Pamela Chu

Quantification of ER/PR expression in ovarian low-grade serous carcinoma

OBJECTIVE Case reports suggest that hormonal therapy may be a useful treatment option for low-grade serous carcinomas (LGSC) but the clinical value remains uncertain. We hypothesized that LGSCs show a constitutive high hormone receptor expression and that type diagnosis may be sufficient to initiate hormonal therapy. METHODS We assessed ER and PR expression on 27 LGSC, 69 high-grade serous carcinomas (HGSC), 36 serous borderline tumors (SBOT), and five normal fallopian tubes using three different platforms/antibodies on tissue microarrays. Staining from the Leica Bond Max and DAKO PharmDx platforms was evaluated using the Allred score. Quantitative fluorescence immunohistochemistry was performed using the HistoRx AQUAnalysis platform. A second cohort of 12 LGSC and 183 HGSC was assessed using the HistoRx AQUAnalysis platform. Welch ANOVA or Fishers Exact Test was used to compare differences in the histological types for each platform. Nonparametric bivariate density plots were used to graphically demonstrate the relationship between ER and PR for the various histological types. RESULTS LGSC have higher ER and PR expression compared to HGSC but significantly less than FT and SBOT. Nonparametric bivariate density revealed two populations of LGSC: one fifth of LGSC are ER high/PR high expressers similar to SBOT but the majority show low ER/PR expression more like HGSC. CONCLUSIONS Quantitative assessment of ER/PR expression using the HistoRx AQUAnalysis platform may be useful as a predictive diagnostic for hormonal therapy in LGSC, assuming that only the fraction of double high expressers benefit from hormonal treatment.

The diagnostic utility of TP53 and CDKN2A to distinguish ovarian high-grade serous carcinoma from low-grade serous ovarian tumors

Low-grade serous carcinomas and serous borderline tumors, combined herein and referred to as low-grade serous tumors, show distinct molecular alterations and clinical behaviors compared with high-grade serous carcinomas. The discrimination between low-grade serous tumors and high-grade serous carcinomas can be challenging on small tissue samples, such as cell blocks of paracentesis fluid or biopsies from omental disease. The purpose of this study was to test the ability of TP53 and CDKN2A immunohistochemistry to distinguish between high-grade serous carcinomas and low-grade serous tumors on small tissue samples. Tissue microarrays containing 582 high-grade serous carcinomas, 45 low-grade serous carcinomas, and 49 serous borderline tumors, confirmed by contemporary histopathological review, were stained for TP53 and CDKN2A (DO7 and E6H4 antibody clones, respectively). TP53 was scored as completely absent, wild-type pattern or overexpressed (>60%), and CDKN2A was scored as either negative/patchy (<90%) or block expression (>90%). The combination of the two markers, ie, the TP53 wild-type pattern and CDKN2A patchy expression, had sensitivity for low-grade serous tumors of 89%, a specificity of 93%, a positive predictive value of 68%, and a negative predictive value of 98%. These markers can, therefore, be used on small biopsies/cell blocks to refute a diagnosis of low-grade serous tumors. These findings may inform emerging neoadjuvant therapeutic strategies in advanced ovarian cancers and may be crucial for future clinical trials on molecular-based therapies.

Uterine sarcoma and aromatase inhibitors: Tom Baker Cancer Centre experience and review of the literature.

Objectives Uterine sarcomas are a rare group of mesenchymal tumors with a poor prognosis and aggressive biology. Standard treatment involves surgical staging. The role of further adjuvant treatment is unclear. The goals of this study were to determine the response rates to treatment of patients with uterine sarcomas and to review the currently available literature on the use of aromatase inhibitors (AIs). Materials and Methods We performed a retrospective analysis on all patients with uterine sarcoma treated with an AI between 2000 and 2010 at the Tom Baker Cancer Centre in Calgary, Alberta. Results Four patients with endometrial stromal sarcoma and 3 patients with leiomyosarcoma received treatment with an AI. A literature search resulted in 10 case reports and 4 retrospective studies of patients with endometrial stromal sarcoma and 1 case report and 2 retrospective studies of patients with leiomyosarcoma. On the basis of the available literature, combined with the current findings, the overall response rate of endometrial stromal sarcoma to AIs is 67% (complete response of 7% and partial response of 60%), and the partial response rate of leiomyosarcoma to AIs is 11%, with no reported complete responses. Conclusions Aromatase inhibitors are a well-tolerated class of medications that are effective in the treatment of endometrial stromal sarcomas. These medications may also have a role to help stabilize disease progression in the treatment of leiomyosarcoma. More large, prospective, multicentered trials will be needed to clarify this issue.

Architectural patterns of ovarian/pelvic high-grade serous carcinoma.

