Assessing the risk of ovarian malignancy algorithm for the conservative management of women with a pelvic mass.

OBJECTIVE: To evaluate the use of as an aid in the identification of women who can safely undergo conservative, non-surgical management. METHODS: All patients referred to the Program in Women's Oncology for surgery with a pelvic mass are evaluated at a prospective multidisciplinary tumor board (TB) where ROMA and imaging are used for management recommendations. This study evaluated women presented to TB with a pelvic mass between 2009 and 2013 who had either surgical or conservative management. RESULTS: Of the 498 patients assessed, 392 (79%) had benign disease, 22 (4%) had LMP tumors, 28 (6%) had stage I-II epithelial ovarian cancer (EOC), 36 (7%) had stage III-IV EOC and 20 (4%) had non-EOC. Using clinical assessment in conjunction with ROMA, the TB recommended observation in 188 (37.8%) women. All patients diagnosed with an invasive malignancy were recommended for surgery by the TB. In the 315 patients managed surgically, 212 were found to have benign disease and 84 women were diagnosed with an invasive malignancy. The sensitivity for the initial TB recommendations using ROMA in conjunction with clinical judgment for detecting malignancy was 100% with a specificity of 47.7% and a NPV of 100%. When including low malignant potential tumors the sensitivity was 99.1%. For stage I-IV EOC ROMA alone had a sensitivity of 95.3%. CONCLUSIONS: ROMA in conjunction with clinical assessment can safely identify women for conservative management.

Long-term follow-up of vulvar cancer patients evaluated with sentinel lymph node biopsy alone.

OBJECTIVE: The objective of this study was to examine SLN evaluation alone in women with squamous cell carcinoma (SCC) of the vulva and evaluate the inguinal recurrence and complication rates. METHODS: An IRB approved prospective study enrolled patients with SCC of the vulva. Peritumoral injection of Tc-99 sulfur colloid and blue dye was used to identify SLNs intraoperatively. Patients with negative SLN for metastasis were followed clinically without further treatment. Patients with metastasis to a SLN underwent full groin node dissection followed by standard treatment protocols. RESULTS: A total of 73 women were enrolled onto protocol with 69 patients undergoing SLN dissection. Mean age was 66.9years (range: 29-91) with 47 stage I, 12 stage II, 9 stage III, 2 stage IV and 3 unstaged patients. SLN dissections were successful in 63 patients. Of the 111 groins evaluated with a SLN dissection 93% had a SLN identified with an average of 2 SLN per groin. There were 92 groins with negative SLN and 11 groins with positive SLN. 57 patients had negative SLN and underwent conservative management with the median follow-up of 58.3months. Three patients experienced groin recurrences (2 unilateral, 1 bilateral) for a recurrence rate of 5.2% (3/57). The complication rate for the inguinal incisions was 17.5% (1 cellulitis, 1 abscess, 2 lymphoceles, 5 lymphedema and leg pain). CONCLUSIONS: Isolated SLN dissection alone has a low inguinal recurrence rate with decreased complications and should be considered as an option for women with SCC of the vulva.

Isolated sentinel lymph node dissection with conservative management in patients with squamous cell carcinoma of the vulva: a prospective trial.

OBJECTIVES: Sentinel lymph node (SLN) dissections have a high sensitivity and negative predictive value for the detection of metastatic disease. The objective of this study was to examine the inguinal recurrence rate along with complication rates for patients undergoing inguinal SLN dissection alone for vulvar carcinoma. METHODS: An IRB approved prospective study enrolled patients with biopsy proven squamous cell carcinoma of the vulva. Peritumoral injection of Tc-99 sulfur colloid and methylene blue dye was used to identify SLNs intraoperatively. Patients with SLNs negative for metastatic disease were followed clinically. Patients with metastasis detected in a SLN subsequently underwent a full groin node dissection followed by standard treatment protocols. RESULTS: Thirty-six patients were enrolled onto study with 35 undergoing a SLN dissection. All SNL dissections were successful with a mean of 2 SLN obtained per groin. There were 24 patients with stage I disease, 8 stage II, 3 stage III and 1 stage IV. A total of 56 SLN dissections were performed with 4 patients found to have inguinal metastasis by SLN dissection. There were 31 patients with a total of 46 SLN dissections found to be negative for metastatic disease. The median follow-up has been 29 months (range 8 to 51) with 2 groin recurrences for a groin recurrence rate of 4.3% and a recurrence rate per patient of 6.4%. There have been no reports of groin breakdown, extremity cellulitis or lymphedema. CONCLUSIONS: The recurrence rate for patients undergoing inguinal sentinel node dissection alone is low. These patients did not experience any complications as seen with complete groin node dissections. Sentinel lymph node dissection should be considered as an option for evaluation of inguinal nodes for metastatic disease.

