Metastatic Serous Ovarian Carcinoma Research Articles

Metastatic ovarian cancer spreading into mammary ducts mimicking an in situ component of primary breast cancer: a case report

BackgroundAccurate diagnosis of metastatic tumors in the breast is crucial because the therapeutic approach is essentially different from primary tumors. A key morphological feature of metastatic tumors is their lack of an in situ carcinoma component. Here, we present a unique case of metastatic ovarian carcinoma spreading into mammary ducts and mimicked an in situ component of primary carcinoma. To our knowledge, this is the second case (and the first adult case) confirming the in situ-mimicking growth pattern of a metastatic tumor using immunohistochemistry.Case presentationA 69-year-old Japanese woman was found to have a breast mass with microcalcifications. She had a known history of ovarian mixed serous and endocervical-type mucinous (seromucinous) carcinoma. Needle biopsy specimen of the breast tumor revealed adenocarcinoma displaying an in situ-looking tubular architecture in addition to invasive micropapillary and papillary architectures with psammoma bodies. From these morphological features, metastatic serous carcinoma and invasive micropapillary carcinoma of breast origin were both suspected. In immunohistochemistry, the cancer cells were immunoreactive for WT1, PAX8, and CA125, and negative for GATA3, mammaglobin, and gross cystic disease fluid protein-15. Therefore, the breast tumor was diagnosed to be metastatic ovarian serous carcinoma. The in situ-looking architecture showed the same immunophenotype, but was surrounded by myoepithelium confirmed by immunohistochemistry (e.g. p63, cytokeratin 14, CD10). Thus, the histogenesis of the in situ-like tubular foci was could be explained by the spread of metastatic ovarian cancer cells into existing mammary ducts.ConclusionMetastatic tumors may spread into mammary duct units and mimic an in situ carcinoma component of primary breast cancer. This in situ-mimicking growth pattern can be a potential pitfall in establishing a correct diagnosis of metastasis to the breast. A panel of breast-related and extramammary organ/tumor-specific immunohistochemical markers may be helpful in distinguishing metastatic tumors from primary tumors.

Widespread subacute cutaneous lupus erythematosus in a patient receiving checkpoint inhibitor immunotherapy with ipilimumab and nivolumab

Checkpoint inhibitor immunotherapy, including ipilimumab and nivolumab, is associated with numerous immune-related adverse events including dermatitis, pruritus, hepatitis, diarrhea, and hypophysitis. As the number of patients undergoing immunotherapy treatment increases, however, rare and unusual immune-related adverse events are observed. Many of these resemble known autoimmune phenomenon, such as subacute lupus erythematosus and myositis. Herein, we report a patient with metastatic serous ovarian carcinoma undergoing treatment with combination ipilimumab and nivolumab who developed subacute cutaneous lupus erythematosus (SCLE). Recent case reports have documented SCLE as a novel immune-related adverse event. In our case, she was able to successfully restart immunotherapy after a course of oral corticosteroids and maintenance oral hydroxychloroquine and topical corticosteroid therapy.

Utility and pitfalls of GATA3 immunocytochemistry for diagnosis of metastatic breast carcinoma and urothelial carcinoma on cytology specimens

