Synchronous Metastatic Lymph Nodes Research Articles

Expression of Biomarkers Estrogen Receptor, Progesterone Receptor, HER2 in Primary Breast Tumour and Synchronous Metastatic Axillary Lymph Node

Introduction: Estrogen Receptor (ER), Progesterone Receptor (PR), Human Epidermal growth factor Receptor 2 (HER2) status are routinely used to guide treatment decision for breast cancer. Treatment protocol in breast cancer is currently based on biomarker characteristic of primary tumour. But this biomarker status may change as the tumour progresses from primary to synchronous metastatic lymph node. Hence, it is important to know the biomarker status of these synchronous metastatic lymph nodes as it may serve as an important tool to guide management, evaluate prognosis and to anticipate the possibility of recurrent risk of primary invasive breast cancer. Aim: To study the expression of ER, PR, HER2 status in primary breast carcinoma and synchronous metastatic lymph node and to evaluate concordance and discordance between them. Materials and Methods: This study was observational, retrospective and prospective study conducted over a period of one and half years from February 2015 to October 2016 at ESI-PGIMSR, Maniktala, Kolkata, India, where 50 cases of breast carcinoma with positive axillary lymph node metastasis were studied. Haematoxylin and Eosin (H&E) sections were reviewed and representative paraffin blocks were selected. Immunostains were performed and scoring was done following standard protocols. Standard statistical methods were applied for analysis of data using chi-square test and kappa statistics and data was analysed using Statistical Package for the Social Sciences (SPSS) version 6.1.3 software. Results: Out of 50 cases the mean age of the patients was 50.56±10.5 years. Amongst ER and PR status, 24 out of 50 (48%) and 18 out of 50 (36%) were ER and PR positive respectively. HER2 positive cases were 48% i.e., 24 out of 50 cases. The overall discordance rates of ER, PR and HER2 was found to be 10%, 8%, 18%, respectively. The discordance rates of ER positive and ER negative cases were 4.2% and 15.4%, respectively. The discordance rates of PR positive and PR negative cases were 5.6% and 9.4% respectively, whereas 29.2% of HER2 positive cases were discordant in lymph node metastases. Conclusion: There was discordance between ER, PR, HER2 status of primary tumour and metastatic lymph node. Hence, assessment of these biomarker status in axillary lymph node metastases may be considered along with primary tumour in breast carcinoma work-up.

Changes in human epidermal growth factor receptor 2 status between primary breast/gastric carcinomas and synchronous metastatic lymph nodes: how can we explain them?

Aim: Previous studies demonstrated discordant expression of human epidermal growth-factor receptor 2 (HER2) between primary cancer and their recurrence/metastasis. This study further evaluated HER2 status between primary gastric and breast invasive carcinomas and paired metastatic disease to lymph nodes. Methods: This study collected formalin-fixed paraffin-embedded representative tissue blocks from 62 gastric and 65 breast primary carcinomas as well as synchronous metastatic lymph nodes (male:female = 39:88; age ranged between 44 and 95 years with mean age of 69.32 years) for immunohistochemical staining of HER2 expression (DAKO HercepTest ™ kit). If immunohistochemical HER2 score reached to 2+, HER2 amplification was then assessed using fluorescence in situ hybridization (PharmDx ™ kit DAKO). Results: The discordant HER2 pooled rate, regardless either negative or positive conversion, was 9.67% in primary gastric carcinoma and corresponding nodal metastasis, while the changes in HER2 expression were revealed in 4.61% of mammary and lymph node neoplastic samples. A high-level concordance in HER2 expression between primary carcinoma and synchronous metastatic lymph nodes was confirmed in both types of cancer; the observed event of discordant HER2 status should be ascribed to intra-tumor heterogeneity, mostly appreciable in gastric cancer. Conclusion: In any case, the shift from positive to negative HER2 expression suggests that trastuzumab could be the targeted treatment choice whereas the opposite shift should be evaluated by a simultaneous HER2 determination in both primary and metastatic lymph nodes.

Discordance rate of HER2 status in primary gastric carcinomas and synchronous lymph node metastases: a multicenter retrospective analysis.

Background: The assessment of human epidermal growth factor receptor 2 (HER2) gene amplification is essential in order to identify those patients affected by advanced gastric cancer who may benefit from Trastuzumab targeted therapy. Materials and Methods: With the aim to investigate the concordance rate in HER2 status between primary gastric carcinoma (GC) and synchronous lymphnode metastases, we investigated HER2 status in a cohort of 108 surgical formalin-fixed paraffin-embedded specimens of GC and matched synchronous metastatic lymph nodes collected from three different units of Anatomic Pathology in southern of Italy. Fleiss-Cohen weighted k statistics were used to assess the concordance rate of HER2 status. Results: HER2 amplification was observed in 17% of primary GCs and the overall concordance rate with corresponding nodal metastases was 90.74%. Changes in HER2 status between primary GC and matched synchronous metastases were evidenced in 10 (9.26%) cases. Of these, 6 cases were HER2 amplified in the primary GC and not amplified in the metastases, while 4 were HER2 not amplified in the primary tumour and amplified in the lymph node metastases. Conclusions: Although at present the simultaneous determination of HER2 in advanced gastric cancer and corresponding metastatic lymph nodes is not mandatory, the possibility that the synchronous metastases of GC have a different HER2 status from that of the primary tumour is of remarkable significance; Indeed this may have influence on the therapeutic management and prognosis of the patients.

