黏液细胞构成。根据腔面细胞下衬基底细胞(免疫组化标记p40、p63、C K5/6阳性)连续性分为基底细胞连续的经典型BA(4例)和部分区域缺乏基底细胞的非典型BA(11例)。非典型BA中5例伴腺癌(1例同病灶),1例伴黏液腺癌(同病灶),1例伴原位腺癌(adenocarcinoma in situ,AIS),1例伴非典型腺瘤样增生(atypical adenomatous hyperplasia,AAH)。基因检测示与腺癌同病灶的非典型BA中EGFR基因19号外显子缺失、TP53基因4号外显子点突变。患者均完整切除病灶,术后随访1～53个月,未见肿瘤复发或转移。结论 非典型BA可能具有恶变潜能,免疫组化有助于鉴别诊断。     

大肠癌中EGFR、nm23、Ki-67的表达及临床意义

目的 探讨EGFR、nm23及Ki-67蛋白在大肠癌组织中的表达情况及其生物学意义.方法 采用高通量的组织芯片技术及免疫组织化学SP法检测115例大肠腺癌组织、19例大肠腺瘤组织和12例正常大肠组织中EGFR、nm23及Ki-67蛋白的表达.结果 在正常黏膜、腺瘤及腺癌组织中EGFR蛋白的阳性表达率分别为25%、47.37%、71.30%,nm23的阳性表达率分别为83.3%、68.42%和41.74%,Ki-67的阳性表达率分别为25%、36.82%、63.48%.腺癌组织中EGFR、Ki-67的表达明显高于腺瘤及正常黏膜组织,而nm23的后两者表达要明显高于前者,且均具有统计学意义(P<0.05).结论 EGFR、nm23、Ki-67的表达分别与大肠腺癌的分化、浸润程度、Dukes分期及淋巴结转移密切相关,可为大肠癌的早期诊断、治疗及预后的判断提供可靠的参考依据.     

肺毛细血管瘤病二例临床病理观察及文献复习

目的 探讨肺毛细血管瘤病的临床病理特征,提高对其临床及病理改变的认识.方法 对2例肺毛细血管瘤病的临床资料和组织学形态进行回顾性分析,并采用组织化学染色和免疫组织化学染色(EnVision法)研究其形态和免疫表型特点.结果 患者主要临床表现为喘憋,影像学(CT及肺动脉造影)特点为双肺多发结节影,肺动脉增宽,组织学表现为灶状分布的肺问质和肺泡壁毛细血管增生,小动脉肌性化,免疫组织化学染色提示病灶中肥大细胞数量增多,血小板衍生生长因子受体(PDGFR)-β表达上调,Ki-67阳性指数小于1％,p53阴性.结论 肺毛细血管瘤病是一种肺毛细血管增生性疾病,其发病机制可能与肥大细胞数量和PDGFR-β上调有关.病理医师在肺毛细血管瘤病的正确诊断和治疗中起重要作用,应提高对该病的认识.     

