Comparing indocyanine green, technetium, and blue dye for sentinel lymph node mapping in endometrial cancer.

BACKGROUND AND AIMS: With the debate over extent of lymphadenectomy in endometrial cancer, sentinel lymph node (SLN) mapping may provide a focused approach to evaluate the most relevant lymph nodes (LN) while minimizing the complications. We evaluated SLN mapping using filtered technetium(99), indocyanine green (ICG), and blue dye. METHODS: Prospective evaluation of 100 patients who underwent SLN mapping by using submucosal and deep stromal cervical injections of technetium(99), ICG, and blue dye as part of the staging for endometrial cancer. RESULTS: 286 SLNs were mapped (2.9 per patient) in 92% of patients. The bilateral detection rate was 76%. ICG had a significantly higher SLN detection rate than blue dye in both overall (87% vs 71%, respectively; p=0.005) and bilateral (65% vs 43%, respectively; p=0.002) detection, but similar SLN detection rates compared to technetium(99) in both overall (87% vs 88%, respectively; p=0.83) and bilateral (65% vs 71%, respectively; p=0.36) detection. In eight cases, the SLN was in the para-aortic area and in 14 cases in the pre-sacral, hypogastric vein, or parametrial area. In nine cases, the SLN was positive for metastasis, and in seven cases the SLN was the only positive node. One SLN was falsely negative. No complications or anaphylactic reactions occurred. CONCLUSION: Intra-operative SLN mapping using cervical injection is feasible in patients with endometrial cancer and yields adequate detection rates. It allows mapping of SLNs in areas (pre-sacral, hypogastric vein, parametrial) not routinely sampled. Given the poorer performance of blue dye, surgeons may omit its use if a combination of ICG and technetium(99) is used.

Assessment of the performance of algorithms for cervical cancer screening: evidence from the Ludwig-McGill cohort study.

OBJECTIVE: There are currently multiple tests available for cervical cancer screening and the existing screening policies vary from country to country. No single approach will satisfy the specific needs and variations in risk aversion of all populations, and screening algorithms should be tailored to specific groups. We performed long term risk stratification based on screening test results and compared the accuracy of different tests and their combinations. METHODS: A longitudinal cohort study of the natural history of HPV infection and cervical neoplasia enrolled 2462 women from a low-income population in Brazil. The interviews and cervical screening with cytology and HPV DNA testing were repeated according to a pre-established protocol and the subjects were referred for colposcopy and biopsy whenever high grade lesions were suspected. We compared the specificity, sensitivity and predictive values of each screening modality. Long term risk stratification was performed through time-to-event analyses using Kaplan-Meier analysis and Cox regression. RESULTS: The best optimization of sensitivity and specificity was achieved when using dual testing with cytology and HPV DNA testing, whereby the screening test is considered positive if either component yields an abnormal result. However, when allowing 12months for the detection of lesions, cytology alone performed nearly as well. Risk stratification revealed that HPV DNA testing was not beneficial for HSIL cases, whereas it was for ASCUS and, in some combinations, for negative and LSIL cytology. CONCLUSION: Our results suggest that some high risk populations may benefit equally from cytology or HPV DNA testing, and may require shorter intervals between repeat testing.

Scanning electron microscopy of the human fallopian tube.

Fallopian tubes from women of reproductive and postmenopausal ages were examined by scanning electron microscopy. The surface topography of these Fallopian tubes is described and illustrated.

Efficacy of a Carrageenan gel Against Transmission of Cervical HPV (CATCH): interim analysis of a randomized, double-blind, placebo-controlled, phase 2B trial.

OBJECTIVES: To evaluate the efficacy of a carrageenan-based lubricant gel in reducing the risk of genital human papillomavirus (HPV) infections in women. METHODS: We conducted a planned interim analysis of a randomized, double-blind, placebo-controlled, phase 2B trial. Women aged 18 years and older were randomly assigned (1:1) to a carrageenan-based gel or a placebo gel to be self-applied every other day for the first month and before and after each intercourse during follow-up. Assessments were performed at 0.5, 1, 3, 6, 9 and 12 months. The primary outcome was incidence of a new infection by an HPV type that was not present at baseline. Intention-to-treat analyses were performed. RESULTS: Between January 2013 and June 2017, a total of 280 participants were randomly assigned to the carrageenan (n = 141) or the placebo (n = 139) arm. All participants were included in safety analyses, but three (1%) were excluded from efficacy analyses (HPV results unavailable for two participants in the carrageenan and one participant in the placebo arm). The median follow-up time was 9.2 months (interquartile range, 1.9-13.2 months). A total of 59 (42%) of 139 participants in the carrageenan arm and 78 (57%) of 138 participants in the placebo arm became infected by at least one new HPV type (hazard ratio = 0.64, 95% confidence interval = 0.45-0.89, p 0.009). A total of 62 (44%) of 141 participants in the carrageenan arm versus 43 (31%) of 139 participants in the placebo arm reported an adverse event (p 0.02), none of which was deemed related to the gels. CONCLUSIONS: Our trial's interim analysis suggests that using a carrageenan-based lubricant gel can reduce the risk of genital HPV infections in women.

