The significance of extracapsular extension of axillary lymph node metastases in early-stage breast cancer

PURPOSE: To investigate if extracapsular extension (ECE) of axillary lymph node metastases predicts for a decreased rate of disease-free survival or an increased rate of regional recurrence of breast carcinoma. METHODS: The study population consisted of 368 patients with T1 or T2 breast cancer and pathologically-positive lymph nodes treated with breast-conserving therapy between 1968 and 1986. The median number of sampled lymph nodes was 10. Median follow-up time for the surviving patients was 139 months (range 70-244). Twenty percent of the patients were treated with supraclavicular RT, and 64% received both axillary and supraclavicular RT, with a median dose to the nodes of 45 Gy. The following factors were evaluated: presence of ECE, number of sampled lymph nodes (LN), number of involved LN, size of primary tumor, histologic grade of tumor, presence of lymphatic vessel invasion (LVI), presence of an extensive intraductal component (EIC), radiation dose, use of adjuvant chemotherapy, and age of patient. Recurrences were reported as the 5-year crude sites of first failure, and were divided into breast recurrences (LR), regional nodal failure (RNF, defined as isolated axillary, supraclavicular, or internal mammary recurrence), and distant metastases (DM). RESULTS: One hundred twenty-two patients (33%) had ECE and 246 patients did not. The median number of LN with ECE was 1 (range 1-10) and 20% of patients had ECE in > or =4 LN. Patients with ECE tended to be older (median age 51 vs. 47, p = 0.01), and had a higher number of involved LN (median 3 vs. 2, p = 0.005) than patients without ECE. Forty-three percent of patients with ECE had > or =4 involved LN compared to 15% of patients without ECE (p<0.0001). Models of ECE and the above factors revealed no significant correlation between ECE and either disease-free or overall survival. There was no statistically significant increase in local, regional nodal, or distant failures in patients with ECE as compared to patients without ECE. CONCLUSION: In this population of patients with nodal involvement, the presence of ECE correlates with the number of involved LN but does not appear to add predictive power to models of local, regional, or distant recurrence when the number of positive LN is included.     

腋淋巴结阳性乳腺癌结外侵犯的临床意义

目的 探讨乳腺癌患者淋巴结外侵犯(ECE)的临床意义.方法 回顾性分析1230例腋窝淋巴结阳性乳腺癌,观察ECE与临床病理指标之间关系及对患者预后的影响.结果 腋窝淋巴结阳性乳腺癌患者中,ECE阳性率为39.5%.绝经前和绝经后患者ECE的发生率分别为35.5%和47.5%(P＜0.001).ECE阳性组和阴性组的肿瘤直径分别为5.11±2.53 cm和3.90±1.80 cm(P＜0.001),肿瘤直径越大,ECE阳性比例越高(P＜0.001).ECE阳性患者和ECE阴性患者的阳性淋巴结数目分别为16.96±12.16和5.24±6.60(P＜0.001),随腋窝阳性淋巴结数目增多,ECE阳性率明显增加(P＜0.001).ECE的发生与ER、PR状态无显著相关(P=0.706).ECE足乳腺癌患者局部或区域复发的危险因素(P＜0.001),复发时间差异无统计学意义(P=0.559).ECE阳性组和ECE阴性组的远处转移时问分别为30.0个月和37.5个月(P=0.006).首发骨、皮肤和远隔淋巴结组及内脏转移组的ECE阳性率分别为60.4%和42.0%(P=0.001).ECE阳性患者的无转移生存时间、无局部或区域复发生存时间及总生存时间均小于ECE阴性患者.预后单因素和多因素分析显示,ECE是影响乳腺癌患者无转移生存时间、无局部或区域复发生存时间及总生存时间的独立危险因素.结论 乳腺癌患者ECE的发生与肿瘤直径和受累淋巴结数日呈正相关;ECE是乳腺癌局部或区域复发和远处转移的危险因素;ECE是影响乳腺癌患者无转移生存时间、无局部或区域复发生存时间及总生存时间的危险因素.     