免疫组织化学标记物在乳腺细针吸取细胞学鉴别诊断中的意义

目的探讨免疫标记物对鉴别乳腺细针吸取细胞学（FNAC）良性病变和癌的意义。方法收集135例有随访资料、活检和组织病理学诊断对照的乳腺FNAC资料：良性病变88例,包括非增生性病变43例和增生性病变45例;乳腺癌47例,对其FNAC涂片和相应的石蜡切片作细胞周期蛋白（cyclin）D1、c—erbB-2、Ki-67、p21^CIP1/WAF1（简称p21）和34βE12的免疫组织化学APAAP和ABC法检测。利用SPSS11．5软件进行分析。结果（1）以上各标记物在良性非增生性和增生性病变中的标记差异无统计学意义。（2）以上各标记物在良、恶性病变中的标记差异均有统计学意义（P〈0．001）。多因素的logistic回归分析显示最有意义的组合标记物为cyclinD1（P〈0．001）、34βE12（P〈0．001）和c—erbB-2（P=0．003）．cyclinD1、c—erbB-2阳性和34βE12阴性提示为癌,其组合诊断的敏感性和特异性最高。组合标记物共同判断,cyclinD1和34βE12任一判断为癌,诊断的敏感性和特异性分别为95．7％和94．3％;这三个标记物任一判断为癌,诊断的敏感性进一步上升至97．9％,特异性下降至92．0％;这三个标记物任两个共同判断为癌,诊断的敏感性为72．3％,特异性为100．0％。（3）在癌组中,根据Robinson细胞学分级把癌分为3级,cyclinD1、34βE12和p21在各级癌中的表达差异不大,而c—erbB-2和Ki-67在1级癌的阳性表达率最低,仅为40．0％和33．3％,在3级癌中阳性表达率最高。组合cyclinD1和34βE12,cyclinD1和34βE12,任一判断为癌,1级和2级癌的检出率为93．3％和96．2％。结论所检测的免疫标记物对良、恶性病变的鉴别诊断价值较大,组合cyclinD1、34βE12和c—erbB-2可最有效地提高癌的诊断敏感性和特异性。对鉴别分化好的乳腺癌和乳腺良性病变,最有效的组合为cyclinD1和34βE12。     

肺纤毛黏液结节性乳头状肿瘤5例临床病理分析

目的探讨肺纤毛黏液结节性乳头状肿瘤(ciliated muconodular papillary tumor, CMPT)的临床病理学特征、诊断及鉴别诊断。方法回顾性分析5例肺CMPT的临床病理、免疫表型、分子生物学特征及预后,并复习相关文献资料。结果患者年龄30～77岁(平均52岁),其中女性3例,男性2例,均为体检时发现肺外周部结节。眼观:肿瘤境界欠清。镜检:以基底细胞、纤毛柱状细胞和黏液细胞乳头状增生为主,可见少量腺管样结构及黏液湖形成。免疫表型:纤毛柱状细胞呈CK7、TTF-1阳性;基底细胞表达p63、p40及CK5/6;黏液细胞可弱阳性表达TTF-1和CK7;三类细胞Ki-67增殖指数均较低(1%～2%)。随访1～36个月(平均18个月)均未见肿瘤复发或转移。结论肺CMPT是罕见的肺原发良性/低度恶性潜能肿瘤,生物学行为惰性。在诊断工作中,特别是在术中快速冷冻诊断时极易与原发或继发肺黏液性腺癌相混淆。仔细寻找典型的CMPT形态学特点并辅以免疫组织化学染色有助于诊断和鉴别诊断。     

肺腺癌罕见部位转移3例并文献复习

目的探讨3例罕见部位肺腺癌转移病例的临床病理学特征、诊断、鉴别诊断及预后。方法收集3例肺腺癌转移至卵巢、十二指肠、前列腺的临床资料,对其进行HE及免疫组化染色,并复习相关文献。结果例1女性,47岁,单侧附件囊实性占位,形态学有管囊状结构,首先考虑原发性肿瘤。免疫表型:Napsin A、TTF-1、CK7、CK(AE1/AE2)、ALK(D5F3)、CA125、Mucin-1、CEA阳性;例2女性,70岁,内镜提示十二指肠多发新生物,形态学示小肠黏膜间出现分化差的癌细胞。免疫表型:CK(AE1/AE2)、CK8/18、Napsin A、TTF-1阳性;例3男性,73岁,前列腺穿刺标本,形态学显示前列腺组织间可见分化差的癌伴坏死。免疫表型:CK(AE1/AE3)、CK8/18、TTF-1阳性,Ki-67增殖指数较低,结合肺部占位,可考虑肺腺癌转移。结论 3例患者均以转移灶就诊,为肺腺癌罕见转移部位,尤其例1以单侧附件单囊性附壁结节形式出现的转移癌极其罕见,ALK基因为融合型,值得关注;肺腺癌转移至小肠及前列腺可能提示患者预后较差。     

