乳腺复发性叶状肿瘤临床病理分析

目的:探讨乳腺复发性叶状肿瘤临床及病理特征。方法:收集2011年01月至2019年12月在我院进行手术治疗的叶状肿瘤病例,并找出其中复发的病例,分析复发病例的临床及病理组织学特征。结果:叶状肿瘤137例,共有10例为复发病例,其中9例为单次复发,1例复发两次,复发病例中良性叶状肿瘤7例,交界性叶状肿瘤2例,恶性叶状肿瘤1例。所有的肿物均为局部复发,良性、交界及恶性叶状肿瘤复发率分别为5.9%、15.4%、20%。其中3例（30%）出现组织学升级,1例良性叶状肿瘤复发为交界性叶状肿瘤,1例交界性叶状肿瘤复发为恶性叶状肿瘤,1例良性叶状肿瘤第一次复发为交界性叶状肿瘤,第二次复发为恶性叶状肿瘤。免疫组化标记CD117、CD34、CD10、p53、p16在原发及复发肿瘤中表达无差异。Ki67增殖指数在复发病例中均升高,并且核分裂数也增多。结论:良性、交界性、恶性叶状肿瘤均可复发,其中恶性叶状肿瘤复发率最高,肿瘤多为局部复发,部分肿瘤复发后出现组织学升级,复发后肿瘤细胞增殖活性增强。     

The prognostic value of p53 and c-erbB-2 expression, proliferative activity and angiogenesis in node-negative breast carcinoma

AIMS AND BACKGROUND: p53, c-erbB-2 and Ki-67 protein expression and microvessel density (MVD) determined by CD34 antibody were evaluated by immunohistochemistry and their correlation with clinicopathological parameters including estrogen (ER) and progesterone (PR) receptor status and survival were investigated in patients with axillary lymph node-negative infiltrating ductal breast carcinoma. METHODS: The study population consisted of 47 patients with axillary lymph node-negative infiltrating ductal breast carcinoma. RESULTS: p53 and c-erbB-2 expression was detected in 36.2% and 31.9% of patients, respectively. Median Ki-67 expression was 10%. There were no statistically significant differences in the distribution of p53, Ki-67 and c-erbB-2 protein expression in relation to the age of the patients or to the size, histological grade or ER and PR status of the tumors. p53 protein expression correlated positively with c-erbB-2 and Ki-67 protein expression (P < 0.05). The mean MVD was 63.65 +/- 29.1 and it correlated positively with histological grade and Ki-67 expression (P < 0.05). Survival analysis revealed that age, tumor size, p53 and c-erbB-2 expression and PR status had no significant prognostic impact, whereas histological grade, proliferative activity and angiogenic activity were significant prognostic factors. Although ER-positive patients had a statistically significant overall survival advantage, the difference in disease-free survival was not significant. CONCLUSION: In axillary lymph node-negative breast carcinoma the histological grade and the proliferative and angiogenic activity of the tumor could be useful prognostic indicators.     

乳腺叶状肿瘤预后因素的统计学分析

目的:探讨乳腺叶状肿瘤的预后因素。方法:对有随访结果的203例肿瘤的15个临床、病理学参数作统计学Log-Rank检验和Cox单及多因素分析。 结果和结论:术式、核分裂、瘤细胞异型性、肿瘤性坏死、瘤组织分化方向、瘤实质内薄壁血管数、单视野内核分裂增多、病理性核分裂、切除后复发、组织学等级和间质细胞密度11个参数为单风险因素,核分裂和肿瘤性坏死是独立的风险因素。     

Immunohistochemical profile of phyllodes tumors of the breast

The immunohistochemical profiles of 16 cases of phyllodes tumor of the breast (9 benign and 7 malignant) from 15 patients were examined by the labeled streptavidin biotin method. The expression of Ki-67, p53, bcl-2, alpha-smooth muscle actin (alpha-SMA), desmin, S-100 protein, estrogen receptor (ER), and progesterone receptor (PgR) was analyzed. The number of Ki-67-positive stromal cell nuclei of malignant phyllodes tumor were significantly more prominent than the benign tumors. The p53 expression on the stromal cell nuclei showed a significant difference between malignant and benign cases (86% vs 22%; p<0.05). bcl-2 was regularly seen on the luminal cell cytoplasm and stromal cell labeling showed no significant difference between malignant and benign cases (29% vs 33%). Stromal cells were alpha-SMA positive but refractory among cases, and desmin and S-100 protein were negative. PgR was expressed in all 16 cases and ER in most cases (12/16) the expression of which was restricted to luminal epithelial cell nuclei. These findings indicate that the Ki-67 labeling index and p53 expression in the stroma would be a good diagnostic parameter distinguishing benign tumors from malignant tumors. However, the absence of steroid receptor expression in stromal cells suggests the ineffectiveness of hormonal therapy for phyllodes tumor of the breast.     