HPV-related vulvar intraepithelial neoplasia: outcome of different management modalities.

OBJECTIVE: To evaluate the outcome of various management schemes for HPV-related vulvar intraepithelial neoplasia (VIN, usual type). METHODS: Retrospective chart review of patients with histologically diagnosed grade 2/3-VIN who had at least one year of follow-up. The variables that were collected included patient characteristics, management modalities, and clinical outcome. RESULTS: Fifty patients with a median age of 45 years old were evaluated. The median duration of follow-up was 43.5 months (12-186). Complete response (CR) and partial response occurred in 28 (56%) and 4 (8%), respectively. Nineteen of 28 patients with CR recurred with VIN. Surgical excision yielded higher CR (77%) than did either ablational techniques (21-33%) or topical immunotherapy (33%). CONCLUSION: In this experience, surgical excision for VIN, usual type, resulted in better therapeutic success rates than other treatment modalities. Management schemes should be individualized based on extent of disease and patient compliance.

Continuous combined hormone replacement therapy with 1 mg 17beta-oestradiol and 5 mg dydrogesterone (Femoston-conti): endometrial safety and bleeding profile.

OBJECTIVES: The aim of the study was to confirm the endometrial safety and describe the bleeding profile of continuous combined 1 mg 17beta-oestradiol and 5 mg dydrogesterone in post-menopausal women. METHODS: An open, multicentre study was carried out in 290 healthy, non-hysterectomised post-menopausal women receiving oral continuous combined 1 mg 17beta-oestradiol and 5 mg dydrogesterone (Femoston-conti) for 1 year. Aspiration endometrial biopsies were performed at baseline and at the end of the study; those classified as hyperplasia or malignancy were considered treatment failures. RESULTS: Only one woman developed simple hyperplasia without atypia at the end of the study; the treatment failure rate was therefore 0.4%. Cross-sectional analysis showed that the percentage of women without bleeding increased from 71% during the first cycle to around 80% by the end of the study. Approximately 50% of the bleeding episodes occurred in the form of spotting; severe bleeding was rare and only seven women withdrew prematurely from the study due to uterine bleeding. Overall, 41% of the women were amenorrhoeic throughout the study. CONCLUSIONS: Continuous combined 1 mg 17beta-oestradiol and 5 mg dydrogesterone provides excellent endometrial safety and is associated with an acceptable bleeding profile.

Immunocytochemical study of progesterone receptors in hyperplastic and neoplastic endometrial tissues.

Endometrial carcinoma is the most common genital malignancy in North America. However its pathogenesis, in particular its relationship with hyperplasia is not clear. To understand steroid hormonal interactions in the genesis and growth of human endometrial hyperplasia and carcinoma, we have assayed progesterone receptors in hyperplasia and neoplastic human endometrium by immunocytochemistry. The presence of progesterone receptors in target tissues is known to be a marker of both estrogen and progesterone action. The receptors were identified in fresh-frozen sections using a mouse monoclonal antiprogesterone receptor antibody (alpha PR6). The progesterone receptor content was high in the epithelium of hyperplasia without cytological atypia and low in the epithelium of endometrial intraepithelial neoplasia (hyperplasia with cytological atypia). In carcinomas there was a heterogenous distribution of progesterone receptors in the epithelium but low as compared to hyperplastic endometria without cytological atypia. The stroma contained relatively high progesterone receptor levels irrespective of whether the epithelium was hyperplastic or neoplastic.

Papillomavirus in cervical condylomas with and without associated cervical intraepithelial neoplasia.

The aim of this study was to analyze the cytohistologic features of cervical condylomas with respect to the presence of associated cervical intraepithelial neoplasia (CIN) and to evaluate whether or not the prevalence of virus antigen, as detected by immunologic staining with peroxidase-antiperoxidase technique, varies with the histologic appearance of the lesions. In a series of 94 histologically confirmed condylomas of the cervix, almost half (43) had features of CIN grades 1 and 2, corresponding to mild and moderate dysplasia. The prevalence of papillomavirus antigen decreased markedly as the features of associated dysplasia became more severe. The antigen prevalence was 82% in pure condylomas, 32% in condylomas with CIN 1, and 0% in condylomas with CIN 2. The evidence that virus production decreased as the lesion became more severe does not preclude papillomavirus etiology for the CIN lesions. Cells transformed by papillomavirus may be expected to cease production of virus particles even as they continue to harbor the viral genome.

