Out-of-protocol concurrent use of cisplatin and radiation therapy in locally advanced cervical cancer: feasibility and survival.

PURPOSE OF INVESTIGATION: We assessed the feasibility, response rates, and overall survival of patients with locally advanced cervical cancer treated with cisplatin-based chemotherapy during radiation therapy on an out-of-protocol basis. METHODS: Sixty-nine consecutive newly diagnosed untreated patients with locally advanced cervical cancer who received chemoradiation between 1999 and 2003 were retrospectively reviewed. Treatment consisted in external beam radiation followed by one 137-cessium intracavitary application. Cisplatin was administered for six weeks during external beam radiation. RESULTS: Treatment was well tolerated, although 52 patients presented some degree of acute adverse toxicity (gastrointestinal 65%, hematological 48%, genitourinary 10%). The 3-year survival rate was 61.8% (95% CI 54.5-69.0), with a mean 41.8 months (95% CI 35.7-48.3). Overall survival after adjusting by FIGO Stage IB2-IIA and IIB-IVA was 73.9% and 50%, respectively (p = 0.1839). Overall survival according to Stages IB2-IIb and III-IVA was 74.8% and 34.9%, respectively (P = 0.0376). CONCLUSION: In patients with locally advanced cervical cancer, adding a weekly regimen of cisplatin to standard pelvic radiation in an out-of-protocol basis is feasible, effective, and showed no unexpected toxicity.

Risk of recurrence during follow-up for optimally treated advanced epithelial ovarian cancer (EOC) with a low-level increase of serum CA-125 levels.

BACKGROUND: Our group evaluated the risk of recurrence for optimally treated advanced epithelial ovarian cancer (adEOC) in patients with a low-level rising serum CA-125 concentration within the normal range (0-35 kU/l). In addition, we tested the new proposed early CA-125 signal of progressive disease (EPD) criterion in the same study population. PATIENTS AND METHODS: Patients treated from 1998 to 2006 for adEOC were identified at our institution. Inclusion criteria were as follows: CA-125 at time of diagnosis (>35 kU/l); International Federation of Gynecology and Obstetrics stages III-IV treated with optimal primary treatment; and complete response (CR) to primary treatment with normalization of CA-125. RESULTS: Median progression-free survival and overall survival for the recurrence group (n = 60) were 17.7 and 38.2 months, respectively. The median follow-up time from CR to last contact was 40.2 months for patients in the nonrecurrence group (n = 36). An absolute increase in serum CA-125 levels of >or=5 kU/l compared with baseline CA-125 nadir values was significantly predictive of recurrence (odds ratio for recurrence = 402.98, P < 0.0001). The progression date was predated by the EPD criterion in 77% of patients with known progressive disease (median, 58 days early) with a sensitivity of 90%, a positive predictive value of 96.4%, and a false-positive rate of 5.6%. CONCLUSIONS: Among patients with optimally treated adEOC in complete remission, a low-level increase in serum CA-125 concentration within the normal range is a strong independent predictive factor for disease recurrence. In this patient population, future prospective randomized trials should consider the evaluation of the EPD criterion.

Nadir CA-125 concentration in the normal range as an independent prognostic factor for optimally treated advanced epithelial ovarian cancer.

BACKGROUND: The amount of residual disease after surgery is considered the most important factor influencing the survival of patients with advanced epithelial ovarian cancer (adEOC). In optimally treated patients with adEOC, there are no well-established prognostic factors [excluding International Federation of Gynecology and Obstetrics (FIGO) stage]. The aim of this retrospective study is to analyze the prognostic value of the CA-125 nadir after the completion of an optimal primary treatment. PATIENTS AND METHODS: Patients treated for adEOC were identified from January 1998 to December 2006. INCLUSION CRITERIA: elevated CA-125 at time of diagnosis (>35 kU/l); FIGO stage III-IV treated with optimal primary treatment (residual tumor <1 cm and carboplatin/taxane-based combination chemotherapy); and complete response to optimal primary treatment with normalization of CA-125. RESULTS: Patients, n = 96: 44 group A (< or =10 kU/l); 52 group B (11-35 kU/l). Median progression-free survival (PFS) was 42 and 20 months for groups A and B, respectively (P = 0.0087). Median overall survival (OS) was 84 and 43 months for groups A and B, respectively (P < 0.0001). The Cox model showed a highly significant impact on PFS and OS in relation to CA-125 nadir levels. CONCLUSIONS: The CA-125 nadir value is a strong independent prognostic factor for optimally treated adEOC after achieving a complete response.