Ultrasound detection of axillary lymph node metastases in breast cancer

Presence or absence of lymph node metastases is the most accurate prognostic indicator in breast cancer. Clinical examination is unreliable in detecting involved nodes. Preoperative ultrasound scan of the axilla has been performed in 140 consecutive women with breast cancer. The sensitivity for involved nodes was 66% which was significantly higher than clinical examination (42%) (P = less than 0.01). However ultrasound gave more false positives than clinical examination and thus no overall improvement in prognostic information was achieved.     

Diagnosis of axillary lymph node metastases in patients with breast cancer

Summary The diagnosis of axillary (AX) metastases remains a challenge in the management of breast cancer and is a subject of controversy. Clinical node staging clearly is limited in the assessment of AX lymph nodes. AX mammography, ultrasonography, and computed tomography (CT) do not provide histologic information. Although nuclear magnetic resonance imaging may have considerable value in the diagnosis of AX metastases, it does not detect micrometastases. The use of biologic markers in the assessment of AX metastases remains a subject of investigation. On the other hand, biopsy of selected AX nodes or tissue with examination of histology or cytology generally would not identify a significant percentage of patients with AX node involvement. Sentinel lymph node biopsy, however, might be potentially useful for assessing AX metastases, although it remains investigational. In order to simplify diagnosis and reduce morbidity and mortality, alternatives to AX dissection must be sought and imaging and staging modalities refined. We present a review of the literature pertaining to the diagnosis of AX metastases in patients with breast cancer and a discussion of some current areas of controversy.     

Intraoperative assessment of axillary lymph node metastases in operable breast cancer

The diagnostic value of intraoperative histologic examination of frozen sections of axillary lymph nodes was investigated in 243 patients with operable breast cancer. One to six hard or enlarged axillary nodes were sampled from the axillary pad which was derived from a partial axillary dissection (including level 1 and 2 nodes). Half of these nodes were histologically examined using frozen sections during surgery. After a total axillary dissection, both the axillary nodes in the partial axillary dissection and the nodes dissected at level 3 were histologically examined on permanent section. A mean of four nodes were sampled (range: 1 to 6). Axillary dissection yielded a mean of 22 nodes (range: 6 to 60). Axillary sampling detected the presence of metastases in 65 of 84 (77%) patients with positive axillary lymph nodes. In the patients in whom the axillary involvement was not identified by axillary sampling, however, the extent of axillary involvement was limited to levels 1 and 2. Therefore, a partial axillary dissection may be justified for patients in whom axillary involvement is not found on frozen section of nodes from axillary sampling, whereas a total axillary dissection should be performed for patients in whom axillary involvement is found by these procedures.     

乳腺癌腋窝淋巴结声像图联合免疫组织化学与淋巴结转移的相关性研究

背景与目的：乳腺癌腋窝淋巴结转移对于乳腺癌患者的预后及治疗方案的选择有重要的指导意义。本研究旨在探讨乳腺癌腋窝淋巴结声像图表现联合免疫组织化学与腋窝淋巴结转移的相关性。方法：回顾性分析应用超声检出的366例乳腺癌患者共计728枚腋窝淋巴结的声像图表现,采用单因素分析、多因素logistic回归及受试者工作特征(receiver operating characteristic,ROC)曲线分析的方法,分别检验乳腺癌腋窝淋巴结皮质最大厚度、长短径之比、皮髓质之比和淋巴结血流特征,联合乳腺癌术后免疫组织化学结果,研究其与病理学腋窝淋巴结转移的相关性。结果：依据单因素分析,腋窝淋巴结皮质最大厚度、长短径之比、血流特征以及乳腺癌病灶p53的阳性表达率与淋巴结转移有关(P<0.05)。依据多因素分析及ROC分析,腋窝淋巴结皮质最大厚度是判定腋窝淋巴结转移的最佳指标。腋窝淋巴结皮质最大厚度大于3 mm的患者,其乳腺癌病灶的p53阳性表达率(42.78%)明显高于皮质最大厚度小于等于3 mm的患者(25.82%),差异有统计学意义(P<0.01)。结论：乳腺癌腋窝淋巴结声像图表现联合免疫组织化学评价腋窝淋巴结转移,对乳腺癌的临床诊疗方法选择具有重要价值。     

