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Rationale: Prepubertal unilateral gynecomastia is extremely rare, whose etiology and management strategy are not familiar. We would like to present a case and a literature review of unilateral prepubertal gynecomastia., Patient Concerns: A 11-year old male patient with complaints of unilateral enlargement of breast tissue presented in our clinic, whose physical examination, biochemical, hormonal and oncologic findings were normal., Diagnoses: This patient was diagnosed as idiopathic unilateral prepubertal gynecomastia (IUPG) and self-abasement, social isolation and sensitive of interpersonal relationship., Interventions: The patient received subcutaneous mastectomy. Histopathological examinations showed idiopathic gynecomastia of ductal epithelial hyperplasia and active interstitial fibrous hyperplasia, with no evidence of any pathological finding. Immunohistochemical examination showed estrogen receptor (ER)-α positive (70%), epidermal growth factor receptor (EGFR) positive, Her-2 positive (1+), Progesterone Receptor (PR) positive (80%)., Outcomes: A remarkable improvement was observed both in the physical and mental conditions at the post-surgical 6-month follow-up visit, showing no evidence of recurrence., Lessons: Further investigation is needed to clarify the pathogenesis of IUPG. All patients with IUPG should have a full endocrine and oncologic evaluation, and surgical excision may be the individually designed for each patient with the help of MRI of breast.

Background: We evaluated the relationship between the age at first use of oral contraceptives (OC) and breast cancer (BC) risk., Methods: We searched PubMed, Embase, and related reviews published through June 28, 2018, and used summary relative risk (RR) and 95% confidence intervals (CIs) to evaluate the cancer risks, and fixed-effects dose-response meta-analysis to assess potential linear and non-linear dose-response relationships., Results: We included 10 studies, with 8585 BC cases among 686,305 participants. The pooled RR for BC was 1.24 (95% CI: 1.10-1.41), with moderate heterogeneities (I = 66.5%, P < .001). No significant publication bias was found (P = .584 for Begg test, P = .597 for Egger test). A linear dose-response relationship between the age at first OC use and BC risk was detected (P = .518 for non-linearity). Subgroup analyses were restricted to studies done by BC subtypes, region, sample size, follow-up time and study quality. Inconsistent consequences with no statistical significance were explored when limited to studies from Western countries, study quality <7, sample size <10,000, follow-up time <5 years, and BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER-2) expression status in tumor tissue. Sensitivity analyses indicated that our results were stable and reliable after removing each study in turn and omitting studies of adjusted unreported variables., Conclusion: A significant linear relationship between the age at first OC use and BC risk was confirmed. No further consistent differences are noted in multiple aspects of BC subtypes defined by progesterone or ER status.

Metadherin (MTDH), also known as astrocyte elevated gene-1 (AEG-1), is an oncoprotein closely related to the development of breast cancer. However, few studies have been done on the expression and clinical significance of MTDH in human epidermal growth factor receptor-2 (HER-2) positive breast cancer patients.This study aimed to investigate the expression of MTDH in locally advanced HER-2 positive breast cancer, and evaluate the clinical significance of MTDH in predicting the prognosis of patients with HER-2 positive advanced breast cancer who received the neoadjuvant chemotherapy plus trastuzumab.In 144 HER-2 positive breast cancer tissues, 79 cases showed high expression of MTDH and 65 cases showed low expression. The expression of MTDH in locally advanced HER-2 positive breast cancer tissues was correlated with TNM stage, lymph node metastasis, Miller-Payne (MP) grade, and pathologic complete response (pCR) status (P < .05), but was not correlated with patient age, estrogen receptor (ER) expression level, progesterone receptor (PR) expression level, and Ki-67 expression level (P > .05). Kaplan-Meier univariate analysis revealed a negative correlation between MTDH expression and the disease-free survival (DFS) and overall survival (OS) in the post-operative patients with locally advanced HER-2 positive breast cancer (log rank test: P < .001). By using the COX proportional hazard regression model, it was found that MTDH expression, TNM stage, lymph node metastasis, and Ki-67 expression were closely related to DFS in patients. The hazard ratio (HR) of high MTDH expression was 1.816 (95% CI: 1.165-2.829). In addition, MTDH expression, TNM stage, and lymph node metastasis were also closely related to the OS of patient. The HR of the high expression of MTDH was 2.512 (95% CI: 1.472-4.286). The expression of MTDH in tumor tissues of patients with HER2-positive locally advanced breast cancer was significantly elevated, which was related to the poor pathological features.High MTDH expression was closely correlated with poor prognosis of patients and was an important factor affecting tumor progression.

PAX8, estrogen receptor-α (ERα) and progesterone receptor (PR) are markers usually expressed in neoplasms of müllerian origin. We report a subdiaphragmal mass in a 41-year-old woman corresponding to a malignant biphasic tumor with nests of epithelial-like cells forming variably sized cyst-like spaces alternating with spindle cells forming intersecting fascicles. The later were juxtaposed to coalescent densely cellular nodules of spindle cells with appreciable cytologic atypia and mitotic counts up to 30/10 high-power fields. The tumor cells were AE1/AE3, EMA, ERG, ERα, PR, and PAX8 positive whereas spindle cells showed reduced immunopositivity for these markers, especially marked in coalescent nodular areas, with notable exception of PAX8, which was diffuse and strongly positive. The possibility of an endometrioid carcinoma with spindle cells was considered by the referring pathologist, but fluorescent in situ hybridization showed rearrangement of SS18 gene in 48 of 50 tumor nuclei, rendering a diagnosis of biphasic synovial sarcoma, the first reported in the English literature to the best of our knowledge expressing PAX8, ERα, and PR. Further studies evaluating the expression of these markers in synovial sarcoma and other sarcomas are needed, as sometimes the findings may lead to misdiagnosis as other neoplasms including those of the female genital tract. Additional molecular tests may be helpful to determine the molecular mechanism of this aberrant immunoprofile, which could be directly or indirectly related to t(X:18).

