Node-positive Cases Research Articles

Immunohistochemical BAG1 expression improves the estimation of residual risk by IHC4 in postmenopausal patients treated with anastrazole or tamoxifen: a TransATAC study

BAG1 is a multifunctional anti-apoptotic protein located on chromosome 9q12, which binds to Bcl-2. BAG1 is present as a separate module in the GHI-RS 21-gene panel. It may provide additional prognostic information as an immunohistochemical marker when added to IHC4. Analysis of BAG1 was performed on archival tumour blocks from patients from the anastrozole and tamoxifen arms of the ATAC trial of 5years endocrine therapy in postmenopausal women with oestrogen receptor (ER)-positive primary breast cancer. Staining was scored separately as nuclear or cytoplasmic. Statistical analyses were performed on data from median 10-year follow-up with distant recurrence as primary endpoint. Data on both nuclear and cytoplasmic BAG1 as well as the IHC4 markers (ER, PgR, HER2 and Ki67) were available on 963 ER-positive cases of which 860 were HER2-negative. Cytoplasmic and nuclear BAG1 were highly correlated (Spearman r=0.79, p<00001). Women with higher BAG1 expression developed 30% fewer distant recurrences compared to those with low expression. Nuclear BAG1 contributed significantly to the clinical and IHC4 models with added information being greater in node-positive cases. Similar results were seen if all recurrences were the endpoints. BAG1 expression provides significant prognostic information when added to the classical clinicopathological parameters and IHC4, particularly in node-positive patients.

Expression of thyroid transcription factor-1 is associated with a basal-like phenotype in breast carcinomas

BackgroundThe differential diagnosis between primary and secondary breast cancers might be difficult, especially in poorly differentiated tumors. Thyroid Transcription Factor-1 (TTF-1) has been regarded as a reliable marker for lung or thyroid origin, with only occasional positive staining in other tumors. However, positive cases have recently been reported among primary breast carcinomas.Methods and resultsHere, we analyzed expression of TTF-1 protein (clone SPT24) by immunohistochemical staining of sections from paraffin embedded tumor samples in 247 primary breast cancers from the population-based Norwegian Breast Cancer Screening Program. Positive staining (weak or strong) was observed in 7 cases (2,8%). As novel observations, positivity was demonstrated more frequently in estrogen receptor negative cases (14,0% vs. 1,4%; p = 0,004), highly proliferative tumors (8,8% vs. 1,1%; p = 0,008), tumors with a basal-like phenotype by showing expression of CK5/6 and/or P-cadherin (11,1% vs. 1,4%; p = 0,01), and tumors with blood vessel invasion (9,7% vs. 1,9%; p = 0,04). Also, TTF-1 was associated with histological grade 3 tumors compared with grade 1 or 2 tumors (7,7% vs. 1,5%; p = 0,04) as well as lymph node positive cases (5,2% vs. 1,8%; p = 0,03).ConclusionsOur population-based findings indicate that TTF-1 may be positive in approximately 3% of primary breast cancers, and positivity indicates an association with adverse prognostic factors.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/8313753509421182

OP148: Salivary gland adenoid cystic carcinoma with cervical lymph node metastasis: A preliminary study of 62 cases

Adenoid cystic carcinoma is an infrequent malignant neoplasm that originates most commonly in the major and minor salivary glands. The purpose of this study is to provide new information on salivary glands adenoid cystic carcinoma with cervical lymph node metastasis. Based on 616 patients who underwent primary tumor resection from 1995 to 2008, 62 cases with cervical lymph node metastasis were chosen and analyzed accordingly. General incidence of cervical lymph node metastasis was approximately 10%.The base of tongue, mobile tongue and mouth floor were the most three frequent sites reporting lymph nodes metastasis, with incidences of 19.2%, 17.6% and 15.3% respectively. Majority of cases occurred via a classic “tunnel-style” metastasis and the level Ib and II regions were the most frequently involved regions. Primary site and lymphovascular invasion were found to be significantly associated with lymph nodes metastasis. High patient mortality was also significantly correlated with lymph node positive cases. Tongue-mouth floor complex have a high propensity for lymph node metastasis, which occurs through a classic “tunnel-style” metastasis. Peritumoral lymphovascular invasion could be taken as strong predictor for lymph node metastasis, which ultimately leads to poor prognosis of ACC patient. Selective neck dissection should be performed in such cases.

Abstract LB-341: Immunohistochemical features differentiating newly formed from pre-existing vasculatures .