15例硬化性肺细胞瘤冰冻切片与临床病理特征分析

目的：回顾性分析肺硬化性肺细胞瘤组织学及临床病理特点,提高快速冰冻诊断的准确性。方法：对15例经手术切除并诊断为硬化性肺细胞瘤的病例及2例冰冻误诊为硬化性肺细胞瘤的其他病变进行回顾性分析,包括冰冻及常规切片、免疫组织化学染色,结合临床病理特征进行总结。结果：本组15例硬化性肺细胞瘤,女性13例,平均年龄46岁;临床诊断肺癌6例,余9例为其他良性病变;冰冻切片诊断6例硬化性肺细胞瘤,1例炎性假瘤,1例错构瘤,2例肺癌,3例良性病变,2例延迟诊断;肿瘤常由乳头、硬化、实性、出血4种结构中的2种或多种混合而成。冰冻切片中10例见2种组织结构,4例见3种组织结构,1例见4种组织结构;圆形细胞TTF-1、EMA(+),表面上皮细胞TTF-1、EMA和CK(+),两种细胞Ki-67指数<2%。冰冻误诊为硬化性肺细胞瘤的2例,石蜡证实1例为混合亚型腺癌,1例为肺泡性腺瘤。结论：硬化性肺细胞瘤临床和影像学易误诊为癌,冰冻切片诊断准确率低。冰冻及石蜡切片中,常可见2种或2种以上组织结构;冰冻切片中以乳头状为主时,易误诊为腺癌;以实性为主时,易误诊为类癌。借助免疫组织化学指标,常可确诊。     

星形细胞肿瘤表皮生长因子受体与p53基因的异常表达

目的研究星形细胞肿瘤中癌基因表皮生长因子受体（EGFR）过表达与抑癌基因p53突变、表达与肿瘤病理类型、恶性程度及两者的相互关系。方法对37例不同恶性程度的星形细胞肿瘤及6例正常脑组织,采用免疫组织化学、逆转录聚合酶链反应（RT—PCR）方法检测EGFR的表达;采用免疫组织化学、PCR—SSCP及DNA测序方法检测同一标本的p53基因突变和异常表达,分析它们的异常改变和内在联系。结果p53突变率在弥漫性星形细胞瘤、间变性星形细胞瘤、原发性胶质母细胞瘤、继发性胶质母细胞瘤分别为1／10,4／19（21．1％）,4／6和2／2,而EGFR过表达分别为5／10,10／19（52．6％）,5／6和2／2。随着胶质瘤级别增高,p53积聚与EGFR过表达在同一标本中发生率升高。结论在低度恶性胶质瘤中p53基因突变少见,EGFR过表达不少见;在原发性和继发性胶质母细胞瘤中p53基因突变及EGFR过表达均常见。提示p53与EGFR分子通路可能对胶质瘤的恶性进展不是相互排斥而是协同产生促进作用。     

A subset of lung adenocarcinomas and atypical adenomatous hyperplasia-associated foci are genotypically related: an EGFR, HER2, and K-ras mutational analysis

Atypical adenomatous hyperplasia (AAH) is considered the preinvasive lesion of pulmonary adenocarcinoma, and mutations of EGFR, HER2, and K-ras are involved in the early stage of lung adenocarcinoma carcinogenesis, also predicting clinical response to anti-EGFR small molecule inhibitors. We analyzed 18 cases of primary lung adenocarcinoma with concomitant AAH foci from 13 patients for mutations of EGFR (exons 18-21), HER2 (exons 19-20), and K-ras (exon 2) by direct sequencing polymerase chain reaction. Among mutated cases, concordant mutations of EGFR or K-ras in adenocarcinoma and related AAH were observed in 5 (63%) of 8 cases. In particular, 3 of 4 adenocarcinomas with EGFR mutations (all L858R point mutations in women, never or former smokers) had a concomitant and identical mutation in AAH, and 2 of 4 adenocarcinomas with K-ras mutations (both at codon 12 in women, a never and a current smoker) showed the same mutation in concomitant AAH. All cases were wild-type for HER2. Mutations of EGFR and K-ras genes represent an early event in lung adenocarcinomagenesis, and AAH convincingly seems to be a precursor lesion in a subset of cases of adenocarcinoma.     