Although GATA3 expression has been studied extensively on histology specimens and has demonstrated a high level of accuracy in detecting carcinomas from breast or urothelial origin, its utility on cytology samples, especially the influence of different sample (fine-needle aspiration [FNA] versus effusion fluid) and preparation (cell block versus smear) on the staining, is understudied. We retrospectively searched our institution's pathology database for cytologic cases where GATA3 immunostaining was performed during diagnostic workup and identified a total of 178 cases, consisting of 89 metastatic breast carcinomas, 22 metastatic urothelial carcinomas, and 67 malignant neoplasms of other origin. Frequency of GATA3 expression was evaluated in each group. For metastatic breast carcinomas, 75% expressed GATA3; 74% on FNA samples and 77% on fluid samples; 71% on cell block and 89% on smear. GATA3 was positive in 44% triple-negative breast carcinomas. Of the 22 metastatic urothelial carcinomas (21 FNA samples and 1 fluid; 21 cell blocks and 1 smear), all were positive for GATA3. Of the 67 malignancies of other origin, 4 (6%) were positive for GATA3 (ie, a metastatic ovarian serous carcinoma, a metastatic squamous cell carcinoma, a recurrent poorly differentiated skin adnexal carcinoma, and a metastatic thymic carcinoma). GATA3 is a useful biomarker for detecting carcinomas of breast or urothelial origin on cytologic specimens. It may detect breast cancers with the triple-negative phenotype. Both cell block and smear preparations can be reliably used for the staining. GATA3-positive immunostaining is occasionally seen in other tumors, which may cause diagnostic confusion.

CIAPIN1 and ABCA13 are markers of poor survival in metastatic ovarian serous carcinoma.

BackgroundThe objective of this study was to investigate the expression and clinical role of 14 genes previously shown to be associated with chemotherapy response and/or progression-free survival in a smaller series of ovarian serous carcinoma effusions.MethodsAdvanced-stage serous ovarian carcinoma effusions (n = 150) were analyzed for mRNA expression of AKR1C1, ABCA4, ABCA13, ABCB10, BIRC6, CASP9, CIAPIN1, FAS, MGMT, MUTYH, POLH, SRC, TBRKB and XPA using quantitative real-time PCR. mRNA expression was studied for association with clinicopathologic parameters, including chemotherapy response and survival.ResultsABCA4 mRNA expression was significantly related to better (complete) chemotherapy response at diagnosis in the entire cohort (p = 0.018), whereas higher POLH mRNA levels were significantly related to better chemoresponse at diagnosis in analysis to 58 patients with pre-chemotherapy effusions treated with standard chemotherapy (carboplatin + paclitaxel; p = 0.023). In univariate survival analysis for patients with pre-chemotherapy effusions (n = 77), CIAPIN1 mRNA expression was significantly related to shorter overall (p = 0.007) and progression-free (p = 0.038) survival, whereas ABCA13 mRNA expression was significantly related to shorter OS (p = 0.024). Higher CIAPIN1 mRNA expression was an independent marker of poor overall survival in Cox multivariate analysis (p = 0.044).ConclusionsOur data identify ABCA4 and POLH as markers of better chemotherapy response in metastatic serous carcinoma. CIAPIN1 and ABCA13 may be novel markers of poor outcome in pre-chemotherapy serous carcinoma effusions.

The clinical role of epithelial-mesenchymal transition and stem cell markers in advanced-stage ovarian serous carcinoma effusions.

We recently identified gene signatures that allow classification of ovarian carcinoma into 5 distinct clinically relevant groups. In the present study, we investigated the clinical role of 10 protein products of the discriminating genes, with focus on epithelial-mesenchymal transition and stem cell markers. Expression of E-cadherin, N-cadherin, P-cadherin, Zeb1, HMGA2, Rab25, CD24, NCAM (CD56), Sox11, and vimentin was assessed in 100 advanced-stage (International Federation of Gynecology and Obstetrics stages III-IV) serous ovarian carcinoma effusions using immunohistochemistry. Results were analyzed for association with clinicopathological parameters, including chemotherapy response, and survival. All 10 proteins were frequently expressed in carcinoma cells. HMGA2 expression was related to older age (P = .015). HMGA2 and NCAM expression was related to stage III disease (P = .011 and P = .023, respectively), and NCAM was overexpressed in peritoneal compared with pleural effusions (P = .001). Vimentin and Zeb1 expression was significantly related to poor chemotherapy response at diagnosis (P = .005 and P = .017, respectively). The associations between NCAM and peritoneal localization and of vimentin and poor chemoresponse were retained after Bonferroni correction. NCAM expression was associated with a trend for shorter overall survival in univariate survival analysis (P = .187), but emerged as an independent prognosticator in Cox multivariate analysis (P = .042). This study identifies vimentin and Zeb1 as markers of poor chemoresponse in metastatic serous ovarian carcinoma effusions and suggests NCAM as potential prognostic marker in metastatic disease. The generally limited prognostic role of the studied markers emphasizes the difficulty in applying data obtained in studies of primary ovarian carcinomas to analyses of ovarian carcinoma effusions, reflecting the unique biology of the latter.