Predicting axillary lymph node metastases in breast carcinoma patients

Routine axillary dissection is primarily used as a means of assessing prognosis to establish appropriate treatment plans for patients with primary breast carcinoma. However, axillary dissection offers no therapeutic benefit to node negative patients and patients may incur unnecessary morbidity, including mild to severe impairment of arm motion and lymphedema, as a result. This paper outlines a method of evaluating the probability of harbouring lymph node metastases at the time of initial surgery by assessment of tumour based parameters, in order to provide an objective basis for further selection of patients for treatment or investigation. The novel aspect of this study is the use of Maximum Entropy Estimation (MEE) to construct probabilistic models of the relationship between the risk factors and the outcome. Two hundred and seventeen patients with invasive breast carcinoma were studied. Surgical treatment included axillary clearance in all cases, so that the pathologic status of the nodes was known. Tumour size was found to be significantly correlated (P < 0.001) to the axillary lymph node status in the multivariate analysis with age (P = 0.089) and vascular invasion (P = 0.08) marginally correlated. Using the multivariate model constructed, 38 patients were predicted to have risk of nodal metastases lower than 20%, of these only 4 (10%) patients had lymph node metastases. A comparison with the Multivariate Logistic Regression (MLR) was carried out. It was found that the predictive quality of the MEE model was better than that of the MLR model. In view of the small sample size, further verification of this model is required in assessing its practical application to a larger population.     

Occult axillary lymph node metastases are of no prognostic significance in breast cancer

The significance of occult metastases in axillary lymph nodes in patients with carcinoma of the breast is controversial. Additional sections were cut from the axillary lymph nodes of 477 women with invasive carcinoma of the breast, in whom no metastases were seen on initial assessment of haematoxylin and eosin stained sections of the nodes. One section was stained with haematoxylin and eosin, and one using immunohistochemistry with two anti-epithelial antibodies (CAM5.2 and HMFG2). Occult metastases were found in 60 patients (13%). The median follow-up was 18.9 years with 153 breast cancer related deaths. There was no difference in survival between those with and those without occult metastases. Multivariate analysis, however, showed that survival was related to tumour size and histological grade. This node-negative group was compared with a second group of 202 patients who had one involved axillary node found on initial assessment of the haematoxylin and eosin sections; survival was worse in the patients in whom a nodal metastasis was found at the time of surgery. Survival was not related to the size of nodal metastases in the occult metastases and single node positive groups. Some previous studies have found a worse prognosis associated with occult metastases on univariate analysis, but the evidence that it is an independent prognostic factor on multivariate analysis is weak. We believe that the current evidence does not support the routine use of serial sections or immunohistochemistry for the detection of occult metastases in the management of lymph node negative patients, but that the traditional factors of histological grade and tumour size are useful.     

临床腋淋巴结阳性乳腺癌患者行全腋窝淋巴结清扫的应用探讨

背景与目的:临床腋淋巴结阳性乳腺癌患者常规行全腋窝淋巴结清扫,本研究探讨改良根治术时采用改进L3组淋巴结清扫方式的临床应用及意义.方法:322例临床腋淋巴结阳性的乳腺癌患者中,154例采用改进的L3组淋巴结清扫方式,168例行常规Auchinclos改良根治术,对两种手术方式所用时间和术后不良反应进行比较,同时随访观察患者的无病生存率.结果:两种手术方式所用手术时间、术后不良反应差异无统计学意义(P＞0.05),行改进术式患者腋下淋巴结总数及L3组淋巴结数较常规术式多,两组差异有统计学意义(P＜0.05),L3组淋巴结未转移患者5年无病生存率为68.6％,L3组淋巴结转移患者5年无病生存率为35.7％,差异有统计学意义(P＜0.05).结论:对临床腋淋巴结阳性乳腺癌患者行L3组淋巴结清扫具有一定的临床应用价值,采用改进的淋巴结清扫方式,便于L3组淋巴结的清扫.     

