Clinical significance of p95HER2 overexpression, PTEN loss and PI3K expression in p185HER2-positive metastatic breast cancer patients treated with trastuzumab-based therapies.

Retraction to: British Journal of Cancer (2014) 110, 1968-1976; doi:10.1038/bjc.2014.72. It has been brought to our attention that, as a result of a miscommunication, the antibody used in this study in order to determine the expression of p95 HER2 in metastatic breast cancer patients is in fact directed against p95 NBS1, a component of the MRN complex, and is completely unrelated to p95 HER2. Therefore, a relationship between p95 HER2 overexpression and outcome cannot be established based on the results described and we wish to retract our paper. The authors, the editors of British Journal of Cancer, and the referees of this paper are grateful to colleagues in the field who have brought this problem to our attention and we apologise for any confusion that has, inadvertently, been caused.

Clinical significance of p95HER2 overexpression, PTEN loss and PI3K expression in p185HER2-positive metastatic breast cancer patients treated with trastuzumab-based therapies.

BACKGROUND: Overexpression of p185HER2 is an established poor prognostic factor in breast cancer, portending an aggressive course and potential for early metastasis. On the other hand, monoclonal antibody trastuzumab is widely used in the clinic to target this overexpressed oncogene. Unfortunately, ~30-40% of all patients overexpressing HER2 respond to trastuzumab, warranting further research regarding the structure and additional modulation of the receptor. In this study, we aimed to investigate the response to trastuzumab in terms of the potential roles of several oncogenic pathways (phosphatase and tensin homologue (PTEN) and phosphatidylinositol 3-kinase (PI3K)) and a truncated receptor protein, p95HER2, retrospectively. MATERIALS AND METHODS: Paraffin-embedded primary tumour tissues of 100 HER2-positive metastatic breast cancer patients who received trastuzumab with combination cytotoxic chemotherapy were analysed with immunohistochemical method for p95HER2, p85 (PI3K) and PTEN. Relationship between variables were tested via χ(2), Fischer's exact test and Mann-Whitney U tests, wherever appropriate. Progression-free survival (PFS) and overall survival (OS) periods were calculated with Kaplan-Meier method and survival curves of subgroups were compared with log-rank test. RESULTS: Percentage of patients was found to be 33%, 57% and 42% positive for p95 expression, PTEN and PI3K, respectively. p95-expressing tumours had statistically lower response rates for trastuzumab than tumours not expressing p95 (P=0.001). On the contrary, PTEN-expressing tumours had statistically higher response rates for trastuzumab than tumours not expressing PTEN (P=0.012). PI3K expression had no significant effect on trastuzumab response. Median PFS for p95-expressing and not expressing tumours were 8 months (95% CI, 2.5-13.4 months) and 22 months (95% CI, 9.9-34 months), respectively (P=0.0001). Median PFS for PTEN-expressing and not expressing tumours were 15.3 months (95% CI, 12.6-34 months) and 12.1 months (95% CI, 7.9-16.2 months), respectively (P=0.04). Median OS for p95-expressing and not expressing tumours were 24 months (95% CI, 8.3-40.4 months) and 29.1 months (95% CI, 8.6-43.2 months), respectively (P=0.045). Median OS for PTEN-expressing and not expressing tumours were 25.1 months (95% CI, 7.5-40.1 months) and 26.8 months (95% CI, 8.1-42 months), respectively, which was not statistically significant (P=0.5). Level of PI3K expression had no effect on PFS and OS in our patient population. Presence of visceral metastases HR=2.38 ((95% CI, 1.2-4.5), P=0.009), p95 expression HR=2.1 ((95% CI, 1.1-3.7), P=0.03) and response to trastuzumab HR=2.2 ((95% CI, 1.18-4.47), P=0.014) are identified as factors independently affecting PFS. Response to trastuzumab HR=1.7 ((95% CI, 1.14-3.47), P=0.013) was identified as the single parameter influencing survival by Cox regression analysis. CONCLUSIONS: Presence of p95 predicted a poorer response to trastuzumab treatment, shorter PFS and OS in our HER2-positive metastatic breast cancer cohort. In addition, loss of PTEN predicted a poorer response to trastuzumab treatment and shorter PFS but not OS. We could not find an effect of PI3K expression on the above-mentioned parameters.

Clinicopathologic and prognostic evaluation of invasive breast carcinoma molecular subtypes and GATA3 expression.

