[Ovarian cancer: molecular pathology and molecularly targeted therapy]. / Ovarialkarzinom: Molekularpathologie und molekular gesteuerte Therapie.

Ovarian cancer is a common malignant genital neoplasm in women. Due to its frequent diagnosis only in advanced stages, prognosis is poor, although biomarker-driven targeted therapeutic approaches are evolving. These are currently based on molecular pathological analyses of homologous recombination deficiency (HRD) and the BRCA1/2 mutational status. The current CME article focuses on the histo- and molecular pathology of ovarian cancer, relevant molecular mechanisms, and test systems. These are discussed in the context of biomarker-driven targeted therapy.

TERT Promoter Mutation c.-124C>T Commonly Occurs in Low-Grade Fibromatosis-like Metaplastic Breast Carcinoma.

CONTEXT.­: Low-grade fibromatosis-like metaplastic carcinoma (FLMC) is a very rare subtype of triple-negative metaplastic (spindle cell) breast carcinoma. It is characterized by the proliferation of spindle cells closely resembling fibromatosis, which represents a benign fibroblastic/myofibroblastic breast proliferation. Unlike most triple-negative and basal-like breast cancers, FLMC has a very low potential for metastases, but demonstrates frequent local recurrences. OBJECTIVE.­: To genetically characterize FLMC. DESIGN.­: To this end, we analyzed 7 cases by targeted next-generation sequencing for 315 cancer-related genes and performed comparative microarray copy number analysis in 5 of these cases. RESULTS.­: All cases shared TERT alterations (6 patients with recurrent c.-124C>T TERT promoter mutation and 1 patient with copy number gain encompassing the TERT locus), had oncogenic PIK3CA/PIK3R1 mutations (activation of the PI3K/AKT/mTOR pathway), and lacked mutations in TP53. TERT was overexpressed in all FLMCs. CDKN2A/B loss or mutation was observed in 4 of 7 cases (57%). Furthermore, tumors displayed chromosomal stability, with only few copy number variations and a low tumor mutational burden. CONCLUSIONS­: We conclude that FLMCs typically show the recurrent TERT promoter mutation c.-124C>T, activation of the PI3K/AKT/mTOR pathway, low genomic instability, and wild-type TP53. In conjunction with previous data of metaplastic (spindle cell) carcinoma with and without fibromatosis-like morphology, FLMC is most likely distinguished by TERT promoter mutation. Thus, our data support the notion of a distinct subgroup within low-grade metaplastic breast cancer with spindle cell morphology and associated TERT mutations.

Development and validation of a cell cycle progression signature for decentralized testing of men with prostate cancer.

Aim: The 46-gene Prolaris® cell cycle progression test provides information on the risk of prostate cancer progression. Here we developed and validated a 16-gene kit-based version. Methods: RNA was extracted from prostate cancer biopsy tissue. Amplification efficiency, minimum tumor content, repeatability, reproducibility and equivalence with the 46-gene test were evaluated. Results: Amplification efficiencies for all genes were within the acceptable range (90-110%), and samples with ≥50% tumor content were appropriate for the 16-gene test. Results were repeatable (standard deviation: 0.085) and reproducible (standard deviation: 0.115). Instrument, operator and kit lot had minimal impact on results. Cell cycle progression scores from the 46- and 16-gene tests were highly correlated (r = 0.969; bias = 0.217). Conclusion: The 16-gene test performs consistently and similarly to the 46-gene test.

Prostate cancer does not always require aggressive treatment, and some men with low risk of disease progression may chose active surveillance. One way to measure the risk of disease progression is the Prolaris^® cell cycle progression test, which is performed at a commercial testing facility and measures the expression of 46 genes. However, certain European countries would prefer to run this test at a centralized testing facility. To this end we developed a streamlined kit measuring 16 genes to be used in these testing facilities, and showed that the cell cycle progression scores derived from the kit test are robust and equivalent to those obtained with the larger 46-gene test.