Aurora B expression in metastatic effusions from advanced-stage ovarian serous carcinoma is predictive of intrinsic chemotherapy resistance

The aim of the present study was to investigate the expression and clinical role of the aurora A and aurora B kinases in primary and metastatic serous ovarian carcinoma. AURKA and AURKB messenger RNA expression was investigated in 178 tumors (88 effusions, 38 primary carcinomas, and 52 solid metastases) from 144 patients with advanced-stage disease using quantitative real-time polymerase chain reaction. Aurora A and aurora B protein expression by immunohistochemistry was additionally analyzed in 147 tumors. Messenger RNA and protein expression at different anatomical sites were studied for association with clinicopathologic parameters, including chemotherapy resistance and survival. AURKA and AURKB messenger RNA and their protein product were demonstrated in all primary carcinomas, solid metastases, and effusions. The expression of AURKA messenger RNA and aurora A protein was higher in effusions compared with solid specimens (P = .003 and P = .006, respectively). AURKB messenger RNA expression was higher in primary carcinomas, and solid metastases obtained prechemotherapy compared with postchemotherapy (P < .001 and P = .012, respectively), with no such difference in effusions (P > .05). Low aurora B protein expression was associated with primary chemotherapy resistance (P = .006) and poor treatment response (P = .013) in prechemotherapy effusions. No significant association was found between messenger RNA levels or protein expression and progression-free or overall survival. The present study documents for the first time frequent aurora A and aurora B expression in metastatic ovarian carcinoma, suggesting a role in cancer progression, with higher aurora A expression in effusions compared with primary carcinomas and solid metastases. Low AURKB messenger RNA expression in prechemotherapy effusions might be predictive of intrinsic chemotherapy resistance.

Isolated Axillary Lymph Node Metastasis from Serous Ovarian Cancer

A 68-year-old female with past medical history of stage IIIc serous ovarian cancer after cytoreductive surgery and adjuvant chemotherapy came to clinic for regular follow-up visit. Physical examination was completely normal except for an isolated left axillary lymph node enlargement. Patient's abdominal sonogram and CT scan of abdomen and pelvis did not show any other new metastasis. Surgical excisional biopsy of the lymph node was performed and pathology revealed features of metastatic serous ovarian carcinoma.

Utility of paired box gene 8 (PAX8) expression in fluid and fine‐needle aspiration cytology

Metastases from ovarian neoplasms are commonly encountered in peritoneal fluids. In addition, reactive mesothelial cells in effusion specimens can mimic ovarian serous carcinoma, making the diagnosis difficult. Calretinin has been recognized as a reliable immunohistochemical marker for mesothelial cells, whereas WT1 has proven useful in the diagnosis of ovarian serous carcinoma. This can present a diagnostic pitfall in effusion cytology, because mesothelial cells can demonstrate immunoreactivity for WT1. Recently, paired box gene 8 (PAX8) has been used in distinguishing ovarian from mammary carcinoma. To the authors' knowledge, no studies using PAX8 have been performed on peritoneal cytology specimens to date, and its expression in metastatic ovarian serous carcinoma has not been studied. These markers, along with BerEP4 and MOC-31, were evaluated in cytology cell block preparations from 30 fluid cytology specimens and 11 fine-needle aspiration specimens. PAX8 was found to be positive in 37 of 41 (90%) ovarian carcinoma cases studied, and was a sensitive (90%) and specific (100%) marker for the detection of metastatic ovarian carcinoma. In addition, calretinin was found to be useful for identifying mesothelial cells in fluid cytology. Furthermore, although PAX8 and WT1 have demonstrated comparable sensitivity (90% and 93%, respectively) in diagnosing metastatic ovarian carcinoma, PAX8 appears to have superior specificity because staining is not observed in mesothelial cells. BerEP4 and MOC-31 were found to have a lower sensitivity and specificity compared with PAX8. PAX8-positive, calretinin-negative staining appears to be highly specific and sensitive for detecting metastatic ovarian serous carcinoma in cytologic preparations and can be useful in distinguishing it from mesothelial cells in fluid cytology.

