Scott E. Lentz

Identification of micrometastases in histologically negative lymph nodes of early-stage cervical cancer patients.

OBJECTIVE: Despite histologically negative lymph nodes, approximately 15% of patients with early-stage cervical cancer will develop recurrence. Micrometastases have been shown to be important in staging and treatment of breast cancers and melanoma and have been identified by polymerase chain reaction analysis in cervical cancers. This study sought to estimate the frequency of micrometastases identified by immunohistochemistry in histologically negative lymph nodes and compare this to other known risk factors for recurrence of cervical cancer. METHODS: Early-stage (stages IA2, IB1, and IB2) cervical cancer patients of all histologic subtypes were identified from the surgical logs of the Los Angeles County–University of Southern California Medical Center for the period 1994–2000. One hundred thirty-two patients had histologically negative lymph nodes. Immunohistochemical assay was performed on 3,106 lymph nodes by using antibodies against cytokeratins AE-1 and CAM 5.2 in combination according to standard protocols. The stained nodes were then evaluated for the presence of micrometastases and compared against the respective clinicopathologic information in each case. RESULTS: Micrometastases were detected in 19 of 132 (15%, 95% confidence interval [CI] 9%, 22%) patients, found in 29 of the 3,106 (0.9%) lymph nodes evaluated. Vascular space invasion was seen in 50 of 132 cases (38%, 95% CI 30%, 47%) and in 8 of 19 (42%, 95% CI 21%, 66%) cases with micrometastases. Surgical margins of the resected specimen were negative in 120 of 132 cases (91%, 95% CI 84%, 95%) and in 16 of 19 (84%, 95%CI 60%, 96%) of those cases with micrometastases. Micrometastases were seen most frequently in pelvic lymph nodes (25 of 29, 86%). Patients with more than 20 lymph nodes removed were more likely to demonstrate metastasis (P < .001). There was no statistically significant association between micrometastasis and vascular space invasion or tumor volume. CONCLUSION: Micrometastases are identifiable in histologically negative lymph nodes in 15% (95% CI 9%, 22%) of early-stage cancer patients, a frequency which approximates the recurrence rate for patients with negative nodes. In this series, patients with greater numbers of lymph nodes analyzed were more likely to have lymph node micrometastasis identified. There appears to be no relationship between tumor volume and the identification of micrometastases. Although micrometastases can be identified in histologically negative lymph nodes, their presence is not strongly associated with other known factors of cervical cancer recurrence. Further research is needed to determine whether the presence of lymph node micrometastases is associated with an unfavorable prognosis. LEVEL OF EVIDENCE: II-3

Lymphovascular and perineural invasion in the parametria: A prognostic factor for early-stage cervical cancer

OBJECTIVE To estimate the impact of parametrial lymphovascular and perineural involvement on nodal metastasis and failure pattern of women with early-stage, surgically treated cervical cancer. METHODS Clinical records and pathologic slides of 93 patients with early-stage cervical cancer (2 IA2, 52 IB1, 31 IB2, and 8 IIA) treated with radical hysterectomy and pelvic lymphadenectomy with or without paraaortic lymphadenectomy were reviewed. The study group comprised 80 patients with squamous cell carcinoma and 13 patients with adenocarcinoma of the cervix. Median follow-up time was 33 months. The association among the various histopathologic predictors of outcome was determined with χ2 analysis. The influence of the predictors on outcome was examined with log rank survival methods and the Cox regression model. RESULTS The presence of parametrial lymphovascular space invasion is a predictor of disease in the pelvic (P < .001) and paraaortic (P < .05) lymphatics independently. Large tumor size (greater than 4 cm), parametrial perineural invasion, cervical lymphovascular space invasion, and tumor depth (greater than two thirds) were found to be simultaneous predictors of recurrence on multivariate analysis (P < .05). Using these four binary predictor variables, we have computed a model-based relative risk. Based on this model, the presence of perineural invasion in the parametria more than doubles the risk of recurrence in the cohort of patients with large (greater than 4 cm) tumors (P < .05). In a subset analysis of patients with negative nodal disease, parametrial perineural invasion and tumor size were independent predictors of poor outcome (P < .05). CONCLUSION Presence of parametrial lymphovascular space invasion correlates significantly with the risk of nodal metastasis in women with early-stage cervical cancer. Parametrial perineural invasion is an independent poor prognostic factor. Histopathologic findings within the parametria are a valuable independent predictor of recurrence and thus may influence the selection of patients for adjuvant treatment.