Clinically high-risk breast cancer displays markedly discordant molecular risk predictions between the MammaPrint and EndoPredict tests.

Inter-test concordance between the MammaPrint and the EndoPredict tests used to predict the risk of recurrence in breast cancer was evaluated in 94 oestrogen receptor-positive, HER2-negative breast cancers. We correlated histopathological data with clinical risk estimation as defined in the MINDACT trial. 42.6% (40/94) of cases were high-risk by MammaPrint, 44.7% (42/94) by EndoPredict (EPclin), and 45.7% (43/94) by clinical risk definition. Thirty-six percent of genomic risk predictions were discordant with a low inter-test correlation between EndoPredict and MammaPrint (p = 0.012; κ = 0.27, 95% CI [0.069, 0.46]). Clinical risk stratification did not correlate with MammaPrint (p = 0.476) but highly correlated with EndoPredict (p < 0.001). Consequently, clinically high-risk tumours (n = 43) were more frequently high-risk by EndoPredict than by MammaPrint (76.6% vs. 46.5%, p = 0.004), with 44% of cases discordantly classified and no significant association between genomic risk predictions (p = 0.294). Clinicians need to be aware that clinical pre-stratification can profoundly influence multigenomic test performance.

The influence of breast cancer subtypes on axillary ultrasound accuracy: A retrospective single center analysis of 583 women.

INTRODUCTION: Axillary ultrasound staging (AUS) is an important tool to guide clinical decisions in breast cancer therapy, especially regarding axillary surgery but also radiation therapy. It is unknown whether biological subtypes influence axillary staging using ultrasound (AUS). METHOD: This is a retrospective single center analysis. All patients with breast cancer, a preoperative axillary ultrasound and a complete surgical axillary staging were included between 1999 and 2014, except patients with neoadjuvant chemotherapy (NACT). The results of the AUS were compared with final pathological results. Biological subtypes were identified by immunohistochemistry. RESULTS: 583 women were included in the study. Sensitivity, Specificity, positive and negative predictive value for AUS were 39%, 96%, 91% and 83%. While sensitivity was significantly lower in Luminal A and B patients (25.0%; 39.8%) as compared to non Luminal breast cancer patients (TN 68.8%; Her2+ 71.4%; p = 0.0032), there were no significant differences between the groups with respect to specificity, PPV and NPV. CONCLUSION: Solely regarding sensitivity of AUS, our study could show significant differences between biological subtypes of breast cancer with lower sensitivity in Luminal patients. While PPV was excellent, standing for a low overtreatment rate using AUS for clinical decision making, sensitivity was poor overall, comparable to the results of other studies.

One-stop clinical assessment of risk for endometrial hyperplasia (OSCAR-Endo): a fast-track protocol for evaluating endometrial pathologies.

PURPOSE: To evaluate a one-stop clinical assessment of risk for assessing endometrial pathologies (OSCAR-Endo), consisting of a fast-track protocol with hysteroscopy, dilation and curettage (D&C) with intraoperative frozen section analysis of the removed tissue in cases of hysteroscopic suspicion of malignancy. METHODS: In this prospective clinical trial, a total of 304 consecutive women with sonographically suspected endometrial hyperplasia and/or postmenopausal bleeding, underwent D&C with intraoperative frozen section analysis between May 2013 and September 2015. Based on the results of the hysteroscopy and/or frozen section, the OSCAR-Endo score was reported: negative, when no frozen section was regarded necessary or the frozen section yielded a negative result; equivocal, when the frozen section reported an equivocal result; positive, when frozen section reported either complex hyperplasia with atypia or cancer. RESULTS: Frozen sections were required by the surgeons in 59 (19.4%) of cases. When compared with the final histology after D&C, frozen section showed a sensitivity, specificity, PPV, NPV, and overall test accuracy of 91.3, 100, 100, 94.1, and 96.3% for predicting malignant disease, respectively. The OSCAR-Endo score showed a sensitivity, specificity, PPV, NPV, and overall test accuracy of 84, 100, 100, 98.6, and 98.7% for predicting malignant disease, respectively. CONCLUSION: The OSCAR-Endo protocol is easy to perform in daily clinical practice reaching an excellent test accuracy. It helps in immediate postoperative counseling of affected patients. Clinical Trial Registration http://www.clinicaltrials.gov ; NCT01961102.

