Myofibroblast activation in colorectal cancer lymph node metastases

Background:

Myofibroblasts have an important role in regulating the normal colorectal stem cell niche. While the activation of myofibroblasts in primary colorectal cancers has been previously described, myofibroblast activation in lymph node metastases has not been described before.

Methods:

Paraffin-embedded lymph node sections from patients with macrometastases, micrometastases and isolated tumour cells were stained to identify myofibroblasts and to characterise the distribution of different cell types in tumour-containing lymph nodes. The extent of myofibroblast presence was quantified and compared with the size of the metastasis and degree of proliferation and differentiation of the cancer cells.

Results:

We show substantial activation of myofibroblasts in the presence of colorectal metastases in lymph nodes, which is intimately associated with glandular structures, both in micro- and macrometastases. The degree of activation is positively associated with the size of the metastases and the proportion of Ki67+ve cancer cells, and negatively associated with the degree of enterocyte differentiation as measured by CK20 expression.

Conclusion:

The substantial activation of myofibroblasts in tumour-containing lymph nodes strongly suggests that these metastatic cancer cells are still significantly dependent on their microenvironment. Further understanding of these epithelial–mesenchymal interactions could lead to the development of new therapies in metastatic disease.     

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.     

Feasibility and accuracy of sentinel lymph node biopsy after preoperative chemotherapy in breast cancer patients with documented axillary metastases

BACKGROUND: The feasibility and accuracy of sentinel lymph node (SLN) biopsy in patients with breast cancer after preoperative chemotherapy has been demonstrated in a number of large, single-institution studies. However, a relative contraindication to SLN biopsy after preoperative chemotherapy is the presence of axillary metastases at initial diagnosis. The objective of this study was to determine the feasibility and accuracy of SLN biopsy after preoperative chemotherapy in patients with documented axillary metastases at presentation. METHODS: Between 1994 and 2002, 69 patients who had axillary metastases identified by ultrasound-guided, fine-needle aspiration underwent SLN biopsy after treatment on prospective, preoperative chemotherapy protocols. All but 8 patients underwent axillary lymph node dissection (ALND). Those 8 patients either declined additional surgery or were offered enrollment in other institutional protocols. RESULTS: The median patient age was 49 years, and the median primary tumor size was 4 cm. The SLN identification rate was 92.8%. Thirty-one of 64 patients (48.4%) had successfully mapped, positive SLNs. Sixty-one patients underwent ALND, including 5 patients who did not have an SLN identified. In the 56 patients in whom a SLN was identified and an ALND was performed, 10 patients had a false-negative SLN (25%). CONCLUSIONS: SLN biopsy was feasible after preoperative chemotherapy, even in patients who initially presented with cytologically proven, lymph node-positive disease. However, the false-negative rate of SLN biopsy in this group of patients was much higher than that observed in clinically lymph node-negative patients. Based on the current results, the status of the SLN cannot be used as a reliable indicator of the presence or absence of residual disease in the axilla in this patient population.     

Comparative efficacy of positron emission tomography and ultrasonography in preoperative evaluation of axillary lymph node metastases in breast cancer

PURPOSE: In primary breast cancer, axillary nodal status is the most powerful predictive factor of recurrence. However, axillary lymph node dissection may cause surgical complications. If preoperative evaluation of axillary lymph node metastases is possible, unnecessary axillary lymph node dissections can be avoided. The purpose of this study was to evaluate the efficacy of positron emission tomography (PET) on detection of axillary lymph node metastases in breast cancer. METHODS: PET scans of the axilla were obtained in 32 patients with primary breast cancer. All patients fasted for at least 4 hours before the examination. After transmission scans for attenuation correction were performed, emission scans after intravenous injection of 2-[18F]-fluoro-2-deoxy-D-glucose (FDG) were obtained. RESULTS: Overall accuracy of PET alone, ultrasonography alone, and in combination in the detection of axillary metastases were 82%, 79%, and 85% respectively. CONCLUSION: There were no significant differences between PET, ultrasonography, and PET in combination with ultrasonography regarding sensitivity, specificity and accuracy in the detection of axillary metastases.     

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.     