PURPOSE: recently, molecular subclassification of breast carcinomas has been proposed as a new prognostic parameter. METHODS: we classified 222 invasive breast carcinoma cases in 5 molecular subtypes by using tissue microarray (TMA) and immunohistochemistry methods. These subtypes were luminal A (estrogen receptor/ER and/or progesterone receptor/ PR positive), luminal B (ER and/or PR positive + HER2 positive), HER2-expressing type (ER and PR negative, HER2 positive), basal-like type (ER, PR and HER2 negative, positive with at least one of these myoepithelial markers: CK5/6, CK14, EGFR) and null type (ER, PR, HER2 and myoepithelial markers negative). We compared these subtypes according to their clinicopathological features and GATA3 expression. RESULTS: luminal A was the most frequent subtype. According to overall survival rates, HER2-expressing and basal- like types had the worst prognosis, while luminal A had the best. However, luminal B had the worst prognosis according to disease free survival. Most of the squamous differentiated metaplastic carcinomas were basal-like type. Tubular and mucinous carcinomas were luminal A. Most basal-like tumors were grade III. The majority of grade I tumors were luminal A. GATA3 positivity was associated with low grade tumors and luminal A subtype. CONCLUSION: molecular classification can be accepted as an independent prognostic factor for invasive breast carcinomas. GATA3 expression was associated with luminal A and low histological grade. However, it wasn't shown as an independent parameter.

Metastasis from breast carcinoma to endometrial polyp.

Metastasis of a breast carcinoma to an endometrial polyp is extremely rare, with only ten cases having been reported in the literature up to now. We present the case of a 60-year-old woman with invasive ductal carcinoma who complained of vaginal bleeding. She underwent hysteroscopy with biopsy. Microscopic examination revealed an endometrial polyp which contained foci of adenocarcinoma. The morphologic features of the tumor were identical to the original breast carcinoma.

Determining predominating histologic component in malignant mixed müllerian tumors: is it worth it?

Malignant mixed müllerian tumors (MMMT) are highly aggressive tumors, usually diagnosed in advanced stage. Cases of MMMT derive from either ovary or uterus. In our study, we investigated the role of carcinomatous and sarcomatous component on response to chemotherapy and disease outcome. We retrospectively analyzed 25 patients with MMMT who were treated in our outpatient clinic from 1998 to 2003. All the paraffin specimens were reevaluated according to the histopathologic features (primary site and percentages of carcinomatous and sarcomatous component) and the effect of predominant histologic type on response to treatment. Primary tumor sites were ovary and endometrium in 36% and 64% of patients, respectively. Ten of 25 patients (40%) were treated with a combination chemotherapy regimen of cisplatin-ifosfamide (PI) and 7 patients (28%) were treated with paclitaxel-carboplatin (PC) protocol. Despite chemotherapy, 17.6% of patients had progressive disease. The remaining 13 patients (54.2%) responded to chemotherapy. Response rates of patients treated with PC (100%) were remarkably higher than the response rates of patients treated with PI (66.6%). Moreover, patients with predominating carcinomatous component had a higher response rate (87.5%) than patients with predominating sarcomatous component (66.6%). MMMT are highly chemoresponsive tumors, irrespective of primary site. One of the best predictors to response is the histologic pattern. Predominating histopathologic feature (carcinoma or sarcoma) should be taken into consideration in predicting the response and planning the chemotherapy regimen.

Skin metastasis in ovarian carcinoma.

We report a case of 69-year-old woman who presented with pleural metastasis of a serous papillary adenocarcinoma of the ovary. After chemotherapy and surgery, she had 2 years disease-free survival. After this period of time, she presented with a swollen leg, a cellulitis-like syndrome and erythematous nodules at lower abdominal wall and upper leg skin. The skin biopsy revealed metastasis of adenocarcinoma in the dermis. She died after 4 months of the diagnosis of the skin metastasis. In 20 years experience in our unit, it is the first time that we recognize a cutaneous metastasis in ovarian cancer.

Placental apoptosis and adhesion molecules expression in the placenta and the maternal placental bed of pregnancies complicated by fetal growth restriction with and without pre-eclampsia.