Pathological Complete Response to Neoadjuvant Trastuzumab Is Dependent on HER2/CEP17 Ratio in HER2-Amplified Early Breast Cancer.

Purpose: To evaluate whether pathologic complete response (pCR) to neoadjuvant trastuzumab is dependent on the level of HER2 amplification.Experimental Design: 114 HER2-overexpressing early breast cancer patients who had received neoadjuvant trastuzumab were included in this study. Absolute HER2 and chromosome 17 centromere (CEP17) were measured by in situ hybridization analysis, and associations were examined between HER2/CEP17 ratio and tumor pCR status (commonly defined by ypT0 ypN0, ypT0/is ypN0, and ypT0/is).Results: In trastuzumab-treated patients, ypT0 ypN0 was achieved in 69.0% of patients with high-level amplification (HER2/CEP17 ratio > 6), but only in 30.4% of tumors with low-level amplification (ratio ≤ 6; P = 0.001). When pCR was defined by ypT0/is ypN0 or ypTis, 75.9% and 82.8% of tumors with high-level amplification had a complete response, whereas only 39.1%, and 38.3% with low-level amplification achieved pCR (P = 0.002 and P < 0.001, respectively). Logistic regression revealed that tumors with high-level amplification had a significantly higher probability achieving ypT0 ypN0 (OR, 5.08; 95% confidence interval, 1.86-13.90; P = 0.002) than tumors with low-level amplification, whereas no other clinicopathologic parameters were predictive of pCR. The association between high-level HER2 amplification and pCR was almost exclusively confined to hormone receptor (HR)-positive tumors (ypT0 ypN0: 62.5% vs. 24.0%, P = 0.014; ypT0/is ypN0: 75.0% vs. 28.0%, P = 0.005; and ypT0/is: 87.5% vs. 28.0%, P < 0.001), and was largely absent in HR-negative tumors.Conclusions: An HER2/CEP17 ratio of >6 in the pretherapeutic tumor biopsy is associated with a significantly higher pCR rate, particularly in HER2/HR copositive tumors, and can be used as a biomarker to predict response before neoadjuvant trastuzumab is initiated. Clin Cancer Res; 23(14); 3676-83. ©2017 AACR.

Potential Targets' Analysis Reveals Dual PI3K/mTOR Pathway Inhibition as a Promising Therapeutic Strategy for Uterine Leiomyosarcomas-an ENITEC Group Initiative.

Purpose: Uterine sarcomas are rare and heterogeneous tumors characterized by an aggressive clinical behavior. Their high rates of recurrence and mortality point to the urgent need for novel targeted therapies and alternative treatment strategies. However, no molecular prognostic or predictive biomarkers are available so far to guide choice and modality of treatment.Experimental Design: We investigated the expression of several druggable targets (phospho-S6S240 ribosomal protein, PTEN, PDGFR-α, ERBB2, and EGFR) in a large cohort of human uterine sarcoma samples (288), including leiomyosarcomas, low-grade and high-grade endometrial stromal sarcomas, undifferentiated uterine sarcomas, and adenosarcomas, together with 15 smooth muscle tumors of uncertain malignant potential (STUMP), 52 benign uterine stromal tumors, and 41 normal uterine tissues. The potential therapeutic value of the most promising target, p-S6S240, was tested in patient-derived xenograft (PDX) leiomyosarcoma models.Results: In uterine sarcomas and STUMPs, S6S240 phosphorylation (reflecting mTOR pathway activation) was associated with higher grade (P = 0.001) and recurrence (P = 0.019), as shown by logistic regression. In addition, p-S6S240 correlated with shorter progression-free survival (P = 0.034). Treatment with a dual PI3K/mTOR inhibitor significantly reduced tumor growth in 4 of 5 leiomyosarcoma PDX models (with tumor shrinkage in 2 models). Remarkably, the 4 responding models showed basal p-S6S240 expression, whereas the nonresponding model was scored as negative, suggesting a role for p-S6S240 in response prediction to PI3K/mTOR inhibition.Conclusions: Dual PI3K/mTOR inhibition represents an effective therapeutic strategy in uterine leiomyosarcoma, and p-S6S240 expression is a potential predictive biomarker for response to treatment. Clin Cancer Res; 23(5); 1274-85. ©2017 AACR.