Occult Uterine Sarcoma and Leiomyosarcoma: Incidence of and Survival Associated With Morcellation.

OBJECTIVE: To estimate the incidence of occult uterine sarcoma and leiomyosarcoma in hysterectomies for leiomyomas and the risk associated with their morcellation. METHODS: We conducted a population-based cohort study. All uterine sarcomas from 2006–2013 in an integrated health care system were identified. Age- and race-specific incidences of occult uterine sarcoma were calculated. Kaplan-Meier survival analysis was performed. Crude and adjusted risk ratios of recurrence and death associated with morcellation at 1, 2, and 3 years were estimated using Poisson regression with inverse probability weighting. RESULTS: There were 125 hysterectomies with occult uterine sarcomas identified among 34,728 hysterectomies performed for leiomyomas. The incidence of occult uterine sarcoma and leiomyosarcoma was 1 of 278 or 3.60 (95% confidence interval [CI] 2.97–4.23) and 1 of 429 or 2.33 (95% CI 1.83–2.84) per 1,000 hysterectomies. For stage I leiomyosarcoma (n=111), eight (7.2%) were power and 27 (24.3%) nonpower-morcellated. The unadjusted 3-year probability of disease-free survival for no morcellation, power and nonpower morcellation was 0.54, 0.19, and 0.51, respectively (P=.15); overall survival was 0.64, 0.75, and 0.68, respectively (P=.97). None of the adjusted risk ratios for recurrence or death were significant except for death at 1 year for power and nonpower morcellation groups combined (6/33) compared with no morcellation (4/76) (5.12, 95% CI 1.33–19.76, P=.02). We had inadequate power to infer differences for all other comparisons including 3-year survival and power morcellation. CONCLUSION: Morcellation is associated with decreased early survival of women with occult leiomyosarcomas. We could not accurately assess associations between power morcellation and 3-year survival as a result of small numbers.

Is older age a poor prognostic factor in stage I and II endometrioid endometrial adenocarcinoma

OBJECTIVE Prior studies have shown that age ≥70 years is associated with more aggressive non-endometrioid histology and worse survival in endometrial cancer. The purpose of this study is to assess if age is an independent poor prognostic factor in endometrioid histologies. METHODS Under an IRB-approved protocol, we identified patients with surgical stage I to II endometrioid endometrial adenocarcinoma from 1995 to 2008 at two institutions. Patients were divided into two groups based on age at diagnosis: Group A (age 50-69 years) and Group B (age≥70 years). All patients underwent hysterectomy, bilateral salpingoophorectomy, +/-pelvic/aortic lymphadenectomy and adjuvant therapy. Prognostic factors were evaluated by univariate and multivariate analyses. RESULTS We identified 338 patients with stage IA to IIB endometrioid endometrial adenocarcinoma. The median age in Group A was 59 years (range 50-69) and Group B was 75 years (range 70-92). Patients in Group B were more likely to have hypertension (51% vs. 68%, p=0.006) and coronary artery disease (9% vs. 18%, p=0.03). There were no differences in progression-free or disease-specific survival, however, Group B had a worse overall survival (OS) (50.1 vs. 62.6 months, p=0.03). On univariate analysis, age (p=0.04), grade (p=0.006), and coronary artery disease (p=0.01) were associated with worse OS. After adjusting for grade and coronary artery disease, age was no longer a significant variable for OS (p=0.17). CONCLUSIONS After adjusting for other poor prognostic factors, age ≥70 years alone may not be a significant variable affecting overall survival in patients with early stage endometrioid endometrial adenocarcinoma.