Abstract Objectives of the study: A great number of in vitro and in vivo studies have suggested that a number of pathways and factors can stimulate angiogenesis and lymphangiogenesis, which facilitate tumor progression and metastasis. The morphological and immunohistochemical profile of newly formed vasculatures, however, has not been elucidated, making it difficult, if not impossible, to differentiate them from the pre-existing ones, and to identify their unique molecular profiles for therapeutic interventions. Methodology: Consecutive tissue sections from 100 age- and type-matched colorectal cancer (CRC) patients with and without positive lymph nodes were subjected to double or triple immunohistichemistry with a panel of stem cell and vasculature-related markers, including cytokeratin (CK) 19, CD133, D2-40, CD31, and CD34. Expression of these markers in morphologically distinct large and small vasculatures with and without disseminated tumor cells was compared. Results: Our study revealed that the endothelial cells of all morphologically distinct large and small vasculatures without disseminated tumor cells within their lumen only expressed either lymphatic duct or blood vessel phenotypic markers. Our study also revealed that a subset of lymph node-positive cases harbored some isolated normal epithelial structures with distinct CK-19 immunostaining within an otherwise CK-19-negative background. These epithelial structures were exclusively located within or adjacent to lymphoid follicles and were often surrounded by tube-like structures that express high levels of lymphatic endothelial marker D2-40. These tube-like structures were more frequently seen at the junctions between pre-invasive and invasive CRC with the following features: (1). they consist of a single layer of endothelial cells that express high levels of both lymphatic duct and blood vessel phenotypic markers, (2). their endothelial walls are often incomplete with disseminated cells physically connected with the adjacent stromal cells or tumor cells within the stroma, and (3). disseminated tumor cells within their lumen express high levels of CK-19. Conclusions: Based on these and other findings, we propose that these tube-like structures represent newly formed vasculatures, which are derived by the convergence of aberrant lymphocyte infiltration and tumor stem cells. Because of their close physical proximity, tumor stem cells within the epithelial and stromal components contribute equally and coordinately to the morphogenesis of new vasculatures that constitutes the basis for the unique morphologic and immunohistochemical features of newly formed vasculatures. Citation Format: Bin Jiang, Myron Arlen, Hongyan Yuan, yan-gao man. Immunohistochemical features differentiating newly formed from pre-existing vasculatures . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-341. doi:10.1158/1538-7445.AM2013-LB-341

Preoperative Imaging for Resectable Periampullary Cancer: Clinicopathologic Implications of Reported Radiographic Findings

BackgroundHigh-resolution, multiphase, computed tomography (CT) is a standard preoperative test prior to pancreatectomy, yet the clinical significance of routinely reported findings remains unknown. MethodsWe identified patients who underwent a pancreaticoduodenectomy for a periampullary adenocarcinoma (PA) over the previous 5 years and had a pancreas protocol CT at our institution. Clinicopathologic implications of reported CT findings were evaluated. ResultsThere were 155 pancreatic ductal adenocarcinomas (PDA) and 47 non-pancreatic PAs. No mass was visualized on CT in 6 % of PDAs and 23 % of non-pancreatic PA. A size discrepancy of ≥1 cm between radiographic and pathologic tumor diameters was observed in 40 % of PAs, with CT underestimating the size in most instances (75 %). Radiographically enlarged lymph nodes were not associated with true lymph node metastases in PDAs (70 % lymph node positive cases were enlarged on CT vs 74 % lymph node negative, p = 0.5), but were associated with a preoperatively placed biliary endoprosthesis (63 % with endoprosthesis were enlarged vs 37 % no endoprosthesis, p = 0.013). Major visceral vessel involvement on CT was not associated with a vascular resection (3 % with CT vessel involvement vs 2 % without, p = 0.8) or a positive uncinate resection margin (24 vs 20 %, respectively, p = 0.6). DiscussionWhile dedicated pancreas protocol CT provides unprecedented detail, the test may lead to overinterpretation of the extent of disease in some instances. A radiographic suggestion of enlarged lymph nodes and vascular involvement does not necessarily preclude exploration with curative intent. CTs with local disease should be reported in an objective template and carefully reviewed by a multidisciplinary group of surgeons, radiologists, and oncologists to avoid missing an opportunity for neoadjuvant therapy or cure by resection.

Level of arterial ligation in sigmoid colon and rectal cancer surgery.