Exploring chromosomal abnormalities and genetic changes in uterine smooth muscle tumors.

Smooth muscle tumors of the uterus are a diagnostically challenging group of tumors. Molecular surrogate markers reliably distinguishing between benign and malignant tumors are not available. Therefore, the diagnosis is based on morphologic criteria. The aim was to investigate a well-characterized group of challenging uterine smooth muscle tumors consisting of 20 leiomyomas, 13 leiomyomas with bizarre nuclei, and 14 leiomyosarcomas for copy number alterations, MED12 mutations and FH deletions to search for potential diagnostically useful surrogate markers. MED12 mutations were detected in 47, 15, and 25% of leiomyomas, leiomyomas with bizarre nuclei and leiomyosarcomas, respectively. MED12 mutations in leiomyomas with bizarre nuclei were detected outside the hotspot region. FH-deletions were seen in 27, 30.8, and 25% of leiomyomas, leiomyomas with bizarre nuclei and leiomyosarcomas, respectively. By using copy number alteration profiling a clear separation of leiomyomas, leiomyomas with bizarre nuclei and leiomyosarcomas could not be observed. Copy number alterations revealed clear genetic similarities between leiomyomas with bizarre nuclei and leiomyosarcomas. Leiomyosarcomas showed a similar pattern of gains and losses as leiomyomas with bizarre nuclei, with additional copy number alterations and more homozygous losses and high-level amplifications compared to leiomyomas with bizarre nuclei. In conclusion, this study demonstrates that known FH-deletions, a recurrent molecular change in leiomyomas, occur in morphologically challenging variants of leiomyomas, leiomyomas with bizarre nuclei and leiomyosarcomas. Although MED12 mutations are common in leiomyomas, they infrequently occur in leiomyomas with bizarre nuclei and leiomyosarcomas. The genetic similarities between leiomyomas with bizarre nuclei and leiomyosarcomas raise the intriguing possibility that uterine leiomyomas with bizarre nuclei and leiomyosarcomas are closely related and challenge the traditional concept that leiomyoma with bizarre nuclei is a tumor with just marked 'degenerative' cellular changes. These findings support the hypothesis that tumor progression within uterine smooth muscle tumors might occur.

Expression of C-KIT, CD24, CD44s, and COX2 in benign and non-invasive apocrine lesions of the breast.

Benign apocrine metaplasia (AM) of the adult breast is a very common, but enigmatic lesion. It has been speculated that AM might be a precursor of malignancy or an indicator of a susceptibility of the breast tissue to develop neoplasia, mainly based on comparing the frequency of AM in breast cancer and non-breast cancer patients [1]. Studies using comparative genomic hybridization have supported this by showing similar molecular alterations in benign and malignant apocrine lesions [2]. Few studies, however, have compared expression of biomarkers involved in tumor progression in AM and progressively more advanced atypical apocrine lesions. The expression of C-KIT, COX2, CD24, and CD44s was evaluated by immunohistochemistry in formalin-fixed, paraffin-embedded material of 9 AM, 20 apocrine ductal intraepithelial neoplasia (DIN1c-3) and 40 atypical apocrine lesions (not qualifying for DIN1c-3) and compared to expression of the same biomarkers in adjacent normal ductal epithelium. Of the 66 apocrine lesions, 62 (94 %) did not express C-KIT compared to 4/63 (6 %) of the normal glands (Fisher's exact, p < 0.001). COX2 was expressed in a significantly higher proportion of apocrine lesions than of normal glands (49 vs. 14 %, p < 0.001), and the number of apocrine lesions positive for CD24 was found to be higher with increasing aggressiveness of the lesions (Spearman, p < 0.001). In conclusion, benign and non-invasive proliferative apocrine lesions of the breast display immuno-phenotypical characteristics previously ascribed mainly to malignant transformation. This could lend support to the theory that AM is an early step towards malignant transformation, albeit associated with slow progression to carcinoma.