Mammary fat pad may be a potential site for initiation of estrogen action in normal mouse mammary glands.

The effect of estradiol (E2) on mammary and uterine DNA synthesis has been examined in castrated virgin mice. In both these target tissues for E2, in vitro incorporation of thymidine into DNA begins 12 h after E2 treatment, and by 24 h there is approximately a 3-fold increase in the mammary glands and a 9-fold increase in the uterus. Whereas in the uterus by 48 h after E2 the rate of DNA synthesis has basically returned to control values, in the mammary gland a maximal stimulation of DNA synthesis is observed at this time, and even at 72 h after E2 there is still approximately a 2-fold increase in DNA synthesis. In vivo histoautoradiography reveals that, unlike in the uterus, 24 h after E2 there is virtually no uptake of labeled thymidine in the mammary epithelium; the increase in the uptake of thymidine is now mostly confined to the mammary adipose and connective tissues. However, 48 and 72 h after E2 there is extensive labeling of the mammary epithelium in addition to the adipose and connective tissues. These data lead us to suggest that both the mammary fat pad and epithelium are responsive to E2, and that, at least with respect to mammary cell proliferation, the mammary fat pad may be the site of initiation of estrogen action.

The nonresponsiveness of lactating mammary gland to estradiol.

The effect of estradiol on mammary glucose metabolism and DNA synthesis has been studied. Estradiol causes a significant increase in both the rate of glucose oxidation and DNA synthesis in the mammary glands of virgin mice, but is without any stimulatory effect on the glands of lactating mice. The reason for the inability of lactating mammary gland to respond to estradiol appears to reside in the lactating tissue itself and does not seem to be related to the hormonal milieu of lactation. Previously, we have shown that, in contrast to mammary gland of virgin mice, lactating mammary glands do not respond to estradiol with an increase in progesterone receptor levels. Therefore, all of these studies taken together reveal that during lactation, mammary glands may be nonresponsive with respect to most known parameters of estrogen action.

Human papillomavirus testing for primary screening of cervical cancer precursors.

Our objective was to determine whether the addition of human papillomavirus (HPV) testing to screening cytology improves the detection of cervical cancer precursors. Women of ages 18-69 years underwent conventional Pap cytology and HPV DNA testing in a multicenter study in Newfoundland, Canada. Those with positive cytology and/or HPV and a random sample of those with dual negative results were referred for colposcopy. The study enrolled 2098 women. The relative sensitivity of HPV testing was significantly higher than cytology for all-grade squamous intraepithelial lesions [SILs; 73%; 95% confidence interval (CI), 62-82] and high grade SILs (HSILs; 90%; 95% CI, 74-97) but had lower relative specificity (62% for all-grade SILs and 51% for HSILs) than most cytological cutpoints. The rate of combined correct results for all-grade lesions was higher for HPV testing (68.8%) than for any cytological cutpoint (equivocal, 52.3%; LSILs, 51.6%; HSILs, 44.5%). The combination of HPV and an LSIL cutpoint had a negative predictive value of 68% (95% CI, 52-80) for all SILs and 100% (95% CI, 91-100) for HSILs, while referring for colposcopy only 12% of the women. We concluded that HPV testing in conjunction with cytology improved the screening efficacy of cytology alone and may allow for a more effective and safe primary screening program with increased screening intervals.

Therapeutic approaches to genital warts.

Although many treatments are available for genital warts caused by human papillomavirus (HPV), none are uniformly successful in the treatment of this disease. Most current treatment options work by destroying affected tissue, either by a cytotoxic or a physically ablative mode of action. Interferons have antiviral, antiproliferative, and immunomodulatory activities, but these have not translated into a high level of cure rates against warts. With all current treatments, recurrent warts are common. Therapies currently being investigated include a 5-fluorouracil/epinephrine collagen gel that achieves high concentrations of 5-fluorouracil at the site of injection. Other new treatment modalities focus on activating the host's immune system or improving the delivery of therapeutic compounds to the affected site. Imiquimod, a novel immune-response modifier, induces interferon and a number of other endogenous cytokines. A cream formulation containing 5% imiquimod resulted in good total clearance rates and generally tolerable side effects in controlled clinical trials of patients with external genital warts. Perhaps the most effective means for managing HPV disease would be a vaccine that prevents the occurrence of genital warts. Although it is unlikely that such a vaccine will be introduced in the near future, preliminary studies indicate that it may be possible to develop suitable prophylactic and therapeutic vaccines.