358 Background: Curative resection of sigmoid colon and rectal cancer includes "high tie" of the inferior mesenteric artery (IMA). However, IMA ligation compromises blood flow to the anastomosis, which may increase the leakage rate and it is unclear whether this confers a survival advantage. Accodingly, IMA may be ligated at a point just below the origin of the left colic artery (LCA) ("low tie"), with lymph node (LN) dissection around IMA. No study has investigated the detailed prognostic results between "high tie" and "low tie, with LN dissection around IMA". The aim of this study was to assess the utility of "low tie, with LN dissection around IMA" on survival in patients with sigmoid colon or rectal cancer. Methods: A total of 268 sigmoid colon or rectal cancer patients who underwent curative operation from 1998 to 2007 were enrolled in this study. The patient's medical records were reviewed to obtain information about operative method, the number of LN dissection, the number of metastatic LN, the site of metastatic LN, recurrence pattern, complication. Overall survival and relapse-free survival were calculated using the Kaplan-Meier method, with differences assessed using logrank test. Results: We divided all patients into three groups according to the ligation level of IMA. 41 patients were ligated at the level of IMA root (Group A: "high tie"). 164 patients were ligated just caudally to the origin of the LCA ("low tie"), with LN dissection around IMA. 63 patients were ligated at the level of superior rectal artery just caudally to the sigmoid artery. The significant difference was not observed in a complication rate in three groups. The significant difference was not observed in the survival rate and the relapse-free survival rate according to each stage in group A and group B either. Also, the significant difference was not observed in the survival rate and the relapse-free survival rate in node-positive cases in group A and group B. Conclusions: "Low tie,with lymph node dissection aroud IMA" is anatomically less invasive and is not inferior to the ligation in the IMA root ("hige tie") in prognostic point.

40. How thoroughly should regional lymph nodes be sampled in colorectal cancer

<h3>Aim</h3> To determine if a single nodal slice is sufficient in determining nodal involvement in single node positive colorectal carcinoma. <h3>Background</h3> Nodal status is critical in predicting risk of recurrence and likely benefit from adjuvant chemotherapy in colorec-tal carcinoma. Adjuvant chemotherapy is associated with an approximate 10–15% improvement in overall survival compared with surgery alone. Chemotherapy is also considered when adverse pathological features, such as tumour perforation, peritoneal involvement, venous invasion and involved surgical margins (Peterson criteria) are present as these also confer a poorer prognosis.¹ <h3>Methods</h3> During a 12 year period (2000–2012) we retrieved and reviewed all colorectal cancer resection specimens, received at the Department of Pathology, Royal Darwin Hospital, Darwin, NT. A total 137 cases were reviewed, of which 57 (41%) were node positive. We focussed on patients with only one positive lymph node and reviewed the H&E slides of these cases to identify the proportion of nodal involvement in single node positive colorectal carcinoma. <h3>Results</h3> From 2000–2012 there were 137 colorectal carcinoma specimens of which 80 were node negative and 57 (41%) were node positive. Of the node positive cases 12 out of 57 (21%) cases had single lymph node involvement. The average lymph node size in the single node positive cases was 5.87mm and the average size of the metastatic deposit in these cases was 4.52mm. The proportion of nodal involvement was 77%. <h3>Conclusion</h3> In our study 12/137 (8.8%) cases were single node positive. The average metastatic deposit occupied 77% of the involved node. This finding suggests that metastatic carcinoma can be easily identified if a single nodal slice is selected for microscopic assessment.

The clinical impact of the American College of Surgeons Oncology Group Z-0011 trial – Results from the BreastSurgANZ National Breast Cancer Audit

IntroductionThe publication of the American College of Surgeons Oncology Group (ACOSOG) Z-0011 Trial concluded that axillary lymph node clearance is no longer necessary for women having breast conserving treatment with 1–2 positive axillary sentinel lymph glands. The current study was designed to investigate the clinical impact of the Z-0011 Trial in breast surgical practice. Materials and methodsThe BreastSurgANZ National Breast Cancer Audit database was interrogated for women treated between 2005 and 2010 who would have met the entry criteria for the Z-0011 Trial. This group was then calculated as a proportion of the total breast cancer episodes treated during this period. ResultsA total of 64,883 cases of breast cancer were eligible for analysis. 22,731 underwent breast conserving surgery and sentinel node biopsy for invasive breast cancer. A total of 4482 cases (6.9%) fulfilled the criteria for Z-11 Trial. ConclusionAlthough the ACOSOG Z-0011 Trial has important implications for sentinel node positive cases undergoing breast conserving treatment, the overall impact of the Trial in breast clinical practice is small. It cannot be described as “practice changing”. Women who fulfil the entry criteria for the Z-0011 Trial should be informed of the clinical relevance of the trial and be permitted to participate in informed discussions with members of the multidisciplinary team regarding their treatment options.

Cell Budding from Normal Appearing Epithelia: A Predictor of Colorectal Cancer Metastasis?

