Background
Mucinous and serous borderline ovarian tumours (mBOTs and sBOTs) are controversial diseases.
Objectives
With this systematic review we aim to evaluate the different high‐risk ...histopathological features and recurrence rates.
Search strategy
The PubMed database was searched using two terms: {serous AND (borderline) OR (low malignant potential) AND ovarian AND tumour} and {mucinous AND (borderline) OR (low malignant potential) AND ovarian AND tumour}.
Selection criteria
Cohorts of either sBOT or mBOT, peer‐reviewed, retrospective, or prospective.
Data collection and analysis
Lethal recurrence data for micropapillary patterns (MPs), microinvasion, non‐invasive and invasive implants, and intraepithelial carcinoma (IECA). The primary measure of effect was the odds ratio of lethal recurrence reduction.
Results
Data from patients in 42 studies including 4414 sBOTs and 12 studies including 894 mBOTs were pooled. Of these, 53.3% presented early‐stage typical sBOTs, 24.4% presented with MPs, 22.3% presented with microinvasion, 34.4% presented with non‐invasive implants, and 7.3% presented with invasive implants. The pooled lethal recurrence rates were, respectively: 18.3, 16.8, 10.7, 16.2, and 33.8%. Patients with MPs were more likely to suffer lethal recurrence when compared with high‐stage sBOTs (odds ratio, OR 0.501; P = 0.003), whereas the trend in microinvasive sBOTs did not reach statistical significance. Regarding mBOTs, 61.6% presented with early‐stage typical mBOTs, 19.6% presented with microinvasion, 34.8% presented with IECA, and six patients presented with non‐invasive implants; none presented with invasive implants. The lethal recurrence rates were, respectively: 3.6, 0, 3.7, and 0%.
Conclusion
Micropapillary patterns (MPs) showed a higher risk for lethal recurrence when compared with high‐stage sBOTs. Regarding mBOTs, IECA and microinvasion do not play a role in the lethal recurrence rate.
Tweetable
Micropapillary pattern confirmed as high‐risk in BOT. IECA and microinvasion don't play a role in mucinous BOT.
Tweetable
Micropapillary pattern confirmed as high‐risk in BOT. IECA and microinvasion don't play a role in mucinous BOT.
In April 2013 our group published a review on predictive molecular pathology in this journal. Although only 2 years have passed many new facts and stimulating developments have happened in diagnostic ...molecular pathology rendering it worthwhile to present an up-date on this topic. A major technical improvement is certainly given by the introduction of next-generation sequencing (NGS; amplicon, whole exome, whole genome) and its application to formalin-fixed paraffin-embedded (FFPE) tissue in routine diagnostics. Based on this 'revolution' the analyses of numerous genetic alterations in parallel has become a routine approach opening the chance to characterize patients' malignant tumors much more deeply without increasing turn-around time and costs. In the near future this will open new strategies to apply 'off-label' targeted therapies, e.g. for rare tumors, otherwise resistant tumors etc. The clinically relevant genetic aberrations described in this review include mutation analyses of RAS (KRAS and NRAS), BRAF and PI3K in colorectal cancer, KIT or PDGFR alpha as well as BRAF, NRAS and KIT in malignant melanoma. Moreover, we present several recent advances in the molecular characterization of malignant lymphoma. Beside the well-known mutations in NSCLC (EGFR, ALK) a number of chromosomal aberrations (KRAS, ROS1, MET) have become relevant. Only very recently has the clinical need for analysis of BRCA1/2 come up and proven as a true challenge for routine diagnostics because of the genes' special structure and hot-spot-free mutational distribution. The genetic alterations are discussed in connection with their increasingly important role in companion diagnostics to apply targeted drugs as efficient as possible. As another aspect of the increasing number of druggable mutations, we discuss the challenges personalized therapies pose for the design of clinical studies to prove optimal efficacy particularly with respect to combination therapies of multiple targeted drugs and conventional chemotherapy. Such combinations would lead to an extremely high complexity that would hardly be manageable by applying conventional study designs for approval, e.g. by the FDA or EMA. Up-coming challenges such as the application of methylation assays and proteomic analyses on FFPE tissue will also be discussed briefly to open the door towards the ultimate goal of reading a patients' tissue as 'deeply' as possible. Although it is yet to be shown, which levels of biological information are most informative for predictive pathology, an integrated molecular characterization of tumors will likely offer the most comprehensive view for individualized therapy approaches. To optimize cancer treatment we need to understand tumor biology in much more detail on morphological, genetic, proteomic as well as epigenetic grounds. Finally, the complex challenges on the level of drug design, molecular diagnostics, and clinical trials make necessary a close collaboration among academic institutions, regulatory authorities and pharmaceutical companies.