Sentinel lymph node identification in a primary ductal carcinoma arising in the vulva.

Primary or metastatic breast-like carcinoma of the vulva is a rare event. Because of the similarity with breast ductal carcinoma, we think that the same principles used for treatment of orthotopic breast cancer can be applied, as well as the use of sentinel lymph node technique, which is widely accepted in the management of early-stage breast cancer. We report a 49-old-year postmenopausal woman who was referred to our institution after small biopsy of a 3.5- x 3-cm right vulvar tumor. Histopathologically, infiltration of the vulvar dermis by a ductal carcinoma of mammary gland type was reported. At operation, the sentinel node technique revealed two sentinel nodes in the right inguinal area. Although these nodes proved negative for malignancy, the patient underwent wide local excision of tumor and complete ipsilateral inguinofemoral lymphadenectomy. The remaining excised nodes were negative. Surgical specimen proved estrogen- and progesterone-positive receptors, the reason for which the patient received tamoxifen adjuvant therapy. This report represents the first case in the world literature of primary breast carcinoma arising in the vulva in which sentinel lymph node identification has been possible. Because of the rarity of this condition, the pathologic similarity of this tumor along with currently accepted guidelines for the management of breast cancer supports the possibility of local excision and sentinel lymph node identification as a possible alternative to inguinofemoral lymphadenectomy.

Modified approach for extraperitoneal laparoscopic staging for locally advanced cervical cancer.

Describe a modified approach to the technique for staging laparoscopic extraperitoneal aortic and common iliac lymph node dissection for locally advanced cervical cancer.Retrospective, nonrandomized clinical study. (Canadian Task Force classification II-2), setting in an acute-care, teaching hospital. Thirty-six patients with locally advanced cervical cancer underwent laparoscopic surgical staging via extraperitoneal approach with the conventional or the modified technique from August 2001 through September 2004. Clinical outcomes in 23 patients who were operated on with the conventional technique using index finger for first trocar entrance; 12 patients with the modified technique using direct trocar entrance, were compared. One patient was excluded due to peritoneal carcinomatosis. Technique, baseline characteristics, histopathologic variables and surgical outcome were measured. There were no significant differences in patients basal characteristics on comparative analysis between conventional and modified technique. With our proposed modified technique, we obtained a reduced surgical procedure duration and blood loss. The proposed modified surgical technique offers some advantages, is an easier approach because the parietal pelvic peritoneum is elastic and this helps to avoid its disruption at time of trocar insertion, size of incision is shorter, we achieved no CO2 leak through the trocar orifice, and wound suture is fast and simple.

Extraperitoneal laparoscopic para-aortic lymphadenectomy for lymph node recurrence of fallopian tube carcinoma.

The endoscopic retroperitoneal approach is a minimally invasive method for surgical staging of cervical cancer. A 57-year-old woman had an intraoperative diagnosis of carcinoma of the left fallopian tube and undergone a retroperitoneal pelvic and para-aortic lymphadenectomy with no peritonization during surgical staging. Small suspicious nodes in the serous membrane of the sigmoid colon and peritoneal washings were positive for malignancy. A total of 12 nodes were obtained, all of which were negative. She received six cycles of paclitaxel and platinum-based chemotherapy and showed a complete clinical response. Thirty-two months after surgery, the abdominal computed tomography scan showed a left para-aortic lymph node, 19 mm in diameter, which was successfully removed through an extraperitoneal laparoscopic approach. The extraperitoneal laparoscopic approach of the para-aortic region is a feasible procedure after previous transperitoneal lymphadenectomy and chemotherapy.

