Patterns of clinicopathological features and outcome in epithelial ovarian cancer patients: 35 years of prospectively collected data.

OBJECTIVE: Investigate the clinical landscape of ovarian carcinoma (OC) over time. DESIGN: Register-based prospectively collected data. SETTING: South East Scotland. SAMPLE: A total of 2805 OC patients diagnosed in 1981-2015. METHODS: Survival times were visualised using the Kaplan-Meier method; median survival, 5-year survival probabilities and associated restricted mean survival time analyses were used to quantify survival differences. MAIN OUTCOME MEASURES: Disease-specific survival. RESULTS: A significant increase in disease-specific survival (DSS) from 1981-1985 to 2011-2015 was observed (median 1.73 versus 4.23 years, P < 0.0001). Corresponding increase in progression-free survival (PFS) was not statistically significant (median 1.22 versus 1.58 years, P = 0.2568). An increase in the proportion of cases with low residual disease volume (RD) (<2 cm RD) following debulking was observed (54.0% versus 87.7%, P < 0.0001). The proportion of high grade serous (HGS) cases increased (P < 0.0001), whereas endometrioid and mucinous cases decreased (P = 0.0005 and P = 0.0002). Increases in stage IV HGS OC incidence (P = 0.0009) and stage IV HGS OC DSS (P = 0.0122) were observed. Increasing median age at diagnosis correlated with increasing Eastern Cooperative Oncology Group Performance Status (ECOG PS) over time (r = 0.86). CONCLUSIONS: OC DSS has improved over the last 35 years. PFS has not significantly increased, highlighting that improvement in outcome has been limited to extending post-relapse survival. Distribution of stage at diagnosis, histological subtype and RD following debulking has changed over time, reflecting evolution in tumour classification, staging and optimal debulking definitions (from low RD to minimal or zero RD). Histology, stage, RD and ECOG PS remain reliable outcome predictors. Increasing median age at diagnosis and ECOG PS indicates demographic shifts in the clinical population. TWEETABLE ABSTRACT: Significant improvement in ovarian carcinoma survival has been seen over time. Most of this improvement is due to an extension of survival following disease relapse.

Viruses and disease: emerging concepts for prevention, diagnosis and treatment.

Viruses cause a wide range of human diseases, ranging from acute self-resolving conditions to acute fatal diseases. Effects that arise long after the primary infection can also increase the propensity for chronic conditions or lead to the development of cancer. Recent advances in the fields of virology and pathology have been fundamental in improving our understanding of viral pathogenesis, in providing improved vaccination strategies and in developing newer, more effective treatments for patients worldwide. The reviews assembled here focus on the interface between virology and pathology and encompass aspects of both the clinical pathology of viral disease and the underlying disease mechanisms. Articles on emerging diseases caused by Ebola virus, Marburg virus, coronaviruses such as SARS and MERS, Nipah virus and noroviruses are followed by reviews of enteroviruses, HIV infection, measles, mumps, human respiratory syncytial virus (RSV), influenza, cytomegalovirus (CMV) and varicella zoster virus (VZV). The issue concludes with a series of articles reviewing the relationship between viruses and cancer, including the role played by Epstein-Barr virus (EBV) in the pathogenesis of lymphoma and carcinoma; how human papillomaviruses (HPVs) are involved in the development of skin cancer; the involvement of hepatitis B virus infection in hepatocellular carcinoma; and the mechanisms by which Kaposi's sarcoma-associated herpesvirus (KSHV) leads to Kaposi's sarcoma. We hope that this collection of articles will be of interest to a wide range of scientists and clinicians at a time when there is a renaissance in the appreciation of the power of pathology as virologists dissect the processes of disease.

The terminology of pre-invasive cervical lesions in the UK cervical screening programme.

The terminology of non-invasive epithelial abnormalities associated with an elevated risk of having or developing invasive cervical carcinoma (pre-invasive lesions) has been modified frequently over time as understanding of the underlying biology, and approaches to disease management, have changed. The arguments are now converging on the conclusion that the most appropriate terminology for cervical squamous intraepithelial abnormalities should be two-tier rather than three-tier. Given the findings of the Lower Anogenital Squamous Terminology (LAST) project in the USA, which have recently been endorsed by the World Health Organisation classification of tumours of female reproductive organs, the recommended terms are low-grade and high-grade squamous intraepithelial lesion (SIL), with the option of including the relevant cervical intraepithelial neoplasia (CIN) grade in parentheses. Although, at first sight, this appears to represent only a small change, there is a fundamental conceptual difference between the systems. The CIN system requires, first, the identification of a CIN lesion and, second, the determination of its grade on a continuum, with subsequent division into three grades. The SIL system is based on the existence of two different forms of human papillomavirus (HPV) infection, with productive infection leading to low-grade SIL and transforming infection leading to high-grade SIL.