Most available therapies for endometriosis are hormone-based and generally broadly used without taking into consideration the ovarian hormone receptor expression status. This contrasts strikingly with the standard of care for other hormone-based conditions such as breast cancer. We therefore aimed to characterize the expression of ovarian steroid hormone receptors for estrogen alpha (ESR1), estrogen beta (ESR2), and progesterone (PGR) in different types of endometriotic lesions and eutopic endometrium from women with endometriosis and controls using a tissue microarray (TMA). Nuclear expression levels of the receptors were analyzed by tissue (ie, ectopic vs. eutopic endometrium) and cell type (ie, glands vs. stroma). Ovarian lesions showed the lowest expression of ESR1 and PGR, and the highest expression of ESR2, whereas the fallopian tube lesions showed high expression of the 3 receptors. Differences among endometria included lower expression of ESR1 and higher expression of ESR2 in stroma of proliferative endometrium from patients versus patients, and a trend towards loss of PGR nuclear positivity in proliferative endometrium from patients. The largest ESR2:ESR1 ratios were observed in ovarian lesions and secretory endometrium. The highest proportion of samples with >10% Ki67 positive nuclei was in glands of fallopian tube (54%) and extrapelvic lesions (75%); 60% of glands of secretory endometrium from patients had >10% Ki67 positivity compared with only 15% in controls. Our results provide a better understanding of endometriosis heterogeneity by revealing lesion type-specific differences and case-by-case variability in the expression of ovarian hormone receptors. This knowledge could potentially predict individual responses to hormone therapies, and set the basis for the application of personalized medicine approaches for women with endometriosis.

Women diagnosed with breast cancer at young age often have poorprognoses. Yet, few studies have focused on the prognoses of young men with breast cancer. We therefore used Surveillance, Epidemiology, and End Results (SEER) population-based data and identified 151 male patients with breast cancer aged <40 years between 1988 and 2012. Propensity score matching analysis was used to balance the clinical variables among different groups. Kaplan-Meier curves were applied to compare the survival differences. The subgroup variables on cancer-specific survival (CSS) and overall survival (OS) were analyzed by the Cox proportional hazard model. Results showed that male patients with breast cancer aged <40 had a significant OS benefit compared with those aged ≥40 years (P < .001). The significant difference of the CSS was not found (P > .05). Compared with the male patients with breast cancer aged ≥40, those aged <40 had significant OS benefit in most subgroups (P < .05). Compared with the female patients with breast cancer aged <40, the male patients with breast cancer aged <40 had worse OS and CSS benefit only in the subgroup with progesterone receptor and estrogen receptor positive (P < .05). In conclusion, we demonstrated that young male patients with breast cancer had better OS compared with elder male patients with breast cancer. However, the survival benefit was not found compared with young female patients with breast cancer.

We conducted a heterogeneous risk assessment of breast cancer based on the hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) calculating the risks and population-based attributable fractions (PAFs) for modifiable and nonmodifiable factors.Using matched case-control study design from the Seoul Breast Cancer Study and the national prevalence of exposure, the risks and PAFs for modifiable and nonmodifiable factors were estimated for total breast cancers and subtypes.The attribution to modifiable factors was different for each subtype (luminal A, PAF = 61.4% [95% confidence interval, CI = 54.3%-69.8%]; luminal B, 21.4% [95% CI = 18.6-24.9%]; HER2-overexpression, 59.4% [95% CI = 47.8%-74.3%], and triple negative tumors [TNs], 27.1% [95% CI = 22.9%-32.4%)], and the attribution to the modifiable factors for the luminal A and HER2-overexpression subtypes was higher than that of the luminal B and TN subtypes (P heterogeneity  ≤  0.001). The contribution of modifiable reproductive factors to luminal A type in premenopausal women was higher than that of the other subtypes (18.2% for luminal A; 3.1%, 8.1%, and -3.1% for luminal B, HER2-overexpression, and TN subtypes, respectively; P heterogeneity  ≤  0.001). Physical activity had the highest impact preventing 32.6% of luminal A, 14.5% of luminal B, 38.0% of HER2-overexpression, and 26.9% of TN subtypes (P heterogeneity = 0.014). Total reproductive factors were also heterogeneously attributed to each breast cancer subtype (luminal A, 65.4%; luminal B, 24.1%; HER2-overexpression, 57.9%, and TN subtypes, -3.1%; P heterogeneity  ≤  0.001).Each pathological subtype of breast cancer by HRs and HER2 status may be associated with heterogeneous risk factors and their attributable risk, suggesting a different etiology. The luminal B and TN subtypes seemed to be less preventable despite intervention for alleged risk factors, even though physical activity had a high preventable potential against breast cancer., Competing Interests: The authors report no conflicts of interest.

Estrogen receptor (ER) and progesterone receptor (PR) overexpression can be used to predict patient prognosis in breast cancer (BC). Human epidermal growth factor receptor 2 (HER2) is a reliable predictive marker in invasive breast cancer (IBC). Thin-Prep (TP) specimens are commonly utilized for immunocytochemistry (ICC) in fine needle aspiration cytology (FNAC). Thus, we sought to investigate if the incorporation of molecular diagnosis performed on TP-processed specimens is applicable in clinical practice. Hormone receptors (HRs) and HER2 immunocytochemistry was performed on 542 primary breast cancer FNAC specimens using the TP method. One hundred fourteen HER2 fluorescence in situ hybridization (FISH) analyses were performed on HER2 ICC 2+ FNAC specimens and the corresponding tissue samples. HRs results of TP slides and those of formalin-fixed paraffin-embedded (FFPE) slides were correlated well for ER (concordance rate =  3.3%, kappa value = 0.85) and PR (concordance rate = 88.6%, kappa value = 0.75). HER2 results for the TP slides and those of the matched FFPE slides also correlated well (concordance rate = 80.0%, kappa value = 0.62). The specificity of HER2 was 97.3%; however, the sensitivity was only 67.1%. Cytological specimens and histological samples showed a strong correlation (concordance rate = 99.1%, kappa value = 0.98) while being used to evaluate HER2 gene amplification. FNAC is a minimally invasive technique that can be used as an alternative method to collect tissue especially in cases where an excisional or core biopsy is difficult to obtain, or when recurrence is present. The results of ICC HRs in FNAC TP specimens may be used instead, but HER2 assessment may not be reliable enough for clinical use. FISH testing is necessary in this setting.