p53突变型乳腺癌中Ki67表达水平的临床意义

目的：探讨乳腺癌组织中p53的突变情况及Ki67的表达水平,明确p53与Ki67联合作用在乳腺癌临床病理因素上的体现。方法：应用免疫组化SP法检测165例乳腺癌组织中p53、Ki67的表达,分析其与临床病理因素之间的关系。结果：p53的突变率为55.8%（92/165）,Ki67的阳性表达率为69.1% （114/165）。p53的突变情况与患者年龄、肿块大小、淋巴结转移、TNM分期、ER和PR的表达水平无关,但与HER-2的表达水平呈正相关。在总人群中Ki67的表达水平与肿块大小和淋巴结转移无关。亚组分析显示在p53突变的患者中,Ki67的表达水平与肿块的大小呈正相关（r=0.311,P=0.003）,与淋巴结转移呈正相关（r=0.342,P=0.001）。结论：在p53突变型乳腺癌中Ki67的表达与T分期及N分期均呈正相关,在p53突变人群中Ki67对乳腺癌的生物学行为和患者的预后可能有更高的预测价值,二者联合检测与解读可能更有助于判断乳腺癌患者的预后。     

Histologic features predict local recurrence after breast conserving therapy of phyllodes tumors

Background: Pathologists can distinguish benign phyllodes tumors, which very rarely metastasize, from malignant phyllodes tumors, which metastasize in approximately one fourth of patients. However, whether these same histologic criteria can be used to predict the likelihood that a phyllodes tumor will locally recur after breast conserving therapy remains controversial.Study Design: Since few patients with malignant phyllodes tumors have been treated with breast conserving surgery in any individual series, the literature was reviewed using a Medline search.Results: After local excision, 21 (111/540), 46 (18/39), and 65 (26/40) of patients with benign, borderline, and malignant phyllodes tumors, respectively, recurred in the breast. Following wide local excision, 8 (17/212), 29 (20/68), and 36 (16/45) of patients with benign, borderline, and malignant phyllodes tumors recurred in the breast.Conclusions: Malignant phyllodes tumors are much more likely than benign phyllodes tumors to recur in the breast after breast conserving surgery. This high rate of local recurrence of borderline and malignant phyllodes tumors suggests that wide local excision is less than optimal therapy, and challenges us to look for methods to improve local tumor control.     

乳腺肿瘤雌、孕激素受体表达与细胞增殖

目的：观察乳腺肿瘤雌、孕激素受体表达与细胞增殖的关系。方法：用免疫细胞化学技术（ＡＢＣ法）对经病理确诊２５５例恶性和６６０例良性乳腺肿瘤进行了ＥＲ、ＰＲ、ｃ－ｅｒｂＢ－２、ｐ５３基因蛋白表达和Ｋｉ－６７抗原检测。结果：良、恶性乳腺肿瘤间,ＥＲ、ＰＲ阳性率均有极显著差异。良性肿瘤组中,ＥＲ＋ＰＲ＋组和ＥＲ－ＰＲ－组间差异有显著性;ｐ５３表达率在ＥＲ、ＰＲ阴、阳性组间差异有显著性;ｃ－ｅｒｂＢ－２表达     

Immunoreactivity of p53, Ki-67, and c-erbB-2 in phyllodes tumors of the breast in correlation with clinical and morphologic features

