Conservative treatment of microinvasive squamous cell carcinoma of the cervix stage IA1: Defining conization height to an optimal oncological outcome.

OBJECTIVE: This paper searches an ideal cone height for stage definition and safe treatment of cervical microinvasive squamous carcinoma stage IA1 (MIC IA1), avoiding excessive cervix resection, favoring a future pregnancy. METHODS: A retrospective study was performed involving 562 women with MIC IA1, from 1985 to 2013, evaluating cone margin involvement, depth of stromal invasion, lymph vascular invasion, conization height, and residual uterine disease (RD). High-grade squamous lesions or worse detection was considered recurrence. Univariate and multivariate regression analyses were performed, including age, conization technique (CKC, cold-knife, or ETZ, excision of transformation zone), and pathological results. Conization height to provide negative margins and the risk of residual disease were analyzed. RESULTS: Conization was indicated by biopsy CIN2/3 in 293 cases. Definitive treatments were hysterectomy (69.8%), CKC (20.5%), and ETZ (9.7%). Recurrence rate was 5.5%, more frequent in older women (p = 0.030), and less frequent in the hysterectomy group (p = 0.023). Age ≥40 years, ETZ and conization height are independent risk factors for margin involvement. For ages <40 years, 10 mm cone height was associated with 68.6% Negative Predictive Value (NPV) for positive margins, while for 15 mm and 25 mm, the NPV was 75.8% and 96.2%, respectively. With negative margins, the NPV for RD varied from 85.7-92.3% for up to 24 mm cone height and 100% from 25 mm. CONCLUSION: Conization 10 mm height for women <40 years provided adequate staging for almost 70%, with 10% of RD and few recurrences. A personalized cone height and staging associated with conservative treatment are recommended.

Gonadoblastoma-Associated Mixed Gonadal Germ Cell Tumor with Dysgerminoma and Hepatoid Yolk Sac Tumor Components in 46XY Gonadal Dysgenesis.

BACKGROUND: Disorders of sex development are congenital conditions with atypical chromosomal, gonadal, or anatomical sex development. Gonadal dysgenesis in patients containing a Y chromosome have a high risk of developing germ cell tumors with potential for malignant transformation. CASE: We present the case of a 17-year-old phenotypic female with primary amenorrhea and 46,XY complete gonadal dysgenesis. Pelvic ultrasound showed a solid cystic lesion in the right gonad. Pathology showed a gonadoblastoma-associated mixed gonadal germ cell tumor with dysgerminoma and hepatoid yolk sac tumor. SUMMARY AND CONCLUSION: To our knowledge, this mixed neoplasm association has not been previously reported and this case illustrates the challenges for the diagnosis of gonadal dysgenesis-associated tumors, emphasizing its recognition and prognostic implications.

Preoperative measurement of serum C-reactive protein: is it useful in the differential diagnosis of adnexal masses?

BACKGROUND: Serum biomarkers may help to discriminate malignant from benign adnexal masses with equivocal features on imaging. Adequate discrimination of such tumors is crucial for referring patients to either a specialized cancer center or a nonspecialized gynecology service. AIM: We aimed to investigate whether the preoperative level of serum C-reactive protein (CRP), alone or combined with CA125 and menopausal status in the Ovarian Score (OVS), is useful in the prediction of malignancy in women with ovarian tumors. METHODS: This cross-sectional study included 293 patients who underwent surgery in a tertiary cancer center. Receiver operating characteristic (ROC) areas under the curves (AUC) for CRP, CA125 and OVS were calculated in different scenarios, as well as their sensitivity and specificity, using standard cutoff points (for CRP, 10 mg/L; for CA125, 35 U/mL). RESULTS: CA125 and the OVS performed significantly better than CRP alone in the differentiation of benign disease from epithelial ovarian cancer (EOC) (AUC = 0.86 for CA125, 0.79 for OVS, and 0.73 for CRP). OVS and CRP alone were superior to CA125 only in the differentiation of borderline ovarian tumors from advanced stages of EOC and non-EOC. Sensitivity and specificity were 52.5% and 83%, respectively, for CRP, 77.9% and 66.7% for CA125, and 71.3% and 67.8% for OVS. CONCLUSIONS: OVS is as good as CA125 in the differentiation of benign tumors from ovarian cancer. The addition of CA125 and menopausal status to CRP enhanced the relatively low discriminatory power of isolated CRP.

Human vaginal histology in long-term users of the injectable contraceptive depot-medroxyprogesterone acetate.