Background: Colorectal carcinogenesis is believed to be a multi-stage process that originates with a localized adenoma, which linearly progresses to an intra-mucosal carcinoma, to an invasive lesion, and finally to metastatic cancer. This progression model is supported by tissue culture and animal model studies, but it is difficult to reconcile with several well-established observations, principally among these are that up to 25% of early stage (Stage I/II), node-negative colorectal cancer (CRC) develop distant metastasis, and that circulating CRC cells are undetectable in peripheral blood samples of up to 50% of patients with confirmed metastasis, but more than 30% of patients with no detectable metastasis exhibit such cells. The mechanism responsible for this diverse behavior is unknown, and there are no effective means to identify patients with pending, or who are at high risk for, developing metastatic CRC.Novel findings: Our previous studies of human breast and prostate cancer have shown that cancer invasion arises from the convergence of a tissue injury, the innate immune response to that injury, and the presence of tumor stem cells within tumor capsules at the site of the injury. Focal degeneration of a capsule due to age or disease attracts lymphocyte infiltration that degrades the degenerating capsules resulting in the formation of a focal disruption in the capsule, which selectively favors proliferating or “budding” of the underlying tumor stem cells. Our recent studies suggest that lymphocyte infiltration also triggers metastasis by disrupting the intercellular junctions and surface adhesion molecules within the proliferating cell buds causing their dissociation. Then, lymphocytes and tumor cells are conjoined through membrane fusion to form tumor-lymphocyte chimeras (TLCs) that allows the tumor stem cell to avail itself of the lymphocyte's natural ability to migrate and breach cell barriers in order to intravasate and to travel to distant organs. Our most recent studies of human CRC have detected nearly identical focal capsule disruptions, lymphocyte infiltration, budding cells, and the formation of TLCs. Our studies have further shown that age- and type-matched node-positive and -negative CRC have a significantly different morphological and immunohistochemical profile and that the majority of lymphatic ducts with disseminated cells are located within the mucosa adjacent to morphologically normal appearing epithelial structures that express a stem cell-related marker.New hypothesis: Based on these findings and the growth patterns of budding cells revealed by double immunohistochemistry, we further hypothesize that metastatic spread is an early event of carcinogenesis and that budding cells overlying focal capsule disruptions represent invasion- and metastasis-initiating cells that follow one of four pathways to progress: (1) to undergo extensive in situ proliferation leading to the formation of tumor nests that subsequently invade the submucosa, (2) to migrate with associated lymphocytes functioning as “seeds” to grow in new sites, (3) to migrate and intravasate into pre-existing vascular structures by forming TLCs, or (4) to intravasate into vascular structures that are generated by the budding cells themselves. We also propose that only node-positive cases harbor stem cells with the potential for multi-lineage differentiation and unique surface markers that permit intravasation.

Abstract P1-14-04: Long- term outcome after neoadjuvant radiochemotherapy in locally advanced non-inflammatory breast cancer and predictive factors for a pathologic complete remission; results of a multi-variate analysis

Abstract Background: An earlier published series of neoadjuvant radio-chemotherapy (NRT-CHX) in locally advanced non-inflammatory breast cancer (LABC) has now been updated with a follow up of more than 15 years. Long- term outcome data and predictive factors for pathologic complete response (PCR) were analyzed. Patients and Methods: 315 LABC patients (cT1-cT4/cN0-N1) were treated during 1991–1998 with NRT-CHX. Preoperative radiotherapy (RT) consisted of external beam radiation therapy (EBRT) of 50 Gy (5 × 2 Gy/week) to the breast and the supra-/infraclavicular lymph nodes combined with an electron boost in 214 cases afterwards or – in case of breast conservation – an 10-Gy interstitial boost with 192Ir afterloading before EBRT. Chemotherapy was administered prior to RT in 192 patients, and concomitantly in 113; 10 patients received no chemotherapy. The update of all follow up ended in November 2011. Age, tumor grade, nodal status, hormone receptor status, simultaneous vs. sequential CHX and the time interval between end of RT and surgery were examined in multivariate terms with as endpoint pCR and overall survival. Results: The total PCR rate after neoadjuvant RT-CHX reached 29.2 % with LABC breast conservation becoming possible in 50.8%. In initially node-positive cases (cN+), a complete nodal response (pN0) after NRT-CHX was observed in 56% (89/159). The multivariate analysis revealed that a longer time interval to surgery increased the probability for a pCR (HR 1,17 [95% CI 1,05-1,31], p &amp;lt; 0,01). However, in large tumors (T3-T4) a significantly reduced pCR rate (HR 0.89 [95% CI 0.80 to 0.99], p = 0.03) could be obtained. Importantly, a pCR was the strongest prognostic factor for long term survival (HR 0.28 [95% CI 0.19–0.56], p &amp;lt; 0.001). Conclusions: A PCR identifies patients with a significant better prognosis for long-term survival. However, a long time interval to surgery (&amp;gt; 2 months) increases the probability of a pCR after NRT-CHX. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-14-04.