Colonic or coelomic?

In June, 2007, a 47-year-old woman of Irish descent presented with rectal bleeding, decreased appetite, weight loss, and decreased calibre of her stool. Her family history was signifi cant for reported, but unconfi rmed, early-onset colon cancer in three male and female fi rst-degree and second-degree relatives. Colonoscopy in May, 2006, had shown no abnormalities. Current colonoscopy showed an area of fi rm bulging with oedematous mucosa in the upper rectum. Biopsy showed small fragments of poorly diff erentiated invasive adenocarcinoma (fi gure A). MRI showed a 5·7 cm mass in the posterior wall of the rectosigmoid (fi gure B), with perirectal fat infi ltration and involvement of lymph nodes. Narrowing of the rectosigmoid lumen was seen, but the tumour seemed to be growing by extension into the perirectal fat rather than into the intestinal lumen. Endoscopic ultrasonography confi rmed these fi ndings. The staging was T3/T4 N1 M0, and the patient received neoadjuvant chemoradiation treatment, before undergoing a low anterior resection and diverting ileostomy in February, 2008. A six-cycle regimen of FOLFOX adjuvant chemotherapy was initiated. The pathological diagnosis was a pleiomorphic poorly diff erentiated adenocarcinoma involving the rectosigmoid colon. However, there was no defi nite origin from the colonic mucosal surface and highly bizarre cells with atypical mitotic activity were present. The immunohistochemistry profi le was CK7+, CK20–, CA-125+, ER+, CEA–, CDX2–, WT-1+, which raised the possibility of a gynaecological cancer. The presentation, location, and pathological fi ndings all suggested the diagnosis of a primary serous carcinoma arising from the visceral coelomic peritoneum or, less likely, a metastatic serous ovarian carcinoma, rather than rectal cancer. The patient underwent a subtotal abdominal hysterectomy with bilateral salpingo-oophorectomy in September, 2008. The pathology report mentioned only a few microscopic foci of high-grade serous carcinoma on the left paratubal and superfi cial cortex of the left ovary. These fi ndings were consistent with the fi nal pathological diagnosis of primary peritoneal serous adenocarcinoma. Given this diagnosis, genetic testing was done, showing a deleterious BRCA1 mutation, c.427 G>T, resulting in E143X, previously reported in Ireland. Our patient received three cycles of carboplatin and paclitaxel starting in December, 2008, and was in complete remission in February, 2010. Primary peritoneal adenocarcinoma, like ovarian cancer, often presents with non-specifi c gastrointestinal symptoms. A high degree of suspicion is needed for prompt identifi cation of this entity. In our case, as previously reported, the patient presented with symptoms of rectal bleeding and altered bowel habit, which are both suggestive of colorectal cancer. Also, secondary involvement of the colon by peritoneal carcinoma can mimic the colonoscopic appearance of a primary colon carcinoma—even modern imaging modalities cannot always distinguish between these two entities. An initial small biopsy showing “poorly diff erentiated adenocarcinoma” can, in the clinical context, be easily overlooked and interpreted as a primary cancer of the rectum if no immunohistochemistry is done. Any doubt, or presence of atypical morphologic features, should prompt careful pathological review and immunohistochemical assess ment. Notably, primary peritoneal serous adeno carcinoma is histologically and immunohisto chemically indis tinguish able from primary ovarian serous adeno carcinoma, and primary ovarian cancer must be excluded to establish the diagnosis. About 20% of women diagnosed with ovarian carcinoma at age 40–50 years carry a BRCA germline mutation. Female BRCA mutation carriers are also at a high risk for primary peritoneal carcinoma. Unusual presentations can delay the prompt identifi cation and appropriate management of this cancer.