Lack of efficacy of lymphoscintigraphy in detecting axillary lymph node metastases from breast cancer

Preoperative detection of metastases in regional lymph nodes should constitute a fundamental step towards a better management of breast cancer. The National Cancer Institute of Milan has traditionally been engaed in this particular problem, that is, the search for a new imaging technique for detecting lymph nodal metastases from breast cancer. In 1984 axillary lymphoscintigraphy was performed on 26 patients with operable breast cancer by periareolar injection of 100 μCi of ^99mTc sulphur microcolloid. The regional lymph nodes were identified as spot areas and a comparison was made between the number of primary draining axillary lymph nodes and their pathological examination. In only 2 of the 26 patients have more than 3 spot areas been revealed by axillary scintiscan, but this finding did not correspond to metastatic invasion. The lymphoscintigraphy pattern of the other 24 patients did not suggest any pathological condition. From our experience the method does not appear to help either a precise diagnosis of breast disease or the definition of the extent of mammary cancer.     

PET—C畛断乳腺癌及其腋窝淋巴结转移的价值

目的探讨PET—CT对诊断乳腺癌及腋窝淋巴结转移情况的临床价值。方法选取行PET—CT检查的乳腺肿瘤患者40例，根据术后病理检查结果评价PET—CT对原发病灶定性和判断腋窝淋巴结转移情况的准确性并与腋窝淋巴结清扫情况进行比较；检验原发肿瘤病灶病理直径大小与超声、PET—CT诊断的一致性及其与标准化摄取值（SUV）值的相关性。结果PET—CT对乳腺癌的定性诊断准确率95％、灵敏度94％、特异度100％；根据腋窝淋巴结清扫术情况，PET—CT诊断腋窝淋巴结转移准确率88．2％、灵敏度89．2％、特异度83．3％；肿瘤病灶病理直径大小与PET-CT诊断相关性最高（P〈0．05），与SUV则无相关性（P〉0．05）。结论PET—CT对乳腺癌及腋窝淋巴结转移的诊断与病理诊断基本相符，灵敏度、特异度较高，两者诊断原发病灶大小的一致性最佳，可为取舍腋窝淋巴结清扫术和选择合理治疗方案提供有益参考。     

Prognostic significance of occult axillary lymph node metastases after chemotherapy‐induced pathologic complete response of cytologically proven axillary lymph node metastases from breast cancer

BACKGROUND:

Primary systemic chemotherapy has been a standard of care for the management of locally advanced breast cancer (LABC) patients and has increasingly been used for patients with large operable breast cancer. Pathologic complete response (pCR) of axillary lymph node metastases predicted an excellent probability of long‐term disease‐free and overall survival. Although the clinical significance of occult lymph node metastases in patients with breast cancer was extensively studied, their prognostic value in patients with LABC after primary chemotherapy was not known. This study evaluated the detection rate and clinical significance of occult lymph node metastases in lymph nodes that contained metastatic carcinoma at the time of initial diagnosis and converted to negative based on routine pathologic examination after primary systemic chemotherapy.

METHODS:

Fifty‐one patients with LABC and cytologically involved axillary lymph nodes that converted to negative after preoperative chemotherapy were identified from 2 prospective clinical trials. All lymph node sections were reviewed, 1 deeper level hematoxylin and eosin‐stained section of each lymph node was obtained and immunohistochemical staining for cytokeratin (CK) was performed. A total of 762 lymph nodes were evaluated for occult metastases. Kaplan‐Meier survival curves were used for calculating disease‐free and overall survival times.

RESULTS:

Occult axillary lymph node metastases were identified in 8 of 51 (16%) patients. In 6 patients, occult metastases were found in only 1 lymph node. In 7 patients, only isolated CK‐positive cells were identified. In all cases, occult carcinoma cells were embedded within areas of fibrosis, foreign body giant cell reaction, and extensive histiocytosis. Patients with occult lymph node metastases tended to have a higher frequency of residual primary breast tumors than those without occult metastases (4 of 8 vs 7 of 43, respectively). There was no statistically significant difference in disease‐free or overall survival times between patients with and without occult metastases after a median follow‐up 63 months.

CONCLUSIONS:

Persistent occult axillary lymph node metastases were not uncommon in patients with axillary lymph node‐positive LABC who experienced a pCR in involved lymph nodes after preoperative chemotherapy. However, such occult metastases did not adversely affect the good prognosis associated with axillary lymph node pCR. Therefore, routine lymph node CK evaluation was not recommended after primary chemotherapy. Cancer 2009. © 2009 American Cancer Society.     