BACKGROUND AND OBJECTIVES: Phyllodes tumor (PT) is a biphasic tumor with unpredictable behavior. Our study aimed to evaluate clinicopathologic factors and biomarkers that may be helpful in predicting the outcome of these tumors. METHODS: We evaluated immunoreactivity of p53, c-erbB-2, and Ki-67 in 23 PT treated over a 10-year period. The proliferative activity in PT and expression of p53 and c-erbB-2 were correlated with clinicopathologic features of the tumors and patients' outcome. RESULTS: Positive stromal p53 immunoreactivity was found in PT with atypia, infiltrative borders, high cellularity, as well as in PT that displayed higher then average proliferation index, although none of these parameters reached statistical significance. There was a good correlation between proliferative stromal cell activity expressed Ki-67-labeling index and the malignant features of the tumors. Primary tumors that recurred displayed high proliferative activity. Three of four recurrent tumors showed a progression toward higher malignant phenotype with concomitant increase in proliferative stromal cell activity. c-erbB-2-positive tumors had no particular histologic features or association with either p53 positivity or higher proliferative indices. CONCLUSIONS: p53 expression tends to be more frequent in PT with higher malignant potential but did not predict recurrence. Incompletely excised tumors that recurred displayed high proliferative activity in their primary tumors. Progression toward more malignant phenotype in the recurrent PT was accompanied with increase in stromal cell proliferative activity, suggesting the presence of biological continuity between benign, borderline, and malignant PT.     

乳腺叶状肿瘤局部复发的临床风险因素分析

目的分析乳腺叶状肿瘤局部复发的临床风险因素。方法使用SPSSCox比例风险模型分析2002年12月至2008年12月中国医科大学附属第一医院66例乳腺叶状肿瘤患者各种临床风险因素与局部复发的关系。单因素分析采用X2检验。结果本组患者的发病年龄为17—83岁（中位年龄41岁）,良性40例,交界性24例,恶性2例。局部复发15例,其中12例复发发生于区段切除术。在不同手术方式、不同组织学等级的叶状肿瘤患者之间,复发率的差异均有统计学意义（P〈0．05）。手术方式为保护因素（RR=0．151）,扩大切除术和乳房切除术者的复发风险较区段切除术者下降至66／1000和53／1000;组织学等级为危险因素（RR=5．803）,恶性和交界性叶状肿瘤患者的局部复发风险分别为良性肿瘤者的12．26倍和4．37倍。结论恶性程度高和手术方式选择不当影响预后。叶状肿瘤以手术治疗为首选,应选择切除范围扩大的手术方式,尤其是对恶性程度高的患者。     

Prognostic relevance of disseminated tumor cells in the bone marrow and biological factors of 265 primary breast carcinomas

Introduction

The prognostic significance of disseminated tumor cells in the bone marrow (DTC-BM) of breast cancer patients has been demonstrated in many studies. Yet, it is not clear which of the primary tumors' biological factors predict hematogenous dissemination. We therefore examined 'tissue micro arrays' (TMAs) of 265 primary breast carcinomas from patients with known bone marrow (BM) status for HER2, Topoisomerase IIα (Top IIa), Ki 67, and p53.

Methods

BM analysis was performed by cytospin preparation and immunocytochemical staining for cytokeratin (CK). TMAs were examined by immunohistochemistry (IHC) for HER2, Top IIa, Ki 67 and p53, and fluorescence in situ hybridization (FISH) for HER2.

Results

HER2 (2+/3+) was positive in 35/167 (21%) cases (FISH 24.3%), Top IIa (>10%) in 87/187 (46%), Ki 67 in 52/184 (28%) and p53 (>5%) in 61/174 cases (34%). Of 265 patients, 68 (25.7%) showed DTC-BM with a median of 2/2 × 10⁶ cells (1 to 1,500). None of the examined factors significantly predicted BM positivity. Significant correlation was seen between HER2 IHC and Top IIa (p = 0.06), Ki 67 (p = 0.031), and p53 (p < .001). Top IIa correlated with Ki 67 and p53, and Ki 67 also with p53 (p = 0.004). After a median follow-up of 60.5 months (7 to 255), the presence of DTC-BM showed prognostic relevance for overall survival (p = 0.03), whereas HER2 (IHC, p = 0.04; FISH, p = 0.03) and Ki 67 (p = 0.04) correlated with disease free survival, and HER2 with distant disease free survival (IHC, p = 0.06; FISH, p = 0.05).