Primary sporadic gene-inactivating events within the progesterone response cascade might explain the presence of individual dyssynchronous (outlier) glands commonly observed in a secretory background. We queried morphologically dyssynchronous glands in mid-secretory endometrium with a series of markers normally downregulated by progesterone. Seventy-nine mid-secretory endometrial biopsies were stained with hematoxylin and eosin, MIB-1, PAX2, estrogen and progesterone receptors, and PTEN. Aberrant staining of glands was independently scored for each marker. Outlier glands overlapping between stains were enumerated. A total of 63% of cases had hematoxylin and eosin stained outlier glands (average 9), which often demonstrated failed progesterone-mediated downregulation of PAX2 (43%), estrogen (40%), and/or progesterone receptors (28%). Aberrations of progesterone response was seen in 70% to 85% of cases overall, averaging 10 to 30 glands/affected case. The frequency and burden of affected glands was similar to that seen for primary inactivating events of the PAX2 and PTEN genes (35% and 41% of cases, respectively, averaging 32 and 38 glands per affected patient). Sporadic gene-inactivating events are common during endometrial regeneration, and may cause morphologic changes unmasked by the hormonal context. Some of these dyssynchronous "outlier" glands, whether evident on hematoxylin and eosin stain or not, have an interrupted progesterone response.

Background: Accurate determination of hormonal receptors (HR) status is crucial in therapeutic planning for women with breast cancer. Since the introduction of Oncotype DX, discordance with immunohistochemical (IHC) analysis has emerged to pose a clinical dilemma for the treating oncologist. The purpose of the study was to determine the accuracy of Oncotype DX RT-qPCR assay compared with IHC., Material and Methods: Consecutive breast carcinoma cases (n=114) that had Oncotype DX scoring for HR from 2009 to 2011 were included in the study. All cases were stained with Dako antibodies and scored using image analysis. Thereafter, cases with low RT-qPCR scores were stained with antibody clones from Ventana and Leica., Results: Estrogen receptor (ER) and progesterone receptor (PR) tested by RT-qPCR were positive in 109 of 114 (97.3%) and in 85 (74.6%) samples, respectively. The Spearman correlation was 65% for ER and 91% for PR. For ER, the recommended H-score, percentage score, and the Allred score cutoffs had high concordance rate with RT-qPCR. These cutoffs were inaccurate to determine PR status, with false results seen in 14 (12.3%), 12 (10.5%), and 17 (14.9%) cases, respectively. Although the established cutoff for ER detected by RT-qPCR of 6.5 had high accuracy, PR cutoff of 5.5 was inaccurate. The best cutoffs to correlate with different scoring systems were 3.8, 4.9, and 3.5, respectively. In the low HR expression group, marked variability was detected using different antibody clones., Conclusions: We conclude that although there was minimal difference in ER status between these 2 assays, PR had considerable discordance.

Objective: The indolent nature and expression of progesterone receptor (PR), a well-known estrogen-induced gene, in a subset of pancreatic neuroendocrine tumors (PanNETs), raise the possibility of hormonal regulation in these tumors., Methods: Immunohistochemical expression of estrogen receptors (ERs) α and β as well as messenger RNA expression of estrogen-induced genes (PR, EIG121, IGF-1, IGF-1R, sFRP1, and sFRP4) by quantitative reverse transcription-polymerase chain reaction were examined in 131 World Health Organization grade G1 and G2 PanNETs and correlated their expression with clinicopathological features., Results: Thirty-nine PanNETs (30%) showed high positive ERβ staining, and 87 cases (66%) had low positive ERβ staining; only 5 cases (4%) had no nuclear staining. Pancreatic neuroendocrine tumors with small size (P = 0.02), low World Health Organization grade (P = 0.02), and low American Joint Committee on Cancer stage (P = 0.006) more frequently showed high positive ERβ staining. Among the estrogen-induced genes studied, PanNETs had significantly higher expression of PR, EIG121, IGF-1, sFRP1, and sFRP4 compared with normal pancreas, independent of age or sex. High positive ERβ staining was associated with an increased expression of PR (P < 0.001) and EIG121 (P = 0.02)., Conclusions: Our study showed that PanNETs with favorable prognostic features have higher ERβ expression, which is associated with up-regulated PR and EIG121 messenger RNA expression. Estrogen regulation in PanNETs could potentially help in risk stratification and provide a rational target for novel treatment strategies.

Background: Vascular malformations frequently enlarge during adolescence, suggesting that hormones may be involved. The purpose of this study was to determine whether pubertal hormone receptors are present in vascular malformations and whether they differ from normal tissue., Methods: Tissue specimens (arteriovenous malformation, lymphatic malformation, and venous malformation) were prospectively collected from patients undergoing resection. Immunohistochemistry was used to determine the presence of androgen, estrogen, progesterone, and growth hormone receptors. The effects of age, sex, location, and malformation type on receptor expression were analyzed. Age-, sex-, and location-matched normal tissues served as controls., Results: Forty-five vascular malformation specimens were collected: arteriovenous malformation (n = 11), lymphatic malformation (n = 20), and venous malformation (n = 14). Growth hormone receptor expression was increased in arteriovenous malformation (72.7 percent), lymphatic malformation (65.0 percent), and venous malformation (57.1 percent) tissues compared with controls (25.8 percent) (p < 0.05). Growth hormone receptor was present primarily in the endothelium/perivasculature of malformations (93.1 percent), whereas in normal tissue growth hormone receptor was located only in the stroma (p < 0.0001). Neither age, nor sex, nor location influenced receptor expression (p = 0.9). No differences in androgen receptor, estrogen receptor, and progesterone receptor staining were found between malformations and control samples (p = 0.7)., Conclusions: Growth hormone receptor is overexpressed and principally located in the vessels of vascular malformations. Growth hormone might contribute to the expansion of vascular malformations.