Biomarker expression and St Gallen molecular subtype classification in primary tumours, synchronous lymph node metastases and asynchronous relapses in primary breast cancer patients with 10 years’ follow-up

Molecular profiles of asynchronous breast cancer metastases are of clinical relevance to individual patients' treatment, whereas the role of profiles in synchronous lymph node metastases is not defined. The present study aimed to assess individual biomarkers and molecular subtypes according to the St Gallen classification in primary breast tumours, synchronous lymph node metastases and asynchronous relapses and relate the results to 10-year breast cancer mortality (BCM). Tissue microarrays were constructed from archived tissue blocks of primary tumours (N=524), synchronous lymph node metastases (N=147) and asynchronous relapses (N=36). The samples were evaluated by two independent pathologists according to oestrogen receptor (ER), progesterone receptor (PR), Ki67 and human epidermal growth factor receptor 2 (HER2) by immunohistochemistry and in situ hybridisation. The expression of biomarkers and molecular subtypes in the primary tumour was compared with that in the synchronous lymph node metastases and relapses, and related to 10-year BCM. Discordances were found between primary tumours and relapses (ER: p=0.006, PR: p=0.04, Ki67: p=0.02, HER2: p=0.02, St Gallen subtypes: p=0.07) but not between primary tumours and metastatic lymph node. Prognostic information was gained by the molecular subtype classification in primary tumours and nodal metastases; triple negative subtype had the highest BCM compared with the luminal A subtype (primary tumours: HR 4.0; 95% CI 2.0-8.2, p<0.001, lymph node metastases: HR 3.5; 95% CI 1.3-9.7, p=0.02). When a shift in subtype inherence between primary tumour and metastatic lymph node was identified, the prognosis seemed to follow the subtype of the lymph node. Molecular profiles are not stable throughout tumour progression in breast cancer. Prognostic information for individual patients appears to be available from the analysis of biomarker expression in synchronous metastatic lymph nodes. The study supports biomarker analysis also in asynchronous relapses.

Flow cytometric analysis of DNA ploidy in primary, metastatic and recurrent breast cancers

Although there have been many studies analyzing the heterogeneity of DNA ploidy either in primary breast cancer or between the primary and synchronous metastatic lesions of breast cancer, few studies have been made regarding a comparison of DNA ploidy between the primary and recurrent lesions of breast cancer. Flow cytometric analyses for DNA ploidy were performed on both the primary lesions and the matching synchronous metastatic lymph nodes of 104 breast cancers and on both the primary and matching recurrent lesions of 31 breast cancers. A concordance of DNA ploidy between the primary lesions and the matching metastatic lymph nodes was found in 80 (77%) cases, while a concordance of DNA ploidy between the primary and matching recurrent lesions was found in 22 (71%) cases. Forty-six (94%) of 49 cases showed less than an 8.0% difference in the DNA indices of the aneuploid peaks between the primary lesions and the metastatic lymph nodes, while 13 (87%) of 15 cases showed less than 15.0% difference in the DNA indices between the primary and recurrent lesions. The aneuploid group and the heterogeneity group, divided according to the comparison of DNA ploidy between the primary and synchronous metastatic lesions, had a worse disease-free survival than that of the diploid group (p=0.0426 and p=0.0503, respectively). In conclusion, the majority of DNA ploidies are consistent among the primary, synchronous metastatic and recurrent lesions of breast cancer. The existence of aneuploidy itself may also play a prognostic role in breast cancer.

Bcl-2 expression in pancreas development and pancreatic cancer progression.

Apoptosis is important for both tissue development and differentiation; its deregulation may contribute to tumourigenesis. In order to clarify the role of Bcl-2, an apoptosis-inhibiting protein, in pancreatic morphogenesis and tumour progression, its immunohistochemical expression was evaluated in 12 samples of fetal pancreas, in 10 samples of adult pancreas with ductal hyperplastic lesions, in 120 cases of primary pancreatic ductal adenocarcinoma, and in 43 synchronous metastatic lymph nodes. To evaluate the role of apoptosis in pancreatic cancer, p53 expression was also studied in tumour samples. Bcl-2 cytoplasmic acinar and ductal immunostaining was found in all fetal and adult tissue samples; ductal hyperplastic lesions were constantly negative. Thirty out of 120 (25%) tumours and 3 out of 43 (7%) lymph nodes expressed Bcl-2, whereas 67 out of 120 (56%) expressed nuclear p53. Well-differentiated tumours (G1) were more frequently Bcl-2-positive (p=0.002); furthermore, there was an inverse correlation between Bcl-2 and p53 expression in primary tumours (p=0.02). Neither Bcl-2 nor p53 influenced patients' prognosis, which was instead affected by N (p=0.02) and M (p<0.0001) status and stage of the disease (p=0.002). It is concluded that Bcl-2 regulates pancreatic morphogenesis and tissue homeostasis from early fetal to adult life and can be considered a phenotypic marker of normal exocrine pancreas. On the other hand, the lack of expression in preneoplastic lesions and the low positivity found in primary tumours and lymph node metastases suggest that Bcl-2 does not play a centralrole in pancreatic tumourigenesis and cancer progression.