Mutation Profiling of Usual Ductal Hyperplasia of the Breast Reveals Activating Mutations Predominantly at Different Levels of the PI3K/AKT/mTOR Pathway.

Usual ductal hyperplasia (UDH) of the breast is generally regarded as a nonneoplastic proliferation, albeit loss of heterozygosity has long been reported in a part of these lesions. To gain deeper insights into the molecular drivers of these lesions, an extended mutation profiling was performed. The coding regions of 409 cancer-related genes were investigated by next-generation sequencing in 16 cases of UDH, nine unassociated with neoplasia (classic) and seven arising within papillomas. Phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (mTOR) activation was investigated by phosphorylated AKT, mTOR, and S6 immunohistochemistry. Of 16 lesions, 10 (63%) were mutated; 56% of classic lesions were unassociated with neoplasia, and 71% of lesions arose in papillomas. Fourteen missense mutations were detected: PIK3CA [6 (43%) of 14], AKT1 [2 (14%) of 14], as well as GNAS, MTOR, PIK3R1, LPHN3, LRP1B, and IGF2R [each 1 (7%) of 14]. Phosphorylated mTOR was seen in 83% and phosphorylated S6 in 86% of evaluable lesions (phospho-AKT staining was technically uninterpretable). In conclusion, UDH displays mutations of the phosphatidylinositol 3-kinase/AKT/mTOR axis at different levels, with PIK3R1, MTOR, and GNAS mutations not previously described. Specifically, oncogenic G-protein activation represents a yet unrecognized route to proliferation in UDH. On the basis of evidence of activating mutations, loss of heterozygosity, and a mass forming proliferation, we propose that UDH is most appropriately viewed as an early neoplastic intraductal proliferation.

Genomic characterization of endometrial stromal sarcomas with array comparative genomic hybridization.

INTRODUCTION: The endometrial stromal sarcoma (ESS) is a very rare uterine sarcoma, counting for 1-3% of all gynecologic malignancies. ESS represents 0.2-8% of all uterine malignant tumors and accounts for about 10% of all uterine sarcomas. With regard to chromosomal aberrations, very little is known about benign and malignant endometrial stromal tumors. METHODS: 30 tumors, consisting of 4 cases of benign endometrial stromal nodule (ESN), 22 cases of low-grade ESS and 4 cases of undifferentiated endometrial sarcoma (UES), were analyzed by array-comparative genomic hybridization (aCGH). RESULTS: ESN did not show many copy number changes (CNCs) by aCGH. Frequent losses could be identified on chromosomes 7p and 19, and gains on chromosomes 1q, 6p and 8q. Low-grade ESS presented as a very heterogeneous group. 90% (20/22) of cases displayed aberrations. Most frequent changes were losses on chromosomes 7 and 22, and gains on chromosome 1q or 11. UES showed a high number of chromosomal aberrations and on every chromosome CNCs were detected. Most frequent changes were losses on chromosomes 1q, 2q (3/4, 75%) and 13, and gains on chromosomes 1q and 17p. CONCLUSION: Our data shows an increasing number of CNCs from ESN to low-grade ESS and to UES. However, the chromosomal aberrations differ considerably between the investigated ESN-, low-grade ESS- and UES cases and thus, a linear tumor progression seems to be unlikely.

Tumour-to-tumour metastasis: male breast carcinoma metastasis arising in an extrapleural solitary fibrous tumour - a case report.