Purpose of Review: Triple-negative breast cancer (TNBC) is defined by a lack of expression of hormone receptors, oestrogen and progesterone, as well as human epidermal factor receptor 2. This review focuses on the increasing understanding of the molecular heterogeneity of TNBC subtypes and the therapeutic implications of this subclassification., Recent Findings: Emerging evidence clearly indicates that TNBC is a heterogeneous disease with varying prognosis according to clinical, pathological and genetic factors. Some distinct histological special types within this clinically defined collection of entities have been shown to have a particularly good prognosis (e.g. medullary carcinomas), and others very poor outcome (e.g. metaplastic carcinomas), whereas the broader immunohistochemically defined 'core-basal-like' or gene expression defined 'basal' groups generally have a poor prognosis. This molecular subclassification has implicated several biological processes as potential therapeutic targets: the DNA damage response, drivers of deregulated proliferation, angiogenesis, epithelial-mesenchymal transition and immune deregulation., Summary: Molecular stratification of these prognostic groups has been critical in identifying novel therapeutic targets for future drug development. The development of poly-(ADP)ribose polymerase inhibitors for BRCA1-mutation carriers with TNBC has led the ongoing efforts to translate fundamental biological insights into improved therapies for a difficult-to-treat breast cancer subgroup.

Aggressive angiomyxoma (AA) is a benign, slow-growing tumor that characteristically occurs in women of reproductive age. Local recurrence is cited in 30% to 40% of cases. Wide local excision is the treatment of choice. However, recent reports suggest a role for hormone manipulation in the management of these tumors. The morphology and immunophenotype of AA overlap with that of other, mainly benign vulvovaginal mesenchymal tumors. Diagnosis rests primarily on hematoxylin and eosin staining features, and distinction is important in determining appropriate treatment and follow-up. Rearrangement of HMGA2 has been shown in AA, and reports suggest that HMGA2 immunohistochemistry may have a role in the routine diagnosis of AA, its distinction from mimics, and in the evaluation of margins. Furthermore, CDK4 immunopositivity has been described in AA. We describe a series of 9 cases of AA with typical histology and long-term follow-up, and evaluate the role of HMGA2, CDK4, estrogen, and progesterone immunohistochemistry. One of 9 women (11%) experienced recurrence, with the second at 17 years, which is the longest recorded in the English literature. HMGA2 immunohistochemistry was positive in 37.5% of cases, consistent with the reported frequency of HMGA2 gene rearrangement, and negative in all benign mimics. CDK4 immunoreactivity was weak, diagnostically not helpful, and of uncertain significance. Immunohistochemistry for estrogen and progesterone were positive in 87.5% of AAs, and were widely positive in control groups.

Background: Adenoma of the nipple is rare in men. It must be distinguished from a breast carcinoma and from Paget disease. In this sense, immunohistochemistry can be of some help. In women, for instance, immunoexpression of c-erbB-2 favors a diagnosis of Paget disease, according to some studies. Nevertheless, we have not found any studies on HER2/neu status, estrogen receptors, or progesterone receptors in nipple adenoma of male patients., Methods: We present a case of an adenoma of the nipple in a 21-year-old man in which we carried out a wide immunohistochemical study., Results: The lesion did not express estrogen receptors, progesterone receptors, or androgen receptors. The HercepTest was negative. Smooth muscle Actin and p63 were remarked in the basal layer of the tumoral tubules, supporting the benignancy of the lesion., Conclusions: This case of adenoma of the nipple in a male shows an immunophenotype that is similar to the ones reported in female patients.

The aim of this meta analysis was to evaluate the benefit of adding concomitant trastuzumab to neoadjuvant(anthracycline and taxane-based) chemotherapy, which was assessed based on two published randomized controlled trials. The eligible patients were randomized to receive either neoadjuvant chemotherapy alone or with concurrent administration of trastuzumab. Relative risks(RRs) with 95% confidence intervals of pathologically complete response in breast and nodes, relapse-free survival, overall survival, and cardiotoxicity were calculated.The RR of obtaining a pathologically complete response in breast and nodes was 2.07 in the experimental arms(1.41–3.03; P = 0.0002; P for heterogeneity 0.63; fixed effect model). The RR of being disease free was 0.67 in favor of the experimental arms (0.48–0.94; P = 0.02; P for heterogeneity 0.22; fixed affect model). The RR of being alive was 0.67 in favor of the experimental arms (0.39–1.15;P= 0.15). The RR of a cardiac event was 1.09 in the arms treated with chemotherapy and concomitant trastuzumab, but that is not significant (0.6–1.98; P =0.77). The addition of concomitant trastuzumab to neoadjuvant chemotherapy doubles the risk of obtaining a pathologically complete response in both breast and nodes compared with controls. Trastuzumab significantly reduces the risk of relapse and does not increase the risk of cardiotoxicity,despite being associated with anthracyclines. The largest benefit was observed in a locally advanced patient study.

We examined the induction of progesterone receptor-immunoreactive (PR-ir) cells by estrogen in the rat preoptic area and ventromedial hypothalamic nucleus. Ovariectomized young (3-month-old) and old (24-month-old) female rats were treated with estrogen or cholesterol for 4 days. Estrogen significantly increased PR-ir cells in the preoptic area and ventromedial hypothalamic nucleus in young rats. Cholesterol-treated old rats had very few PR-ir cells; estrogen treatment significantly increased the number of PR-ir cells in both the preoptic area and the ventromedial hypothalamic nucleus in old rats, although less than in young rats. Therefore, the ability of estrogen to induce PR immunoreactivity in the hypothalamus in ovariectomized rats is attenuated in old rats compared with young rats.

Phyllodes tumor occurring in the vulva is extremely rare; only 6 cases have been previously reported in the literature. The histogenetic origin of this tumor is controversial as it is being debated whether such lesions evolve from ectopic breast tissue, cutaneous apocrine glands, and most recently, anogenital mammary-like gland. We report an 18-year-old Kuwaiti girl who presented with a painless mass in the left labium majus, which was subsequently excised. Microscopic examination revealed morphologic pattern characteristic of benign phyllodes tumor. Immunostaining demonstrated the presence of estrogen receptors and progesterone receptors in the epithelial component. We present this case to emphasize the importance of recognizing this uncommon lesion occurring at an extremely unusual site. We also discuss the histogenesis of phyllodes tumor and related lesions occurring in the anogenital region in light of the current literature along with a brief review of the previously reported cases of vulvar phyllodes tumor.

