Contrast of Mastoscopic and Conventional Axillary Lymph Node Dissection of Patients With Breast Cancer: Meta-Analysis.

Mastoscopic axillary lymph node dissection (MALND) is a currently used and safe surgical treatment option for breast cancer. However, the extensive application of MALND is still debatable because of the use of conventional axillary lymph node dissection (CALND). Therefore, in the current study, we aimed to compare the efficacy and safety of MALND and CALND for obtaining evidence-based conclusions about the short-term and long-term outcomes of MALND for patients with breast cancer. PubMed, Web of Science, Cochrane Library, and CNKI were comprehensively searched for articles published between January 1998 and January 2019. Then Newcastle-Ottawa scale was used for quality assessment. The Review Manager software version 5.0 was utilized for generating forest maps and funnel plots. Twelve studies including 2157 patients were selected for the meta-analysis. There were no significant differences in the number of lymph node dissections, tumor recurrence rate, axillary drainage, postoperative hospitalization time, and tumor size between the MALND and CALND groups (P > .05). In the MALND group, the surgery time was longer, while the incidence of intraoperative bleeding was lesser and the duration of drainage was shorter than those in the CALND group (P < .01). The complications in the MALND group were also fewer than those in the CALND group (P < .05). The results of the current study showed that MALND is reliable and feasible for breast cancer owing to the lesser incidence of intraoperative bleeding, shorter drainage duration, and lower incidence of complications compared to CALND.

Lin28 promotes Her2 expression and Lin28/Her2 predicts poorer survival in gastric cancer.

The main purpose of this study is to investigate the interactions between Lin28 and Her2 in gastric cancer. Lin28 and Her2 expression were evaluated in surgically resected samples of 298 gastric cancer patients using immunohistochemical staining. The correlations between Lin28/Her2 expression and clinical variables were retrospectively analyzed. The mRNA level of LIN28 and HER2 was detected by reverse-transcriptase polymerase chain reaction. Among all gastric cancer patients, 33.9% (101/298) were determined as Her2-positive, and 43.0% (128/298) were defined as Lin28-positive. Lin28 was significantly associated with Her2, advanced tumor stage, lesion size, and Ki67 level (p<0.05 for each). Kaplan-Meier analysis illustrated that both Lin28 and Her2 are poor prognostic factors in gastric cancer; Lin28(+)/Her2(+) patients have the poorest survival (median survival = 17 months, p<0.01). Multivariate Cox analysis showed that Lin28 is a significant prognostic factor (hazard ratio (HR) = 1.79, 95% confidence interval (CI) 1.23-2.62). Further stratification analysis indicated that Lin28 may be a prognostic factor in chemotherapy. In vitro data on MKN-28 and MKN-45 cells showed that Lin28 can upregulate Her2 expression at translational level. Both Lin28 and Her2 are poor prognostic factors in gastric cancer. Lin28 may regulate Her2 post-transcriptionally in gastric cancer cells, which indicates it might be a potential target in the treatment of gastric cancer.

Occurrence of Residual Breast Tumors and Efficacy of MRI in their Detection after Vacuum-assisted Excisional Biopsy.

BACKGROUND: Residual breast tumors may remain after vacuum-assisted excisional biopsy (VAEB). OBJECTIVE: To determine the incidence of residual breast tumors in patients after VAEB and the efficacy of magnetic resonance imaging (MRI) in detecting these tumors. METHODS: This retrospective analysis examined patients who received VAEB before a diagnosis of breast cancer (BC) at our hospital from 2015 to 2019. The incidence of residual tumors after VAEB was determined by MRI and pathological examination. The diagnostic value of MRI in detecting residual tumors was determined for all patients and different subgroups. Logistic regression analysis was used to identify factors associated with residual tumors. RESULTS: We examined 147 patients and obtained pathological samples from 146 patients, including 103 (70.5%) with residual tumors and 43 (29.5%) without residual tumors. The MRI examinations demonstrated the complete tumor resection rate was 48.9%. Compared to the pathological results, MRI had a positive predictive value of 77.8%, negative predictive value of 48.8%, specificity of 65.6%, and sensitivity of 60.7%. Further analysis indicated that MRI had moderate accuracies for patients with stage pT-1 (71.9%), stage pTNM-IA (73.1%), and luminal B subtype (78.3%). Binary logistic regression analysis showed that the risk of tumor residue correlated with the pathological stage. CONCLUSION: Tumor residue is common after VAEB, and MRI has limited accuracy in detecting these residual tumors. However, for small breast tumors and luminal B subtype BC, MRI had higher accuracy in the detection of residual tumors. The risk of tumor residue is closely associated with the pathological stage.