We describe the architectural patterns of advanced ovarian/pelvic high-grade serous carcinomas that have been treated with upfront surgery, followed by adjuvant chemotherapy or neoadjuvant chemotherapy, followed by interval debulking to explore the association with the chemotherapeutic response. For 70 cases of advanced (i.e. stage III/IV) high-grade serous carcinomas (33 platinum resistant/intermediate, 37 platinum sensitive; 24 neoadjuvantly treated, 44 primary surgery), all tumor-containing histologic slides were reviewed by 1 of 3 pathologists. Histologic type was confirmed and the following features were assessed: major architectural pattern and the presence of any of 8 predefined minor architectural patterns (papillary, transitional cell carcinoma-like, micropapillary, microcystic, nested papillary, slit-like, glandular, solid). A semiquantitative assessment of psammoma bodies, histiocytic response, necrosis, nuclear atypia, and single-cell invasion was performed. Mitotic count was performed in 10 HPF and 1 HPF was counted for intraepithelial lymphocytes. The morphologic features were tested for an association with previous neoadjuvant chemotherapy and response to chemotherapy (resistant/intermediate versus chemotherapy-sensitive cases stratified by neoadjuvant chemotherapy), which was carried out using &khgr;2 tests for categorical variables and analysis of variance for continuous data. Combinations of features were analyzed using unsupervised clustering (Wald). Although 8 of 18 features were significantly different when samples from neoadjuvantly treated patients were compared with those not previously treated, no individual histomorphologic feature or a combination of features was associated with response to chemotherapy. Further subtyping of high-grade serous carcinomas will likely need ancillary molecular markers that may have a greater potential to identify cases that will not respond to platinum-based chemotherapy.

Use of Aromatase Inhibitors as First- and Second-Line Medical Therapy in Patients With Endometrial Adenocarcinoma: A Retrospective Study

OBJECTIVES The primary objective of this study was to examine the role of aromatase inhibitors (AIs) as first- or second-line medical treatment in women with endometrial adenocarcinoma who were not candidates for surgical management. The secondary objective was to examine the role of AIs in adjuvant and palliative treatment. METHODS Thirty women with endometrial adenocarcinoma who were treated with aromatase inhibitors between 2000 and 2010 at the Tom Baker Cancer Centre in Calgary, Alberta were assessed in a retrospective analysis. Disease response was based on response evaluation criteria in solid tumours. Kruskal-Wallis test was used to compare non-parametric variables and Fisher exact test was used to compare the health variables. RESULTS Seventeen patients received AIs as first- or second-line medical treatment, five received adjuvant therapy, and eight received palliative treatment. The median age of patients in the first or second line medical treatment group was significantly greater than that of patients in the adjuvant or palliative group (P = 0.042). There was no significant difference in median weight or body mass index. The subjective clinical response rate with medical treatment was 70%. In the first- or second-line medical treatment group, only seven patients had available response data. Our study showed stable disease in 5/7 (71%), partial response in 1/7 (14%), and progression in 1/7 (14%) patients. CONCLUSION This retrospective clinical series examining use of an aromatase inhibitor as first- or second-line medical therapy in women with endometrial carcinoma showed that AIs are a potential treatment for patients who have a contraindication to surgery and who either have failed or cannot use megestrol therapy.

Cutaneous Metastatic Disease in Cervical Cancer: A Case Report

BACKGROUND Cervical cancer metastasizes to skin in < 2% of patients. Cutaneous metastases can be confused with dermatitis. Their presence signals a poor prognosis. CASE A 66-year-old postmenopausal woman with a diagnosis of stage IVa cervical carcinoma was treated with radical concurrent chemotherapy and radiation. Two months after completing treatment, the patient noted maculopapular skin lesions in the lower abdomen. These were confirmed on biopsy as metastases from the cervical cancer. The cutaneous metastases progressed rapidly to involve the inguinal regions, vulva, and perineum. Further assessment ruled out metastases to other organs. Despite six courses of palliative combination chemotherapy, the patients disease progressed, and she died six months after the appearance of the cutaneous metastases. CONCLUSION We reviewed the details of 47 reported cases of cutaneous metastases of cervical carcinoma. In the majority of these cases, patients presented within 10 years of initial diagnosis and died within a mean of 8.5 months from cutaneous metastasis.

Intraperitoneal Chemotherapy for Advanced Ovarian and Peritoneal Cancers in Patients Following Interval Debulking Surgery or Primary Cytoreductive Surgery: Tom Baker Cancer Centre Experience From 2006 to 2009

