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Long interspersed element 1 (LINE-1), a non-coding genomic repeat sequence, methylation status can influence tumor progression. In this study, the clinical significance of LINE-1 methylation status was assessed in primary breast cancer in young versus old breast cancer patients. LINE-1 methylation index (MI) was assessed by absolute quantitative assessment of methylated alleles (AQAMA) PCR assay. Initially, LINE-1 MI was assessed in a preliminary study of 235 tissues representing different stages of ductal breast cancer development. Next, an independent cohort of 379 primary ductal breast cancer patients (median follow-up 18.9 years) was studied. LINE-1 hypomethylation was shown to occur in DCIS and invasive breast cancer. In primary breast cancer it was associated with pathological tumor stage ( p  = 0.026), lymph node metastasis ( p  = 0.022), and higher age at diagnosis (>55, p  < 0.001). In multivariate analysis, LINE-1 hypomethylation was associated with decreased OS (HR 2.19, 95 % CI 1.17–4.09, log-rank p  = 0.014), DFS (HR 2.05, 95 % CI 1.14–3.67, log-rank p  = 0.016) and increased DR (HR 2.83, 95 % CI 1.53–5.21, log-rank p  = 0.001) in younger (≤55 years), but not older patients (>55 years). LINE-1 analysis of primary breast cancer demonstrated cancer-related age-dependent hypomethylation. In patients ≤55 years, LINE-1 hypomethylation portends a high-risk of DR.

Comprehensive pathologic evaluation of the sentinel lymph node using step sections and cytokeratin immunohistochemistry enhances detection of micrometastases and optimizes the staging of breast carcinoma. This review discusses our current understanding of the pathologic and molecular techniques for sentinel node examination.

Background The purpose of this study was to report our experience with sentinel lymph node dissection (SLND) for papillary thyroid carcinoma, to evaluate the feasibility and safety of the procedure, and to examine its potential utility as a guide for central neck dissection. Materials and Methods A retrospective chart review of patients undergoing total thyroidectomy from January 1998 thru January 2010 was conducted. Intratumoral injection of blue dye was used to identify the SLN. Central neck dissection (CND) was performed if the SLN was positive on frozen section. Locally advanced disease, previous thyroid surgery, or lymphadenopathy on preoperative imaging or intraoperative palpation were exclusion criteria. Results A total of 211 patients underwent SLN mapping. Of these, 165 patients (78%) were female and 46 (22%) were male. Also, 75 (36%) were ≤45 years of age, and 136 (64%) were older than 45. Tumors were ≤2.0 cm (T1) in 142 patients (67%), 2–4 cm (T2) in 35 patients (17%), >4 cm with minimal invasion (T3) in 32 patients (15%), and locally invasive (T4) in 2 patients (1%). At least 1 blue node was found in 192 patients (91%). Also, 47 patients had a positive SLN on frozen section, with an additional 24 node-positive patients on permanent section, for a total of 71 (37%). There were 43 patients (91%) who underwent central neck dissection; 26 (60%) had additional metastases. Conclusions Sentinel lymphadenectomy for papillary thyroid carcinoma is feasible, safe, and can identify patients who may benefit from central neck dissection.