The use of multiple novel tumor biomarkers for the detection of ovarian carcinoma in patients with a pelvic mass.

OBJECTIVES: The CA125 tumor marker is used to help predict the presence of ovarian cancer in patients with an adnexal mass. Because elevated CA125 levels occur in many benign gynecologic conditions, we set out to identify other novel biomarkers that would increase the sensitivity and specificity of CA125. METHODS: Serum and urine samples were obtained preoperatively from women undergoing surgery for an adnexal mass. The samples were analyzed for levels of CA125, SMRP, HE4, CA72-4, activin, inhibin, osteopontin, epidermal growth factor (EGFR), and ERBB2 (Her2) and were compared to final pathology results. Logistic regression models were estimated for all markers and combinations, with cross-validation analysis performed to obtain the sensitivities at set specificities of 90%, 95%, and 98%. RESULTS: Two hundred and fifty-nine patients with adnexal masses were enrolled. Of these, 233 patients were eligible for analysis with 67 invasive epithelial ovarian cancers and 166 benign ovarian neoplasms. Mean values for all marker levels except Her2 differed significantly between patients with benign masses and cancer. As a single marker, HE4 had the highest sensitivity at 72.9% (specificity 95%). Comparatively, combined CA125 and HE4 yielded the highest sensitivity at 76.4% (specificity 95%), with additional markers adding minimally to the sensitivity of this combination. HE4 was the best single marker for Stage I disease, with no increase in sensitivity when combined with CA125 or any other marker. CONCLUSIONS: As a single tumor marker, HE4 had the highest sensitivity for detecting ovarian cancer, especially Stage I disease. Combined CA125 and HE4 is a more accurate predictor of malignancy than either alone.

Utility of a novel serum tumor biomarker HE4 in patients with endometrioid adenocarcinoma of the uterus.

OBJECTIVE: Tumor markers with increased sensitivity and specificity for endometrial cancer are needed to help monitor response to therapy and to detect recurrent disease. Currently, the tumor maker CA125 is utilized in this role with limited value. The objectives of this study were to examine the levels of several novel tumor markers HE4, SMRP, CA72.4 and CA125 as potential markers in patients diagnosed with endometrioid adenocarcinoma of the uterus. METHODS: Pre-operative serum samples from surgically staged patients with endometrioid adenocarcinoma of the uterus were analyzed for levels of HE4, SMRP, CA72-4 and CA125. Control samples were obtained from healthy postmenopausal women. Logistic regression models and receiver operating characteristic (ROC) curves were constructed for each tumor marker and for all combinations, with cross-validation analyses to obtain average sensitivities at set specificities of 90%, 95%, and 98%. RESULTS: Serum samples from 156 healthy subjects and 171 patients with endometrial cancer (122 stage I, 17 stage II, 26 stage III, and 6 stage IV) were analyzed. At a 95% specificity, the sensitivities for differentiating between healthy subjects and all stages of cancer were 45.5% for HE4 and 24.6% for CA125. For stage I disease, HE4 yielded a 17.1% improvement in sensitivity compared with CA125. CONCLUSION: HE4 is elevated in all stages of endometrial can100cer and is more sensitive in early-stage endometrial cancer compared to CA125. Further investigation of HE4 as a marker for early detection of recurrent endometrial cancer and monitoring response to therapy is warranted.

Oral thalidomide as palliative chemotherapy in women with advanced ovarian cancer.