Histologic Criteria and Pitfalls in the Diagnosis of Lymphovascular Invasion in Radical Prostatectomy Specimens

Lymphovascular invasion is a known independent prognostic factor in prostate cancer. The objective of this study is to describe reliable morphologic features for identification of lymphovascular invasion in prostatectomy specimens and avoid misinterpretation of its mimickers. A total of 364 foci of lymphovascular invasion were analyzed in 264 slides from 170 prostatectomies. The average tumor volume was 25.5%. Tumor emboli were seen inside the tumor (8%), at the front edge of the tumor (30%), separated from the tumor (32%), and distant from the tumor (30%). Tumor emboli were more frequent per case and more often in an extraprostatic location in lymph node-positive cases (P<0.05). One hundred thirty-four emboli were in a single thin-walled vessel, 227 were in a thin-walled vessel next to an artery, and 3 were seen inside an artery. Twenty-eight tumor emboli were attached to a vessel wall, 18 had proteinaceous material in the vascular lumen, and 14 were surrounded by erythrocytes. The following mimickers were seen: retraction artifact and perineural invasion-all cases; cancer impinging upon vascular space-45 foci; tangential sections of endothelium-10 foci; displacement of benign and collapsed malignant glands-16 and 27 foci, respectively; retraction with erythrocytes-3 cases; intravascular degenerating tumor cells-3 foci; malignant glands in atrophic ducts-4 foci; and myofibroblastic proliferation in thrombosed vessels-2 foci. In 50 stained blocks, CD31 and D2-40 immunostaining studies confirmed all lymphovascular invasions diagnosed by hematoxylin and eosin staining and demonstrated emboli in 47 lymphatic and 16 blood vessels. In summary, the current study identifies features of true lymphovascular invasion and how to distinguish them from mimickers on routine hematoxylin and eosin sections.

Detection of promoter methylation of tumor suppressor genes in serum DNA of breast cancer cases and benign breast disease controls

Tumors are capable of shedding DNA into the blood stream. This shed DNA may be recovered from serum or plasma. The objective of this study was to evaluate whether pyrosequencing promoter DNA in a panel of 12 breast cancer-related genes (APC, BRCA1, CCND2, CDH1, ESR1, GSTP1, HIN1, P16, RARβ, RASSF1, SFRP1 and TWIST) to measure the degree of methylation would lead to a useful serum-based marker of breast cancer. Serum was obtained from women who were about to undergo a breast biopsy or mastectomy at three hospitals from 1977 to 1987 in Grand Rapids, MI USA. We compared the methylation status of 12 genes in serum DNA obtained from three groups of postmenopausal women (mean age at blood collection: 63.0 y; SD 9.9; range 35–91): breast cancer cases with lymph node-positive disease (n = 241); breast cancer cases with lymph node-negative disease (n = 63); and benign breast disease control subjects (n = 234). Overall, median levels of promoter methylation were low, typically below 5%, for all genes in all study groups. For all genes, median levels of methylation were higher (by 3.3 to 47.6%) in lymph node-positive breast cancer cases than in the controls. Comparing mean methylation level between lymph-node positive cases and controls, the most statistically significant findings, after adjustment of the false-positive rate (q-value), were for TWIST (p = 0.04), SFRP1 (p = 0.16), ESR1 (p = 0.17), P16 (p = 0.19) and APC (p = 0.19). For two of these four genes (TWIST, P16), the median methylation level was also highest in lymph-node positive cases, intermediate in lymph node-negative cases and lowest in the controls. The percent of study subjects with mean methylation scores ≥ 5% was higher among lymph node-positive cases than controls for ten genes, and significantly higher for HIN1 and TWIST (22.0 vs. 12.2%, p = 0.04 and 37.9 vs. 24.5%, p = 0.004, respectively). Despite relatively consistent variation in methylation patterns among groups, these modest differences did not provide sufficient ability to distinguish between cases and controls in a clinical setting.

Preoperative systemic therapy in locoregional management of early breast cancer: highlights from the Kyoto Breast Cancer Consensus Conference

Data reviewed at the Kyoto Breast Cancer Consensus Conference (KBCCC) showed that preoperative systemic therapy (PST) could optimize surgery through the utilization of information relating to pre- and post-PST tumor stage, therapeutic sensitivity, and treatment-induced changes in the biological characteristics of the tumor. As such, it was noted that the biological characteristics of the tumor, such as hormone receptors, human epidermal growth factor receptor-2, histological grade, cell proliferative activity, mainly defined by the Ki67 labeling index, and the tumor's multi-gene signature, should be considered in the planning of both systemic and local therapy. Furthermore, the timing of axillary sentinel lymph node diagnosis (i.e., before or after the PST) was also noted to be critical in that it may influence the likelihood of axillary preservation, even in node positive cases. In addition, axillary diagnosis with ultrasound and concomitant fine needle aspiration cytology or core needle biopsy (CNB) was reported to contribute to the construction of a treatment algorithm for patient-specific or individualized axillary surgery. Following PST, planning for breast surgery should therefore be based on tumor subtype, tumor volume and extent, therapeutic response to PST, and patient preference. Nomograms for predicting nodal status and drug sensitivity were also recognized as a tool to support decision-making in the selection of surgical treatment. Overall, review of data at the KBCCC showed that PST increases the likelihood of patients receiving localized surgery and individualized treatment regimens.