Human papillomavirus (HPV) in condylomatous lesions of cervix.

Ninety-seven cervical condylomata classified histologically as flat condyloma (planum), papillary condyloma (acuminatum), and endophytic condyloma were studied by transmission electron microscopy (TEM) and by immunoperoxidase technique (IPT) for the presence of human papillomavirus (HPV) particles and antigen, respectively. Both techniques localized HPV chiefly in nuclei of koilocytotic cells. HPV particles were found in 25% of the cases by TEM and HPV antigen was detected in 48% of the cases by IPT. All cases positive by TEM were also positive by IPT, thus confirming the specificity of the immunological staining. The viral antigen was detected in 56% of 68 flat condylomata, 35% of 26 papillary condylomata, and in none of 3 cases of endophytic condylomata. However, when histiotypes of virus-positive condylomata were controlled for the intraepithelial extent of koilcytotic cells, the prevalence of HPV correlated with the extent of koilocytosis rather than with the histiotype. The immunologic technique will be of value for the further characterization of cervical condylomata and of the relationship between HPV infection and cervical intraepithelial neoplasia.

Cytodynamics of endometrial hyperplasia and neoplasia, Part II: in vitro DNA histoautoradiography.

The cytokinetics of normal, hyperplastic, and neoplastic human endometrium were evaluated by in-vitro double labeling with low- and high-dose radiothymidine. Relative to cyclic, proliferative endometrium, the mean S-phase duration was shorter in anovulatory, persistent proliferative endometrium, cystic glandular hyperplasia, and adenomatous hyperplasia without atypia, similar in adenomatous hyperplasia with severe atypia (AAH), and significantly prolonged in carcinoma in situ and invasive carcinoma. The S-phase patterns suggest a pathogenetic relationship between hyperplasias of increasing atypia as well as between hyperplasia and carcinoma, with carcinoma in situ as a transitional state between AAH and invasive carcinoma.

Aggressive angiomyxoma of pelvic soft parts: a clinicopathologic study of nine cases.

Nine cases of aggressive angiomyxoma (AAM) of the pelvic soft parts were studied by light and electron microscopy and immunohistochemistry. The tumors were confined to the vulva, vagina, pelvic floor, and perineum in the seven women. The perineum and the para-anal region were involved in the two men. The patients ranged in age from 18 to 63 years. Aggressive angiomyxoma presented as a slowly growing, polypoid or cyst-like tumor. Six of the nine cases were followed up; all of the tumors recurred within nine to 84 months, and one recurred for the second time at 144 months. Recurrences were attributed to incomplete tumor excision. None of the six patients died or had metastases. The aggressive angiomyxomas had infiltrative borders and rubbery, white or soft, gelatinous cut surfaces. Histologically, the lesions were composed of stellate and spindle-shaped neoplastic cells embedded in a collagenous and hyaluronic acid-containing stroma. Nuclear atypia and mitoses were absent. Typically, the lesions had an important vascular component, often displaying medial hypertrophy and vascular grouping. Ultrastructurally, the neoplastic cells resembled fibroblasts rather than myofibroblasts. They showed strong immunoreactivity for actin but were negative for S-100 protein, Factor VIII, carcinoembryonic antigen, and keratin. The morphoimmunocytochemical characteristics of AAM cells favor a fibroblastic origin and differentiation. Aggressive angiomyxoma should be distinguished from the more common benign and malignant myxoid neoplasms or tumor-like conditions of the pelvic soft parts. Recurrence of AAM may be avoided by wide, local excision.

Extraskeletal myxoid chondrosarcoma with "chordoid" features (chordoid sarcoma).

The light and electron microscopic features of a so-called chordoid sarcoma arising in the area of the gastrocolic ligament are described and illustrated. Despite the tumor's histologic resemblance to chordoma, the ultrastructural markers are those of chondroid rather than chordoid neoplasms. These are well-developed, vesciular granular endoplasmic reticulum, intracytoplasmic glycogen, lipid bodies, and a collagen-poor extracellular matrix with electron-dense granules, presumably representing chondroitin sulfate. Similar submicroscopic alterations have been observed in extraskeletal myxoid chondrosarcomas. Because of the distinctive morphologic appearance of this peculiar lesion, the term "myxoid chondrosarcoma with chordoid features" is suggested to reconcile histologic and ultrastructural features and histogenesis.