Usefulness of sentinel lymph node detection in early stages of cervical cancer.

PURPOSE: Sentinel lymph node (SLN) mapping in combination with surgical biopsy is an emerging technique for use in the early stages of cervical cancer. The purpose of this study was to evaluate the technique in a series of 40 consecutive women with early stage cervical cancer. METHODS: Forty patients with early stage cervical cancer [FIGO stage IA2 (2), IB1 (34), IB2 (1) or IIA (3)] were referred for radical hysterectomy with pelvic lymphadenectomy. Patients were submitted to preoperative lymphoscintigraphy (four 99mTc-nanocolloid injections around the tumour) and intraoperative SLN detection. Hand-held or laparoscopic gamma probes were used to locate SLNs during surgery. RESULTS: The mean number of SLNs was 2.5 per patient (interiliac 49%, external iliac 19%). Of the total of 99 SLNs, six, in four women, showed metastases (all 68 non-SLNs removed were negative). In the other 36 patients, all the removed lymph nodes (sentinel and non-sentinel) were negative (0% false negative rate). During the follow-up (median 25 months), only two patients presented distant metastases: one died 6 months after surgery (two of three SLNs positive, both hot and blue), while the second patient is alive 4 years after surgery (lung metastasis, no isotope drainage, negative blue SLN). The survival rate was 95% and disease-free survival, 97%. CONCLUSION: SLN surgical biopsy based on lymphoscintigraphy and blue dye is a feasible and useful technique to avoid lymph node dissection in the early stages of cervical cancer. It has a high negative predictive value, can be incorporated into clinical routine (laparoscopy or open surgery) and is close to achieving validation in this setting.

Metástasis inguinal como primera manifestación de carcinoma de ovario con carcinoma concomitante de mama / Inguinal metastasis as the first manifestation of ovarian carcinoma with concomitant breast carcinoma

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Endometrial carcinoma in tamoxifen-treated breast cancer patient: clinicopathological, immunohistochemical, and genetic analysis.

Endometrial polyps and endometrial neoplasms are a recognized complication of chronic tamoxifen treatment. This study describes an endometrial carcinoma that developed in a woman receiving low-dose tamoxifen treatment for breast cancer. Little is known about steroid receptor status, somatic alterations in oncogenes and tumor suppressor genes, and inherited susceptibility in endometrial carcinomas associated with tamoxifen use. In the present case, the endometrial carcinoma was negative for estrogen receptors and weakly positive for progesterone receptors. In addition, analysis of K-ras, c-erbB2/neu, cyclin D1, and p53 status revealed a codon 12 point mutation in the K-ras oncogene. The patient was determined not to be a carrier of germ-line mutations in cytochrome P-450 1A1 (CYP1A1), an estrogen-metabolizing gene previously associated with enhanced endometrial cancer risk, but she was a carrier of a methylenetetrahydrofolate reductase gene variant related with putative alterations in DNA methylation.

Clinicopathologic features and genetic alterations in endometrioid carcinoma of the uterus with villoglandular differentiation.

Serious and endometrioid carcinomas differ dramatically in their clinical behavior; however, the specific significance of villoglandular (papillary) differentiation in endometrioid carcinoma has been studied rarely. We compared the clinicopathologic features and genetic alterations in 28 villoglandular endometrioid carcinomas compared with 60 nonvilloglandular endometrioid carcinomas and 60 healthy women. The study revealed a slight increase in the frequency of early-stage disease in villoglandular tumors compared with nonvilloglandular tumors. No differences were observed in the age at onset or cellular grade. The oncogene and susceptibility gene analyses revealed a positive association of K-ras oncogene mutation and germline variants of the cytochrome P-450 1A1 (CYP1A1) gene and an inverse association of the p53PIN3 variant with villoglandular carcinomas, whereas no differences were observed in the c-erbB2/neu oncogene amplification or the methylenetetrahydrofolate reductase germline variant. Finally, a positive association was found between CYP1A1 and methylenetetrahydrofolate reductase variants and the presence of papillary differentiation in the myometrial component. The results suggest that the villoglandular differentiation pattern arises without aggressive clinicopathologic features in a genetic background of transforming and carcinogen-metabolism genes, characteristic of estrogen-related endometrial tumors (type 1) not exhibiting an unfavorable prognosis.