Metformin and breast and gynecological cancer risk among women with diabetes

Objective We investigated if metformin lowers breast, endometrial, and ovarian cancer risk in women with type 2 diabetes mellitus compared with women who used other antidiabetic medications. Research design and methods We followed a cohort of 66 778 female patients with diabetes for a maximum of 12 years (median 6 years). We examined breast, endometrial, and ovarian cancer risk, and the composite cancer risk. We examined drug categories using pharmacy records: metformin only; metformin combination regimens; non-metformin regimens; and non-users. We used χ2 analyses to examine categorical variables. We conducted multivariable Cox regression models with time-dependent drug use status. Results Women who used metformin combination regimens versus metformin only had a 15% lower breast cancer risk (adjusted HR=0.85, 95% CI 0.69 to 1.04). After stratifying by glycated hemoglobin (HbA1c), the association attenuated in those who had poorly controlled HbA1c (adjusted HR=1.06, 95% CI 0.73 to 1.55). Given the small numbers of ovarian and endometrial cancer outcomes, we examined these as a composite. The risk of all cancers combined was similar in those who used metformin combination regimens versus metformin only (adjusted HR=0.92, 95% CI 0.78 to 1.10). We found no significant differences for breast cancer or all cancers combined when we compared risks in non-metformin users versus metformin only users. Conclusions Women who used metformin and other antidiabetic drugs had a lower breast cancer risk compared with women who used metformin only, but the results were not significant. We also found no difference in overall cancer risks when we compared women who used other antidiabetic drugs (no metformin) versus metformin users.

Role of adjuvant chemotherapy in patients with early stage uterine papillary serous cancer

Objective: Uterine papillary serous carcinoma (UPSC) is an aggressive subtype of endometrial cancer. We studied survival outcomes in patients with stages I/II UPSC. Materials: A retrospective, multi-institutional study of patients with stages I/II UPSC was conducted. Patients underwent surgical staging followed by observation, adjuvant platinum-based chemotherapy (CT), or radiation therapy (RT). Continuous variables were compared via Wilcoxon rank sum test; Fisher exact test was used for the unordered categorical variables. Kaplan-Meier curves were used to estimate survival. Results: Thirty-nine women were diagnosed with stage I (n = 30) or II (n = 9) UPSC, with a median follow-up of 52 months. Of the 26 patients who did not receive adjuvant CT, 9 developed recurrences and 8 died of their disease. Of the 10 patients with no myometrial invasion who did not receive adjuvant CT, 3 developed recurrences and died. Of the 7 patients who underwent RT, 2 developed distant recurrences and died. Of the 13 patients who underwent CT, 1 developed vaginal recurrence. The 5-year overall (OS) and progression-free survival (PFS) rates for the adjuvant CT group were 100% and 92%, respectively, compared with 69% and 65% for those who did not receive CT (P = 0.002 OS, P = 0.002 PFS). The 5-year OS and PFS rates for RT group were both 71%. Conclusions: Patients with stages I/II UPSC are at significant risk for distant recurrence and poor survival. Platinum-based adjuvant CT may decrease recurrence rate and improve survival in women with early and well-staged UPSC.

Adjuvant gemcitabine-docetaxel chemotherapy for stage I uterine leiomyosarcoma: Trends and survival outcomes

OBJECTIVE To assess recent trends of administering adjuvant gemcitabine-docetaxel (GD) chemotherapy for Stage I uterine leiomyosarcoma, and to compare disease-free and overall survival between women who received and did not receive adjuvant GD chemotherapy. METHODS All patients diagnosed with Stage I uterine leiomyosarcoma in a California-Colorado population-based health plan inclusive of 2006-2013 were included in a retrospective cohort. Adjuvant GD chemotherapy rates, clinico-pathologic characteristics and survival estimates were assessed. RESULTS Of 111 women with Stage I uterine leiomyosarcoma, 33 received adjuvant GD (median 4cycles), 77 received no chemotherapy, and 1 patient excluded for non-GD chemotherapy. GD-chemotherapy and no-chemotherapy groups were similar with respect to age, stage (IA/IB), uterine weight, mitotic index, body mass index, and Charlson comorbidity score. Non-Hispanic white women were twice as likely to receive adjuvant chemotherapy as non-white or Hispanic women (37.7 vs. 17.1%, P=0.02). The proportion of women receiving adjuvant GD chemotherapy increased from 6.5% in 2006-2008 to 46.9% in 2009-2013 (P<0.001). There was no significance difference in unadjusted Kaplan-Meyer estimated disease-free (P=0.95) or overall survival (P=0.43) between GD-chemotherapy and no-chemotherapy cohorts. Corresponding adjusted Cox proportional hazard ratios for adjuvant GD chemotherapy compared to no chemotherapy were 1.01 (95% confidence interval [CI] 0.57-1.80, P=0.97) for recurrence and 1.28 (95% CI 0.69-2.36, P-0.48) for mortality. CONCLUSIONS Use of adjuvant GD chemotherapy for Stage I uterine leiomyosarcoma has increased significantly in the last decade, despite unclear benefit. Compared to no chemotherapy, 4-6cycles of adjuvant GD chemotherapy does not appear to alter survival outcomes.