中晚期宫颈癌腹主动脉旁淋巴结转移治疗的临床研究

目的:研究中晚期（Ⅱb-Ⅲb期）宫颈癌腹主动脉旁淋巴结(PALN)转移采用手术和放疗治疗的疗效。方法:选择中晚期（Ⅱb-Ⅲb期）腹主动脉旁淋巴结转移的宫颈癌患者76例,观察组43例,行腹主动脉旁淋巴结清扫术,术后行同步放化学治疗。对照组33例,行宫颈癌同步放化学治疗。分析与患者3年生存率有关的临床病理因素,探讨影响患者预后的因素。结果:手术分期、病理分级、SCCA水平、局部肿瘤大小、腹主动脉旁淋巴结大小、治疗方法与患者的3年生存率有关。多因素分析表明影响患者生存期的因素是分期、分级、局部肿瘤大小、腹主动脉旁淋巴结大小、治疗方法。结论:中晚期宫颈癌腹主动脉旁淋巴结转移,行腹主动脉旁淋巴结切除并辅以术后延伸放疗联合同期化疗,对于病人治疗有重要意义。     

Genetic and epigenetic alterations in primary colorectal cancers and related lymph node and liver metastases

BACKGROUND:

Colorectal cancer (CRC) prognosis and survival are strictly related to the development of distant metastases. New targeted therapies have increased patient survival, but the objective response rate is still very limited, partially because of a traditional focus on designing treatment according to the molecular profile of the primary tumor regardless the diversity between the primary tumor and metastases. The objective of this study was to evaluate the presence of molecular heterogeneity during metastatic progression and its potential impact on clinical treatment.

METHODS:

The authors analyzed v‐Ki‐ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) codon 12 mutations, the v‐Raf murine sarcoma viral oncogene homolog B1 (BRAF) thymine to adenine substitution at codon 1788, and tumor protein 53 (p53) mutations and investigated promoter methylation of Ras association (RalGDS/AF‐6) domain family member 1 protein (RASSF1a), E‐cadherin, and cyclin‐dependent kinase inhibitor 2A (p16INK4a) in 101 primary CRCs (67 stage III and 34 stage IV) and related lymph node and liver metastases.

RESULTS:

Lymph node metastases were characterized by fewer alterations compared with primary tumors and liver metastases, especially KRAS (P = .03) and p16INK4a (P = .05). Genetic changes, when detectable in metastases, mostly were retained from the primary tumor, whereas epigenetic changes more frequently were acquired de novo. Overall, 31 distinct CRC molecular profiles were detected, none of which characterized a particular tumor stage. When the metastatic lesions also were included in the profiles, there were 53 distinct molecular profiles in 67 patients with stage III disease and 34 distinct molecular profiles in 34 patients with stage IV disease.

CONCLUSIONS:

Lymph node and liver metastases appear to originate in clonally different processes, with more molecular alterations occurring in distant metastases than in lymph node metastases and with elevated heterogeneity of the primary tumor. Thus, potential prognostic targets should be carefully evaluated for their heterogeneity in both primary tumors and distant metastases to avoid erroneous misclassification. Cancer 2013. © 2012 American Cancer Society.     

T1 breast cancer: identification of patients at low risk of axillary lymph node metastases

Objective. The status of the axillary lymph nodes is one of the most important prognostic factors in patients with breast cancer. A panel of molecular markers of tumor aggressiveness in addition to conventional clinical and histopathologic features were analyzed in an attempt to identify a subgroup of patients with a low risk of axillary lymph node metastases. Material and methods. Data from 358 patients with T1 breast cancer who underwent level I/II axillary lymph node dissection (ALND) were investigated. Hormone receptor status, Ki-67, S-phase fraction, DNA ploidy, HER-2/neu, p53, epidermal growth factor receptor, urokinase type plasminogen activator, plasminogen activator inhibitor-1, bone marrow micrometastases as well as patient age, menopausal status, tumor site, tumor size, histologic type, tumor grade, carcinoma in situ, multifocality, and lymph vascular invasion (LVI) were studied to predict axillary lymph node status. Results. In a multivariate logistic regression analysis LVI (present v.s. not present), Ki-67 (18% v.s. <18%), tumor size (1.1–2 cm v.s. 1 cm), and histologic grade (G3 v.s. G1/2) were identified as independent predictive factors of axillary lymph node metastases. Approximately 13% of patients (n = 47) with well or moderately differentiated tumors less than or equal to 1 cm, no lymph vascular invasion, and a low Ki-67 staining were identified as having a low risk of axillary lymph node metastases of 4.3%. However, 20 patients with all four unfavorable predictive factors had a 75% incidence of axillary lymph node involvement. Conclusion. Primary tumor characteristics can be used to identify a subgroup of patients with a low risk of axillary lymph node metastases in T1 breast cancer. Preoperative risk assessment might be used to omit routine ALND in those patients at low risk of axillary lymph node metastases.     