The influence of preoperative biopsy on the surgical method in breast cancer patients: a single-center experience of 3,966 cases in China.

BACKGROUND: The National Surgical Adjuvant Breast and Bowel Project (NSABP) B32 trial reported that the detection rate of sentinel lymph nodes by core needle biopsy (CNB) is higher than that by segmental resection. However, there are few reports regarding the detection rate of sentinel lymph nodes by vacuum-assisted breast biopsy (VABB). Therefore, we analyzed the impact of preoperative biopsy methods on the surgical modes of 3,966 patients with breast cancer in our center. METHODS: In total, 3,966 female breast cancer patients [clinical tumor node metastasis (TNM) stage I-III] were enrolled in this study. Preoperative pathological diagnosis methods included fine needle aspiration (FNA) biopsy, CNB, excision biopsy, and VABB. According to the time of diagnosis. The data were analysis by chi square test, variance analysis and the Kaplan-Meier time series in SPSS 22.0. RESULTS: There was a decrease in the number of patients that underwent excision biopsy (7.3% to 2.7%) and intraoperative freezing (89.4% to 28.9%) over time, while CNB exhibited an increasing trend (1.6% to 55.3%). The positive rates of VABB, CNB, excision biopsy, and FNA were 99.5%, 97.1%, 97.9%, and 82.2%, respectively, and the false negative rates were 0%, 1.8%, 0.34%, and 8.9%, respectively. The overall breast-conserving rate was 36.7%, while the breast-conserving rate for VABB was 57.1%. The axillary sentinel lymph node biopsy rate of cN0 patients was 48.3%, and the intraoperative frozen group (36.7%) and excision biopsy group (39.5%) were lower than the CNB (57.1%) and VABB (77.9%) groups. Until December 2019, there were 350 cases with tumor recurrence or metastasis. The methods of biopsy were not correlated to the cumulative survival time. CONCLUSIONS: Changes to the diagnosis and treatment of breast cancer has a profound impact on the method of tumor biopsy. VABB biopsy offers advantages such as accurate diagnosis, a greater volume of tissue taken at one time, minimally invasive and repeatable, and does not affect the surgical approach and prognosis of patients. It will gradually become the primary method of preoperative pathological evaluation of breast cancer.

Pegylated Liposomal Doxorubicin Versus Epirubicin as Adjuvant Therapy for Stage I-III Breast Cancer.

Background: Conventional anthracyclines, like epirubicin, are cornerstone drugs for breast cancer treatment of all stages, but their cumulative toxicity could cause life-threatening side effects. Pegylated liposomal doxorubicin (PLD), an effective anti-breast cancer drug, has lower toxicity than conventional anthracyclines. This retrospective study compared the efficacy and toxicity profiles between PLD and epirubicin as adjuvant therapy for breast cancer. Patients and Methods: A total of 1,471 patients diagnosed with stage I-III breast cancer between 2000 and 2018 were included in this study, among which 661 were treated with PLD and 810 with epirubicin, with 45.9 months as the median follow-up time. Anti-breast cancer efficacy was assessed with overall survival (OS) and disease-free survival (DFS), while cardiac toxicity was assessed with left ventricular ejection fraction (LVEF) and electrocardiogram (ECG). Results: The Kaplan-Meier method and Cox proportional hazards model revealed that there was no statistical difference in OS or DFS between patients treated with PLD and epirubicin, regardless of cancer stages or molecular subtypes (all p-values > 0.05). In addition, patients had significantly better LEVF and ECG data after adjuvant therapy with PLD (both p-values < 0.05). Conclusion: Based on the large sample size and the long follow-up time of this study, we conclude that PLD has a similar anti-breast cancer efficacy as epirubicin while inducing lower level of cardiac toxicity in Han Chinese. This study suggests that PLD-based adjuvant chemotherapy could be a better option than epirubicin for breast cancer patients especially with existing cardiac disease.

