Filomena Marino Carvalho

The role of the Hoxa10/HOXA10 gene in the etiology of endometriosis and its related infertility: a review

PurposeEndometriosis and its associated infertility have been the object of continuous research for over a century. To understand the molecular mechanisms underlying the disease, it has become necessary to determine the aspects of its etiology that are not explained by the retrograde menstruation theory. This could in turn elucidate how various clinical and surgical treatments might affect the evolution and remission of the disease.MethodsThis review is focused on the most recent clinical and laboratory findings regarding the association of HOXA10 with endometriosis and infertility.ResultThe homebox (Hox/HOX) proteins are highly conserved transcription factors that determine segmental body identities in multiple species, including humans. Hoxa10/HOXA10 is directly involved in the embryogenesis of the uterus and embryo implantation via regulation of downstream genes. Cyclical endometrial expression of Hoxa10/HOXA10, with a peak of expression occurring during the window of implantation, is observed in the adult in response to estrogen and progesterone. Women with endometriosis do not demonstrate the expected mid-luteal rise of HOXA10 expression, which might partially explain the infertility observed in many of these patients. Recent studies also demonstrated HOXA10 expression in endometriotic foci outside the Müllerian tract.ConclusionsMultiple lines of evidence suggest that the actions of the homeobox A10 (Hoxa10/HOXA10) gene could account for some aspects of endometriosis.

Accuracy of magnetic resonance imaging for diagnosis and preoperative assessment of deeply infiltrating endometriosis

To evaluate the accuracy of preoperative magnetic resonance imaging (MRI) findings relative to surgical presence of deeply infiltrating endometriosis (DIE).

A novel missense mutation (S18N) in the 5' non-HMG box region of the SRY gene in a patient with partial gonadal dysgenesis and his normal male relatives

Abstract Mutations in the sex-determining region of the Y chromosome (the SRY gene) have been reported in low frequency in patients with 46,XY gonadal dysgenesis. We investigated 21 Brazilian 46,XY sex-reversed patients, who presented either complete or partial gonadal dysgenesis or embryonic testicular regression syndrome. Using Southern blotting, polymerase chain reaction, denaturing gradient gel electrophoresis and direct sequencing, we analyzed deletions and point mutations in the SRY gene. We found a missense mutation at codon 18 upstream of the 5′ border of the HMG box of the SRY gene in one patient with partial gonadal dysgenesis. This variant sequence was also found in DNA obtained from blood and sperm cells of his father and in blood cells of his normal brother. The S18N mutation was not found in 50 normal males, ruling out the possibility of a common polymorphism. We identified a novel familial missense mutation (S18N) in the 5’ non-HMG box of the SRY gene in 1 of 21 patients with 46,XY sex reversal.

Endometriosis Lesions That Compromise the Rectum Deeper Than the Inner Muscularis Layer Have More Than 40% of the Circumference of the Rectum Affected by the Disease

STUDY OBJECTIVE To estimate the relationship between the depth of lesions of rectal endometriosis and the percentage of the circumference of the bowel segment affected by the disease. DESIGN A prospective pathologic analysis of 45 surgical specimens of bowel endometriosis obtained by laparoscopic segmental resection of the rectosigmoid (Canadian Task Force classification II-1). SETTING Tertiary referral hospital. PATIENTS forty-five patients were submitted to a segmental resection of the rectum due to endometriosis between July 2004 and September 2006. INTERVENTIONS Morphometric aspects of endometriotic lesions were analyzed, such as size and thickness of the lesion, deepest layer of bowel affected by lesion, and percentage of circumference of bowel affected by endometriosis. MEASUREMENTS AND MAIN RESULTS Results showed that in lesions that reached the submucous layer of the bowel, the circumference affected was 31.6% greater than in lesions that reached only the outer muscular layer, whereas in lesions that reached the mucous layer, the circumference affected was 52.5% greater than in those that reached the outer muscular layer of the bowel. In addition, 89.3% of lesions with an affected circumference greater than 40% were those affecting the submucous or mucous layers of the bowel. These results suggest that when a lesion reaches these 2 deepest layers of the rectosigmoid, risk increases that the circumference affected will be greater than 40% (relative risk = 1.5; 95% CI: 1.0-2.3; p = .03). CONCLUSION In endometriotic lesions affecting the rectosigmoid beyond the inner muscular layer of the bowel wall, more than 40% of the circumference of the rectosigmoid is affected by the disease, confirming the recommendation of segmental resection of the bowel for this form of the disease.