The aim of the study was to examine the expression of adhesion molecules VCAM-1 and ICAM-3 in placental tissue samples and placental bed (maternal decidual tissue) biopsies of pregnancies complicated by pre-eclampsia (PE) and fetal growth restriction (FGR), and to determine whether PE and FGR are associated with an increase in placental apoptosis. We studied placentas and placental bed samples of 49 third trimester pregnancies complicated by FGR (26 with associated PE, 23 without PE) and 25 normotensive healthy pregnant women. Placental apoptosis was assessed by the TUNEL method. Immunohistochemistry was used to assess expression of the VCAM-1 and ICAM-3. There was no significant difference in the staining intensity of VCAM-1 in placentas (p=0.472) and placental bed biopsies (p=0.754) of women delivering appropriate for gestational age and growth restricted fetuses (with and without associated PE). The amount of lymphocytes staining positively with ICAM-3 was significantly higher in both placental and placental bed biopsies of women delivering growth restricted fetuses compared with control pregnancies (p<0.001). Fetal growth restricted pregnancies with associated PE showed higher staining of ICAM-3 in placental compared with placental bed samples (p=0.049). In fetal growth restricted placentas, apoptotic nuclei were more abundant compared with control placentas (p<0.001). Increased expression of ICAM-3 on lymphocyte surface of both maternal and fetal side, suggests lymphocyte overactivation in PE and FGR. Increased placental apoptosis may play an important role in the pathogenesis or sequelae of PE.

Lymphangioma of the ovary: a case report and review of the literature.

Lymphangioma of the ovary is a very rare tumor which is usually silent and identified incidentally at operation or autopsy. We report on a 61-year-old woman with lymphangioma of the ovary and review the relevant literature. The microscopic examination of the left ovary revealed numerous vascular spaces of different dimensions of which the inner surfaces were lined with flattened endothelial cells with neither cellular atypia nor extraluminal or intraluminal proliferation. There was no evidence of haemorrhage or necrosis. The stroma was formed by fibrocollagenous tissue infiltrated by rare lymphocytes. The cells lining vascular spaces were immunoreactive for CD31 by immunohistochemical staining.

A case with multiple gynecological malignancies.

A patient with cervical non-Hodgkin lymphoma was treated with chemotherapy. Fourteen months after the diagnosis of the lymphoma, an endometrial adenocarcinoma was detected as a secondary malignant tumor. The patient was treated with surgery followed by radiotherapy. Approximately 7 years after the diagnosis of endometrial cancer, vaginal invasive squamous cell carcinoma was diagnosed as the third primary malignancy, and a second-line palliative radiotherapy was applied. Seven months after the last radiotherapy, postradiational sarcoma in the vagina was diagnosed. Congenital and acquired immune system disorders, viral oncogenes, and various human leukocyte antigen (HLA) types were investigated. Total blood count and lymphocyte subset analysis were performed, and CD4+ lymphopenia was detected. Serologic tests were carried out for human immunodeficiency virus, hepatitis B virus, human papillomavirus, Epstein-Barr virus, and herpes simplex virus infection. Epstein-Barr virus viral capsid antigen IgG was found positive. Low-risk human papillomavirus panel was detected by Hybrid Capture method in the cervical smear. The HLA investigation revealed HLA-A2, HLA-A3, HLA-B57, HLA-B35, HLA-B4, HLA-B6, HLA-DR3, HLA-DR1, HLA-DR51, HLA-DR52, HLA-DQ6(1), and HLA-DQ7(3). The patient died because of the disease.

Immunohistochemical analysis of prostate-specific antigen in female breast cancer.

PURPOSE: Prostate-specific antigen (PSA), a glycoprotein initially thought to be produced only by the epithelial cells of the prostate, has recently been found in various tissues and tumors. It has been suggested that the expression of PSA in breast cancer is a good prognostic indicator and correlated with favorable prognosis. However, in recent years opposite results have been reported. In this study, we investigated the immunoreactivity of PSA in female breast cancer to find out any relationship between PSA and prognostic parameters. PATIENTS AND METHODS: Sections of formalin-fixed, paraffin- embedded samples from 109 invasive ductal carcinomas were immunostained for PSA. The staining results were analyzed in relation to age, tumor size, histologic grade, axillary lymph node status and steroid receptors. RESULTS: PSA immunoreactivity was seen in only 11 (10.1%) out of 109 cases. All PSA positive cases were also estrogen (ER) and progesterone receptor (PR) positive. We found a statistically significant correlation between PSA and the expression of steroid receptors, while no correlation was detected with the other factors. CONCLUSION: The detection of PSA, using immunohistochemistry, does not seem to be a reliable prognostic criterion for female breast cancer patients or a marker of tumor origin.

Sclerosing stromal tumor of the ovary: report of three cases.

We present 3 cases displaying sclerosing stromal tumor (SST) of the ovary and describe their immunohistochemical and electron microscopic findings. The patients were 23, 24 and 28-year-old and had an ovarian mass. Histologically, the tumors had the typical appearance of SST of the ovary. A pseudolobular pattern which was composed of cellular areas and less cellular areas was seen on low-power microscopy.

Extensive pelvic endometriosis with malignant change in tamoxifen-treated postmenopausal women.