Regulation of tamoxifen sensitivity by the PLAC8/MAPK pathway axis is antagonized by curcumin-induced protein stability change.

Tamoxifen resistance remains the major obstacle to the estrogen receptor positive breast cancer endocrine therapy. Placenta-specific 8 (PLAC8) has been implicated in epithelial-mesenchymal transition and tumorigenesis. However, the molecular mechanisms underlying PLAC8 function in the context of tamoxifen resistance are unclear. Curcumin has attracted considerable attention in the last decades. It is isolated from Curcuma longa and has beneficial effects in cancer therapy. We studied this property by using MCF-7 and tamoxifen-resistant breast cancer cells (MCF-7/TAM) cell lines. PLAC8 can regulate MCF-7/TAM cell drug sensitivity through the MAPK/ERK pathway and shows the potential effects of curcumin or as a possible druggable target against tamoxifen failure.

A predictive signature for oxaliplatin and 5-fluorouracil based chemotherapy in locally advanced gastric cancer.

Adjuvant chemotherapy(AC) plays a substantial role in the treatment of locally advanced gastric cancer (LAGC), but the response remains poor. We aims to improve its efficacy in LAGC. Therefore, we identified the expression of eight genes closely associated with platinum and fluorouracil metabolism (RRM1, RRM2, RRM2B, POLH, DUT, TYMS, TYMP, MKI67) in the discovery cohort (N=291). And we further validated the findings in TCGA (N=279) and GEO. Overall survival (OS) was used as an endpoint. Univariate and multivariate Cox models were applied. A multivariate Cox regression model was simulated to predict the OS. In the discovery cohort, the univariate Cox model indicated that AC was beneficial to high-RRM1, high-DUT, low-RRM2, low-RRM2B, low-POLH, low-KI67, low-TYMS or low-TYMP patients, the results were validated in the TCGA cohort. The multivariate Cox model showed consistent results. Cumulative analysis indicated that patients with low C-Score respond poorly to the AC, whereas the high and medium C-Score patients significantly benefit from AC. A risk model based on the above variables successfully predicted the OS in both cohorts (AUC=0.75 and 0.67, respectively). Further validation in a panel of gastric cancer cell (GC) lines (N=37) indicated that C-Score is significantly associated with IC50 value to fluorouracil. Mutation profiling showed that C-Score was associated with the number and types of mutations. In conclusion, we successfully simulated a predictive signature for the efficacy of AC in LAGC patients and further explored the potential mechanisms. Our findings could promote precision medicine and improve the prognosis of LAGC patients.

FKBP4 is a malignant indicator in luminal A subtype of breast cancer.

Purpose: FKBP4 is a member of the immunophilin protein family, which plays a role in immunoregulation and basic cellular processes involving protein folding and trafficking associated with HSP90. However, the relationship between abnormal expression of FKBP4 and clinical outcome in luminal A subtype breast cancer (LABC) patients remains to be elucidated. Methods: Oncomine, bc-GenExMiner and HPA database were used for data mining and analyzing FKBP4 and its co-expressed genes. GEPIA database was used for screening co-expressed genes of FKBP4. Results: For the first time, we found that higher FKBP4 expression correlated with LABC patients and worse survival. Moreover, the upregulated co-expressed genes of FKBP4 were assessed to be significantly correlated with worse survival in LABC, and might be involved in the biological role of FKBP4. Conclusion: The expression status of FKBP4 is a significant prognostic indicator and a potential drug target for LABC.