Metastatic Ovarian Serous Carcinoma Presenting as Inflammatory Breast Cancer: A Case Report

A 42-year-old woman presented with localized irritation, erythema and sharp pain in the one breast. After unsuccessful treatment for mastitis, an oncology consultation was obtained. A breast biopsy revealed an invasive carcinoma and a diagnosis of inflammatory breast cancer was made. The patient was treated with neo-adjuvant chemotherapy and subsequently underwent bilateral mastectomy. A total abdominal hysterectomy and bilateral salpingo-oophorectomy was also performed at the same time due to the presence of a pelvic mass. Morphologic and immunohistochemical examination of the specimens helped to clarify the correct diagnosis of primary ovarian carcinoma with widespread metastases to bilateral breasts.

Mammalian target of rapamycin is a biomarker of poor survival in metastatic serous ovarian carcinoma

The AKT signaling pathway is crucial for cancer cell survival. The objective of this study was to analyze the expression and clinical role of this pathway in serous ovarian carcinoma. Phospho-AKT and phospho-mammalian target of rapamycin protein expression was studied in 269 ovarian carcinomas (159 effusions, 38 primary carcinomas, 72 solid metastases) using immunohistochemistry. The association between AKT, mammalian target of rapamycin, and DJ-1 in effusions was quantitatively analyzed using flow cytometry. AKT phosphorylation status in effusions was further studied using Western blotting. Phospho-AKT and phospho-mammalian target of rapamycin were detected in the majority of tumors at all anatomical sites. Phospho-AKT expression in effusions was higher in grade 3 versus grades 1 and 2 tumors (P = .013). Flow cytometry analysis showed association between AKT, mammalian target of rapamycin, and DJ-1 expression (P < .001). Higher phospho-AKT Thr308/pan-AKT ratio by Western blotting was associated with more advanced International Federation of Gynecology and Obstetrics stage (P = .018) and a trend for poor response to chemotherapy at first disease recurrence (P = .051). Higher phospho-mammalian target of rapamycin protein expression in effusions by immunohistochemistry was associated with poor progression-free survival for patients with postchemotherapy effusions (P = .005). Phospho-mammalian target of rapamycin was an independent predictor of poor progression-free survival for patients with postchemotherapy effusions (P = .03). The association between activated AKT and mammalian target of rapamycin expression and clinicopathologic parameters of aggressive disease, including shorter patient survival, provides further evidence regarding the central role of this signaling pathway in ovarian carcinoma.

PAX 2: A Novel Müllerian Marker for Serous Papillary Carcinomas to Differentiate From Micropapillary Breast Carcinoma