The clinicopathological significance of K-RAS point mutation and gene amplification in endometrial cancer.

The aim of this study was to examine the prevalence and clinicopathological significance of K-RAS oncogene activation in endometrial carcinoma and atypical hyperplasia. We analysed K-RAS point mutation and gene amplification in 55 endometrial carcinomas using polymerase chain reaction associated with restriction fragment length polymorphism and genomic differential polymerase chain reaction. Point mutations at codon 12 of K-RAS oncogene were identified in 8 of 55 (14.5%) tumour specimens. In addition, we were unable to detect any K-RAS gene amplification in any of the endometrial carcinomas studied. No correlation was found between K-RAS gene mutation and age at onset, histological subtype, grade of differentiation, clinical stage or current patient status. We conclude that K-RAS mutation is a relatively common event in endometrial carcinomas, but with no clear prognostic value.

Merkel cell carcinoma of the vulva.

Merkel cell carcinoma is a very rare tumor. This is why it is not known whether this neoplasm behaves differently in the vulvar location than at other sites. We present a patient with a Merkel cell carcinoma assessed with a light optical microscope, immunohistochemistry, and electron microscope. Only eight previous cases have been reported in the literature. We discuss pathologic findings, such as histologic trabecular pattern under the optical microscope and neurosecretory granules (similar to Merkel cell carcinoma of the skin) under the electron microscope. Also discussed are the results of immunohistochemistry for low-molecular-weight cytokeratin, neuron-specific enolase, chromogranin, and Leu 7, and molecular study of N-ras, K-ras, N-myc, and p53 genes. Little is known about Merkel cell carcinoma of the vulva, but it seems to have a more aggressive behavior and poorer prognosis than Merkel cell carcinoma at other sites.

Uterine sarcoma: a clinicopathological study of 93 cases.

OBJECTIVE: To evaluate the clinical outcome of patients suffering from primary uterine sarcoma diagnosed and treated in our Hospital. SETTING: Department of Gynecologic Surgery/Gynecologic Oncology, Hospital Universitario Materno-Infantil Vall d'Hebron de Barcelona, Barcelona, Spain. SUBJECTS AND METHODS: A retrospective review from 1967 to 1995 of clinical and pathological characteristics of 93 patients with primary uterine sarcoma was done. Patients were staged using the 1988 FIGO histological classification for uterine cancer. Clinical features, type of surgery, adjuvant therapy, recurrences, distant metastasis, and survival were recorded. RESULTS: Our study included three main histologic types: 44 patients with leiomyosarcoma, 26 patients with endometrial stromal sarcoma, and 18 patients with mixed Müllerian sarcomas. The mean age for all patients was 54.8 years, and the most common symptom was vaginal bleeding. Other clinicopathological features were examined. Although surgery was the most frequent treatment, adjuvant therapies have been analyzed and discussed. The overall three-year survival rate was 67.9% and the overall five-year survival rate was 64.5%. We found statistical differences (p < 0.001) between the stage I survival rate and other stage survival rates. CONCLUSIONS: Uterine sarcoma is an uncommon neoplasia diagnosed in the 6th decade of life. Leiomyosarcoma is the most frequent histologic type (47.3%). Stage I uterine sarcoma has a better prognosis than other stages.

Susceptibility to endometrial cancer: influence of allelism at p53, glutathione S-transferase (GSTM1 and GSTT1) and cytochrome P-450 (CYP1A1) loci.