OBJECTIVES: Apparently, depot-medroxyprogesterone acetate (DMPA) increases a woman's risk of acquiring HIV. The objective of this study was to test whether the vaginal mucosal thickness and Langerhans cell counts were significantly different in long-term DMPA users compared with women users of an intrauterine device (IUD) who had never used DMPA. STUDY DESIGN: Cross-sectional study. Twenty-three DMPA users were matched with 23 nonusers controlled for age, body mass index (BMI; kg/m²), and duration of contraceptive use. Four groups of women were evaluated according to the duration of DMPA use: >1, <5; ≥5, <10; ≥10, <15 or ≥15 years. Estradiol (E2) levels were compared between the two groups. Histologic sections of vaginal mucosal biopsies were evaluated to measure the mean epithelial thickness and S100 immunostained sections were used to count the number of Langerhans cells/mm. RESULTS: Mean (±S.D.) E2 levels were significantly lower in DMPA users (39.4±26.6 pg/mL) compared with nonusers (102.6±60.3 pg/mL) despite similar ages (42.3±7.4 and 42.4±7.4 years, respectively). Mean (±S.D.) vaginal thickness was 232.6±108.1 and 229.7±112.9 in DMPA users and nonusers, respectively. There were no differences in vaginal thickness or Langerhans cell count/mm between users and nonusers even after controlling for DMPA duration of use. CONCLUSIONS: Vaginal epithelial thinning or Langerhans cell count was not different between long-term DMPA users and copper-IUD users who had never used DMPA. IMPLICATIONS: No differences were found in vaginal epithelial thickness or in Langerhans cell count between long-term users of the injectable contraceptive DMPA and nonusers.

Microinvasive adenocarcinoma of the cervix in a young woman vaccinated against human papillomavirus: the screening must be continued.

OBJECTIVE: This report describes a case that illustrates the limitations of the vaccination screening process for human papillomavirus (HPV) infection. CASE: We report an unexpected microinvasive adenocarcinoma of the cervix arising in a young woman vaccinated against HPV as part of a clinical trial 6 years previously and followed up annually by cytology. In January 2012, at age 23 years, the patient received a cytological result of atypical squamous cells, cannot exclude high-grade cervical squamous intraepithelial lesion, and colposcopy showed slight abnormalities. Biopsy revealed an adenocarcinoma in situ. Conization of the cervix was performed, and the diagnosis was microinvasive adenocarcinoma. Polymerase chain reaction and immunohistochemical study of conization material showed positivity for HPV-18 L1, p16, and Ki-67. Retrospective analysis of the clinical trial information revealed that 7 HPV tests had been performed, and all were positive for HPV-18, including the sample collected before the first vaccination. CONCLUSIONS: HPV-18 was present in the cervix before vaccination. Persistent detection of HPV-18 should be considered an important factor in treatment planning. This case demonstrates the need to vaccinate women before their first sexual contact and highlights the need for keeping adequate screening even in vaccinated individuals.

Second harmonic generation microscopy as a powerful diagnostic imaging modality for human ovarian cancer.

In this study we showed that second-harmonic generation (SHG) microscopy combined with precise methods for images evaluation can be used to detect structural changes in the human ovarian stroma. Using a set of scoring methods (alignment of collagen fibers, anisotropy, and correlation), we found significant differences in the distribution and organization of collagen fibers in the stroma component of serous, mucinous, endometrioid and mixed ovarian tumors as compared with normal ovary tissue. This methodology was capable to differentiate between cancerous and healthy tissue, with clear cut distinction between normal, benign, borderline, and malignant tumors of serous type. Our results indicated that the combination of different image-analysis approaches presented here represent a powerful tool to investigate collagen organization and extracellular matrix remodeling in ovarian tumors.

Quantitative changes in human epithelial cancers and osteogenesis imperfecta disease detected using nonlinear multicontrast microscopy.

We show that combined multimodal nonlinear optical (NLO) microscopies, including two-photon excitation fluorescence, second-harmonic generation (SHG), third harmonic generation, and fluorescence lifetime imaging microscopy (FLIM) can be used to detect morphological and metabolic changes associated with stroma and epithelial transformation during the progression of cancer and osteogenesis imperfecta (OI) disease. NLO microscopes provide complementary information about tissue microstructure, showing distinctive patterns for different types of human breast cancer, mucinous ovarian tumors, and skin dermis of patients with OI. Using a set of scoring methods (anisotropy, correlation, uniformity, entropy, and lifetime components), we found significant differences in the content, distribution and organization of collagen fibrils in the stroma of breast and ovary as well as in the dermis of skin. We suggest that our results provide a framework for using NLO techniques as a clinical diagnostic tool for human cancer and OI. We further suggest that the SHG and FLIM metrics described could be applied to other connective or epithelial tissue disorders that are characterized by abnormal cells proliferation and collagen assembly.