Basal breast cancer molecular subtype predicts for lower incidence of axillary lymph node metastases in primary breast cancer

BACKGROUND: Axillary lymph node involvement remains the most important prognostic factor in early-stage breast cancer. We hypothesized that molecular classification based on breast cancer biology would predict the presence of nodal involvement at diagnosis, which might aid treatment decisions regarding the axilla. PATIENTS AND METHODS: From a clinically annotated tissue microarray of 4444 early-stage breast cancers, expression of estrogen receptor (ER), progesterone receptor (PgR), HER2, epidermal growth factor receptor, and cytokeratin 5/6 was determined by immunohistochemistry. Cases were classified by published criteria into molecular subtypes of luminal, luminal/HER2 positive, HER2 positive/ER negative/PgR negative, and basal. Risk of axillary nodal involvement at diagnosis was determined in 2 multivariable logistic regression models: a "core biopsy model" including molecular subtype, age, grade, and tumor size and a "lumpectomy model," which also included lymphovascular invasion. Luminal was used as the reference group. After internal validation of findings in 2 independent sets, we conducted combined analysis of both. RESULTS: In the core biopsy model, the molecular subtypes had a predictive effect for nodal involvement (P= .000001), with the basal subtype having an odds ratio for axillary lymph node involvement of 0.53 (95% CI, 0.41-0.69). Tumor grade (P=5.43 x 10(-12)) and size (P=8.52 x 10(-35)) were also predictive for nodal involvement. Similar results were found in the lumpectomy model, where lymphovascular invasion was also predictive (P=2.74 x 10(-115)). CONCLUSION: These results indicate that the basal breast cancer molecular subtype predicts a lower incidence of axillary nodal involvement, and including biomarker profiles to predict nodal status at diagnosis could help stratification for decisions regarding axillary surgery and locoregional radiation.     

Lack of efficacy of xeroradiography to preoperatively detect axillary lymph node metastases in breast cancer

Xeroradiography of the axilla was performed in 132 patients with operable breast cancer to investigate the status of the axillary lymph nodes. Pathologic findings were correlated with the results of clinical examination and xeroradiographic findings. Xeroradiography does not appear to have improved our ability to identify axillary lymph node metastases in patients with breast cancer.     

Induction of lymphangiogenesis in and around axillary lymph node metastases of patients with breast cancer

We studied the presence of lymphangiogenesis in lymph node (LN) metastases of breast cancer. Lymph vessels were present in 52 of 61 (85.2%) metastatically involved LNs vs 26 of 104 (25.0%) uninvolved LNs (P<0.001). Furthermore, median intra- and perinodal lymphatic endothelial cell proliferation fractions were higher in metastatically involved LNs (P<0.001). This is the first report demonstrating lymphangiogenesis in LN metastases of cancer in general and breast cancer in particular.     

The role of axillary lymph node dissection in breast cancer management

Although it is generally accepted that axillary dissection provides no survival advantage in patients with breast cancer, it is commonly regarded as a reliable method of assessing nodal status and treating regional disease. However, it is time to consider eliminating routine axillary dissection in patients who are clinically node-negative. A sentinel lymph node biopsy may assess axillary nodal status while obviating a full axillary dissection. At present, axillary dissection remains the standard approach for the surgical management of all patients with invasive carcinoma of the breast, regardless of tumor size or patient age, though it is unnecessary for patients with small intraductal carcinomas.     

Detection of axillary lymph node metastases in breast cancer with Tc-99m tetrofosmin scintigraphy