OBJECTIVE: We prospectively evaluated thalidomide, an oral agent with antiangiogenic and immunomodulatory properties, in patients with recurrent ovarian cancer, comparing the drug to standard intravenous chemotherapy and treatment holiday in terms of both progression-free interval and quality of life. METHODS: Eligible patients had recurrent ovarian or primary peritoneal cancer and had received a minimum of two prior therapeutic regimens. Patients were offered one of three arms: (Arm A) any standard intravenous single-agent chemotherapy; (Arm B) oral thalidomide 200 mg daily; (Arm C) treatment holiday. Computed tomography (CT) scans were performed every two cycles until disease progression by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. CA-125 was measured monthly as was quality of life using the Functional Assessment of Cancer Therapy (FACT-O) questionnaire. RESULTS: Forty patients participated: 18 on Arm A; 18 on Arm B; and 4 on Arm C. The groups were comparable in terms of number of prior regimens and cycles of chemotherapy. The progression- free intervals were similar in Arm A and Arm B (3.7 versus 3.8 months). The PR/SD rate was 6.7%/60% for Arm A, and 7.7%/53.8% in Arm B. Of those treated with thalidomide, 53% had a drop in CA-125 greater than 50%, compared to 13% receiving intravenous chemotherapy. FACT-O scores at baseline and throughout treatment were equivalent. CONCLUSION: The oral chemotherapeutic agent thalidomide appears to be comparable in response and quality of life, compared to single agent intravenous chemotherapy, in our population of heavily pretreated patients with ovarian cancer.

Phase II study of liposomal doxorubicin in platinum- and paclitaxel-refractory epithelial ovarian cancer.

PURPOSE: Stealth liposomal doxorubicin (Alzal Corp, Palo Alto, CA) has a slower clearance rate than free doxorubicin, resulting in sustained serum levels. Liposomal encapsulation also leads to increased concentration of drug in tumor tissue. Meta-analysis of previous studies has shown that doxorubicin has activity in epithelial ovarian cancer. The current study was developed to examine the activity of Stealth liposomal doxorubicin in platinum- and paclitaxel-refractory ovarian cancer. PATIENTS AND METHODS: Patients had epithelial ovarian cancer that either progressed on or recurred within 6 months of completion of platinum and paclitaxel chemotherapy. All patients had measurable disease. Stealth liposomal doxorubicin was administered at 50 mg/m(2) every 4 weeks as a 1-hour infusion. RESULTS: Eighty-nine patients were treated and included in an intent-to-treat analysis. There were 82 patients who were platinum and paclitaxel refractory and met all study criteria. There was one complete response and 14 partial responses, for a total response rate of 16.9% (95% confidence interval [CI], 9.1% to 24.6%). For platinum- and paclitaxel-refractory patients, the response rate was 18.3% (95% CI, 9.9% to 26.7%). Median time to progression was 19. 3 weeks for the entire population. Ten patients (11.2%) withdrew because of adverse events related to the drug (palmar-plantar erythrodysesthesia [PPE], n = 3; asthenia, n = 2; cardiac, n = 2; neutropenia, n = 1; stomatitis, n = 1; and edema, n = 1). There were no drug-related fatal events. There were only eight grade 4 adverse events attributable to the drug. Stomatitis, PPE, and skin lesions were managed with dose reductions and delays in most cases. CONCLUSION: Stealth liposomal doxorubicin has activity in refractory epithelial ovarian cancer. PPE and stomatitis can usually be managed by dose adjustment. The ease of administration makes this an attractive agent.

Predictive factors for the presence of malignant transformation of pelvic endometriosis.