Transcriptional analysis of estrogen receptor alpha variant mRNAs in colorectal cancers and their matched normal colorectal tissues.

Estrogen is involved in suppression of colorectal cancer development and exerts its function via estrogen receptors alpha, beta and their splicing variants. Whether the recently indentified ER-alpha splicing variants, ER-alpha36 and ER-alpha46, play a role in colorectal cancer development is unknown. In this study, we quantified the mRNA copy numbers of wild type ER-alpha (ER-alpha66), ER-alpha46 and ER-alpha36 in 35 colorectal cancers and their matched normal colorectal tissues by quantitative real-time PCR assay, and correlated their mRNA levels with the clinicopathological properties of the tumors. We found that ER-alpha66, ER-alpha46 and ER-alpha36 mRNAs were coexpressed in all colorectal cancers and their matched normal tissues. The decreased mRNA levels of ER-alpha36 and ER-alpha46 whereas no difference of ER-alpha66 mRNA was observed in colorectal cancers compared to their matched normal tissues. Moreover, change in the expression of ER-alpha36 mRNA level was correlated with Dukes' stage of the tumor and the lymph node metastasis. ER-alpha36 mRNA was decreased significantly in Dukes' C+D compared to Dukes' A+B stage tumors (P=0.017), and the expression of ER-alpha36 mRNA in N(1)/N(2) was lower than that in N(0) lymph node metastasis (P=0.049). So ER-alpha36 and ER-alpha46 might be implicated in the development and progression of colorectal cancers.

Estrogen receptor alpha variant ERalpha46 mediates growth inhibition and apoptosis of human HT-29 colon adenocarcinoma cells in the presence of 17beta-oestradiol.

BACKGROUND: Estrogen is involved in suppression of colon cancer development and exerts its function via estrogen receptors alpha and beta (ERalpha, ERbeta). The recently identified ERalpha46 resulted from exon 1-deletion from the 66-kDa full length form of ERalpha66 is devoid of the transactivation domain AF-1, whose function remains largely unknown. METHODS: In this study, we compared the expression of ERalpha46 mRNA in 32 normal colorectal tissues and their matched colorectal cancer tissues by real-time quantitative polymerase chain reaction (PCR). Human colon adenocarcinoma cell HT-29, that has low endogenous expression of ERalpha46, was transfected with ERalpha46-expression vector; methyl thiazolyl tetrazolium (MTT) assay, flow cytometry, DNA fragmentation and TUNEL staining were used to evaluate the proliferation and apoptosis status of the cells in the presence of 17beta-oestradiol. RESULTS: Higher ERalpha46 mRNA levels were observed in normal colorectal tissues than in the corresponding cancer tissues. ERalpha46-transfected cells showed a significantly decreased growth rate than control cells and an accumulation of cells in the G(0/1) phase and a reduced proportion of cells in G(2)/M phase after exposed to 10(-8) mol/L 17beta-oestradiol. There were also more positive TUNEL stained cells in ERalpha46-transfected cells than the control cells in the presence of 17beta-oestradiol (P < 0.05). CONCLUSIONS: These data suggest that ERalpha46 may be involved in the development and/or progression of colorectal cancer via mediating growth inhibition and apoptosis of cancer cells in the presence of 17beta-oestradiol.

Tumor and serum gamma-glutamyl transpeptidase, new prognostic and molecular interpretation of an old biomarker in gastric cancer.