Harmonic optical microscopy and fluorescence lifetime imaging platform for multimodal imaging.

In this work, we proposed and built a multimodal optical setup that extends a commercially available confocal microscope (Olympus VF300) to include nonlinear second harmonic generation (SHG) and third harmonic generation (THG) optical (NLO) microscopy and fluorescence lifetime imaging microscopy (FLIM). We explored all the flexibility offered by this commercial confocal microscope to include the nonlinear microscopy capabilities. The setup allows image acquisition with confocal, brightfield, NLO/multiphoton and FLIM imaging. Simultaneously, two-photon excited fluorescence (TPEF) and SHG are well established in the biomedical imaging area, because one can use the same ultrafast laser and detectors set to acquire both signals simultaneously. Because the integration with FLIM requires a separated modulus, there are fewer reports of TPEF+SHG+FLIM in the literature. The lack of reports of a TPEF+SHG+THG+FLIM system is mainly due to difficulties with THG because the present NLO laser sources generate THG in an UV wavelength range incompatible with microscope optics. In this article, we report the development of an easy-to-operate platform capable to perform two-photon fluorescence (TPFE), SHG, THG, and FLIM using a single 80 MHz femtosecond Ti:sapphire laser source. We described the modifications over the confocal system necessary to implement this integration and verified the presence of SHG and THG signals by several physical evidences. Finally, we demonstrated the use of this integrated system by acquiring images of vegetables and epithelial cancer biological samples.

Image compression impact on quantitative angiogenesis analysis of ovarian epithelial neoplasms.

OBJECTIVE: This study aims to investigate the impact of digital image compression on manual and semiautomatic quantification of angiogenesis in ovarian epithelial neoplasms (including benign, borderline, and malignant specimens). DESIGN: We examined 405 digital images (obtained from a previously validated computer-assisted analysis system), which were equally divided into 5 groups: images captured in Tagged Image File Format (TIFF), low and high compression Joint Photographic Experts Group (JPEG) formats, and low and high compression JPEG images converted from the TIFF files. MEASUREMENTS: Microvessel density counts and CD34 endothelial areas manually and semiautomatically determined from TIFF images were compared with those from the other 4 groups. RESULTS: Mostly, the correlations between TIFF and JPEG images were very high (intraclass correlation coefficients >0.8), especially for low compression JPEG images obtained by capture, regardless of the variable considered. The only exception consisted in the use of high compression JPEG files for semiautomatic microvessel density counts, which resulted in intraclass correlation coefficients of <0.7. Nonetheless, even then, interconversion between TIFF and JPEG values could be successfully achieved using prediction models established by linear regression. CONCLUSION: Image compression does not seem to significantly compromise the accuracy of angiogenesis quantitation in the ovarian epithelial tumors, although low compression JPEG images should always be preferred over high compression ones.

Is the immunohistochemical expression of proliferation (Ki-67) and apoptosis (Bcl-2) markers and cyclooxigenase-2 (COX-2) related to carcinogenesis in postmenopausal endometrial polyps?

OBJECTIVE: To evaluate the pattern of Ki-67, Bcl-2 and COX-2 expression in the glandular epithelium and stroma of malignant and benign endometrial polyps in postmenopause. STUDY DESIGN: A total of 390 postmenopausal women underwent surgical hysteroscopy; women with endometrial polyps were included. Polypoid lesions were histologically classified as benign, premalignant or malignant lesions. Ki-67, Bcl-2 and COX-2 expression were evaluated by immunohistochemistry according to percentage of stained cells, staining intensity, and final score. RESULTS: The prevalence of malignancy in endometrial polyps was 7.1% and was associated with postmenopausal bleeding. The final score showed that only mean COX-2 expression was higher in malignant polyps both in the glandular epithelium (6.1 +/- 2.5) (p < 0.001) and stroma (2.4 +/- 3.0) (p < 0.01). There was a higher Bcl-2 expression, especially in the glandular epithelium, with no differences between benign polyps and premalignant/malignant polyps. Ki-67 expression was low in both benign polyps and premalignant/malignant polyps. CONCLUSION: Polyps in postmenopause have a high COX-2 expression that is higher in malignant polyps than in benign polyps. There was no difference in Ki-67 and Bcl-2 expression between malignant polyps and premalignant/malignant polyps.

Recognition of serous ovarian tumors in human samples by multimodal nonlinear optical microscopy.