Lymph Node Micrometastases in Early-Stage Cervical Cancer are Not Predictive of Survival

Although patients with early-stage cervical cancer have in general a favorable prognosis, 10% to 40% patients still recur depending on pathologic risk factors. The objective of this study was to evaluate if the presence of lymph node micrometastasis (LNmM) had an impact on patient’s survival. We performed a multi-institutional retrospective review on patients with early-stage cervical cancer, with histologically negative lymph nodes, treated with radical hysterectomy and pelvic lymphadenectomy for the study period 1994 to 2004. Tissue blocks of lymph nodes from the patient’s original surgery were recut and then evaluated for the presence of micrometastases. One hundred twenty-nine patients were identified who met inclusion criteria. LNmM were found in 26 patients (20%). In an average follow-up time of 70 mo, there were 11 recurrences (8.5%). Of the 11 recurrences, 2 (18%) patients had LNmM. Patients with LNmM were more likely to have received adjuvant radiation and chemotherapy. In stratified log-rank analysis, LNmM were not associated with any other high-risk clinical or pathologic variables. Survival data analysis did not demonstrate an association between the presence of LNmM and recurrence or overall survival. The presence of LNmM was not associated with an unfavorable prognosis nor was it associated with other high-risk clinical or pathologic variables predicting recurrence. Further study is warranted to understand the role of micrometastases in cervical cancer.

Abdominal aortic resection and Y-graft placement to achieve complete cytoreduction in stage IIIc ovarian carcinoma.

BACKGROUND: Major vascular resection with reconstruction in patients with gynecologic malignancy is rarely performed and infrequently reported. CASE: A 40-year-old woman undergoing surgery for stage IIIc ovarian papillary serous adenocarcinoma was left with a 7-cm aortic metastasis not separable from the infrarenal abdominal aorta. An aortic resection with prosthetic graft placement was performed to achieve complete tumor resection. She remains disease-free in excess of 10 years with no evidence of graft complication. CONCLUSION: Major vascular reconstructive procedures for the management of malignancy need not be precluded in properly selected circumstances.

Operative and anesthetic outcomes in endometrial cancer staging via three minimally invasive methods

The aim of this work is to compare operative and anesthetic outcomes in patients undergoing minimally invasive endometrial cancer staging, with lymphadenectomy performed via transperitoneal, extraperitoneal, or robotic-assisted methods. Sixty-six consecutive patients (24 transperitoneal, 19 extraperitoneal, and 23 robotic) were identified who underwent laparoscopic-assisted endometrial cancer staging with pelvic and para-aortic lymphadenectomy. Patients were divided into three groups based on method of para-aortic lymphadenectomy. Anesthetic and surgical times were longest in the extraperitoneal group. Patients undergoing robotic surgery had the shortest hospital stay and lowest conversion rate to laparotomy. Patients undergoing robotic lymphadenectomy had more pelvic and para-aortic nodes removed compared with the transperitoneal method. There was no difference in number of para-aortic nodes removed in the robotic versus extraperitoneal methods. The extraperitoneal group had highest peak end-tidal CO2 levels and highest narcotic requirements, while patients in the robotic group had highest peak inflation pressures and lowest pain scores. There were no differences in complication rates amongst the three groups. Robotic-assisted staging is superior to other minimally invasive methods in terms of most operative outcomes. Extraperitoneal lymphadenectomy is equivalent to robotic surgery where number of aortic nodes is concerned, but is associated with higher end-tidal CO2 levels and narcotic requirements. Peak inflation pressures were highest in the robotic group, with no apparent adverse consequences.