Aims: We investigated the correlation between protein expression of Aurora-A with hormone receptor expression and clinicopathological parameters in ovarian, breast and prostate cancer., Methods: Subcellular expression of Aurora-A, and androgen receptor (AR), oestrogen receptor (ER) and progesterone receptor (PR) expression, were examined by immunohistochemistry in human tissue microarrays of the three cancer types and by Western blot in cancer cell lines and selected patient tissues., Results: Subgroups of all three cancer types exhibited both nuclear and cytoplasmic expression of Aurora-A. Nuclear presence of Aurora-A was observed in ER positive and negative breast cancer cell lines and tissues. Eighteen of the 126 (14%) tumour tissues that showed nuclear expression of Aurora-A were strongly associated with ER and PR positive breast tumours (p = 0.001). Cytoplasmic expression of AR and Aurora-A was strongly associated in prostate cancer tissues (45% versus 0, p = 0.015). Ovarian tumours (n = 45) with Aurora-A nuclear expression had decreased patient survival (mean survival, 29.5 versus 106.7 months; p < 0.0005) and showed a significant association with recurrence-free survival (mean survival 19.7 versus 95.9 months; p = 0.002)., Conclusion: Association between nuclear Aurora-A with hormone receptors in breast cancer and with poor clinical outcome in ovarian cancer suggests the significance of active Aurora-A in disease initiation and progression.

Atypical leiomyomas are characterized by moderately to severely pleomorphic atypical tumor cells with low mitotic counts and no coagulative tumor cell necrosis. Despite the worrisome histologic features, most tumors have shown benign behavior. However, most studied patients had total hysterectomies, and very few patients who had myomectomy alone have had long-term follow-up. The behavior of atypical leiomyomas treated with myomectomy alone is still not known. We present a study of 13 atypical leiomyomas treated with myomectomy alone with long-term follow-up results and immunohistochemical findings for p16 (p16), p53, Ki-67, estrogen receptors, and progesterone receptors. The lengths of the postoperative intervals ranged from 20 to 151 months (mean=76.1 mo). None of the patients had developed a metastasis of her atypical leiomyoma. However, 1 patient showed local recurrence at the past myomectomy site 22 months after initial myomectomy. Immunostaining for p16 showed moderate to strong diffuse immunoreactivity in 11/13 cases (84.6%) of atypical leiomyomas, and 38.5% showed immunoreactivity for p53, including 1 case with strong, diffuse positive p53. When an atypical leiomyoma is discovered in a myomectomy specimen, the patient should be carefully followed up with or hysterectomy could be recommended. Larger numbers of cases and more long-term follow-up studies are needed to confirm the safety of myomectomy for atypical leiomyomas.

The aim of this study was to evaluate the expression of estrogen, progesterone, and androgen receptors in a large series of gastrointestinal stromal tumors. Clinical and pathologic data were reviewed in 427 cases of gastrointestinal stromal tumor and the expression of such hormone receptors was investigated by immunohistochemistry using tissue microarray technique. All tumors were negative for estrogen receptor expression. Progesterone and androgen receptors expression was observed in 5.4% and 17.6% of tumors, respectively. We found the higher average age at diagnosis, the lower frequency of tumors located in the small intestine, and the higher frequency of extragastrointestinal tumors to be statistically significant in the group of tumors with androgen receptor expression in contrast to the group showing no androgen receptor expression. There was no statistic difference between such groups regarding sex, tumor size, mitotic count, cell morphology, and risk of aggressive behavior. Considering that the expression of androgen receptors in gastrointestinal stromal tumors is not negligible, further studies are encouraged to establish the role of androgen deprivation therapy for gastrointestinal stromal tumors.

If in vitro studies have demonstrated a potential interaction between human papillomavirus (HPV) and androgen receptor (AR), their expression in vivo during cervical carcinogenesis remains unknown. To clarify the issue, we have tested by immunohistochemistry the expression status of AR in low-grade cervical intraepithelial neoplasia (LSIL-CIN1) (n=30), high-grade cervical intraepithelial neoplasia (HSIL-CIN2/3) (n=30), and invasive squamous cell carcinoma (ISCC) (n=13). All the patients with these lesions have got a corresponding liquid-based cytology and were proved to be HPV positive by using hybrid capture II methodology with probes against high-risk oncogenic HPVs (HR-HPVs). Thirty cases of normal exocervix epithelium served as controls. The evaluation of AR expression was performed by using H-score system, and an H-score >50 was considered positive. Androgen receptor expression was observed in 100% of normal epithelium (30/30) and LSIL (30/30), but only in 63% of HSIL (19/30) and 23% of ISCC (3/13). A statistically significant difference (P<0.05) concerning this expression was found between normal epithelium and HSIL or ISCC, between LSIL and HSIL or ISCC, and between HSIL and ISCC. To the best of our knowledge, this is the first study describing that the loss of AR expression is a frequent and common event in HSIL and ISCC resulting probably from complex interactions between HR-HPVs and these receptors. These data provide new insights concerning a potential role of androgen and AR in cervical carcinogenesis, which should be confirmed in furthers studies.