A positive sentinel lymph node (SLN) has been reported in 6% to 13% of patients with ductal carcinoma in situ (DCIS). Although it is well established that nodal status for invasive disease is prognostically important, the clinical relevance of a positive SLN in patients with DCIS remains undetermined. SLN biopsy was performed on 470 high-risk patients with DCIS (22% of all patients with DCIS) at 3 institutions. Of these, 43 (9%) had SLN metastases. Pathology findings of positive cases were reviewed, and follow-up was obtained. At 2 of the 3 institutions, data were also collected on DCIS patients who had negative findings on SLN biopsy. For these 414 patients, univariate analyses of tumor characteristics were performed to identify factors associated with node positivity. Extensive disease requiring mastectomy (p = 0.02) and the presence of necrosis (p = 0.04) were associated with an increased risk of nodal positivity. Three (7%) of the 43 SLN-positive patients had macrometastases (pN1), 4 (9%) had micrometastases (pN1mi), and 36 (84%) had single tumor cells or small clusters (pN0(i+)). Of the 25 women that underwent completion axillary dissection, one was found to have a macrometastasis. On pathological review of the primary lesion, 2 (5%) of 43 patints were found to have microinvasion, and 2 (5%) lymphovascular invasion. Nine of 43 (21%) high-risk DCIS patients with a positive SLN and 9/470 (2%) of all high-risk DCIS patients were upstaged to AJCC stage I or II as a result of the SLN biopsy. At a median (range) follow-up of 27 (3-88) months, 1 patient had developed hepatic metastases. This patient had immunohistochemistry detected isolated tumor cells in her SLN (N0(i+)), and upon pathologic review, was found to have high-grade DCIS with microinvasion. SLN biopsy for high-risk DCIS patients is a mean of detecting those who may have unrecognized invasive disease and therefore are at risk for distant disease.

Controversy exists regarding axillary dissection (ALND) for sentinel node (SLN) metastases detected as isolated tumor cells (ITC). We hypothesized that the number of positive non-SLNs is low and ALND is unnecessary for most patients with ITC. From 1995 to 1999, 634 breast cancer patients underwent SLND. SLNs were examined using immunohistochemistry if hematoxylin and eosin was negative. ALND was recommended for ITC-positive SLNs. Seventy-eight patients (12.3%) with ITC-positive SLNs were offered ALND. Sixty-one consented, whereas 17 refused. Fifty-eight (95.1%) had negative non-SLNs. Three (4.9%) had non-SLN metastases. One patient (1.6%) had macrometastatic disease, whereas 2 (3.3%) had micrometastases. No ITC-only–positive SLN patient experienced axillary recurrence. When ALND was performed for ITC, 1.6% of non-SLNs harbored macrometastases and 3.3% had micrometastases. When ALND was not performed, axillary recurrence was not seen. The low risk of non-SLN disease in this study fails to support the routine use of ALND for ITC-positive SLNs.

Sentinel lymphadenectomy is highly accurate for identifying axillary metastasis from a primary breast carcinoma. Nonsentinel axillary lymph nodes (NSNs) are unlikely to contain tumor cells if the axillary sentinel node (SN) is tumor free. We previously showed that the size of the primary tumor and the size of its SN metastasis predict the risk of NSN tumor involvement detected by hematoxylin and eosin staining. This study used immunohistochemical staining (IHC) to determine the likelihood of NSN axillary metastasis in the presence of SN metastasis. Between 1991 and 1997, axillary lymphadenectomy was performed in 156 women (157 axillary basins) who had primary breast carcinoma with SN metastasis. By hematoxylin and eosin staining, we identified NSN metastasis in 55 axillae (35%). IHC was then used to re-examine all NSNs (1827 lymph nodes) from the remaining 102 axillae. The incidence of IHC-detected NSN involvement was analyzed with respect to clinical and tumor characteristics. By using IHC, we identified NSN metastasis in 15 (14.7%) of the 102 axillae. By multivariate analysis, the size of the SN metastasis (P = .0001) and the size of the primary tumor (P = .038) were the only independent variables predicting NSN metastasis determined by using either hematoxylin and eosin staining or IHC. Only the number of SN metastases (1 vs. >1) was a significant (P = .04) predictor of IHC-detected NSN metastasis. Use of IHC increases the likelihood of detection of NSN metastasis, and the risk of IHC-detected metastasis increases with the size of the SN metastasis and the size of the primary tumor. If SN involvement is micrometastatic (< or =2 mm) or detected by using IHC, tumor cells are unlikely to be found in other axillary lymph nodes in patients with a small primary tumor. The clinical significance of micrometastatic disease in lymph nodes is controversial, and a prospective randomized study is necessary to resolve this important issue.