Discussion

The congruence of the examined factors' expression rates indicates a causal line of suppressor, proliferation, and mitosis markers, and growth factor receptors. Hematogenous tumor cell spread seems to be an independent process. The examination of these factors on DTC-BM is the aim of ongoing research.     

p53、CyclinD1和Ki67在双原发癌第二原发癌中的表达及其意义

目的:探讨双原发癌第二原发癌中p53、CyclinD1和Ki67表达的意义及其与双原发癌临床病理特征的相关性。方法:采用免疫组化法对43例符合标准并确诊为双原发恶性肿瘤的第二原发癌标本进行p53、CyclinD1和Ki67的检测。结果:p53、CyclinD1、Ki67在双原发癌第二原发癌标本的阳性表达率分别为60.5%、30.2%、65.1％。p53的阳性表达与间隔时间、病理分级、淋巴转移密切相关（P＜0.05）,CyclinD1及Ki67阳性表达与病理分级、淋巴转移密切相关（P＜0.05）;p53与CyclinD1、Ki67的表达均呈正相关性（r=0.313,P=0.041;r=0.319,P=0.037）。结论:p53、CyclinD1、Ki67蛋白高表达与双原发癌第二原发癌的恶性生物学行为密切相关,联合检测p53、CyclinD1、Ki67在双原发癌中的表达对评估预后具有指导意义,并提示第二原发癌在基因水平上可能出现了某种程度的异常,尚需进一步研究。     

Phyllodes tumor of the breast: a clinicopathologic study of 34 cases

Thirty-four cases of phyllodes tumor of the breast were studied to evaluate the clinical and pathological features, which correlate with local recurrence. Histologically, local recurrence correlated with the finding of more than ten mitotic figures per ten high-power fields, marked cellularity, prominent nuclear pleomorphism, and stromal overgrowth. Older patients and patients with larger tumors had a higher probability of local recurrence. Stromal overgrowth correlated with the other histological parameters, with rapid tumor growth, a tumor diameter of over 10 cm, and with local recurrence. It was thus considered to be a histological indicator of the malignant potential of phyllodes tumor of the breast.     

Ki-67、p53、CerbB-2表达与乳腺癌彩色超声征象的关系

目的 探讨肿瘤增殖抗原(Ki-67)、肿瘤抑制基因(p53)、原癌基因(CerbB-2)表达与乳腺癌彩色超声征象的临床关系.方法 选取拟行手术切除的乳腺癌患者44例作为研究对象,所有患者手术前均行彩色超声检查,于手术后对切除标本行石蜡包埋切片,然后采用免疫组化方法 对Ki-67、p53、CerbB-2表达情况进行检测,并分析3者和术前彩色超声征象的临床关系.结果 本组44例乳腺癌患者中,肿块直径≥2 cm者共有25例,19例肿块形态散在分布,16例分叶状分布,9例类圆形分布;23例有毛刺征,24例有高回声晕,27例有后方衰减,20例有微小钙化,21例有淋巴结转移,27例血流信号2~3级;Ki-67阳性表达率为61.36%,p53阳性表达率为52.27%,CerbB-2阳性表达率为47.73%;27例Ki-67阳性表达患者中,肿块形态、微小钙化、淋巴结转移以及肿块内血流信号,23例p53阳性表达患者中淋巴结转移和肿块内血流信号,21例CerbB-2阳性表达患者中微小钙化和肿块内血流信号比较,差异均有统计学意义(P<0.05).结论 Ki-67、p53、CerbB-2阳性表达和彩色超声征象均存在一定关联,可作为乳腺癌重要诊断指标.     

Tissue microarray analysis of connexin expression and its prognostic significance in human breast cancer