The biologic role that estrogen receptor (ER) and progesterone receptor (PR) play in ovarian sex cord-stromal tumors is poorly understood. Furthermore, immunohistochemical data on these hormone receptors in this group of neoplasms are limited and conflicting, with many reports suggesting that expression of ERalpha and/or PR is either infrequent or present at low levels in granulosa and Sertoli cell tumors. Immunohistochemical staining for ERalpha and PR was performed in 69 ovarian sex cord-stromal tumors: 41 adult granulosa cell tumors and 28 Sertoli-Leydig cell tumors. Extent of expression was scored based on the percentage of positive cells: 0, 5% or less; 1+, 6% to 25%; 2+, 26% to 50%; 3+, 51% to 75%; and 4+, 76% to 100%. Estrogen receptor alpha and PR were frequently expressed in adult granulosa cell tumors (66% and 98%, respectively) and Sertoli-Leydig cell tumors (79% and 86%, respectively). Diffuse (3+ or 4+) expression of PR was more common in adult granulosa cell tumors (68% vs. 36%; P = 0.013), whereas diffuse (3+ or 4+) expression of ERalpha was more frequent in Sertoli-Leydig cell tumors (50% vs. 20%; P = 0.010). In cases positive for both markers, adult granulosa cell tumors exhibited a focal (1+ or 2+) ERalpha/diffuse (3+ or 4+) PR coordinate profile more commonly than Sertoli-Leydig cell tumors (52% vs. 18%; P = 0.02), whereas Sertoli-Leydig cell tumors displayed a diffuse (3+ or 4+) ERalpha/focal (1+ or 2+) PR profile more frequently than adult granulosa cell tumors (36% vs. 0%; P = 0.0007). We conclude that expression of hormone receptors (based only on frequency of immunostaining) does not allow for distinction from other tumors in the differential diagnosis that are known to be frequently positive for ERalpha and PR such as endometrioid neoplasms. Most adult granulosa cell tumors and Sertoli-Leydig cell tumors share overlapping patterns of expression of ERalpha and PR with each other, but a subset of cases in each tumor category exhibits unique ERalpha/PR immunoprofiles (eg, focal ERalpha/diffuse PR in adult granulosa cell tumors and diffuse ERalpha/focal PR in Sertoli-Leydig cell tumors). These patterns of expression of ERalpha and PR may aid our understanding of the biologic differences between granulosa and Sertoli cell tumors.

A 2-tier system that classifies ovarian serous carcinoma (OSC) as low grade or high grade is gaining acceptance. Women with low-grade OSC generally have higher 5-year survival rates than do women with high-grade OSC. We examined the expression of various markers to further understand the molecular differences between low-grade and high-grade OSCs: the potential therapeutic targets or prognostic markers Her-2/neu, estrogen receptor, and progesterone receptor (PR); the metastasis-associated markers cyclin D1 (BCL1), E-cadherin, matrix metalloproteinase (MMP) 2, and MMP-9; and the cell proliferation-associated markers BCL1, Ki-67 antigen (Ki-67), and p53. For this immunohistochemical analysis, we used paraffin-embedded specimens from 47 patients with advanced-stage low-grade OSC and from 49 patients with advanced-stage high-grade OSC. Our results showed that low-grade tumors expressed significantly higher levels of estrogen receptor, PR, and E-cadherin than did high-grade tumors, suggesting the involvement of gonadal steroid hormones, especially in the pathogenesis of low-grade OSC; the PR positivity was also observed in the stromal component of these low-grade tumors. On the other hand, high-grade tumors trended toward increased expression of MMP-9, BCL1, p53, and Ki-67, and robust MMP-9 positivity was observed in the stromal component of these high-grade tumors. These differences may lead to the development of different therapeutic strategies for women with either the low-grade or the high-grade form of OSC.

Hypoxia-inducible factors-1alpha (HIF-lalpha) and HIF-2alpha are important proteins initiating tumor cell responses to hypoxia. Specifically, the transcription of genes related to erythropoiesis, glycolysis, and angiogenesis depends on the rate of HIFalpha binding to DNA at the hypoxia response elements of target genes. In this study, the authors evaluated the immunohistochemical expression of HIF-2alpha in 62 infiltrating ductal carcinomas of the breast, not otherwise specified, in relation to estrogen and progesterone receptors, the MIB1 proliferation index, the vascular density, and the proteins c-erbB-2, bcl-2, and p53. Extensive and strong cytoplasmic and/or nuclear expression of HIF-2alpha was noted in 23 of the 64 (35.9%) cases, and this was associated with increased vascular density (P=0.0002), increased c-erbB-2 membrane expression (P=0.02), and secondary deposits to multiple axillary lymph nodes (>3). In multivariate analysis, HIF-2alpha and T stage were the only variables related to extensive nodal metastasis. The authors conclude that HIF-2alpha overexpression, a common event in infiltrating ductal carcinomas of the breast, is related to high metastatic potential via increased angiogenic and c-erbB-2 activity.

The progesterone receptor (PR) exists as two isoforms, PRA and PRB. In vitro studies have shown that these proteins are functionally distinct, suggesting that their relative expression can influence progesterone response. Low-grade endometrial stromal sarcoma (LGESS) is an uncommon tumor that usually expresses PR. In normal endometrial stroma, both PR isoforms are present with PRA predominant throughout the menstrual cycle. The relative expression of PRA and PRB in LGESS has not been previously reported. All nine cases of primary LGESS (seven uterine, two extrauterine) expressed PRB. Eight tumors also contained PRA and it was the predominant isoform in seven cases. These tumors had similar histopathologic appearances, whereas a case with approximately equal PR isoform expression showed features of sex cord or smooth muscle differentiation. An extrauterine tumor expressing only PRB had myxoid stroma. Recurrent tumor in two cases, which expressed predominantly PRA in the primary, contained reduced levels of PR consisting predominantly or entirely of PRB after prolonged interval progestin therapy. Most primary LGESSs showed PR isoform expression similar to normal endometrial stroma, consistent with the highly differentiated phenotype of this tumor. Variant differentiation or disease recurrence was accompanied by an altered PR isoform profile that could impact on hormone response.

Sixty cases of uterine adenomatoid tumors (ATs) are reported. All except four were incidental findings in hysterectomy specimens, three of these being discovered preoperatively as large multicystic tumors. ATs were classified into two distinctive macroscopic patterns: small, solid tumors and large, cystic ones. The 56 small, solid ATs ranged from 0.2 to 3.5 cm, (average 2.1 cm); 48 were nodular and 8 diffuse. The four large, cystic tumors ranged from 7 to 10 cm. Inflammation occurred in 65% of the tumors, and a smooth muscle reaction, identified by an increased Ki-67 index, was present in most cases. Both types were histologically similar except for the presence of short papillae in cystic tumors, which also showed serosal involvement. Both were immunoreactive for cytokeratins, calretinin, HMBE-1, and vimentin. Estrogen and progesterone nuclear receptors and EMA were negative. These tumors represent a spectrum ranging from small and solid to large and cystic ATs in the female genital tract, whereas outside the genital tract they are morphologically similar to multicystic mesothelioma. Although a reactive origin for ATs often seems plausible, especially when inflammation is present, their neoplastic nature should not be ignored.