BACKGROUND: Tumour-to-tumour metastasis (TTM) occurs when one tumour metastasises to a separate tumour within the same individual. TTM is observed frequently in breast cancer but has not been described in male breast cancer. In addition reports describing solitary fibrous tumours (SFT) of the pleura hosting other neoplasms' metastases are limited. We report an exceptional case of male breast cancer metastasising to an extrapleural SFT, occurring in the subcutaneous tissue of the back of a 68-year old Caucasian patient. CASE PRESENTATION: A 68-year old male was diagnosed with a metastasising ductal breast cancer. He was treated by mastectomy of the right breast and axillary lymph-adenectomy. Further staging revealed an increasing subcutaneous expansion located on the patient's back. Excision biopsy confirmed a SFT hosting a breast cancer metastasis. The patient received palliative chemotherapy but died of disease seven years after initial diagnosis. CONCLUSIONS: The abundance of blood vessels within these lesions might predispose SFTs for an involvement in TTM. This case describes the possibility of concurrent rare occurrences and reminds clinicians, as well as pathologists, to be open-minded and fastidious about their differential diagnoses, sampling and examination of histological specimens. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_203.

Fractal analysis of cervical intraepithelial neoplasia.

INTRODUCTION: Cervical intraepithelial neoplasias (CIN) represent precursor lesions of cervical cancer. These neoplastic lesions are traditionally subdivided into three categories CIN 1, CIN 2, and CIN 3, using microscopical criteria. The relation between grades of cervical intraepithelial neoplasia (CIN) and its fractal dimension was investigated to establish a basis for an objective diagnosis using the method proposed. METHODS: Classical evaluation of the tissue samples was performed by an experienced gynecologic pathologist. Tissue samples were scanned and saved as digital images using Aperio scanner and software. After image segmentation the box counting method as well as multifractal methods were applied to determine the relation between fractal dimension and grades of CIN. A total of 46 images were used to compare the pathologist's neoplasia grades with the predicted groups obtained by fractal methods. RESULTS: Significant or highly significant differences between all grades of CIN could be found. The confusion matrix, comparing between pathologist's grading and predicted group by fractal methods showed a match of 87.1%. Multifractal spectra were able to differentiate between normal epithelium and low grade as well as high grade neoplasia. CONCLUSION: Fractal dimension can be considered to be an objective parameter to grade cervical intraepithelial neoplasia.

Molecular mechanisms of endometrial stromal sarcoma and undifferentiated endometrial sarcoma as premises for new therapeutic strategies.

Endometrial stromal sarcoma (ESS) and undifferentiated endometrial sarcoma (UES) are very rare gynecologic malignancies. Due to the rarity and heterogeneity of these tumors, little is known about their epidemiology, pathogenesis, and molecular pathology. Our previous studies have described deregulation of histone deacetylases expression in ESS/UES samples. Some of these enzymes can be inhibited by substances which are already approved for treatment of cutaneous T-cell lymphoma. On the basis of published data, they may also provide a therapeutic option for ESS/UES patients. Our review focuses on molecular mechanisms of ESS/UES. It describes various aspects with special emphasis on alteration of histone deacetylation and its possible relevance for novel therapies.

Antiestrogenic effects of the fetal estrogen estetrol in women with estrogen-receptor positive early breast cancer.