OBJECTIVES: To determine predictive factors for the presence of malignant transformation in ovarian endometriotic cysts. STUDY DESIGN: This was an IRB approved, case control study analyzing patient data from 2004 to 2013. Pathology database records were searched to identify patients with benign endometrioma and ovarian carcinoma arising in the background of endometriosis. Inclusion criteria required each patient to have a preoperative diagnosis of adnexal mass and no other findings concerning for malignancy. Patient clinical records were queried for preoperative symptoms, serum CA125 levels and radiologic findings. Pathologic data were collected including histology, tumor grade and stage. RESULTS: A total of 138 patients met inclusion criteria; 42 women with ovarian cancer arising in the background of endometriosis and 96 women with benign endometrioma. Women diagnosed with ovarian cancer were significantly older than women with endometriosis (53.6 vs. 39.2 years). There was no difference in presence of symptoms between the two groups. Women with malignant tumors were found to have significantly larger cysts (14 cm vs. 7.5 cm; p<0.0001) that were more often multilocular (45.7% vs. 12.2%; p<0.0001), and contained solid components (77.1% vs. 14.5%; p<0.0001). Among patients that were observed prior to surgery there was a significant difference in the change in size of the mass over time with 4.2 cm increase for cases vs. 1.0 cm increase for controls (p=0.02). Multiple logistic regression analysis indicated that for every 5 years increase in age there was an adjusted OR of 2.17 (p=0.003). An age of 49 years or greater had an 80.6% sensitivity (95% CI: 62.5-92.5%) and an 82.9% specificity (95% CI: 67.9-92.8%) for malignancy, and solid component on imaging had an adjusted OR of 23.7 (p<0.0001). Serum CA125 levels tended to be higher in patients with malignant tumors but did not reach statistical significance with a mean of 204.9 vs. 66.9 (p=0.1). CONCLUSIONS: Significant predictors for malignant transformation of endometriosis include cyst characteristics and age. Women above the age of 49 with multilocular cysts and solid components are at high risk for malignant transformation of endometriosis. Serum CA125 level is not a significant predictor of malignant transformation.

Endometriosis with myxoid change. A case simulating pseudomyxoma peritonei.

After a diagnosis of endocervical adenocarcinoma was made on examination of a curettage specimen, a 46-year-old woman underwent laparotomy for the purpose of radical hysterectomy. After frozen section of a biopsy specimen obtained from a nodule 2 cm in diameter on the posterior surface of the cervix was interpreted as adenocarcinoma, consistent with pseudomyxoma peritonei, the planned hysterectomy was abandoned; only biopsies of the pelvic and para-aortic lymph nodes and a bilateral salpingo-oophorectomy were performed. Permanent sections of the nodule revealed pools of almost acellular mucin, myxoid fibrous tissue, and typical endometriotic glands and stroma. Similar findings were associated with endometriotic foci in the serosa of a fallopian tube and adjacent to a pelvic lymph node. There was no evidence of adenocarcinoma in any of the specimens. A radical hysterectomy was performed subsequently, and pathological examination of the uterus revealed a superficially invasive adenocarcinoma of the cervix without evidence of extrauterine spread. The diagnosis of endometriosis associated with myxoid change was confirmed in residual cul-de-sac tissue. The patient was alive with no clinical evidence of tumor 6.5 years later. This case illustrates that rare cases of endometriosis can be associated with striking degrees of myxoid change, a finding that should not be confused with mucinous adenocarcinoma on microscopic examination.

Prognostic value of clinical variables in ovarian cancer.

OBJECTIVE: To test the hypothesis that clinical variables, including the patient's symptoms, symptom severity, and co-morbidity, affect the survival rate in patients with ovarian cancer. METHODS: We reviewed the records of 137 cases of ovarian cancer diagnosed and treated between January 1987 and June 1992, and extracted data regarding patients' demographic characteristics, symptoms, medical co-morbidity, stage of disease, tumor histology and grade, treatment, and clinical course. RESULTS: Once cases of borderline tumors were excluded, the overall 3-year and 4-year mortality rate were 38% and 49%, respectively. There was an decrease in 4-year survival with more advanced symptom type ranging from 85% in asymptomatic women to 38% in women with complex symptoms (log rank, p = 0.005). Medical co-morbidity was not found to affect survival in the cohort studied. We performed multivariable analysis using a Cox proportional hazards model and confirmed that the symptom stage was highly prognostic even after controlling for FIGO stage, age and co-morbidity (p = 0.004). CONCLUSION: We found that clinical variables such as patient's symptoms, were associated with prognosis. Symptom classification is a necessary and important component in a system of prognostic stratification for ovarian cancer.

What matters matter? P values, H values, leadership, and us.