BACKGROUND: Gastric Cancer is one of the most lethal malignancies worldwide. Gamma-glutamyl transpeptidase (GGT) is an enzyme mainly involved in cellular glutathione homeostasis. We aim to explore the clinical value of GGT in gastric cancer. RESULTS: Among 322 patients enrolled, 65/82 patients were determined as GGT positive in serum/tumor, respectively. High tumor GGT expression is significantly associated with lymph node metastasis, histological subtype, and Her2 expression. Kaplan-Meier curve shows that high tumor GGT patients have shorter overall survival (P log-rank=0.001) and progress-free survival (P log-rank =0.001). Patients with both high tumor and serum GGT have the poorest prognosis. The multivariable Cox analysis shows that the hazard ratio of overall survival for high tumor GGT is 1.69 (95% CI 1.19-2.37). High serum GGT is a poor prognostic factor in adjuvant chemotherapy hazard ratio=2.18, 95%CI (1.15-4.47). These findings were further validated in six online datasets. Gene Sets Enrichment Analysis showed that GGT promotes cancer progression through EMT, KRAS, SRC and PKCA pathways. METHODS: Tumor GGT and serum GGT levels were evaluated with immuno-histochemistry staining and enzymatic assay, respectively. Kaplan-Meier curve and Cox regression model were used to test the association between GGT and gastric cancer prognosis. Independent datasets from Gene Expression Omnibus and Gene Sets Enrichment Analysis were applied to validate the findings and explore the potential mechanisms. CONCLUSION: Both tumor GGT and serum GGT are poor prognostic factors in gastric cancer. Patients with high tumor and serum GGT levels require more intense treatment and follow-up.

New utility of an old marker: serum low-density lipoprotein predicts histopathological response of neoadjuvant chemotherapy in locally advanced gastric cancer.

BACKGROUND: Although the correlation between metabolic abnormality and gastric cancer has been extensively investigated, the question of whether metabolic parameters might influence the efficacy of chemotherapy in locally advanced gastric cancer is still unanswered. In our present study, we investigated the relationship between serum fasting glucose, lipid levels, and histopathological response of neoadjuvant chemotherapy (NAC) in locally advanced gastric cancers. PATIENTS AND METHODS: A total of 128 patients were identified from a prospectively maintained database of patients with locally advanced gastric cancer who received NAC between July 2004 and December 2012. Histopathological response after NAC was analyzed according to Becker's tumor-regression grade. Univariate analyses and multivariable regression analyses were performed to determine the correlation between tumor size, differentiation, fasting glucose, lipid levels, and tumor histopathological response after NAC. RESULTS: Univariate analysis revealed that low-density lipoprotein level and total cholesterol, as well as tumor size and differentiation, correlated significantly with histopathological response. Low-density lipoprotein levels and tumor size were found to be independent predictors for histopathological response, according to multivariable regression analyses. CONCLUSION: In this observational, hypothesis-generating study, serum low-density lipoprotein measurement was found to be useful in predicting chemosensitivity to locally advanced gastric cancer patients undergoing NAC. Incorporation of serum low-density lipoprotein levels into individualized treatment protocols could be considered in clinical practice.

Overexpression of Lin28 Decreases the Chemosensitivity of Gastric Cancer Cells to Oxaliplatin, Paclitaxel, Doxorubicin, and Fluorouracil in Part via microRNA-107.

Higher Lin28 expression is associated with worse pathologic tumor responses in locally advanced gastric cancer patients undergoing neoadjuvant chemotherapy. However, the characteristics of Lin28 and its mechanism of action in chemotherapy resistance is still unclear. In this study, we found that transfection of Lin28 into gastric cancer cells (MKN45 and MKN28) increased their resistance to the chemo-drugs oxaliplatin (OXA), paclitaxel (PTX), doxorubicin (ADM), and fluorouracil (5-Fu) compared with gastric cancer cells transfected with a control vector. When knockdown Lin28 expression by Lin28 small interfering RNA (siRNA) was evaluated in vitro, we found that the resistance to chemo-drugs was reduced. Furthermore, we found that Lin28 up-regulates C-myc and P-gp and down-regulates Cylin D1. Finally, we found that miR-107 is a target microRNA of Lin28 and that it participates in the mechanism of chemotherapy resistance. Our results suggest that the Lin28/miR-107 pathway could be one of many signaling pathways regulated by Lin28 and associated with gastric cancer chemo-resistance.