A case-control study was designed to identify associations between polymorphisms at p53, cytochrome P-450 (CYP1A1) and glutathione-S-transferases and endometrial cancer susceptibility. Among all polymorphisms analysed, an insertional variant in p53 (P53PIN3) and two polymorphisms in the 3'-end and exon 7 of CYP1A1 showed significant association with enhanced endometrial cancer risk.

Detection of clonality and genetic alterations in endometrial pipelle biopsy and its surgical specimen counterpart.

Carcinoma of the endometrium is the most frequently diagnosed gynecologic malignancy in the western world. Because endometrial carcinoma is monoclonal in origin, the small samples obtained in endometrial pipelle biopsies can be used in PCR clonal studies to distinguish cancerous from noncancerous lesions. The method used for clonal analysis was based on RFLP of the X chromosome-linked phosphoglycerokinase gene and random inactivation of one X chromosome by methylation in women. Among 50 endometrial pipelle biopsies, 26 (52%) were found to be heterozygous for the above-mentioned polymorphism. Of the samples taken from these informative (ie, heterozygous) patients, six were monoclonal including five cases of endometrial carcinoma and one of endometrial atypical hyperplasia. In each case, the same pattern of monoclonality was present in the surgical specimen counterpart. All of the remaining samples were polyclonal and, when the anatomical pathology data were contrasted, they correlated with nonmalignant endometrium (five secretory, five proliferative, seven atrophic, and three simple hyperplasias). In addition, genetic alterations study of monoclonal endometrial samples revealed a K-ras point mutation and a c-erbB2/neu gene amplification in two different endometrial carcinomas. Both alterations were also detected in the surgical specimens. In addition, a diagnosed set of 10 samples of simple hyperplasia and 5 of atypical hyperplasia were subjected to clonal assay. Among eight informative cases, the three that showed that showed the monoclonal pattern corresponded with cases of atypical hyperplasia. No other genetic alterations were detected in these samples. In conclusion, our data indicate that the detection of clonality in endometrial biopsy samples obtained by pipelle would be a useful application for the early diagnosis of endometrial cancer.

Germ line polymorphisms in cytochrome-P450 1A1 (C4887 CYP1A1) and methylenetetrahydrofolate reductase (MTHFR) genes and endometrial cancer susceptibility.

We describe here a case-control study to identify associations between polymorphisms at the methylenetetrahydrofolate reductase (MTHFR) and cytochrome P-450 1A1 (CYP1A1) genes and susceptibility to endometrial cancer. Accordingly, genotype frequencies in 80 endometrial carcinoma patients were compared with frequencies in 60 controls. DNA analysis suggest a significantly increased endometrial cancer risk with an alanine to valine substitution at nucleotide 677 of MTHFR gene with an odds ratio of 2.8 (95% confidence interval: 1.36-6.14, P = 0.002). Moreover, the tumors from patients with the valine allele were more undifferentiated (P = 0.03). On the other hand, a recently described mutation in exon 7 of CYP1A1 gene (threonine exchanged to asparagine in codon 461) showed a strong association with endometrial cancer risk with an odds ratio of 6.36 (95% confidence interval: 1.99-26.5, P = 0.0004). Thus, this study suggests that polymorphisms at MTHFR and a novel CYP1A1 variant could influence susceptibility to endometrial cancer, although larger sample sizes would be required to corroborate these findings.

High rate of MDR-1 and heterogeneous pattern of MRP expression without gene amplification in endometrial cancer.

The present study was undertaken to determine the pattern of expression of 2 molecular markers of multidrug resistance, the MDR-1 and MRP genes, in endometrial carcinomas from 50 untreated patients using a PCR semi-quantitative assay. In addition, PCR analysis of MDR-1 and MRP gene amplification was obtained in each case. High rate of MDR-1 expression without gene amplification was detected in all endometrial-carcinoma samples, as well as in 10 adenomatous hyperplasias and 50 samples of normal endometrium. On the other hand, MRP appeared to be expressed at moderate levels in normal endometrial tissue, while relatively high levels of MRP expression without gene amplification were occasionally observed in endometrial-carcinoma samples.