Expression of cyclin E in stage III colorectal carcinoma

Carcinogenesis is characterized by an abnormal regulation of the cell cycle. Regulators of the cell cycle such as cyclin E play an important role in neoplasia and may be correlated with prognosis. The clinical significance of the expression of cyclin E in stage III colorectal carcinoma has not yet been investigated. The expression of cyclin E was evaluated in 49 patients. Using a multivariate analysis, the expression of cyclin E in the tumor at diagnosis was compared with various clinicopathological variables, including age, gender, tumor site, tumor size, tumor differentiation and lymph node involvement. There were more node-positive cases in the cyclin E-negative group than in the cyclin E-positive group (P=0.003). However, there was no correlation between the degree of cyclin E expression and the clinical data. In conclusion, our data suggest that overexpression of cyclin E does not predict the clinical outcome in colorectal cancer stage III. Negative cyclin E staining may be associated with lymph node involvement.

Long-term outcome after neoadjuvant radiochemotherapy in locally advanced noninflammatory breast cancer and predictive factors for a pathologic complete remission: Results of a multivariate analysis.

154 Background: An earlier published series of neoadjuvant radio-chemotherapy (NRT-CHX) in locally advanced noninflammatory breast cancer (LABC) has now been updated with a follow-up of more than 15 years. Long-term outcome data and predictive factors for pathologic complete response (PCR) were analyzed. Methods: 315 LABC patients (cT1-cT4 /cN0-N1) were treated during 1991-1998 with NRT-CHX. Preoperative radiotherapy (RT) consisted of external beam radiation therapy (EBRT) of 50 Gy (5 × 2 Gy/week) to the breast and the supra-/infraclavicular lymph nodes combined with an electron boost in 214 cases afterwards or—in case of breast conservation—a 10-Gy interstitial boost with 192Ir afterloading before EBRT. Chemotherapy was administered prior to RT in 192 patients, and concomitantly in 113; 10 patients received no chemotherapy. The update of all follow up ended in November 2011. Age, tumor grade, nodal status, hormone receptor status, simultaneous vs. sequential CHX and the time interval between end of RT and surgery were examined in multivariate terms with as endpoint pCR and overall survival. Results: The total PCR rate after neoadjuvant RT-CHX reached 29.2 % with LABC breast conservation becoming possible in 50.8%. In initially node-positive cases (cN+), a complete nodal response (pN0) after NRT-CHX was observed in 56% (89/159). The multivariate analysis revealed that a longer time interval to surgery increased the probability for a pCR (HR 1,17 [95% CI 1,05-1,31], p&lt;0,01). However, in large tumors (T3-T4) a significantly reduced pCR rate (HR 0.89 [95% CI 0.80 to 0.99], p = 0.03) could be obtained. Importantly, a pCR was the strongest prognostic factor for long-term survival (HR 0.28 [95% CI 0.19-0.56], p&lt;0.001). Conclusions: A PCR identifies patients with a significant better prognosis for long-term survival. However, a long time interval to surgery (&gt; 2 months) increases the probability of a pCR after NRT-CHX.

Will neoadjuvant chemotherapy affect the lymphatic routes to the sentinel lymph node? Investigation using indocyanine green fluorescence method.

164 Background: Neoadjuvant chemotherapy (NAC) is a standard therapy for breast cancer. However, the changes in the lymphatic route to the sentinel lymph node (SLN) before and after NAC are unclear. Indocyanine green (ICG) fluorescence method of SLN biopsy (ICG-SLNB) is useful because of its high identification rate of the SLN and ability to visualize lymphatic routes. Using ICG-SLNB, we compared the lymphatic routes to the SLN (sentinel lymphatic routes) before and after NAC and investigated whether chemotherapy affects the sentinel lymphatic routes. Methods: From October 2010 to April 2012 20 patients received NAC. In 13 cases of clinical node-negative cancer, we performed SLNB before NAC. We recorded the sentinel lymphatic routes before NAC and confirmed the routes at surgery after NAC by using the same method. In 7 cases of clinical node-positive cancer, we recorded the localization of SLN and lymphatic routes by using the ICG fluorescence method before NAC. After NAC, we performed SLNB with axillary dissection and recorded the sentinel lymphatic routes by photography and drawing. Results: Regardless of the presence or absence of lymph node metastasis, the SLN and sentinel lymphatic routes could be detected before and after NAC in all cases. All sentinel lymphatic routes reached the same location of the SLN before and after NAC. In 3 cases, the number of sentinel lymphatic routes had increased after NAC, but the location of the SLN was the same before and after NAC. Other cases showed no changes in the sentinel lymphatic routes. In clinical node-positive cases of pathological complete response, there was no metastasis to the SLN, but there were 2 metastases in the lymph nodes after back-up dissection. Conclusions: ICG fluorescence method provided visual confirmation that the sentinel lymphatic routes were not affected by NAC. This result suggests that SLNB after NAC can be used to safely and positively identify the SLN in clinical node-negative patients. Further investigation would be required to safely perform SLNB after NAC in clinical node-positive patients.