Atypical alveolar hyperplasia: Relationship with pulmonary adenocarcinoma,p53, and c-erbB-2 expression

Atypical alveolar hyperplasia (AAH) has recently been described in human lungs in association with primary lung cancer, particularly adenocarcinoma. Unlike proximal bronchogenic carcinoma, peripheral (parenchymal) adenocarcinoma of the lung does not have a well-recognized progenitor lesion. Epidemiological, morphometric, and cytofluorometric data in the literature suggest that AAH is a candidate premalignant entity. In this study, 97 AAH lesions were found in lungs resected from 29 patients (1–13 lesions per case, mean 3·5) being treated for presumed carcinoma (25/29 had adenocarcinoma). From a study case-load of 285 adenocarcinoma-bearing lungs, the AAH incidence was 8·8 per cent. Sections of 67 AAH lesions from 19 patients were stained using monoclonal antibodies against Ki67 (MIB1), p53 (DO7), and c-erbB-2 (NCL-CB11). Ki67 was expressed in up to 10 per cent of AAH nuclei. Thirty-nine lesions (58 per cent) showed stainable p53 protein, while five (7 per cent) expressed membrane c-erbB-2 oncoprotein. These latter five lesions were all strongly positive for p53, and both p53 and c-erbB-2 staining was associated with increased cellular crowding and pleomorphism in AAH. These data demonstrate that AAH exhibits some genetic changes associated with malignancy and thereby support the hypothesis that AAH is premalignant.     

Lung adenocarcinoma with bronchioloalveolar carcinoma component is frequently associated with foci of high-grade atypical adenomatous hyperplasia

We assessed the occurrence of atypical adenomatous hyperplasia (AAH) in whole lung lobes with primary cancer lesions. Following surgical resection, tissue specimens were sliced to a thickness of 4 mm (3,641 specimens from 61 cases; mean = 59.7 specimens per case). A total of 119 AAH foci were found and an association was evident in 25 (57%) of 44 adenocarcinomas, 3 (30%) of 10 squamous cell carcinomas, and 2 (29%) of 7 other lung cancers. Histologic evaluation showed that 108 AAH foci were categorized as low-grade and the other 11 as high-grade AAH. These 11 foci of high-grade AAH were present in 7 patients with adenocarcinoma, and in 1 patient there was a synchronous double primary lung adenocarcinoma. High-grade AAH was closely associated with bronchioloalveolar carcinoma (BAC) type adenocarcinoma, and low-grade AAH with non-BAC adenocarcinoma. The mean +/- SD Ki-67 labeling index in high-grade AAH (3.5%+/-2.9%) was significantly higher than for the low-grade index (1.4%+/-1.6%). We propose that foci of high- but not low-grade AAH may be potential precursor lesions of lung adenocarcinoma, especially with the BAC component.     

Immunohistochemical typing of non-small cell lung cancer on cryostat sections: correlation with clinical parameters and prognosis