Ovarian serous papillary carcinoma, although rarely metastasizing to the breast, is often challenging based on morphology alone, particularly from the micropapillary variant of breast carcinoma. Gross cystic disease fluid protein-15, although a specific marker, can be negative in up to 50% of breast carcinomas. Wilm's tumor gene 1 (WT-1) has been identified as a useful marker to differentiate metastatic ovarian serous papillary carcinoma from primary breast carcinoma; however, it has recently been shown in the micropapillary variant of the primary breast carcinoma making it a less specific marker. PAX 2, a nuclear transcription factor, was recently observed in ovarian serous papillary carcinomas. In this study of 89 breast carcinoma cases, 26 micropapillary carcinoma, and 63 nonmicropapillary carcinoma types were retrieved from our pathology archives, represented on a single tissue microarray (TMA) with a 3-fold redundancy (TMA-1, TMA-2). In addition, whole tissue sections of a variety of benign and neoplastic müllerian tissues were surveyed with the PAX 2 immunostain. All cases were stained with rabbit polyclonal PAX 2 antibody and, in addition, the 5 metastatic ovarian serous carcinoma cases were stained with WT-1 as well for comparison. Only nuclear staining was considered positive. All primary breast carcinomas represented on TMA-1 and TMA-2 were entirely negative for PAX 2 100% (89/89), whereas 100% (5/5) of all metastatic ovarian serous carcinomas showed moderate-to-strong staining. PAX 2 expression was comparable with WT-1 as well in the metastatic ovarian serous carcinoma group. We therefore conclude that PAX 2 is a promising new, sensitive, and specific müllerian immunomarker for ovarian serous carcinomas (primary and metastatic).

Cleaved caspase-3 and nuclear factor- κB p65 are prognostic factors in metastatic serous ovarian carcinoma

Tumor progression and treatment failure in ovarian carcinoma are frequently associated with metastasis to effusions. The present study analyzed the expression and clinical role of nuclear factor-kappaB p65, nuclear factor-kappaB inhibitor alpha, and parameters of apoptosis in serous carcinoma. Cleaved caspase-3 and caspase-8 levels and deoxyuridine triphosphate incorporation were measured in 65 effusions using flow cytometry. Effusions (n = 209) and corresponding primary carcinomas and solid metastases (n = 114) were immunohistochemically analyzed for nuclear factor-kappaB p65 and nuclear factor-kappaB inhibitor alpha expression. Effusions (n = 75) were further analyzed for nuclear factor-kappaB phospho-p65 (Ser536) levels using immunoblotting. Results were analyzed for association with anatomic site, clinicopathologic parameters, and survival. Caspase cleavage and deoxyuridine triphosphate incorporation were limited to less than 10% of cells in most effusions. Nuclear factor-kappaB p65 expression was frequently detected at all anatomic sites, with less frequent cytoplasmic nuclear factor-kappaB p65 and nuclear factor-kappaB inhibitor alpha expressions. Immunoblotting showed nuclear factor-kappaB p65 phosphorylation in 72 (96%) of 75 effusions. Higher than median cleaved caspase-3 levels correlated with improved overall and progression-free survival in univariate analysis of all patients (P = .024 and P = .046, respectively) and of those with postchemotherapy effusions (P = .042 and P = .036, respectively). Cleaved caspase-3 expression was an independent predictor of longer progression-free survival for patients with postchemotherapy effusions (P = .029). Nuclear factor-kappaB p65 expression correlated with poor progression-free survival for all patients (P = .048) and for those with postchemotherapy effusions (P = .025). Ovarian carcinoma cells in effusions undergo little apoptosis, but high levels of cleaved caspase-3 are associated with improved survival. Nuclear factor-kappaB p65 is frequently expressed in advanced-stage serous ovarian carcinoma, and its nuclear localization is associated with poor progression-free survival.

A Mouse Model for the Molecular Characterization of Brca1-Associated Ovarian Carcinoma