The most important prognostic factor in breast (B) cancer (C) is axillary (A) lymph (L) node (N) status, and virtually all patients with BC undergo ALN dissection to assess N involvement. The aim of this study was to evaluate the accuracy of planar and tomographic Tc-99m tetrofosmin scintigraphy in the detection of ALN involvement in BC. A group of 85 female patients (age range: 31-82 years) with 87 BCs were studied before surgery. Three planar images, right and left prone lateral and supine anterior thoracic views, and 360 degrees supine thoracic single photon emission tomography (SPET) were acquired after Tc-99m tetrofosmin injection (740 MBq i.v.). ALN status was evaluated by histological exam after A dissection: metastatic ALN involvement was proved in 31 out of 87 cases. Sensitivity was 87.1% (27/31) for SPET and 61.3% (19/31) for planar images (p<0.01); specificity was 92.9% (52/56) and 94.6% (53/56), respectively, with a global accuracy of 90.8% (79/87) for SPET and 82.8% (72/87) for planar imaging (p<0.05). Sensitivity rose from 75% in non-palpable Ns to 94.7% in palpable ones for SPET, and from 41.7 to 73.7% for planar scans. SPET was positive in 17/18 (94.4%) patients with >3 metastatic Ns and in 10/13 (76.9%) with < or = 3 involved Ns, whereas planar images were positive in 14/18 (77.8%) and in 5/13 (38.5%) cases, respectively. In conclusion, our findings indicate that Tc-99m tetrofosmin scintigraphy is useful in the presurgical detection of ALN metastases in BC, with SPET more accurate than conventional planar images, thus suggesting its more frequent use in scintimammography; moreover, the total number of histologically involved Ns can affect the scintigraphic results.     

Variability in axillary lymph node dissection for breast cancer

BACKGROUND: The axillary nodal status may influence the prognosis and the choice of adjuvant treatment of individual breast cancer patients. The variation in number of reported axillary lymph nodes and its effect on the axillary nodal stage were studied and the implications are discussed. METHODS: Between 1994 and 1997, a total of 4,806 axillary dissections for invasive breast cancers in 4,715 patients were performed in hospitals in the North-Netherlands. The factors associated with the number of reported nodes and the relation of this number with the nodal status and the number of positive nodes were studied. RESULTS: The number of reported nodes varied significantly between pathology laboratories, the median number of nodes ranged from 9 to 15, respectively. The individual hospitals explained even more variability in the number of nodes than pathology laboratories (range in median number 8-15, P < 0.0001). The number of reported nodes increased gradually during the study period. A decreasing trend was observed with older patient age. A higher number of reported nodes was associated with a markedly increased chance of finding tumor positive nodes, especially more than three nodes. The frequency of node positivity increased from 28% if less than six nodes to 54% if >/=20 nodes were examined, the percentage of tumors with >/=4 positive nodes increased from 4 to 31%. Multivariate analysis confirmed these results. CONCLUSIONS: This population-based study showed a large variation in the number of reported lymph nodes between hospitals. A more extensive surgical dissection or histopathological examination of the specimen generally resulted in a higher number of positive nodes. Although the impact of misclassification on adjuvant treatment will have varied, the impact with regard to adjuvant regional radiotherapy may have been considerable.     

Size of breast cancer metastases in axillary lymph nodes: clinical relevance of minimal lymph node involvement.

BACKGROUND: Overt ipsilateral axillary lymph node metastases of breast cancer are the most significant prognostic indicators for women who have undergone surgery, yet the clinical relevance of minimal involvement (isolated tumor cells and micrometastases) of these nodes is uncertain. PATIENTS AND METHODS: We evaluated biologic features, adjuvant treatment recommendations, and prognosis for 1,959 consecutive patients with pT1-3, pN0, minimal lymph node involvement (pN1mi or pN0i+), or pN1a (single positive node) and M0, who were operated on and counseled for medical therapy from April 1997 to December 2000. RESULTS: Patients with pN1a and pN1mi/pN0i+, when compared with patients with pN0 disease, were more often prescribed anthracycline-containing chemotherapy (39.1% v 33.2% v 6.1%, respectively; P < .0001) and were less likely to receive endocrine therapy alone (9.8% v 19.4% v 41.9%, respectively; P < .0001). At the multivariate analysis, a statistically significant difference in disease-free survival (DFS) and in the risk of distant metastases was observed for patients with pN1a versus pN0 disease (hazard ratio [HR] = 2.04; 95% CI, 1.46 to 2.86; P < .0001 for DFS; HR = 2.32; 95% CI, 1.42 to 3.80; P = .0007 for distant metastases) and for patients with pN1mi/pN0i+ versus pN0 disease (HR = 1.58; 95% CI, 1.01 to 2.47; P = .047 for DFS; HR = 1.94; 95% CI, 1.04 to 3.64; P = .037 for distant metastases). CONCLUSION: Even minimal involvement of a single axillary node in breast cancer significantly correlates with worse prognosis compared with no axillary node involvement. Further studies are required before widespread modification of clinical practice.