AIMS: To investigate the immunohistochemical expression of a panel of biologically relevant markers in patients with non-small cell lung cancer using fresh frozen specimens and to test their prognostic relevance for identification of patients at risk. METHODS: Seventy nine tumour infiltrated lung cancer specimens and 66 adjacent histologically tumour free tissues were analysed; 11 postmortem specimens from patients who did not suffer from a malignant disease served as a control group. Cryostat sections were stained with monoclonal antibodies against epidermal growth factor receptor (EGFR), c-erbB-2, c-erbB-3, CD82, Ki-67, p120, p53, bcl-2, and CD31. RESULTS: At least one of the tested markers was raised above the defined cut off point in 75 of the tumours. In 55, three to six factors were increased. EGFR was raised in 32, c-erbB-2 in 29, c-erbB-3 in 46, p53 in 29, bcl-2 in 26, Ki-67 in 36, p120 in 46, and CD31 in 29. None of the tested parameters was significant in univariate survival analysis. In a second step, three variables were combined (c-erbB3, p53, and microvessel density), and cases with increased expression of two or three parameters proved to have a significantly lower survival probability than those expressing none or only one factor. In the tumour free group only 10 showed raised marker expression. CONCLUSION: Characterisation of tumour cells in surgical specimens with immunohistological markers could help identify those patients at risk for early cancer death who could possibly profit from adjuvant treatment after curative tumour resection.     

Atypical adenomatous hyperplasia (adenosis) of the prostate: DNA ploidy analysis and immunophenotype

Atypical adenomatous hyperplasia (AAH) of the prostate is a microscopic proliferation of small acini that may be mistaken for adenocarcinoma. Although some data suggest that AAH is associated with adenocarcinoma arising in the transition zone, the clinical significance of this lesion is uncertain. Therefore we studied the DNA ploidy pattern and immunophenotype of AAH as compared with nodular hyperplasia and well-differentiated adenocarcinoma in 23 formalin-fixed, paraffin-embedded, whole-mounted retropubic prostatectomies. Representative sections were immunostained for keratin 34beta-E12, chromogranin, bcl-2, c-erbB-2, ki67-MIB1, and factor VIII (microvessel density). DNA ploidy was determined by image analysis and Feulgen-stained sections. There were rare scattered immunoreactive cells for chromogranin, bcl-2, and c-erbB-2 in nodular hyperplasia and AAH (mainly in the basal cell compartment) and in carcinoma. The ki67-MIB1 labeling index was different between nodular hyperplasia and AAH (p<0.001) and carcinoma (p=0.003) but not between AAH and carcinoma (p=0.203). Microvessel density was different between AAH and carcinoma (p=0.001) but not between nodular hyperplasia and AAH (p=0.105) or carcinoma (p=0.0820). All foci of nodular hyperplasia, AAH, and carcinoma were diploid. Ploidy status and our selected panel of antibodies did not discriminate among these 3 entities reliably.     

Immunohistochemical study of Skp2 and Jab1, two key molecules in the degradation of P27, in lung adenocarcinoma

To clarify the association of the P27 degradation pathway proteins, Skp2 and Jab1, with the development and progression of lung adenocarcinoma (AD), we immunohistochemically investigated Skp2 and Jab1 expression together with P27- and Ki-67-labeling in 110 lung AD and 11 atypical adenomatous hyperplasia (AAH) and analyzed the relationship between the expression of these proteins and the clinicopathological factors. High Skp2 or Jab1 expression was frequent in lung AD (52/110, 47%, and 59/110, 54%, respectively), and high expression of Jab1 was also frequent in AAH (4/11, 36%), while it was not observed in normal bronchiolar epithelium. The P27 labeling index (LI) was reciprocally correlated with high Skp2 and Jab1 expression, and a higher Ki-67 LI was significantly correlated with high Skp2 and Jab1 expression. However, low P27 expression did not correlate with a higher Ki-67 LI. High Skp2 lung AD showed significant correlation with blood and lymphatic vessel invasion, which low P27 expression did not correlate with. Furthermore, high Skp2 expression in lung AD was significantly correlated with a poor outcome for patients. Thus, Skp2 and Jab1 regulate P27 degradation, and might contribute to the development and progression of lung AD through P27-mediated and -unmediated mechanisms.     