LZTFL1 suppresses gastric cancer cell migration and invasion through regulating nuclear translocation of ß-catenin.

PURPOSE: Our previous work identified leucine zipper transcription factor-like 1 (LZTFL1) as a novel tumor suppressor gene, with its expression correlated with survival outcome in gastric cancer (GC) patients. This study focuses on the role of LZTFL1 in GC aggression and metastasis as well as its underlying molecular mechanisms. METHOD: LZTFL1 immunohistochemical (IHC) staining on 311 paired normal/cancer tissue arrays were used to reconfirm the clinical significance of LZTFL1 expression. Transwell chamber assays were used to determine migration and invasive ability of GC cells. Gelatin zymography was employed to investigate the matrix metalloproteinases (MMPs) activity in tumor cells. Co-immunoprecipitation and Duolink in situ proximity ligation assay were used to analyze the interaction between LZTFL1 and ß-catenin and the cellular localization of the interaction. RESULT: IHC results indicated that patients with high LZTFL1 expression had a longer overall survival time (58 months, 95 % CI 28-128 months) than patients with low LZTFL1 expression (27 months, 95 % CI 23-35 months; p < 0.01). The expression level of LZTFL1 is associated with the degree of cell differentiation. LZTFL1 is necessary and sufficient to inhibit the expression of molecular markers associated with epithelial-mesenchymal transition (EMT) and cellular phenotypes associated with tumor cell EMT including the migration, invasion, and the expression and activities of MMPs of tumor cells. LZTFL1 binds ß-catenin in the cytoplasm of the cell and inhibited its nuclear translocation. CONCLUSION: LZTFL1 suppresses GC cell EMT by inhibiting ß-catenin nuclear translocation. Re-expression of LZTFL1 in GC cells may be a potential therapeutic means to prevent GC metastasis.

Endocrine resistance in breast cancer: Current status and a perspective on the roles of miRNAs (Review).

Current endocrine therapies for females with estrogen receptor-positive breast cancer have facilitated substantial improvements in outcomes. The effectiveness of endocrine therapy is limited by either initial de novo resistance or acquired endocrine resistance. Multiple mechanisms responsible for endocrine resistance have been proposed, including deregulation of various components of the estrogen receptor (ER) pathway, alterations in cell cycle and cell survival signaling molecules, and the activation of escape pathways. Dysregulation of miRNA expression has been associated with experimental and clinical endocrine therapy resistance. miRNAs are pivotal to understanding the complex biological mechanism of endocrine resistance, and may serve as novel candidate predictive and prognostic surrogates and therapeutic targets. This review focuses on current progress concerning the roles of miRNAs in endocrine resistance, and discusses the challenges and opportunities for implementing miRNA-based assays and treatment for patients with endocrine-resistant breast cancer.

Overexpression of ERα inhibits proliferation and invasion of MKN28 gastric cancer cells by suppressing ß-catenin.

The relationship between estrogen receptor (ER)α and patient prognosis has been identified in gastric cancer; however, the definite role of ERα in gastric cancer remains to be fully elucidated. The aim of the present in vitro study was to investigate the impact of ERα on cell proliferation, migration and invasion in gastric cancer cell lines. We investigated the biological effect of ERα overexpression on gastric carcinoma cells. An MKN28 gastric cancer cell line stably overexpressing ERα was established. The effect of ERα overexpression on cell growth was assessed by evaluating cell survival, colony formation, cell cycle progression and apoptosis. Cell migration and invasion were detected by Transwell migration/invasion assays. The protein levels of several potentially involved genes were determined by western blotting to elucidate the underlying molecular mechanisms. The Student's t-test was used to determine the statistical differences between various experimental and control groups, and one-way ANOVA test was used to determine the difference between three or more groups. The results showed that ERα overexpression significantly inhibited cell growth and proliferation, blocked cell entry into the G1/G0 phase and promoted cell apoptosis. In addition, ERα reduced the motility and invasion of gastric cancer cells. These phenotypes may partly be explained by a decrease in ß-catenin expression caused by ERα overexpression. ERα overexpression effectively inhibited cell growth and cancer progression by suppressing ß-catenin in gastric cancer, identifying ERα as a promising target with therapeutic potential for development of new approaches to treat gastric cancer.