Little is known about the mechanisms that underlie Brca1-associated ovarian tumorigenesis, mainly due to the lack of an appropriate experimental model. We developed genetically defined primary mouse ovarian surface epithelial (OSE) cell lines in which the loss of functional Brca1 and p53 recapitulates the events that are thought to occur in early ovarian cancer development in patients with Brca1 mutations. This system allows for the introduction of additional oncogenes that are thought to cooperate with the loss of Brca1 and p53 to induce tumorigenesis. We showed that Myc is sufficient to induce transformation of ovarian cells that are deficient for both Brca1 and p53 but not sufficient for the transformation of cells that are deficient for either Brca1 or p53. The transformed Brca1-deficient OSE cells display an increased number of centrosomes, acquire complex chromosome aberrations, and lack Rad51 nuclear foci in the presence of DNA-damaging agents, such as mitomycin C and cisplatin. Immunocompetent mice injected with transformed OSE cells develop tumors that resemble human metastatic serous ovarian carcinoma, the most common type of ovarian cancer in women. Consistent with the reported platinum chemosensitivity in patients with Brca1-associated ovarian cancer, the Brca1-deficient OSE cells have increased sensitivity to the DNA-damaging agent cisplatin, whereas sensitivity to the microtubule poison paclitaxel is similar between Brca1 wild-type and Brca1-deficient cells. The Brca1 wild-type and Brca1-deficient mouse ovarian tumors and cell lines provide a new experimental system for the evaluation of therapies that target the Brca1 pathway.

Intra-abdominal carcinomatosis after prophylactic oophorectomy in women of hereditary breast ovarian cancer syndrome kindreds associated with BRCA1 and BRCA2 mutations

Objective Prophylactic surgical removal of the ovaries has been offered for many years as a potential preventative of ovarian cancer in women deemed to be at increased hereditary risk for this disease. Now, it is possible to test for specific mutations of the BRCA1 and BRCA2 genes that render members of hereditary breast ovarian cancer (HBOC) syndrome families susceptible to cancer. Widespread intra-abdominal carcinomatosis, which mimics metastatic ovarian serous carcinoma, has been reported following oophorectomy in individuals at increased hereditary risk. This study was undertaken to examine and report particularly the occurrence of intra-abdominal carcinomatosis, as well as other cancers, following prophylactic oophorectomy in patients who carry cancer susceptibility mutations of BRCA1 and BRCA2 and to assess the cumulative risks for this disease in order to assist in developing appropriate surgical interventions, based on currently available information, and to counsel patients who choose prophylactic surgery, concerning the potential prognosis, thereafter. Methods The Creighton University Hereditary Cancer Institute registry was searched for members of HBOC syndrome families who had undergone prophylactic oophorectomy. The histories and results of DNA testing for the BRCA1 and BRCA2 mutations carried in their families were recorded, tabulated and examined, and the aggregate data are reported along with pertinent details of those individuals who developed neoplastic diseases after prophylactic oophorectomy. All available histologic and cytologic materials of patients who were diagnosed with intra-abdominal carcinomatosis were reviewed, and life-table calculations were performed to assess cumulative risks for this disease following prophylactic oophorectomy. Results From 72 HBOC syndrome families that carried either BRCA1 or BRCA2 cancer-associated mutations, 238 individuals who had undergone prophylactic oophorectomy were recorded in our registry between January 1985 and December 2002. During a mean follow-up of 9.3 years, cancers were diagnosed in 27 subjects, including 16 individuals with breast cancer and five patients with intra-abdominal carcinomatosis. Breast cancers were stage I in 10 of 12 proven carriers of cancer-associated mutations. All five cases of intra-abdominal carcinomatosis were serous carcinomas, and all occurred in BRCA1 mutation carriers. Histologic review of the prophylactically removed ovaries found borderline lesions in two cases, one with possible early stromal invasion. Two of the five patients who developed intra-abdominal carcinomatosis were among 78 patients in this series who were diagnosed and treated for breast cancer before prophylactic oophorectomy. A 3.5% cumulative risk for all mutation carriers and a 3.9% cumulative risk for BRCA1 mutation carriers were calculated through 20 years of follow-up after prophylactic oophorectomy. Conclusions Intra-abdominal carcinomatosis in our series was diagnosed only in BRCA1 mutation carriers. The calculated cumulative risks of developing intra-abdominal carcinomatosis after prophylactic oophorectomy in members of HBOC syndrome families, specifically those who carry deleterious mutations, are well below the estimated risks of ovarian cancer published in the literature for similar patients. Breast cancers, which tended to be small and localized, were the most common malignancy in BRCA1 and BRCA2 mutation carriers after prophylactic oophorectomy.