Breast cancer accounts for approximately 15% of all cancer deaths. Currently, axillary nodal status is the most reliable prognostic indicator for breast cancer. Tumor size and histological grade are used to stage breast cancer. Estrogen receptor/progesterone receptor (ER/PR) and HER-2/neu status are useful in predicting patient survival and relapse. Ki67, an indicator of proliferative activity, also correlates well with prognosis. Connexin proteins form gap junction channels, permitting intercellular exchange of ions and small molecules. Reduced connexin protein levels and impaired gap junctional intercellular communication are associated with tumor phenotypes. This study investigated the prognostic value of connexin proteins as breast cancer markers. Tissue microarrays, containing 438 cases of invasive breast carcinoma, were stained with Cx26, Cx32, and Cx43 antibodies. The degree of connexin immunoreactivity was determined and then correlated with patient outcome, tumor grade, tumor size, lymph node status, and immunohistochemical markers, such as p53, ER/PR status, Ki67 and c-erbB-2 expression. Cx26, Cx32, or Cx43 did not correlate well with tumor grade, tumor size, p53 or c-erbB-2 status. There was an inverse correlation between Cx32 and lymph node status (P <0.05) and a positive correlation between Cx43 and PR status (P <0.01). Cx32 and Cx43 correlated positively with ER status (P <0.01). Cx43 correlated negatively with Ki67 expression (P <0.01). Cx26, Cx32, and Cx43 did not correlate with patient outcome. Based on our observations in this study, connexin proteins do not appear to be reliable indicators of breast cancer prognosis.     

胃肠道间质瘤40例Ki-67、PCNA的表达及意义

目的：探讨Ki-67、PCNA的表达与胃肠道间质瘤（GIST）临床病理特征的关系。方法：应用免疫组化SP法检测40例胃肠道间质瘤中Ki-67、PCNA的表达。结果：40例胃肠道间质瘤中Ki-67、PCNA阳性表达率分别为60．0％、65．0％。Ki-67、PCNA表达与GIsT的性别、年龄、部位、组织学分型无关,与肿瘤大小、组织学分级有关。Ki-67、PCNA的表达呈正相关。结论：Ki-67、PCNA联合检测可作为判定GIST良恶性、恶性程度、肿瘤分级及预后的重要指标。     

乳腺叶状肿瘤17例诊疗分析

目的:探讨乳腺叶状肿瘤的治疗原则和影响预后因素。方法:对经手术和病理诊断确诊的17例乳腺叶状肿瘤的临床资料进行回顾性分析。结果:17例患者中良性叶状肿瘤9例,交界性叶状肿瘤5例,恶性3例。行局部肿块切除7例,单纯乳房切除术6例,改良根治术3例,姑息性肿块切除术1例。其中随访13例,平均随访时间21(5~84)个月,1例行乳腺癌改良根治术后2.5年死于远处转移,2例行局部肿块切除术后复发。结论:乳腺叶状肿瘤的预后与手术方式有关,良性和交界性应首选扩大区段切除术,切除肿瘤边缘不少于2cm;复发的交界性和恶性应尽早行单纯乳房切除术。     

Prognostic and predictive value of changes in tumour cell proliferation in locally advanced breast cancer primarily treated with doxorubicin

We previously reported that high tumour cell proliferation evaluated by Ki-67 expression, high mitotic frequency and high histological grade were associated with resistance to primary doxorubicin monotherapy in locally advanced breast cancer harbouring wild-type (wt) TP53. The aim of our present study was to evaluate the predictive and prognostic impact of proliferation parameters assessed in tumour tissue obtained after chemotherapy, and alterations induced in tumour cell proliferation. While we found a significant reduction in Ki-67 expression and mitotic frequency in tumours with wtTP53 (p=0.001 and p=0.008, respectively), no significant change was recorded in tumours expressing mutant TP53. For histological grade there was no significant change in either group. There was a direct correlation between pre- and post-treatment values for Ki-67 and mitotic frequency in tumours harbouring wtTP53 (p=0.0001 for both), but no correlation in tumours harbouring mutated TP53. High post-treatment Ki-67 expression and mitotic frequency were found to predict doxorubicin resistance only in patients with wtTP53 (p=0.04 and p=0.03, respectively). The prognostic importance of proliferation markers and histological grade was found to be similar whether they were determined in the pre- or post-treatment samples (Ki-67; pre: p=0.02; post: p=0.03; mitotic frequency; p=0.002 and p=0.01, respectively; histological grade; p=0.0001 and p=0.002, respectively). While the reduction in mitotic frequency was associated with improved survival (p=0.03), no significant associations between changes in other parameters and outcome were recorded.     

Differences in Ki67 and c-erbB2 expression between screen-detected and true interval breast cancers.