Secreted protein acidic and rich in cysteine (SPARC) has been suggested as a new biomarker and therapeutic target in breast cancer, as well as other tumor types.
We evaluated the frequency of SPARC ...expression among different molecular breast cancer subtypes and its role for therapy response after neoadjuvant chemotherapy. In this study, pretherapeutic core biopsies of 667 patients from the neoadjuvant GeparTrio trial were evaluated for SPARC expression by immunohistochemistry using a standardized immunoreactive score (IRS).
An increased SPARC expression (IRS ≥6) was observed in 26% of all tumors. In triple-negative tumors, SPARC expression was increased in 37% of tumors, compared with other molecular subtypes (23% HR+/HER2-, 29% HR+/HER2+ and 22% HR-/HER2+; P = 0.038). Increased SPARC expression was associated with an increased pathological complete response (pCR) rate of 27%, compared with 15% in tumors with low SPARC expression (P < 0.001). In the triple-negative subgroup, pCR rates were 47% in tumors with high SPARC expression, compared with 26% in tumors with low SPARC expression (P = 0.032). In multivariable analysis, SPARC was independently predictive in the overall population (P = 0.010) as well as the triple-negative subgroup (P = 0.036).
SPARC is frequently expressed in breast cancer with triple-negative breast cancer revealing the highest expression rate. High SPARC expression of the primary tumor is associated with a higher chance of achieving a pathological complete remission after TAC or TAC-NX chemotherapy. As SPARC is an albumin-binding protein and might mediate intratumoral accumulation of albumin bound drugs, SPARC should be further evaluated as a predictive marker especially for response to albumin-bound drugs like nab-paclitaxel.
NCT00544765.
Abstract Background Mutations in BRCA1/2 genes are involved in the pathogenesis of breast and ovarian cancer. Inactivation of these genes can also be mediated by hypermethylation of CpGs in the ...promoter regions. Aim of this study was to analyse the clinical impact of BRCA1 promoter gene methylation status in a homogenous cohort of high-grade serous ovarian cancer (HGSOC) patients. Methods The cohort included 257 primary HGSOC patients treated by cytoreduction and platinum-based chemotherapy. DNA was extracted from fresh frozen tissue samples. BRCA1 gene promoter methylation rate was assessed using polymerase chain reaction (PCR). Results 14.8% of patients presented hypermethylation within a selected region of the BRCA1 promoter. The rate of hypermethylation was significantly higher in younger patients (20.8% hypermethylation in the age group ⩽58 years versus 8.7% hypermethylation in the age group >58 years; p = 0.008). Optimal tumour debulking could be reached in 63% of patients, without significant differences in the extent of residual disease with respect to the methylation status. No impact of BRCA1 gene promoter methylation status on progression free- and overall-survival rates was found. No significant differences within BRCA1 promoter methylation status between primary and metastatic tissue could be observed. These results on BRCA1 promoter methylation status were also confirmed in a subgroup of 107 patients found negative for BRCA1 exon 11 mutations. Conclusions Our data suggest that BRCA1 methylation determines the earlier onset of HGSOC. Furthermore our study supports the idea that BRCAness is not only due to mutations but also to epigenetic changes in BRCA1 promoter gene.
Loss of protein BAF250a (ARID1A) expression is present in women with rectovaginal deep-infiltrating endometriosis (DIE) and endometriosis affecting the pelvic sentinel lymph nodes (PSLN).
Partial ...loss of protein BAF250a was found in some of our patient samples, comprising all endometriosis entities, including rectovaginal DIE and endometriosis affecting the PSLN.
Loss of BAF250a (BRG-associated factor 250a)/ARIDIA (AT-rich interactive domain 1A) protein expression was identified among endometriosis-associated ovarian carcinomas and ovarian endometriosis, and this phenomenon was described as a possible early event in the transformation of endometriosis into cancer. DIE affecting the bowel/rectovaginal site is the most aggressive presentation of endometriosis and its 'risk' of malignant transformation has not been studied so far.