The aim of this study was to document a case of tamoxifen-associated extensive pelvic endometriosis and attract the attention to this side effect of tamoxifen use in the postmenopausal patient. A 74-year-old woman with a history of breast carcinoma who received tamoxifen therapy for 2 years was admitted with uterine bleeding. Hysteroscopic polypectomy revealed a hyperplastic polyp. Extensive pelvic endometriosis was detected at the operation and due to dense adhesions, subtotal hysterectomy and bilateral salpingo-oophorectomy were performed. The patient continued to use tamoxifen. A supracervical pelvic mass was detected 14 months later. The cervix, rectum, and the accompanying mass were resected. Histopathologic examination revealed endocervical adenocarcinoma and endometriosis involving cervix uteri and the rectal muscular wall. The patient had two normal cervical smears within the last 3 years and no abnormal appearance was detected within the cervical canal in the hysteroscopic examination. As cervical cancer occurred in a short period, it might be speculated that tamoxifen might have stimulated the proliferative and mitotic activity of cervical endometrial tissue which has progressed into invasive cancer in time.

Histomorphology of the placenta and the placental bed of growth restricted foetuses and correlation with the Doppler velocimetries of the uterine and umbilical arteries.

The aim of the present study was to evaluate the histomorphology of the placenta and the placental bed and to correlate this with the Doppler study of the uterine and umbilical arteries of intrauterine growth restricted pregnancies. The study group consisted of 47 women with intrauterine growth restricted foetuses. Twenty-five uneventful pregnancies with appropriate for gestational age foetuses were selected as controls. Doppler studies of umbilical and uterine arteries were performed within the last week before delivery. Placental bed biopsies were obtained at Caesarean section with direct visualization of the placental site. The incidence of pathologic bed biopsies in control, IUGR with normal uterine artery Doppler velocimetry and IUGR with abnormal uterine artery Doppler velocimetry was 0 per cent, 16.6 per cent and 79.3 per cent respectively (P< 0.001). Placentae from IUGR cases with abnormal umbilical artery Doppler velocimetries had a significantly increased number of villous infarcts, cytotrophoblast proliferation and thickening of the villous trophoblastic basal membrane (P=0.001, P=0.038 and P=0.02 respectively). Abnormal placental bed biopsy pathology was significantly associated with abnormal uterine artery velocimetry (OR 33.7, 6.5-173.6; P< 0.001). Abnormal placental pathology was significantly associated with abnormal umbilical artery Doppler velocimetry (OR 21.04, 3.8-115.9;P< 0.001). Women with both abnormal uterine and umbilical artery Doppler velocimetries were delivered earlier and their babies had lower mean birth and placental weight (P< 0.001). In conclusion, placental bed biopsy and placental pathologies are best reflected by abnormal uterine and umbilical artery velocity waveforms, respectively. The most severe clinical outcomes and perinatal mortality are present when both uterine and umbilical districts are altered.

Congenital generalized infantile myofibromatosis and neonatal hemochromatosis. An autopsy case report.

An autopsy case of congenital infantile myofibromatosis and neonatal hemochromatosis is reported. A thirty-six-hour-old baby girl had multiple subcutaneous nodules in addition to multiple visceral involvement of heart, lungs, pharynx, larynx, stomach, small bowel, large bowel, pancreas, kidneys, spleen, thyroid, adrenal glands, lymph nodes, peripheral nerves, meninges and soft tissues. In these tumoral nodules, three types of histological patterns were observed: 1-hemangiopericytoma-like, 2-mixed, and 3-pure spindle cell. Tumor cells were immunohistochemically positive for actin, and negative for desmin, muscle-specific antigen, and estrogen, related protein. The histological and immunohistochemical findings of the case suggested that a close relationship may exist between infantile myofibromatosis and infantile hemangiopericytoma. In addition to infantile myofibromatosis, neonatal hemochromatosis characterized by iron deposition in parenchymatous organs such as liver, pancreas, lungs, thyroid, and adrenal glands was another important characteristic of the case.

Bilateral inflammatory breast metastases of epithelial ovarian cancer.

Metastases to the breast are rare. Secondary breast involvement from an epithelial ovarian cancer heralds widespread dissemination and a very poor prognosis. We report an unusual case of a patient who had epithelial ovarian cancer and who showed signs of recurrence with inflammatory metastases to both breasts, 2 years after her diagnosis of ovarian cancer. She died within 3 months of breast involvement. Our case has unique features, with both bilateral breast metastases and also with its inflammatory pattern of metastasis, which is extremely rare.