Breast cancer screening facilitates the early detection of breast cancer, although a significant number of tumors still arise in the interval between screening. The objective of this study was to measure the expression of five markers of proven prognostic significance in symptomatic breast cancer (estrogen receptor, progesterone receptor, p53, Ki67, and c-erbB2) in screen-detected and interval breast cancers to identify biological markers that may be associated with the emergence of symptomatic breast cancer in the screening interval. The expression of estrogen receptor, progesterone receptor, p53, Ki67, and c-erbB2 was assessed in a series of 51 true interval and 84 screened-detected invasive tumors by immunohistochemistry. Interval cancers tended to be of higher histological grade and were of larger pathological size than screen-detected cancers. Expression of estrogen receptor was 1.7-fold lower (P<0.001), whereas expression of p53 was 2.5-fold (P<0.01), Ki67 2.4-fold (P<0.001), and c-erbB2 3.6-fold higher (P<0.01) in true interval cancers compared with screen-detected invasive cancers. There was no significant difference in progesterone receptor expression. The most important differences identified by multiple logistic regression analysis were in the expression of Ki67 and c-erbB2. The differences in the expression of these markers were more important than clinical features such as pathological grade and size. Using the logistic regression model, 83% of the tumors analyzed in this study could be correctly assigned as interval or screen-detected tumors on the basis of Ki67 and c-erbB2 expression. The importance of high expression of Ki67 in interval cancers compared with screen-detected cancers suggests that tumors may become symptomatic in the screening interval as a result of increased levels of cell proliferation. The inclusion of c-erbB2 in the regression equation suggests that this growth factor receptor may play a significant role in stimulating the rapid growth of interval cancers.     

Proliferation markers predictive of the pathological response and disease outcome of patients with breast carcinomas treated by anthracycline-based preoperative chemotherapy

The cell proliferation rate has been correlated to the response of breast carcinomas to preoperative chemotherapy (CT) and to disease outcome. However, this parameter is not yet used to select which tumours should be treated with preoperative CT. Furthermore, there is no consensus in the method used to evaluate cell proliferation. In poor prognosis breast carcinomas (PPBCs) treated by intensive preoperative CT, we compared the predictive value of S phase fraction (SPF), mitotic index (MI) and Ki67. We also evaluated the prognostic significance of the variation of the MI after CT. A series of 55 T2-T4N0N1M0 breast carcinomas were treated with 4 cycles of cyclophosphamide, 5-fluorouracil (5-FU) and doxorubicin. SPF was determined by flow cytometry on pre-therapeutic needle aspiration products. MI and Ki67 were evaluated on pre-therapeutic biopsy samples and on the tumours after CT. Fifteen patients (27%) had a pathological complete response (pCR), whereas 40 (73%) had residual disease. All three proliferative markers were found to have predictive value, but this value was higher for MI than for SPF (P = 0.04) and Ki67 (P = 0.03): the rate of pCR was 50% in cases with MI > 17/3.3 mm2, but was only 7% in cases with MI under this threshold (P = 0.0003). A significant decrease of MI (mean 10.97) was observed after CT (P = 0.001). Furthermore, we observed that even for patients with residual tumour, the variation of MI after CT was a prognostic parameter and overall survival. The sequential analysis of MI in breast cancers treated by preoperative CT thus provides a surrogate for predicting long-term outcome.     

Low proliferative rate of invasive node-negative breast cancer predicts for a favorable outcome: a prospective evaluation of 669 patients

This study was designed to compare outcome in terms of disease-free survival (DFS) in women with histologically negative axillary lymph nodes and documented low proliferative rate cancer to other well-defined prognostic factors including type of adjuvant treatment. Between 1988 and 1998, we studied 669 patients with invasive node-negative breast cancer up to 5 cm in size and low proliferative rate measured by flow cytometry to determine S-phase fraction (SPF) or by histochemistry (Ki67/MIB1). At a median follow-up of 53 months, 5-year DFS for the entire group was 94% and did not differ significantly by type of systemic adjuvant treatment: none (133 patients, 95% DFS), tamoxifen (441 patients, 94% DFS), or chemotherapy with doxorubicin and cyclophosphamide (95 patients, 92% DFS). In a multivariate prognostic factor analysis, only tumor size was significant; 5-year DFS was 96% for T1N0 cancer versus 89% for T2N0 cancer (P = 0.01). We have prospectively confirmed that a low rate of proliferation as measured by SPF or MIB1 determination confers an excellent prognosis in invasive node-negative breast cancer up to 5 cm in size, regardless of adjuvant treatment.