Histology of the human endometrium: from birth to senescence.

Embryologically, the human endometrium is of mesodermal origin, and constitutes the mucosal lining of the fused Mullerian ducts of the uterus. In the adult, premenopausal woman, the endometrium follows a precisely programmed series of morphologic and physiologic events, characterized by growth, secretory differentiation, and in the absence of conception, degeneration and regeneration. Proliferation, secretion and degeneration are confined to the upper functionalis layer, whereas the lower basalis layer is the seat of regenerative endometrium. In the postmenopausal years, absence of biologically significant estrogenic stimulation leads to progressive endometrial involution, from proliferative to inactive in the mid-50s to atrophy in the late-60s. Cyclic endometrial alterations are controlled by the ovarian estrogens and progesterone via their respective endometrial intranuclear receptors, and possibly other peptides and enzymes. They provide appropriate environment for the implanting conceptus. The intimate inter-relationship between endometrial structure/function and steroid hormones during the premenopausal period serves as an indicator of the hypothalamo-pituitary-ovarian axis as related to ovulatory states.

Comparison of cryo- and carbon dioxide laser therapy for cervical intraepithelial neoplasia.

Two hundred ninety-four women with cervical intraepithelial neoplasia were treated once with either cryotherapy or laser vaporization. Treatment results were controlled for grade, size, and distribution of cervical intraepithelial neoplasia. Cervical intraepithelial neoplasia measuring less than 3 cm in diameter without extension into the endocervix had similar low failure rates (4 to 5%), regardless of histologic grade or instrument used. Carbon dioxide laser produced comparatively better results for lesions larger than 3 cm in diameter (92%) and those with up to 5 mm extension into the endocervical canal (89%), compared with 62 and 50%, respectively, with cryotherapy. Complications after cryo- and laser therapy were 0.6 and 7.4%, respectively, and included bleeding and pelvic inflammatory disease. Tailoring treatment modalities according to cervical intraepithelial neoplasia size and location rather than using a single treatment approach provides for the most cost-effective and therapeutically rewarding clinical practice.

Electroconization of the cervix with a fine-needle electrode.

OBJECTIVE: To obtain electroexcised specimens in which the endocervical margin of the lesional tissue is devoid of thermocoagulation injury, facilitating accurate histologic interpretation of early stromal invasion. METHODS: Using local anesthesia, we performed electroexcision with fine-needle electrodes and a tonsillar snare wire; no sutures to the lateral vessels were required. We tried to obtain cylindrical specimens. The procedure was performed in 38 women with deep canal involvement by squamous intraepithelial lesions, without colposcopically visible endocervical margins. RESULTS: The mean duration of the procedure was 12 minutes (range 8-26). Complications occurred in seven of 38 patients (18%): four cases of perioperative bleeding, one of delayed bleeding, and two of asymptomatic stenosis of the external os. All cases were managed on an outpatient basis. Two cases of unsuspected microinvasive carcinoma were discovered. CONCLUSION: In nonpregnant women in whom the endocervical limit of a lesion cannot be visualized with a colposcope, fine-needle electroconization is an attractive alternative to loop electroexcision. With this technique, cervical specimens can be collected without thermal damage to the endocervical margins.

Comparison of 5-fluorouracil and CO2 laser for treatment of vaginal condylomata.

Seventy nonpregnant women with extensive condylomata of the vagina were treated either with intravaginal 5-fluorouracil (5-FU) cream or the CO2 laser. Treatment results were correlated with the morphologic type of condylomata, ie, papillary acuminata (58 patients), and flat condylomata (12 patients). Ten and 31% of women with Condylomata acuminata had persistent disease within nine months after a single course of 5-FU and laser therapy, respectively. Total failure rates after a second either 5-FU or laser treatment were 3.4%. The failure rates for flat condylomata were 50 and 16.6% after 5-FU and laser treatment, respectively. Recurrences, defined as the development of new disease after a nine-month disease-free period were 7.4 and 10% for C acuminata after 5-FU and laser therapy, respectively. Twenty-five and 20% of women with flat condylomata treated respectively with 5-FU and the laser had recurrent disease. Acute urethrovulvar vaginitis occurred in 12.2% of the 5-FU-treated group, whereas complications were absent in those treated with the laser. Although the number of patients in each treatment arm was small and the patients were not randomized, intravaginal 5-FU therapy with protection of the vulva seems more cost effective for C acuminata in nonpregnant women than the laser, which requires general anesthesia. Flat condylomata are best managed by laser therapy. Refractory lesions successfully respond to laser-5-FU combination therapy.