Estetrol (E4) is a fetal estrogen with estrogenic effects on reproductive organs and bone in preclinical models and in postmenopausal women. However, E4 exerts antiestrogenic effects on breast cancer (BC) cell growth in vitro and in vivo. We have investigated the effect of 14 days preoperative treatment with 20mg E4 per day on tumor proliferation markers, sex steroid receptor expression and endocrine parameters in a prospective, randomized, placebo-controlled, preoperative window trial in 30 pre- and post-menopausal women with estrogen-receptor positive early BC. E4 had a significant pro-apoptotic effect on tumor tissue, whereas Ki67 expression remained unchanged in both pre- and post-menopausal women. E4 increased sex-hormone-binding globulin significantly thereby reducing the concentrations of bioavailable estradiol. Follicle-stimulating hormone levels decreased in postmenopausal women only and luteinizing hormone levels remained unchanged. Systemic insulin growth factor-1 levels decreased significantly. Intratumoral epithelial ERα expression decreased significantly and a trend was found towards an increased expression of ERß. This clinical data support the preclinical findings that E4 has antiestrogenic effects on BC cells, whereas earlier studies have shown that E4 has estrogenic effects on reproductive tissues and bone. Further clinical studies seem acceptable and are needed to confirm the safety and efficacy of E4 for the breast in hormone replacement therapy, including hormone replacement therapy in women who have or have had BC, especially in those BC patients treated with aromatase inhibitors and suffering from serious complaints due to estrogen deficiency.

Effects of targeting endometrial stromal sarcoma cells via histone deacetylase and PI3K/AKT/mTOR signaling.

AIM: Endometrial stromal sarcoma (ESS) is a rare gynecological mesenchymal malignancy with only few therapeutic options. This study aimed to investigate the efficacy of the histone deacetylase (HDAC) inhibitor suberanilohydroxamic acid (SAHA) combined with inhibitors of the phosphoinositid-3-Kinase (PI3K) pathway in ESS therapy. MATERIALS AND METHODS: The effects of SAHA combined with inhibitor of PI3K (LY294002, LY), mammalian target of rapamycin mTOR (rapamycin), and their combination on cell growth and the PI3K pathway in two ESS cell lines (ESS-1 and MES-SA) and one non-neoplastic cell line HESC, were investigated. RESULTS: SAHA reduced growth of the three cell lines by inhibiting protein kinase B AKT and mTOR/p70S6K cascade activation. SAHA combined with LY or rapamycin, or both, synergistically reduced p-p70S6K and p-4E-BP1 levels. SAHA combined with LY and rapamycin led to the strongest growth inhibition and slowest growth recovery among the combination treatments. CONCLUSION: SAHA combined with inhibition of PI3K and mTOR could represent an efficient therapy option for patients with ESS.

A case report of an ependymoblastoma in the rectovaginal space and a review of the literature.

INTRODUCTION: Ependymomas are glial neoplasms that arise at or close to the inner ependymal surface of the ventricular system. They are most frequently located intraventricularly, but they may also occur in the spinal cord or, very seldom, at extraneural sites. Here we report a case of an ectopic ependymoma, arising in the pelvic cavity. CASE REPORT: A 35 year-old female patient was diagnosed with a suspect tumor mass in the rectovaginal space, infiltrating the perirectal adipose tissue and the vagina. Three years later, liver and peritoneal metastases of the same tumor were diagnosed. Two years after that, the patient experienced a recidive in the left adnexa. Histological analysis revealed an anaplastic tumor of dual nature, comprising of mesenchymal and epithelial features. There were ependymoma-like rosettes and pseudorosettes, indicating an ependymal differentiation. Immunohistochemically, the tumor was positive for epithelial membrane antigen (EMA) and glial fibrillary acidic protein (GFAP). Accordingly, the diagnosis "grade 3 ependymoma, i.e. ependymoblastoma" was made. REVIEW: Ependymomas are most frequently located in the ventricular system, but may also occur in the spinal cord or rarely at extraneural sites. Extraneural ependymomas represent a diagnostic challenge, since they can mimic other tumor types and the immunohistochemical profile may be non-specific. The most important features of ependymal differentiation are rosette- or pseudorosette formation. Extraneural ependymomas can be located in the ovary or elsewhere in the pelvic cavity. Locations in the lung, liver and the small bowel have also been described. In the present article we review several reported cases of ectopic, extraneural ependymomas. DISCUSSION: The origin of extraneural ependymomas is not completely clarified. They probably arise from glial tissue that is a residue from the embryonic development, pinched-off from the neural tube during its closure. We propose, that extraneural ependymoma should be considered in differential diagnosis for anaplastic tumors of the pelvic cavity.