We evaluated the immunohistochemical expression of BAF250a protein in 70 samples from patients enrolled in this study who were surgically treated at a tertiary center, university Hospital. The samples submitted to investigation were from rectovaginal DIE (n= 25/30), endometriosis affecting the PSLN (n= 5/7), ovarian endometriosis (n= 20/20) and endometrium from patients without endometriosis used as controls (n= 20/20).
Partial loss (i.e. in one tissue section some cells stained positive for BAF250a while other cells, usually an adjacent group, were negative) of BAF250a protein was identified in 36% (9/25) of rectovaginal DIE samples, 40% (2/5) of endometriosis lesions involving the PSLN, 30% (6/20) of endometriomas, and also in 25% (5/20) of endometrium from controls. We found no statistical correlation between occurrence of partial loss of BAF250a protein and the use or not of hormone medications (P = 0.106), cycle phase (P = 0.917) and stage of disease (P = 0.717).
We only found partial loss of BAF250a protein expression, and in a small population of women, with relatively high frequency in all benign tissues assessed in the present analysis. Therefore, this finding alone should not be correlated directly with the risk of malignant transformation in these lesions.
The occurrence of partial loss of BAF250a protein expression in women with rectovaginal DIE and endometriosis affecting the PSLN is described for the first time. The value of this finding as a predictor of malignant transformation in endometriosis must still be clarified and further studied in association with other molecular events, such as PTEN (phosphatase and tensin homolog) deletion and PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) mutation. We might then be able to identify in the future which patients with endometriosis are at higher risk of cancer.
This study was supported by an internal Charité grant to the Endometriosis Research Center and the authors declare no conflicts of interest.
Abstract Objective Granulosa-cell-tumors of the ovary (GCT) constitute a rare group of neoplasms with malignant potential. Due to the rarity of the disease intraoperative tumor-dissemination-patterns ...are not well defined and are mostly based on retrospective data. Aim of the present study was to describe surgical and clinical outcome and dissemination pathways in the primary and recurrent situation of the disease. Methods All primary and relapsed GCT-patients, operated between 01/2001 and 02/2010 in our institution were evaluated using a systematic intraoperative documentation-tool (IMO). Surgical outcome, intraoperative tumor-dissemination-pattern and pathological and findings were separately analyzed for the primary and recurrent situation. Results Overall, 45 patients were analyzed; including eighteen patients with primary and 27 patients with recurrent GCT. Tumor-dissemination-patterns differed significantly between primary and recurrent patients, by the latter having significantly higher rates of diffuse peritoneal involvement (15.8% vs. 52%; p = 0.027) and of extraovarian tumor involvement of the middle (15.8% vs. 48.1%; p = 0.05) and upper abdomen (0 vs. 33.3%; p = 0.006). While all primary patients could be operated tumor-free, this was the case for 85.2% of the relapsed patients ( p = 0.13). A multivisceral operative approach with extensive peritonectomy, intestinal or diaphragmatic resection, splenectomy and partial hepatectomy/panceratectomy had to be performed only in recurrent GCT (55.6%). Conclusions Tumor-dissemination-pathways followed in primary and recurrent GCT differ significantly by higher rates of multivisceral tumor involvement in the recurrent situation of the disease. While at primary presentation extrapelvic involvement with peritoneal carcinosis appears only rare, surgical cytoreduction during relapse is more challenging involving a multivisceral approach.
Neuroendocrine differentiation in high-grade serous ovarian carcinomas has only rarely been described. However, in our consultancy experience, we have been pointed at a case of neuroendocrine relapse ...in a patient with high-grade serous ovarian carcinoma where retrospectively, a minor neuroendocrine component in the primary tumor could be detected. Hypothesizing that immunohistochemical evidence of neuroendocrine differentiation might be more frequent in ovarian carcinoma than suspected by morphology, we immunophenotyped the tissue microarrays (TMAs) of a cohort of 178 high-grade serous carcinomas for chromogranin and synaptophysin expression. Synaptophysin expression was found in 12 (6.7 %) out of 172 patients, and chromogranin A expression was seen in 36 (20.7 %) out of 174 patients. Kaplan-Meier analysis revealed that carcinomas with synaptophysin expression of >20 % of positive cells (
n
= 4) had a significantly shorter survival time than those with 0–20 % of positive cells (
p
< 0.0001). Synaptophysin expression remained a significant prognostic factor in multivariate analysis (HR = 10.82, 95 % confidence interval 3.10–37.71,
p
< 0.0001), independently of age, FIGO stage, and residual tumor after surgery. A trend toward shorter survival was seen in patients with tumors that expressed chromogranin, irrespective of the amount of positive cells (
p
= 0.173). A neuroendocrine differentiation is important to keep in mind when a neuroendocrine tumor of unknown primary is detected in regional or temporal connection with an ovarian carcinoma. A minor neuroendocrine component in ovarian high-grade serous carcinomas might imply a dismal prognosis.