Risk of internal mammary lymph node metastases and its prognostic value in breast cancer patients

The risk of an internal mammary lymph node (IMN) metastasis and its prognostic value for patients with invasive breast cancer were assessed by evaluating 142 patients who had either a mastectomy with lymph node dissection or a biopsy of the IMN. By univariate analysis, overall survival significantly correlated with the patient's age, clinical axillary node status, tumor size, and DNA ploidy, as well as histologically confirmed axillary and IMN metastases. By multivariate analysis, however, only the presence of axillary and IMN metastases appeared to be an important independent factor affecting survival. However, the incidence of IMN metastases was associated significantly with age, clinical tumor and axillary node status, tumor size, axillary lymph node metastases, and DNA ploidy. Accordingly, the patient's age, tumor size, DNA ploidy, and axillary lymph node metastases proved to be effective variable for discrimination. Consequently, in predicting the presence of IMN metastases, a diagnostic accuracy of 82%, a sensitivity of 84%, and a specificity of 82% can be achieved by a discriminant function. We conclude that the discriminant function with these four variables is effective in assessing the risk of IMN metastases. © 1993 Wiley-Liss, Inc.     

超声对甲状腺乳头状癌颈部淋巴结转移规律及特点的评价

目的:探讨超声对甲状腺乳头状癌（papillary thyroid cancer,PTC）颈部淋巴结转移规律及特点的价值。方法:回顾性分析 91例（112侧）颈部阳性淋巴结（cN+）PTC患者的声像图特征,分为术前颈部淋巴结触诊阳性患者61侧和术前颈部触诊阴性而超声提示为颈淋巴转移患者51侧两组。记录术中转移淋巴结的数量及在Ⅱ、Ⅲ、Ⅳ、Ⅴ、Ⅵ 区的分布。结果:PTC颈部转移性淋巴结的超声特点以类圆形及淋巴门消失多见,内部呈低回声伴钙化、囊性变或呈高回声。91例患者中21例双侧颈转移占23.1％,112侧颈清扫标本中89侧（79.5％）为多分区转移;颈转移淋巴结在Ⅱ区57.1％（64/112）、Ⅲ区56.3％（63/112）、Ⅳ区61.6％（69/112）、Ⅵ区67.9％（76/112）。Ⅴ区仅占18.8％（21/112）,差异有统计学意义（P<0.001）。术前超声检查可以发现45.5％（51/112）的颈部触诊漏诊的颈部淋巴转移。结论:PTC的颈部淋巴转移可以多区分布,其中Ⅱ、Ⅲ、Ⅳ、Ⅵ区为主要的转移部位,Ⅵ区相对较高,颈部转移性淋巴结呈类圆形及淋巴门消失多见,内部呈低回声伴钙化、囊性变或呈高回声。超声在PTC颈淋巴转移的诊断中具有重要的价值。     

Parotid lymph node metastases from squamous cell carcinoma of the skin

Nineteen parotid lymph node metastases from squamous cell carcinoma of the skin were treated, seven with irradiation and 12 with surgery and postoperative irradiation. In the group treated with combined therapy, size of nodal metastasis and extent were strong predictors of relapse. Further postoperative irradiation with 60 Gy is not adequate to control extensive parotid nodal disease. Finally, elective treatment of clinically negative parotid nodes is not necessary in patients who can be closely followed, since early nodal disease can be controlled readily.     

Prediction of lymph node metastases in breast cancer by clinicopathological and biological features of the primary tumor

Background  Although histologically confirmed nodal status continues to be the most important and reliable prognostic factor, preoperative assessment of nodal status has been required in order to avoid unnecessary surgery. Methods  The present review was carried out to elucidate the relationship between nodal status and various histologic/biologic factors of the primary tumor, and to evaluate their nodal predictabilities. Results  The incidence of nodal metastases increases with increasing tumor size. Nodal metastases, however, are quite uncommon in Tla (tumor sized 5 mm or less) cancers and in ductal carcimona in situ (DCIS). The use of various promising biological markers for predicting nodal status, however, seems to be still far from clinical use. Conclusion  The probability of nodal metastases is quite low in patients with Tl a cancer or DCIS. Therefore, routine axillary dissection for these patients has no diagnostic or therapeutic value.     

前哨淋巴结活检联合术前超声在老年乳腺癌腋窝淋巴结清扫中的价值

目的:探讨前哨淋巴结活检（SLNB）联合术前超声在老年乳腺癌患者治疗中的临床价值。方法:回顾性分析136例老年乳腺癌患者资料,将其分为三组,A组:SLNB+超声组,B组:SLNB组,C组:超声组。分别统计各组检查结果与术前腋窝淋巴结穿刺病理或SLNB的符合情况,分析三组对腋窝淋巴结转移的评价。结果:结果显示A组较B组、A组较C组均准确率高,差异有统计学意义,而B组与C组差异无统计学意义。诊断试验结果显示:SLNB比术前超声的特异度高,误诊率低。灵敏度和漏诊率差距不大。结论:SLNB联合术前超声在老年乳腺癌患者治疗中准确性高,较单独SLNB或术前超声均具有优势,值得在老年乳腺癌腋窝淋巴结转移情况的评估和治疗中推广应用。     

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.