Lin28 mediates paclitaxel resistance by modulating p21, Rb and Let-7a miRNA in breast cancer cells.

Resistance to chemotherapy is a major obstacle for the effective treatment of cancers. Lin28 has been shown to contribute to tumor relapse after chemotherapy; however, the relationship between Lin28 and chemoresistance remained unknown. In this study, we investigated the association of Lin28 with paclitaxel resistance and identified the underlying mechanisms of action of Lin28 in human breast cancer cell lines and tumor tissues. We found that the expression level of Lin28 was closely associated with the resistance to paclitaxel treatment. The T47D cancer cell line, which highly expresses Lin28, is more resistant to paclitaxel than the MCF7, Bcap-37 or SK-BR-3 cancer cell lines, which had low-level expression of Lin28. Knocking down of Lin28 in Lin28 high expression T47D cells increased the sensitivity to paclitaxel treatment, while stable expression of Lin28 in breast cancer cells effectively attenuated the sensitivity to paclitaxel treatment, resulting in a significant increase of IC50 values of paclitaxel. Transfection with Lin28 also significantly inhibited paclitaxel-induced apoptosis. We also found that Lin28 expression was dramatically increased in tumor tissues after neoadjuvant chemotherapy or in local relapse or metastatic breast cancer tissues. Moreover, further studies showed that p21, Rb and Let-7 miRNA were the molecular targets of Lin28. Overexpression of Lin28 in breast cancer cells considerably induced p21 and Rb expression and inhibited Let-7 miRNA levels. Our results indicate that Lin28 expression might be one mechanism underlying paclitaxel resistance in breast cancer, and Lin28 could be a potential target for overcoming paclitaxel resistance in breast cancer.

Clonal analysis of bilateral, recurrent, and metastatic papillary thyroid carcinomas.

Papillary thyroid carcinoma usually presents as a multifocal disease; and tumors often recur in the contralateral thyroid lobe, raising questions concerning their clonal origins. The clonality of tumors appearing simultaneously in both lobes or recurring in the contralateral lobe remains unknown. Accordingly, we examined 25 pairs of bilateral papillary thyroid carcinomas (synchronous or metachronous) and 15 matched metastatic lymph nodes. BRAF gene mutation analysis combined with X-chromosome inactivation was used to evaluate these tumors' clonal origins. Genomic DNA was prepared from paraffin-embedded tissues after microdissection. In total, 62 tumors yielded DNA of adequate quality. Eighteen (18/21, 85.7%) of 21 informative cases showed concordant BRAF status in tumors from both thyroid lobes, being either BRAF mutation positive (12 patients) or BRAF mutation negative (6 patients). Metastatic lymph nodes in 12 patients (12/15, 80%) had a complete concordance of BRAF state with their primaries. Of the 18 studied female patients, 11 were suitable for X-chromosome inactivation assay. Nine cases (9/11, 81.1%) showed the same pattern of inactivation in bilateral tumors. A close correlation was found between BRAF mutation and X-chromosome inactivation analysis. In conclusion, our data provide evidence that bilateral, recurrent, and metastatic papillary thyroid carcinomas often arise from a single clone and that intrathyroidal metastasis may play an important role in the development of bilateral tumors, as well as in the recurrence of this malignancy.