Comparative Ultrastructural Study of Atypical Adenomatous Hyperplasia and Adenocarcinoma of the Human Lung

Atypical adenomatous hyperplasia (AAH) of the human lung is considered a possible precursor of pulmonary adenocarcinoma. However, its true biological significance remains to be clarified. The authors studied the ultrastructure of AAH in surgically resected lungs and compared it with that of coexisting adenocarcinoma in an effort to define the characteristic features of AAH. Ultrastructurally, AAH possessed oval to irregular nuclei with high nucleo-cytoplasmic ratio and large nucleoli. Development of cytoplasmic organelles was generally poorer in AAH than in adenocarcinoma. However, these differences became less apparent as the degree of atypia of AAH advanced. Both lamellar bodies and electron-dense granules were found in AAH as well as in adenocarcinoma. These results suggest a close relation of AAH with adenocarcinoma of type 2 pneumocyte or Clara cell type. Further, the results of immunohistochemical studies for surfactant apoprotein A, urine protein 1, cytochrome P-450s, CEA, p53, c-erbB-2, Ki67, and bcl-2 well reflected the ultrastructural findings. These results suggest, in accordance with previous studies, that AAH is a lesion closely related to adenocarcinoma. Further, AAH shares some characteristics of type 2 pneumocytes and Clara cells, implying that it might be derived from their common precursor.     

Reduced expression of p27/Kip1 is associated with the development of pulmonary adenocarcinoma

p27/Kip1 (p27), a negative regulator of cell proliferation, is a powerful prognostic marker in non-small cell lung carcinoma. To clarify the significance of p27 aberrations in the tumourigenesis of lung adenocarcinoma, p27 expression was investigated by immunohistochemistry in lung adenocarcinoma and its precursor lesion, atypical adenomatous hyperplasia (AAH), and correlated with the expression of Ki-67, cyclin D1, and cyclin E. The p27 labelling index decreased in parallel with tumour progression (24.0% to 4.5%) and was found to be lower in neoplastic lesions than in normal bronchiolar epithelial cells (48.8%). There was a negative correlation between p27 and Ki-67 expression (rho=-0.384, p<0.001). Cyclin E-positive lesions (with labelling index >/=5%) were found only in overt adenocarcinomas. The Ki-67 labelling index of cyclin E-positive, high (>/=10%) p27 expressers was lower than that of cyclin E-positive, low (<10%) p27 expressers (16.8% vs. 42.6%; p=0. 046) and was similar to that of cyclin E-negative adenocarcinomas (15.0%). These results indicate that reduced p27 expression is associated with and may play a role in progression during the development of pulmonary adenocarcinoma.     

MUC1 (episialin) expression in non-small cell lung cancer is independent of EGFR and c-erbB-2 expression and correlates with poor survival in node positive patients.

AIM: To examine tumour samples immunohistochemically for MUC1 (episialin), epidermal growth factor receptor (EGFR), and c-erbB-2, since the disruption of the cell-cell adhesion system by MUC1 and the c-erbB oncoprotein family is known to be important in the development of metastasis in human cancers. METHODS: 93 tumour samples from patients with early stage non-small cell lung cancer treated with surgery alone were examined for episialin, EGFR, and c-erbB-2. RESULTS: Episialin depolarised expression did not correlate with any of the histopathological variables examined (T,N stage, grade, histology, Ki67 proliferation index). No correlation was observed between episialin and EGFR or c-erbB-2 expression. Survival analysis showed that episialin depolarised expression correlated with poor prognosis (p = 0.003), especially in squamous cell cases (p = 0.0003). Episialin expression defined a group of patients with poor prognosis in the node positive category (p = 0.003). In multivariate analysis episialin was the most significant independent prognostic factor (p = 0.007), followed by N stage (p = 0.04). CONCLUSIONS: Depolarised expression of episialin is associated with poor outcome in early stage non-small cell lung cancer. Despite the similar activity on the cadherin cell-cell adhesion system, the expression of episialin and c-erbB oncoproteins is likely to be activated within different pathogenic pathways.