Framed by the question "What matters matter?," this essay considers today's physicians' need for leadership, the principled road they embarked on, and the reasons to continue. Taken as a whole, the vast problems of health care seem unsolvable. Approached in small tangible steps, if not cure, could direction, even inspiration, appear? When people are sick, they look to physicians. By actually caring for patients, physicians have earned trust and learned, scientifically and artfully, about life in ways others cannot. Meaningful patient-centered care occurs at the junction of logical science and tenuous human needs: "p values" and "h values." Along with the privileged understanding gained from patients comes the responsibility to stand publicly for the rights of all patients to private moments. Standing up in these ways can never be easy; then again, it never was. It is the continued journey toward historic ideals. It is an imprecise place of struggle, where caring "leadership" has always been most needed, fulfilling and truly defining physicians. Despite today's seemingly insurmountable obstacles, in this place each physician can find ways to reenergize around what matters matter.

Intraoperative real-time ultrasonography during intrauterine tandem placement.

Real-time ultrasound is used in the operating room as an aid in the placement of the intrauterine tandem. This method provides excellent imaging of the ongoing procedure, facilitating final tandem placement in the endometrial cavity even in the most difficult case.

Malignant transformation of vaginal endometriosis.

A well-documented case of extraovarian endometriosis undergoing malignant transformation is presented. A vaginal focus of endometriosis was biopsied over a 13-year interval during which time progression from benign to malignant disease was observed. Exogenous estrogen replacement was administered throughout the interval of transformation. The pathology, pertinent literature, and implications of the present case are discussed.

Ultrasound for diagnosing and preventing malplacement of intrauterine tandems.

Postoperative B-mode ultrasound was used to evaluate final tandem position in 50 consecutive placements (28 patients). In 34% (17 of 50), the tandem was found to be suboptimally positioned; in 24% (12 of 50), it penetrated the myometrium; and in 10% (five of 50), it frankly perforated the uterus. The uterine fundus was the region most commonly perforated, and the anterior myometrium was the site most frequently penetrated. In all cases in which postoperative ultrasound showed malpositioning, the clinical and radiographic assessment indicated proper intracavitary placement. Ultrasound affected clinical management in 42% (21 of 50) of the placements involving 61% (17 of 28) of the patients. To improve tandem placement, we used intraoperative real-time ultrasound to guide 73 consecutive surgical insertions. Ultrasound clearly visualized the procedure, allowing tandems to be positioned with confidence even in the most difficult cases. The immediate feedback from intraoperative ultrasound eliminated malplacements and thus the need for a second anesthesia to reposition the tandem.

An ectopic pregnancy in the upper retroperitoneum following in vitro fertilization and embryo transfer.

Thirty-seven days after successful embryo transfer, a chorionic vesicle was recovered from the upper abdominal retroperitoneal space in a patient presenting with an acute life-threatening hemorrhage. This is the first case report of a retroperitoneal ectopic pregnancy which, although uncommon, is a potentially fatal complication of in vitro fertilization-embryo transfer.

The effects of a course in cadaver dissection on resident knowledge of pelvic anatomy: an experimental study.

OBJECTIVE: To determine whether a course in cadaver dissection can significantly increase resident knowledge of pelvic anatomy beyond that of current educational practices. METHODS: Thirteen first- and second-year residents were randomly assigned to a cadaver dissection course (seven) or a control group (six). The dissection group performed dissections with instruction, using a dissection guide designed specifically for the course. The control group received study references on pelvic anatomy and protected study time. Each participant took a practical and written examination at the beginning and end of the study. RESULTS: The two groups did not differ statistically in their scores on the pre-test. Both groups improved on the post-test, but the dissection group scored nearly 50% higher on the test than did the controls. The two groups differed significantly on the post-test, adjusted for pre-test performance (P < .01). In their evaluation of the course, participants from the dissection group emphasized its educational value and urged that it be offered to residents as a regular part of their training. CONCLUSION: Dissection of a human cadaver provides a valuable experience, allowing participants to gain a greater understanding of surgical anatomy and surgical procedures in a no-risk, unhurried setting. Residents who participated in a cadaver dissection course designed specifically for their needs showed a statistically significant increase in knowledge compared with those without this experience. Both objectively and subjectively, a cadaver dissection course is an excellent tool for instructing gynecology residents.