Long-term outcome after neoadjuvant radiochemotherapy in locally advanced noninflammatory breast cancer and predictive factors for a pathologic complete remission

An earlier published series of neoadjuvant radiochemotherapy (NRT-CHX) in locally advanced noninflammatory breast cancer (LABC) has now been updated with a follow-up of more than 15 years. Long-term outcome data and predictive factors for pathologic complete response (pCR) were analyzed. During 1991-1998, 315 LABC patients (cT1-cT4/cN0-N1) were treated with NRT-CHX. Preoperative radiotherapy (RT) consisted of external beam radiation therapy (EBRT) of 50 Gy (5 × 2 Gy/week) to the breast and the supra-/infraclavicular lymph nodes combined with an electron boost in 214 cases afterwards or-in case of breast conservation-a 10-Gy interstitial boost with (192)Ir afterloading before EBRT. Chemotherapy was administered prior to RT in 192 patients, and concomitantly in 113; 10 patients received no chemotherapy. The update of all follow-up ended in November 2011. Age, tumor grade, nodal status, hormone receptor status, simultaneous vs. sequential CHX, and the time interval between end of RT and surgery were examined in multivariate terms with pCR and overall survival as end point. The total pCR rate after neoadjuvant RT-CHX reached 29.2%, with LABC breast conservation becoming possible in 50.8% of cases. In initially node-positive cases (cN+), a complete nodal response (pN0) after NRT-CHX was observed in 56% (89/159). The multivariate analysis revealed that a longer time interval to surgery increased the probability for a pCR (HR 1.17 [95% CI 1.05-1.31], p < 0.01). However, in large tumors (T3-T4) a significantly reduced pCR rate (HR 0.89 [95% CI 0.80-0.99], p = 0.03) was obtained. Importantly, pCR was the strongest prognostic factor for long-term survival (HR 0.28 [95% CI 0.19-0.56], p < 0.001). pCR identifies patients with a significantly better prognosis for long-term survival. However, a long time interval to surgery (> 2 months) increases the probability of pCR after NRT-CHX.

Laparoscopy-Assisted Versus Open Distal Gastrectomy for Early Gastric Cancer

To evaluate the safety and efficacy of laparoscopy-assisted distal gastrectomy (LADG) in patients with early gastric cancer (EGC) to determine whether LADG is an acceptable alternative to open distal gastrectomy (ODG). LADG combined with less than D2 or D2 lymphadenectomy for EGC is still a controversial surgical intervention for its uncertain oncological safety and economic benefit. We conducted this systematic review and meta-analysis that included randomized control trials (RCTs) and non-RCTs of LADG versus ODG to evaluate whether the safety and efficacy of LADG in patients with EGC are equivalent to those of ODG. A comprehensive search of PubMed, EMBASE, Cochrane Library, and China Knowledge Resource Integrated Database was performed. Eligible trials published between January 1, 1994, and December 31, 2010, were included in the study. Data synthesis and statistical analysis were carried out by RevMan 5.0 software. The quality of evidence was assessed by GRADEpro 3.2.2. Twenty-two studies with 3411 participants were included in this study. The mean number of lymph nodes retrieved in LADG was close to that retrieved in ODG (in the less than D2 resection: weighted mean difference [WMD] = -1.79; 95% confidence interval [95% CI], -5.78 to 2.19; P = 0.38; heterogeneity: P < 0.00001, I = 98%; and in the D2 resection: WMD = -1.53; 95% CI, -3.56 to 0.51; P = 0.14; heterogeneity: P = 0.23, I = 26%). The overall postoperative morbidity was significantly less in LADG than in ODG (relative risk = 0.58; 95% CI, 0.46-0.74; P < 0.00001; heterogeneity: P = 0.94, I = 0%). LADG reduced the intraoperative blood loss, postoperative analgesic consumption, and hospital duration, without increasing the total hospitalization costs and cancer recurrence rate. The long-term survival rate of patients undergoing LADG was similar to that of patients undergoing ODG. However, LADG was still a technically dependent and time-consuming procedure. Conversion rate of LADG was 0% to 2.94%. The reported reasons for conversion were bleeding, adhesion, and safety resection margin requirement. : There were potential biases and significant heterogeneity in some clinical outcome measures in this study. Methodologically high-quality controlled clinical trials were sparse for this new surgical intervention. According to The Grading of Recommendations Assessment, Development and Evaluation approach, when assessing the safety and efficacy of LADG by comparing with those of ODG with the defined clinical outcomes in patients with EGC, the quality of the currently available clinical evidence was very low. LADG may be a technically feasible alternative for EGC when it is performed in experienced surgical centers in which patients undergoing LADG may benefit from the faster postoperative recovery. However, the currently available evidence cannot exclude the potential clinical benefits or harms, especially in the node-positive cases. Methodologically high-quality comparative studies are needed for further evaluation.