We used a multimodal nonlinear optics microscopy, specifically two-photon excited fluorescence (TPEF), second and third harmonic generation (SHG∕THG) microscopies, to observe pathological conditions of ovarian tissues obtained from human samples. We show that strong TPEF + SHG + THG signals can be obtained in fixed samples stained with hematoxylin and eosin (H&E) stored for a very long time, and that H&E staining enhanced the THG signal. We then used the multimodal TPEF-SHG-THG microscopies in a stored file of H&E stained samples of human ovarian cancer to obtain complementary information about the epithelium∕stromal interface, such as the transformation of epithelium surface (THG) and the overall fibrillary tissue architecture (SHG). This multicontrast nonlinear optics microscopy is able to not only differentiate between cancerous and healthy tissue, but can also distinguish between normal, benign, borderline, and malignant specimens according to their collagen disposition and compression levels within the extracellular matrix. The dimensions of the layers of epithelia can also be measured precisely and automatically. Our data demonstrate that optical techniques can detect pathological changes associated with ovarian cancer.

Low expression of human histocompatibility soluble leukocyte antigen-G (HLA-G5) in invasive cervical cancer with and without metastasis, associated with papilloma virus (HPV).

Human leukocyte antigen-G (HLA-G) is a non-classical major histocompatibility complex class Ib molecule that acts as a specific immunosuppressor. Some studies have demonstrated that human papillomavirus (HPV) seems to be involved in lower or absent HLA-G expression, particularly in cervical cancer. In this study, we performed a cross-sectional study, systematically comparing the qualitative expression of the HLA-G5 isoform in invasive cervical carcinoma (ICC), stratifying patients according to the presence [ICC with metastasis (ICC(W))] and absence [ICC without metastasis (ICC(WT))] of metastasis, correlating these findings with interference of HPV and demographic and clinical variables. Seventy-nine patients with a diagnosis of ICC were stratified into two groups: ICC(WT) (n=52 patients) and ICC(W) (n=27). Two biopsies were collected from each patient (one from the tumor lesion and one from a lymph node). Immunohistochemistry analyses were performed for the HLA-G5 isoform, for HPV detection, and virus typing. HLA-G5 isoform molecules were detected in 25 cases (31.6%), 17 (32.7%) without metastasis and 8 (29.6%) with metastasis. HPV was detected in the cervical lesions of 74 patients (93.7%), but low expression of the HLA-G5 isoform was observed in all HPV-related cases. These findings are important; however, additional studies are necessary to identify the influence of HPV with HLA-G5 isoform expression on invasive cervical malignancies.

The expression of the hormone receptors in the endometrium and endometrial polyps in postmenopausal women and its relationship to body mass index.

OBJECTIVE: To evaluate and compare the relationship of body mass index (BMI) and the immunoexpression of estrogen (ER) and progesterone receptors (PR) in endometrial polyps (EP) and endometrium, in gland and stromal cells of postmenopausal women. METHODS: Thirty-five postmenopausal women with benign endometrial polyps, who had not been taking medication with hormonal effects for at least 6 months, were submitted to operative hysteroscopy. The presence of ER and PR were evaluated by immunohistochemical method using a semiquantitative analysis. RESULTS: BMI was significantly higher among patients with lower expression of ER in the glands of endometrium (p=0.02). EP and adjacent endometrium showed significantly higher proportion of positive cells in the glands than in the stroma, for both ER (p=0.0015 and 0.0018, respectively) and PR (p=0.0176 and p<0.0001, respectively). Glands and stroma cells showed significantly higher proportion of positive cells in polyps than in the endometrium, for ER (p<0.0001 and p=0.0034, respectively). CONCLUSIONS: The higher proportion of positive gland cells for ER in EP as compared to endometrium supports an implication of these receptors in the pathogenesis of polyps. Association of higher BMI with lower expression of ER in endometrial glands, but not in EP, may indicate that factors influencing ER expression do not affect EP, supporting an autonomous function of polyps.