Mucin-1 (MUC1) is a promising antigen for the development of tumor vaccines. We evaluated the frequency of MUC1 expression and its impact on therapy response and survival after neoadjuvant ...chemotherapy for breast cancer.
Pre-treatment core biopsies of patients from the GeparTrio neoadjuvant trial (NCT 00544765) were evaluated for MUC1 by immunohistochemistry (IHC; N = 691) and quantitative RT-PCR (qRT-PCR; N = 286) from formalin-fixed paraffin-embedded (FFPE) samples.
MUC1 protein and mRNA was detectable in the majority of cases and was associated with hormone-receptor-positive status (P < 0.001). High MUC1 protein and mRNA expression were associated with lower probability of pathologic complete response (P = 0.017 and P < 0.001) and with longer patient survival (P = 0.03 and P < 0.001). In multivariable analysis, MUC1 protein and mRNA expression were independently predictive (P = 0.001 and P < 0.001). MUC1 protein and mRNA expression were independently prognostic for overall survival (P = 0.029 and P = 0.015).
MUC1 is frequently expressed in breast cancer and detectable on mRNA and protein level from FFPE tissue. It provides independent predictive information for therapy response and survival after neoadjuvant chemotherapy. In clinical immunotherapy trials, MUC1 expression may serve as a predictive marker.
Purpose
Hormone receptor (HR)-positive breast cancer (BC) shows a poor response to neoadjuvant chemotherapy (NACT). New treatment targets like the Cyclin D1-CDK4/CDK6 complex are promising ...adjuvant/post-neoadjuvant therapeutic strategies. Evaluating Cyclin D1 overexpression in residual tumor could recognize those patients that benefit most from such post-neoadjuvant treatment. In this study, we determined Cyclin D1 expression in residual BC after NACT. Secondary aims were to correlate Cyclin D1 expression levels with clinicopathological parameters and to assess its prognostic value after NACT.
Methods
We retrospectively assessed the nuclear expression of Cyclin D1 on tissue microarrays with residual tumor from 284 patients treated in the neoadjuvant GeparTrio (
n
= 186) and GeparQuattro (
n
= 98) trials. Evaluation was performed with a standardized immunoreactive score (IRS) after selecting a cut-off value.
Results
A high expression level (IRS ≥ 6) of Cyclin D1 was found in 37.3% of the assessed specimens. An increased Cyclin D1 expression was observed in HR-positive tumors, compared to HR-negative tumors (
p
= 0.02). Low Cyclin D1 levels correlated with clinical tumor stage 1–3 (
p
= 0.03). Among patients with HR-positive/Her2-negative tumors and high Cyclin D1 expression, a better disease-free survival (DFS) was graphically suggested, but not significant (
p
= 0.21).
Conclusion
Our study demonstrates a measurable nuclear expression of Cyclin D1 in post-neoadjuvant residual tumor tissue of HR-positive BC. Cyclin D1 expression was not prognostic for DFS after NACT. Our results and defined cut-off suggest that the marker can be used to stratify tumors according to protein expression levels. Based on this, a prospective evaluation is currently performed in the ongoing Penelope-B trial.
Endometriosis is a prevalent benign disease, despite sharing several similarities with malignancies, such as the possibility of lymphatic spread. In malignancies, chemokines play a sovereign role in ...the process of metastasis. Metastasis-related chemokine axes have not yet been assessed in deep-infiltrating endometriosis (DIE), and this investigation was the aim of our study. The expression of these chemokines was investigated by immunohistochemistry in rectovaginal DIE lesions and in matched pelvic sentinel lymph nodes (PSLNs) of patients with endometriosis (n = 27), and their expression in the eutopic endometrium (EE) of endometriosis-free women (n = 20) was used as controls. Their staining pattern in rectovaginal DIE, in endometriotic lesions affecting the PSLN as well as in the EE of patients without endometriosis was characterized for the first time. Overall, these chemokines were highly expressed in DIE and endometriosis in PSLN. Chemokines might be involved in the spread of endometriosis and should be further investigated.
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