Histological classification of endometriosis as a predictor of response to treatment.

Objectives: To evaluate the usefulness of the histological classification of endometriosis in predicting responses to treatment. Methods: We evaluated 412 biopsy specimens from 241 patients with pelvic endometriosis. Pain and infertility were evaluated before surgery. Disease location and stage of development were analyzed according to the 1985 American Society of Reproductive Medicine (ASRM) classification. Histological findings were classified as stromal, well‐differentiated, undifferentiated, and mixed endometriosis. Clinical response to pain or infertility was evaluated. Results: Histological findings, disease location and stage of development, and response to treatment were compared. Undifferentiated endometriosis was more frequently associated with stages III/IV than the well‐differentiated and stromal histological types. Pure or mixed undifferentiated patterns were more frequently associated with rectovaginal endometriosis. When considering pain symptoms, patients presenting well‐differentiated or stromal histological patterns responded better to therapeutic treatment than those who presented undifferentiated histological patterns. There were no significant differences in cases related to sterility. Conclusions: The histological categorization of endometriosis can help predict the behavioral patterns of the disease.

A comparison of CA125, HE4, risk ovarian malignancy algorithm (ROMA), and risk malignancy index (RMI) for the classification of ovarian masses

OBJECTIVE: Differentiation between benign and malignant ovarian neoplasms is essential for creating a system for patient referrals. Therefore, the contributions of the tumor markers CA125 and human epididymis protein 4 (HE4) as well as the risk ovarian malignancy algorithm (ROMA) and risk malignancy index (RMI) values were considered individually and in combination to evaluate their utility for establishing this type of patient referral system. METHODS: Patients who had been diagnosed with ovarian masses through imaging analyses (n = 128) were assessed for their expression of the tumor markers CA125 and HE4. The ROMA and RMI values were also determined. The sensitivity and specificity of each parameter were calculated using receiver operating characteristic curves according to the area under the curve (AUC) for each method. RESULTS: The sensitivities associated with the ability of CA125, HE4, ROMA, or RMI to distinguish between malignant versus benign ovarian masses were 70.4%, 79.6%, 74.1%, and 63%, respectively. Among carcinomas, the sensitivities of CA125, HE4, ROMA (pre- and post-menopausal), and RMI were 93.5%, 87.1%, 80%, 95.2%, and 87.1%, respectively. The most accurate numerical values were obtained with RMI, although the four parameters were shown to be statistically equivalent. CONCLUSION: There were no differences in accuracy between CA125, HE4, ROMA, and RMI for differentiating between types of ovarian masses. RMI had the lowest sensitivity but was the most numerically accurate method. HE4 demonstrated the best overall sensitivity for the evaluation of malignant ovarian tumors and the differential diagnosis of endometriosis. All of the parameters demonstrated increased sensitivity when tumors with low malignancy potential were considered low-risk, which may be used as an acceptable assessment method for referring patients to reference centers.

No evidence of somatic activating mutations on gonadotropin receptor genes in sex cord stromal tumors

OBJECTIVE To search for somatic activating mutations of gonadotropin receptor (FSH-R and LH/chorionic gonadotropin receptor [CG-R]) genes as a cause of sex cord stromal tumors. DESIGN Molecular studies in human tissue. SETTING University hospital. SPECIMEN(S): Eight granulosa cell tumors collected from paraffin-embedded tissue, eight Leydig cell tumors, and three thecomas collected from fresh-frozen or paraffin-embedded tissue. INTERVENTION(S) Tumor samples were used for DNA extraction. The entire exon 11 of the LH/CG-R gene and a hot spot for gonadotropin receptor activating mutations on exon 10 of the FSH-R gene were amplified by polymerase chain reaction. The former was analyzed by denaturing gradient gel electrophoresis and automatic direct sequencing, and the latter by automatic direct sequencing. MAIN OUTCOME MEASURE(S) Results of denaturing gradient gel electrophoresis and automatic direct sequencing. RESULT(S) No somatic activating mutation was detected in exon 11 of the LH/CG-R gene in eight Leydig cell tumors and three thecomas. In addition, no mutations were detected in eight granulosa cell tumors in the hot spot for activating mutations in exon 10 of the FSH-R gene. CONCLUSION(S) Somatic activating mutations of gonadotropin receptors seem to play no relevant role in the development of sex cord stromal tumors.