Impact of the new FIGO 2009 staging classification for vulvar cancer on prognosis and stage distribution

ObjectiveIn 2009, FIGO modified staging of vulvar cancer — the performance of the new classification relative to the prior system has not been assessed. We sought to investigate the impact of the 2009 FIGO vulvar cancer staging system on stage distribution and prognostic ability of the 2009 sub-stage classifications in a large cohort of uniformly staged cases with long-term followup. MethodsPatients undergoing surgery for vulvar cancer were identified from 2 institutions (Mayo Clinic and Medical University, Gdansk, Poland) using a similar surgical approach. Inclusion criteria required primary surgery for invasive vulvar cancer for cases with >1mm invasion with complete inguinal/femoral lymphadenectomy. The technique of inguinofemoral node dissection used in both institutions was designed to remove both superficial and deep inguinofemoral nodes. A retrospective review was performed and all cases were assigned stage using the 1988 and 2009 FIGO systems after reviewing pathology slides. Cause-specific survival (CSS, death due to cancer) was estimated using the Kaplan–Meier method and compared using the Cox proportional hazards model t for the first 10years after surgery. ResultA total of 468 patients met inclusion criteria. Thirty-one percent (n=155) were down-staged, and 1 case up-staged using 2009 staging. The new system fails to effectively separate 10-yr CSS for stage I and II cases (p=0.52), while FIGO 1988 failed to separate stages II and III (p=0.41). We observed a difference in survival for stage I and II cases based on tumor diameter. For smaller stage II lesion (≤4cm vs. >4cm) we observed no difference in survival compared to all stage IB cases (p=0.25) Considering node positive disease, patients with 2009 FIGO stages ΙΙΙA, ΙΙΙB, and ΙΙΙC were not significantly different in terms of CSS (p=0.17). However, CSS approached significance between patients with extracapsular vs. intracapsular disease (p=0.072). For stages IIIA and IIIB (excluding extracapsular spread, IIIC), we observed that the number of positive nodes and diameter of lymph node metastasis were not significantly associated with CSS. When comparing bilateral nodal involvement vs. unilateral cases with at least 2 involved nodes, we found no statistical difference in CSS (p=0.30). ConclusionThis is the largest cohort study to evaluate the effect and prognostic performance of the new FIGO vulvar cancer staging system. The new staging does not stratify survival between stages I and II and reduces CSS in stage I cases. Our results suggest that lesion size in node negative cases is an important prognostic variable that could be addressed in future staging classifications. Among the node positive cases, the current classification results in slight differences in CSS, primarily between intra- and extra-capsular disease and not according to the number of positive nodes and lymph node metastasis diameter. Finally we observe that bilateral nodal disease does not appear to impact CSS, justifying it being omitted from the 2009 staging system and that separating node positive (2009 stage III) from node negative (2009 stage II) cases is justified.

Salivary gland adenoid cystic carcinoma with cervical lymph node metastasis: a preliminary study of 62 cases

Adenoid cystic carcinoma (ACC) is an infrequent malignant neoplasm that originates most commonly in the major and minor salivary glands of the head and neck region. This study provides new information on head and neck ACC with cervical lymph node metastasis. Of 616 patients who underwent primary tumour resection from 1995 to 2008 in the authors’ hospital, 62 cases with cervical lymph node metastasis were analyzed. The general incidence of cervical lymph node metastasis in ACC was approximately 10%. The base of tongue, mobile tongue and mouth floor were the most frequent sites of lymph nodes metastasis, with incidences of 19.2%, 17.6% and 15.3%, respectively. Most cases occurred via a classic ‘tunnel-style’ metastasis and the level Ib and II regions were the most frequently involved. Primary site and lymphovascular invasion were significantly associated with lymph node metastasis. High patient mortality was significantly correlated with lymph node positive cases. The tongue–mouth floor complex has a high propensity for cervical lymph node metastasis, which occurs through a classic ‘tunnel-style’ metastasis. Peritumoral lymphovascular invasion could be taken as strong predictor for lymph node metastasis, which ultimately leads to poor prognosis of ACC patient. Selective neck dissection should be considered in such cases.