Microwave heating of histologic sections in citrate buffer (MAR) is a widely used method of antigen recovery but often results in loss of tissue sections. Low-temperature antigen retrieval (LTAR), incubation at 80 degrees C in citrate buffer for 2 hours with trypsin pretreatment is an alternative method reported to result in better antigen recovery for specific antigens as well as decreased loss of tissue sections. To optimize our immunohistochemical evaluation of breast carcinomas, we compared the efficacy of these methods of antigen recovery for several important antigens. Ten breast carcinomas were immunostained for estrogen and progesterone receptors (ER and PR), Ki-67/ MIB 1, p27/Kip-1, and Bcl-2 after MAR, LTAR with enzymatic pretreatment, or no antigen recovery. The immunohistochemical staining was scored and compared for each antibody and antigen recovery combination. The proportion of tissue lost from each slide after staining also was assessed. More and stronger positive staining was achieved with antibodies to Ki67/MIB 1 and ER when LTAR was used compared with the other two methods; in contrast, optimal staining with antibodies to Bcl-2 was achieved when MAR was used. Staining with anti-p27/Kip- was nearly equal with either LTAR or MAR. Staining with anti-PR was slightly better with MAR than with LTAR. Tissue loss was greatest for MAR compared with LTAR or with no antigen recovery. For selected cases, LTAR caused focal tissue damage, and either the immunostaining with LTAR had to be repeated or only a portion of some tissue sections would be used for examination. LTAR was the most effective for ER and Ki-67/MIB 1. MAR provided the most intense staining for Bcl-2 and PR, but this enhanced staining must be weighed against the greater tissue section loss from MAR. This study demonstrated that AR methods are not equally applicable to all antibodies.

It was recently reported that certain antigens can be retrieved from paraffin sections of formalin-fixed tissues by ultrasonication using either an expensive and sophisticated ultrasonic cell disrupter probe (cytokeratins 13 and 16) or an inexpensive and generally available ultrasonic cleaning bath (bcl-1). We wished to investigate the routine use of the latter method and therefore tried to retrieve from various tissues 11 antigens that usually require heat-mediated retrieval in citrate buffer. We applied ultrasonic vibration for periods of 30 seconds to 1.5 minutes in a cleaning bath containing citrate buffer or water, with and without the addition of heat, or for 1 minute in hot citrate buffer after microwaving for 10 minutes in the same buffer. Although a slight effect of ultrasound was noted for a few antigens, in no case did the immunostaining reach the level achieved after standard microwave heating in citrate buffer. We conclude that, under the conditions we used, ultrasonic antigen retrieval cannot be used for immunocytochemistry in a routine histopathology laboratory.

Endometrial specimens of 34 (25 premenopausal and 9 postmenopausal) breast cancer patients receiving tamoxifen were immunohistochemically examined using estrogen receptor (ER), progesterone receptor (PR), Ki-67, and epidermal growth factor receptor (EGFR) antibodies. Proliferative (n = 6), secretory (n = 9), and postmenopausal (n = 6) endometria served as controls. The ER and PR expressions of the glandular cells in tamoxifen-treated patients did not differ from those of the glandular cells in the control women regardless of menopausal status. The Ki-67 index of glandular cells in tamoxifen-induced amenorrheic women was found to be lower than that of the proliferative glandular cells in the control women (p < 0.03), whereas the Ki-67 index of glandular cells in the tamoxifen-treated postmenopausal patients was higher than that of the glandular cells in the control women (p < 0.02). No EGFR overexpression was found in the glandular cells of the tamoxifen-treated premenopausal patients, but expression of EGFR was high in glandular cells of the tamoxifen-treated postmenopausal patients associated with a high Ki-67 index. In competition with ovarian estrogen secretion, tamoxifen may have an antiestrogenic effect on the endometrium, but tamoxifen probably has an estrogenic effect in the absence of ovarian estrogen secretion. This estrogenic effect of tamoxifen may be associated with an EGFR autocrine system.

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.

It was recently reported that cervical adenocarcinoma showed an abnormal expression of estrogen receptor (ER) and cell cycle-related molecules (cyclin E, p53, p16, p21, and p27). To investigate whether similar alterations exist in glandular intraepithelial lesions, the expression of ER, progesterone receptor (PR), Ki-67, and the above cell cycle-related molecules was examined in 15 cases of glandular dysplasia (GD) and 10 cases of adenocarcinoma in situ (AIS), using the immunohistochemical technique. An expression of ER and PR was often decreased or missing in GD and, especially, in AIS. The Ki-67 labeling index was significantly higher in AIS than in GD or normal glandular cells. In GD, expression of all the cell cycle-related molecules was not recognized (except for a few p27-positive cases), a situation comparable to normal glands. In contrast, an abnormal expression of all the cell cycle-related molecules examined was demonstrated in AIS. There was a significant positive correlation, in terms of the extent of staining, between cyclin E and p21 in AIS. These results suggest that an altered expression of these molecules occurs in AIS as it does in invasive adenocarcinoma, and provide additional evidence supporting AIS as a precursor of cervical adenocarcinoma.

In order to clarify the factors that affect growth of endometrial carcinoma, immunohistochemical analyses of bcl-2, p53, sex steroid receptors, and Ki-67 were performed in 35 cases of endometrial carcinoma (32 endometrioid and three clear-cell carcinomas). Correlation of antigen expression with clinicopathological features was analyzed. Expression of bcl-2 was found in 58.8, 33.3, and 20.0% of grade 1 (G1), grade 2 (G2), and grade 3 (G3) endometrial carcinomas, respectively. Estrogen receptor (ER) was observed in 70.6, 22.2, and 0% of G1, G2, and G3 cases (p < 0.01), respectively. In contrast, expression of p53 was found in 5.8, 33.3, and 60.0% of G1, G2, and G3 cases, respectively. The labeling index of Ki-67 correlated with p53 overexpression (p < 0.01). Lymph node metastases were observed in 6.6 and 5.5% of ER- and PR (progesterone receptor)-positive carcinomas, whereas metastases were observed in 44.4 and 53.3% of ER- and PR-negative carcinomas, respectively (p < 0.05). Lymph node metastases were observed in 50.0% of p53-positive carcinomas, whereas metastases were observed in 22.2% of p53-negative carcinomas (p < 0.05). These results suggest that bcl-2 expression in endometrial carcinomas is regulated in a hormone-dependent manner. Expression of bcl-2 may occur more frequently in estrogen-related, low-grade endometrial carcinomas, whereas p53 overexpression is found more often in endometrial carcinomas in estrogen-unrelated, high-grade endometrial carcinomas with prominent proliferative activity and a high frequency of lymph node metastases.