Morphologic hysteroscopic criteria suggestive of endometrial hyperplasia

Objectives: To evaluate the morphologic hysteroscopic criteria leading to a diagnosis of endometrial hyperplasia and compare their accuracy with that of histology. Methods: A total of 95 hysteroscopic examinations were evaluated. Of these, 37 had a histologic diagnosis of normal endometrium and the remaining 58 of simple or complex endometrial hyperplasia. We compared the morphologic hysteroscopic criteria for the two groups using Pearsons chi‐squared and Fishers exact test. Results: Only the presence of endometrial glands presenting a cystic pattern at hysteroscopy gave statistically significant results (P < 0.05), with low sensitivity (15.79%), high specificity (97.29%) and a relative risk of 6.75. With a prevalence of endometrial hyperplasia of 22.97% in a population of women with metrorrhagia, the positive predictive value was 63.53% and the negative predictive value was 79.40%. Conclusion: Additional, prospective studies are needed to determine the real value of the diagnostic morphologic parameters under consideration.

Is Chlamydia-infected tubal fimbria the origin of ovarian cancer?

Ovarian cancer is a highly lethal disease and its underlying biology is poorly understood. Prophylactic salpingo-oophorectomies in BRCA + women have recently implicated the fimbria as a site of origin for high-grade serous carcinoma and its intraepithelial precursors. This suggests that at least some ovarian cancers, probably the most aggressive ones, may not originate in the ovary itself, but rather may arise in the uterine tubes. Chronic inflammation is associated with carcinogenesis in several tissues, including liver, esophagogastric junction (cardia), and the uterine cervix. The mechanisms underlying the relationship between inflammation and cancer are complex and involve common pathways, in addition to DNA damage. A critical source of uterine tube inflammation is infection with Chlamydia trachomatis. We hypothesize that C.trachomatis infection may be involved in chronic tubal inflammation and subsequent fimbrial carcinogenesis. Fimbrial intraepithelial precursors can evolve into high grade serous carcinomas that spread rapidly to the ovarian surface and peritoneum; such tumors may appear to be primary ovarian neoplasia, though in reality being a secondary malignancy. This hypothesis must be further investigated to understand the intracellular signaling pathways involved in Chlamydia infection and its healing, and their relationship to carcinogenesis in order to discover potential therapeutic molecular targets. If our hypothesis were confirmed, salpingectomy instead of ovariectomy may also become the recommended surgery for high risk women.

Triple‐negative breast carcinomas are a heterogeneous entity that differs between young and old patients

OBJECTIVE: To compare the frequency and immunohistochemical profiles of triple‐negative breast carcinomas in younger and older women. METHODS AND RESULTS: We selected patients diagnosed with triple‐negative breast carcinomas. The groups examined were women who were 35 years old or younger between 1997 and 2007 (n  =  74) and, for comparison, women who were 60 years old or older (n  =  19, consecutive cases). All formalin‐fixed and paraffin‐embedded tumor samples were reviewed and immunohistochemically stained for ER, PR, HER2, Ki‐67 antigen, epidermal growth factor receptor, cytokeratin 5/6, p53, vimentin, CD117, and p63 using tissue microarrays blocks. Triple‐negative breast carcinomas corresponded to 34.6% (74/213) of the carcinomas from the younger patients and 16.2% (19/117) of the carcinomas from the older patients (p  =  0.002). No significant differences in the frequency of the basal phenotype were observed in the two patient groups based on CK5/6 and/or epidermal growth factor receptor expression (74.3% vs. 68.4%). However, triple‐negative breast carcinomas in the older patients presented a higher frequency of CK5/6 expression compared to those of younger patients (42.1% vs. 9.6%; p  =  0.005), whereas triple‐negative breast carcinomas of younger patients had a higher expression level of epidermal growth factor receptor (71.6% vs. 47.3%). CONCLUSIONS: These results show that there were significant molecular differences between the triple‐negative basal‐like breast carcinomas that were diagnosed in younger women and those that were diagnosed in older women. These findings may provide a basis for describing the more aggressive phenotype of the triple‐negative breast carcinomas observed in younger women.