Malignant mixed mesodermal tumors of the ovary.

OBJECTIVE: To review the experience at Women & Infants Hospital and Hartford Hospital of patients with malignant mixed mesodermal tumors of the ovary, and to review the pertinent literature. METHODS: Fourteen cases of malignant mixed mesodermal tumors of the ovary at the two hospitals over a 5-year period were identified through their tumor registries. Demographic data, pathology, treatment, and survival rates were reviewed. RESULTS: The median survival of the patients in our series was 7 months, with 64% dead of disease in 1 year. A review of the pertinent literature indicated median survivals of 6-12 months, with more than 70% of the patients dead of disease at 1 year, despite treatment. CONCLUSION: Further investigation is needed to determine the proper management for malignant mixed mesodermal tumors of the ovary. Meanwhile, current treatment strategies should recognize the present therapeutic limitations, so as not to diminish any further the quality of life for women with this malignancy.

Absence of estrogen and progesterone receptors in glassy cell carcinoma of the cervix.

OBJECTIVE: To evaluate the estrogen and progesterone receptor status of glassy cell carcinoma of the cervix to assess the possible implications of hormone replacement therapy in these patients. METHODS: The estrogen and progesterone receptor status of 13 glassy cell carcinomas was evaluated by immunohistochemistry using commercial monoclonal antibodies and a streptavidin-biotin detection system. RESULTS: No immunohistochemically detectable estrogen or progesterone receptor protein was present in tumor cells, although both receptors were identified in the adjacent normal cervical tissue. CONCLUSION: The absence of estrogen and progesterone receptors in glassy cell carcinoma suggests that this tumor would not be hormonally responsive and that these patients can be safely treated with hormone replacement therapy. Further studies are indicated to confirm this observation.

Persistence of gestational trophoblastic disease for longer than 1 year following evacuation of hydatidiform mole.

BACKGROUND: A spontaneous fall in the radioimmunoassay for the beta subunit of hCG to less than 2 mIU/mL documents regression of hydatidiform mole following evacuation of a molar pregnancy. Continued negative hCG levels for the year after evacuation indicates the absence of risk for persistent gestational trophoblastic disease. This report describes an unusual case of recurrent nonmetastatic gestational trophoblastic disease 16 months after initial evacuation. CASE: A 29-year-old woman presented at 19 weeks' gestation with severe preeclampsia and vaginal bleeding. Pelvic ultrasonography demonstrated a molar pregnancy. Pathology following uterine evacuation confirmed a hydatidiform mole. Serial hCG levels fell progressively to less than 2 mIU/mL over the following 25 weeks. She remained compliant with oral contraceptive pills despite having no sexual activity. Sixteen months after uterine evacuation, recurrence of gestational trophoblastic disease was documented by a rising beta-hCG, negative pelvic ultrasound, normal liver function tests, and normal computed tomography of the head. Endometrial curettage showed no chorionic villi or molar tissue. She was treated with five courses of actinomycin D and has remained disease-free for the following 5 years. CONCLUSION: This late recurrence of gestational trophoblastic disease suggests that those with a molar pregnancy may benefit from surveillance beyond 1 year after uterine evacuation.

Caelyx/Doxil for the treatment of metastatic ovarian and breast cancer.

Caelyx/Doxil is a novel pegylated liposomal formulation of the first-generation anthracycline, doxorubicin. The pharmacokinetics of this polyethylene-glycol-coated liposome are characterized by a reduced volume of distribution, a long intravascular circulating half-life and slow plasma clearance compared with free doxorubicin. This, coupled with a small vesicular size, uniquely promotes the localization of Caelyx/Doxil at tumor sites and explains its altered toxicity profile. The FDA and EMEA have approved its use for the treatment of AIDS-related Kaposi's sarcoma and, more recently, for recurrent epithelial ovarian cancer (EOC). Numerous investigations have focused on its use in the treatment of metastatic breast cancer, as well as recurrent squamous cell cervical carcinoma, soft tissue sarcoma, squamous head and neck cancers, prostate cancers and malignant gliomas. Ongoing clinical studies of combination regimens incorporating Caelyx/Doxil will further clarify its role in the treatment of advanced solid tumors.