The authors have briefly discussed the molecular structure, regulation, and function of progesterone receptors in the mammalian ovary. Particularly important is the contrast in the regulatory mechanisms of PR induction in the ovary (gonadotropins/membrane receptor mediated) and other well-known progesterone target tissues, such as the uterus and mammary gland (estrogen/nuclear receptor mediated). Future research will focus on how the PR gene responds to these hormonal regulatory signals in this cell-specific manner. Equally important in this discussion has been the mounting evidence indicating that PRs are an essential component of the ovulatory process. The observation that PR-/- knockout mice are incapable of undergoing ovulation, even in response to gonadotropin challenge, further supports the previous physiological evidence indicating that PRs in preovulatory follicles are induced before, and are necessary for, ovulation. Further studies are required to determine the identity of PR-regulated target genes during the periovulatory period. Although our knowledge of PR structure, regulation, and function has increased dramatically during the past decade, many exciting questions remain related to the regulation and function(s) of PRs in the ovary and other tissues.

Background: Clinical and epidemiological observations regarding varicose veins, such as their predominance in women and the occurrence of venous stasis during sex-hormone therapy, the luteal phase of the menstrual cycle, and pregnancy, suggest a sex hormone-dependency of this venous pathology. In the present study, analysis of steroid receptors was used to determine if these effects were due to a direct hormonal action on the saphenous vein., Methods and Results: Biopsy samples were obtained from patients undergoing stripping removal of varicose saphenous veins. Patients were men (n = 5) and premenopausal (n = 15) or postmenopausal (n = 10) women. Progesterone receptors (PR) and estrogen receptors (ER) were determined by both enzyme immunoassay (EIA) and immunocytochemistry by use of monoclonal antibodies. Ninety percent of the biopsy samples showed PR positivity by EIA (range, 5 to 53 fmol/mg cytosol protein). When present, PR staining was observed in the cell nuclei of the tunica media and the subendothelial layer (neointima). No significant variation was observed in the PR content of different regions within the same saphenous vein. In contrast, no ER or extremely low levels of ER (< 5 fmol/mg cytosol protein) were detected by EIA in 25 of 30 varicose biopsy samples. Reverse transcription-polymerase chain reaction (RT-PCR) was used to analyze PR and ER mRNAs in biopsy samples that were PR positive/ER negative. With primers to the hormone-binding region encoded by PR mRNA, a RT-PCR product of the expected size was detected and its identity confirmed by Southern blot by use of a PR cDNA probe. In contrast, no RT-PCR product could be detected by use of primers to the DNA-binding domain, the hinge region, and the ligand-binding domain encoded by ER mRNA., Conclusions: These results indicate that human saphenous veins from both sexes express PR, as previously described for arterial blood vessels. This observation suggests that progesterone acts directly on these veins via a classic receptor-mediated pathway.

HER-2/neu oncogene protein, epidermal growth factor receptor, progesterone receptor, and estrogen receptor were examined immunohistochemically in specimens of normal and neoplastic endometrium. Tissues obtained at the time of hysterectomy were snap-frozen at liquid nitrogen temperature and serially sectioned at 4 microns. Normal endometrial epithelial cells stained with anti-epidermal growth factor receptor and anti-HER-2/neu with intensities graded from 0 to 3+. Of the 49 endometrial malignancies studied, seven (14%) contained tissue exhibiting HER-2/neu staining in excess (4+) of any of the normal tissues or the other 42 cancer specimens. Expression of both HER-2/neu and steroid receptors was heterogeneous within these seven tumors. To examine this heterogeneity more closely, sections of these and other tumors were double-stained for HER-2/neu and progesterone receptor. It was found that the cells exhibiting 4+ HER-2/neu staining were progesterone receptor-negative. Conversely, cells that were progesterone receptor-positive within the same specimen exhibited HER-2/neu immunostaining equal to or less than 3+. All specimens containing 4+ HER-2/neu tissue were graded 1 or 2 adenocarcinomas, stage I. Thus, there is an inverse relationship between overexpression of HER-2/neu and progesterone receptor in endometrial cancer. On the other hand, overexpression of HER-2/neu in endometrial cancer does not seem to be related to loss of other differentiated characteristics. The prognostic value of these observations awaits continued study.

The monoclonal antibody (MAb) 1BE12 has recently been reported to react with several human normal and abnormal tissues. In human endometrium, it reacts more strongly with carcinomas than with normal tissue. To investigate the effectiveness of MAb 1BE12 in identifying cell proliferation in human endometrial cancers, 1BE12 immunocytochemical assays (ICAs) were performed on frozen (n = 47) and paraffin (n = 100) sections with subsequent computer-assisted microcytophotometric (SAMBA) evaluation of immunoprecipitate distribution. MAb 1BE12 immunoreactivity was not impaired by tissue fixation and paraffin embedding. It reacted with normal proliferative endometrium but not with normal secretory endometrium, and immunoreactivity increased with the degree of cell proliferation and malignancy, the amount of immunostaining being greater in invasive carcinomas than in normal proliferative endometrium and endometrial hyperplasia. ICAs showed no correlation between MAb 1BE12 immunoreactivity and estrogen and progesterone receptor antigenic sites. On the other hand, MAb 1BE12 staining in frozen sections increased with Ki67, EGFR, pHER-2/neu, and cathepsin immunostaining. These findings suggest that ICAs on frozen and paraffin-embedded biopsy specimens using MAb 1BE12 along with other markers can be useful for early detection and grading of endometrial carcinoma. The relevance of MAb 1BE12 to the selection of patients for laser ablation of the endometrium rather than hysterectomy is also discussed.