Tumores de células da granulosa do ovário: estadiamento e tratamento / Granulosa cell tumors of the ovary: staging and treatment

O objetivo deste trabalho foi o de analisar a importância dos achados cirúrgicos e histólogicos para a definiçäo dos estadiamento e tratamento dos tumores de células da camada granulosa do ovário. Foram avaliados o estadiamento e os resultados do tratamento de 11 pacientes, atendidas entre janeiro de 1990 e dezembro de 1994, no Centro de Atençäo Integral + Saúde da Mulher, da Universidade Estadual de Campinas, no Estado de Säo Paulo. O seguimento foi atualizado em agosto de 1996. A idade das pacientes variou de 18 a 67 anos, com média de 46 anos. Duas pacientes foram submetidas à salpingo-ooforectomia bilateral, histerectomia total, apendicectomia e omentectomia e, em sete, acrescentou-se a linfadenectomia retroperitoneal. Em dois casos a doença era irressecável. Cinco pacientes encontravam-se com tumor em estádio IIIC; uma, em estádio IC; e cinco, em estádio IA. A revisäo histopatológica revelou 10 neoplasias do tipo adulto e uma do tipo juvenil. Em todos os casos encontrou-se mais de um tipo histopatológico de tumor de células granulosas, sendo dominante o tipo sólido (7/11 casos). O tratamento complementar com antiblásticos - seis ciclos de carboplatina (300 mg/m²) e ciclofosfamida (500 mg/m²) - foi aplicado nas pacientes com doença em estádios IC e IIIC. No último controle, com um seguimento variando de 20 a 71 meses, todas as pacientes com tumores no estádio inicial encomtravam-se sem doença; contudo, das cinco pacientes com neoplasia em estádio IIIC, três apresentavam progressäo da doença apesar do tratamento antiblástico.

Tratamento cirúrgico do carcinoma de ovário / Surgical treatment of ovarian carcinoma

O objetivo deste estudo foi comparar a cirurgia para tratamento do carcinoma de ovário feita fora do nosso Serviço e no nosso Serviço. Analisaram-se o volume da doença residua e o prognóstico, além da importància da cirurgia de revisao, em 100 pacientes com carcinoma de ovário tratadas no Centro de Atençao Integrál à Saúde da Mulher (CAISM) - UNICAMP de janeiro de 1986 a dezembro de 1992. Em 48 por cento das pacientes, a cirurgia inicial foi realizada fora do nosso Serviço; destas, 34 (71 por cento) foram reoperadas para estadiamento. Em relaçao ao volume de doença residual, das 37 pacientes no estádio III e das oito no estádio IV, 24 (53 por cento) ficaram com volume tumoral maior que 2cm e apresentaram progressao da doença. Considerando a cirurgia de revisao, todas as 16 pacientes com doença estádio I submetidas ao procedimento encontravam-se sem doença e, no seguimento, apenas uma apresentou recidiva. Das 18 pacientes com doença estádio III submetidas à cirurgia de revisao, nove (50 por cento) apresentaram doença residual. Por outro lado, das nove pacientes com cirurgia de revisao negativa, cinco recidivaram. Concluiu-se que a cirurgia adequada é fundamental no estadiamento, tratamento e seguimento das pacientes com carcinoma de ovário.

Correlaçåo entre citologia, colposcopia e biópsia em adolescentes com patologia cervical / Correlation among cervical smear, colposcopy and biopsy in teenagers with cervical pathology

Este é um estudo prospectivo referente a 183 adolescentes atendidas por condiloma clínico em genitais ou citologia oncótica alterada no Serviço de Patologia Cervical de Centro de Atençåo Integral à Saúde da Mulher, no período de setembro de 1990 a fevereiro de 1992. Com objetivo de avaliar a propedêutica para patologia cervical em jovens grávidas ou nåo, foram estudados o motivo do encaminhamento, a citologia oncótica, a colposcopia de todo o trato genital baixo, a coleta e o resultado das biópsias do colo, vulva e vagina. Verificou-se que a citologia oncótica alterada era o motivo mais freqüente de encaminhamento; que pacientes grávidas tinham mais condiloma macroscópico que pacientes nåo-grávidas; que a colposcopia realizada em todo o trato genital baixo permite diagnosticas lesöes de vulva ou vagina associadas a lesöes cervicais ou isoladas; e que mais de 70 por cento das pacientes tinham condiloma histologicamente confirmado no colo uterino. Concluiu-se que a patologia cervical constitui-se, neste grupo, principalmente de infecçåo por papilomavírus humano, e que a propedêutica citológica, colposcópica e histológica é relativamente simples e necessária em adolescentes sexualmente ativas

Carcinoma primitivo da uretra masculina / Primary carcinoma of the male urethra

O carcinoma da uretra masculina é uma entidade relativamente rara. A localizaçäo mais freqüente é na porçäo bulbomembranosa e o tipo histológico mais comum é o epidermóide. O tratamento é cirúrgico e o prognóstico é bastante reservado. Os autores apresentam um caso de carcinoma primitivo da uretra masculina em um paciente de 52 anos de idade, que se apresentava em priapismo e retençäo urinária. O tratamento foi penectomia com emasculaçäo e cistostomia