Matrix metalloproteinases (MMP), EMMPRIN (extracellular matrix metalloproteinase inducer) and mitogen-activated protein kinases (MAPK): co-expression in metastatic serous ovarian carcinoma.

Activation or suppression of intracellular signaling via the mitogen-activated protein kinase (MAPK) family has been linked to expression of matrix metalloproteinases (MMP) in experimental models, but this association has not been demonstrated in clinical material. The objective of this study was to investigate the possible association between expression and activity of MMP, expression of the MMP inducer EMMPRIN, and the expression (level) and phosphorylation status (activity) of the extracellular-regulated kinase (ERK), c-Jun amino-terminal kinase (JNK) and high osmolarity glycerol response kinase (p38) in effusions from patients diagnosed with serous ovarian carcinoma. MAPK level and activity were studied in 55 effusions using immunoblotting. MMP-1, MMP-2, MMP-9 and EMMPRIN expression was studied using immunocytochemistry (ICC) and mRNA in situ hybridization (ISH). The gelatinolytic activity of MMP-2 and MMP-9 was measured by zymography. ERK and phospho-ERK (p-ERK) were detected in 54/55 (98%) and 50/55 (91%) specimens, respectively. JNK and p-JNK were detected in 53/55 (96%) and 38/55 (69%) specimens, respectively. p38 was expressed in 54/55 (98%) specimens, and its phosphorylated form was found in 51/55 (92%). MMP-2 mRNA expression (P = 0.048), protein expression (P = 0.046) and gelatinolytic activity (P = 0.039) correlated with ERK phosphorylative activity. MMP-2 activity also correlated with p38 activity (P = 0.017). MMP-9 protein expression correlated with phosphorylation of p38 (P = 0.046), but enzyme activity showed inverse relationship with both p-ERK (P = 0.05) and p-p38 (P = 0.033) expression. EMMPRIN expression correlated with MMP-1 (P < 0.001), MMP-2 (P = 0.042) and MMP-9 (P = 0.029) expression, as well as with ERK activity (P = 0.001). Our results present the first evidence of a possible link between MAPK signaling and MMP expression and activity in vivo. These data may expand our understanding regarding the mechanisms by which MMP synthesis is regulated in effusions and possibly affect treatment strategies for this form of malignancy.

Adenomatous polyposis coli (APC) protein expression in primary and metastatic serous ovarian carcinoma.

The aim of this study was to investigate protein expression of adenomatous polyposis coli (APC) in primary and metastatic serous ovarian carcinoma. The expression of beta-catenin and E-cadherin was additionally analyzed. One hundred and thirteen primary (n = 56) and metastatic (n = 57) lesions were immunohistochemically stained for APC, E-cadherin, and beta-catenin. Staining extent was scored. Possible differences in immunoreactivity in primary and metastatic sites and the association between the proteins analyzed were evaluated statistically. Cytoplasmic immunoreactivity for APC was found in 67/113 (59%) tumors, most often in the majority (> 50%) of cells. E-cadherin was detected in 102/113 (90%) carcinomas, while beta-catenin was expressed in 109/113 (97%) specimens. Nuclear expression of beta-catenin was seen in 3/113 (3%) specimens, all negative for APC. APC and beta-catenin were often coexpressed, but this finding failed to reach statistical significance (p = 0.11). A significant association was seen between E-cadherin and beta-catenin expression (p = 0.001). APC expression was comparable in primary and metastatic tumors (p > 0.05). In conclusion, APC expression is absent in a considerable number of both primary and metastatic ovarian carcinomas, but this finding is only rarely coupled to nuclear accumulation of beta-catenin. These findings support the role for beta-catenin signaling via the Wingless/Wnt pathway in ovarian carcinoma. The mechanism behind the down-regulated expression of APC in serous ovarian carcinoma and its significance has yet to be elucidated.