OBJECTIVE To describe our experience with cisplatin- and paclitaxel-based IP chemotherapy in patients treated initially with either neoadjuvant chemotherapy and interval debulking surgery (IDS) or primary cytoreductive surgery (PCRS). METHODS We performed a retrospective review of the records of 67 patients (38 IDS, 29 PCRS) enrolled in the intraperitoneal (IP) chemotherapy program at the Tom Baker Cancer Centre between 2006 and 2009. Information pertaining to patient demographics, IP chemotherapy toxicity, and catheter complications was extracted, and the median time to recurrence was calculated. RESULTS Most patients in the study were aged 50 to 70 years and had a diagnosis of stage III serous ovarian cancer. Overall, 295/393 IP cycles (75%) were successfully administered. The proportion of patients completing six cycles of chemotherapy in the IDS and PCRS groups was 53% and 59%, respectively. Frequent (> 25%) Grade 1 to 2 chemotherapy toxicities included fatigue, peripheral neuropathy, and nausea. Catheter complications were observed in 34% of patients (23/67). The recurrence rates for patients completing four or more cycles of IP chemotherapy in the IDS and PCRS groups were 58% and 35%, respectively, with the median time to recurrence approximately one year. CONCLUSION Although IP chemotherapy is well tolerated in both IDS and PCRS patients, the median time to recurrence is shorter than expected.

Malignant Chest Wall Endometriosis: A Case Report and Literature Review

BACKGROUND Endometriosis usually affects women in their reproductive years. Most commonly, the pelvic organs are involved. Involvement of the chest wall after hysterectomy is rare. The incidence of malignant transformation is less than 1% for ovarian endometriosis, but is unknown for extraovarian endometriosis. CASE A 47-year-old woman who had undergone hysterectomy and bilateral salpingo-oophorectomy for endometriosis presented four years after surgery with a well-differentiated endometrioid adenocarcinoma arising in the background of endometriosis in the right chest wall. The tumour was resected, and the patient received six courses of adjuvant chemotherapy. CONCLUSION Women with endometriosis-associated cancer require individualized management options, depending upon the histopathology and stage of the cancer.

Dose-Dense Paclitaxel With Carboplatin for Advanced Ovarian Cancer: A Feasible Treatment Alternative

OBJECTIVE Epithelial ovarian cancer is the leading cause of death from gynaecologic cancers in the Western world. If possible, initial cytoreductive surgery is the treatment of choice, followed by adjuvant chemotherapy, usually with a platinum/taxane combination. Increased survival has been recently reported in women who were given adjuvant chemotherapy weekly rather than at three-week intervals, which has been the standard. At our centre, we have been treating patients with advanced ovarian cancer with a dose-dense protocol since March 2010. Treatment is given in an outpatient setting on days 1, 8, and 15 of a 21-day cycle for six cycles. Carboplatin for an AUC of 5 mg/mL/min and paclitaxel 80mg/m² are given on day 1, followed by paclitaxel 80mg/m² on days 8 and 15. Our objective was to determine whether this protocol is a feasible alternative treatment in our population and whether or not the toxicity profile is acceptable. METHODS We performed a chart review of 46 patients undergoing treatment with dose-dense chemotherapy for advanced ovarian cancer. Demographic information, patient characteristics, adverse events, and treatment endpoints were recorded. RESULTS Sixty-one percent of women completed the six-cycle protocol as planned with minimal interruption, which is comparable to the only previously reported trial using this regimen. The most common side effects of treatment were fatigue, neuropathy, and neutropenia. Supplementation with regular magnesium and granulocyte colony-stimulating factor reduced delays. CONCLUSION Dose-dense paclitaxel with carboplatin chemotherapy for the treatment of advanced ovarian cancer shows promise in terms of progression-free and overall survival. We have shown this protocol to be practical and feasible in our population.

The effects of anemia and blood transfusion on patients with stage III-IV ovarian cancer.

Objectives The objective of this study was to examine the overall and recurrence-free survival in patients with advanced ovarian cancer based on hemoglobin and blood transfusions. Methods A retrospective chart review was performed between 2003 and 2007 on patients with pathologically confirmed stage 3–4 ovarian, fallopian, or peritoneal cancers. Data were collected on date of diagnosis, recurrence and death, stage, grade, age, surgery, estimated blood loss, hemoglobin (nadir and average levels), and number of blood transfusions. Results Two hundred sixteen patients were included in the final analysis. In the perichemotherapy, perioperative, and total time frames, 88%, 81%, and 95% of patients were anemic, and 9%, 22%, and 26% of the patients had severe anemia. After adjusting for age, stage, and optimal debulking status, the perichemotherapy hemoglobin level as a continuous variable was weakly associated with recurrence-free survival (adjusted hazard ratio [AHR], 0.98; P = 0.03), and as a categorical variable with both recurrence-free survival (AHR, 2.49; P = 0.003) and overall survival (AHR, 1.91; P = 0.02). The total number of transfusions was also weakly associated with poor recurrence-free survival (AHR, 1.06; P = 0.03). Conclusions Our study is a retrospective analysis of the effects of anemia and transfusion on ovarian cancer. The rates of anemia in chemotherapy patients are higher than previously reported. Although maintaining average hemoglobin greater than 80 g/L during chemotherapy portends an improved overall survival, blood transfusion does not have any effect. The role of transfusion should therefore be limited to symptomatic patients while giving 1 unit at a time. Further prospective studies will be needed to confirm these results.