Individuality in FGF1 expression significantly influences platinum resistance and progression-free survival in ovarian cancer.

BACKGROUND: Ovarian cancer is frequently advanced at presentation when treatment is rarely curative. Response to first-line platinum-based chemotherapy significantly influences survival, but clinical response is unpredictable and is frequently limited by the development of drug-resistant disease. METHODS: We used qRT-PCR analysis to assess intertumour differences in the expression of fibroblast growth factor 1 (FGF1) and additional candidate genes in human ovarian tumours (n=187), and correlated individuality in gene expression with tumour histology, chemotherapy response and survival. We used MTT assays to assess platinum chemosensitivity in drug-sensitive and drug-resistant ovarian cell lines. RESULTS: Marked intertumour differences in gene expression were observed, with each tumour having a unique gene expression profile. Nine genes, including FGF1 (P=1.7 × 10(-5)) and FGFR2 (P=0.003), were differentially expressed in serous and nonserous tumours. MDM2 (P=0.032) and ERBB2 (P=0.064) expression was increased in platinum-sensitive patients, and FGF1 (adjusted log-rank test P=0.006), FGFR2 (P=0.04) and PDRFRB expression (P=0.037) significantly inversely influenced progression-free survival. Stable FGF1 gene knockdown in platinum-resistant A2780DPP cells re-sensitised cells to both cisplatin and carboplatin. CONCLUSION: We show for the first time that FGF1 is differentially expressed in high-grade serous ovarian tumours, and that individuality in FGF1 expression significantly influences progression-free survival and response to platinum-based chemotherapy.

Fluorescence spectroscopy of an in vitro model of human cervical neoplasia identifies graded spectral shape changes with neoplastic phenotype and a differential effect of acetic acid.

BACKGROUND: The clinical utility of spectroscopic methods for the diagnosis of cervical cancer is limited by significant inter-patient variation in the spectroscopic properties of the cervix. Improved understanding of the contributions of the components of cervical tissue to the observed spectra would therefore be helpful in the development of spectroscopic approaches to the study of cervical disease in vivo. METHODS: In this study, we used organotypic epithelial raft culture as an in vitro model system to analyse the fluorescence properties of the surface squamous epithelium specifically. The spectrum of cervical dysplasia was modelled by producing rafts lined by primary human keratinocytes (PHKs) and the HaCaT, SiHa and CaSki human keratinocyte cell lines and fluorescence emission spectra were recorded at a wide range of excitation wavelengths. RESULTS: Statistically significant differences in spectral shape were identified between the different rafts at excitation wavelengths between 250nm and 310nm. A graded, differential effect of acetic acid on fluorescence intensity was also observed, consistent with the visible effects of acetic acid on clinical examination at colposcopy. CONCLUSION: These data suggest that the development of neoplastic changes in the squamous epithelium of the cervix are associated with alterations in its fluorescence properties and that the application of acetic acid has a demonstrable effect on these properties. Identification of these alterations may aid the discrimination of cervical lesions in vivo.

In-fiber common-path optical coherence tomography using a conical-tip fiber.

Common-path optical coherence tomography (CPOCT) is known to reduce group velocity dispersion and polarization mismatch between the reference and the sample arm as both arms share the same physical path. Existing implementations of CPOCT typically require one to incorporate an additional cover glass within the beam path of the sample arm to provide a reference signal. In this paper, we aim to further reduce this step by directly making use of the back-reflected signal, arising from a conical lens-tip fiber, as a reference signal. The conical lens, which is directly manufactured onto the optical fiber tip via a simple selective-chemical etching process, fulfils two functions acting as both the imaging lens and the self-aligning reference plane. We use a Fourier-domain OCT system to demonstrate the feasibility of this technique upon biological tissue. An in-fiber CPOCT technique may prove potentially useful in endoscopic OCT imaging.

Genomic integration of oncogenic HPV and gain of the human telomerase gene TERC at 3q26 are strongly associated events in the progression of uterine cervical dysplasia to invasive cancer.

Recently proposed events associated with the progression of cervical intraepithelial neoplasia (CIN) 2/3 to cervical carcinoma include integration of human papillomavirus (HPV) into the host genome, genomic instability, and an increase in chromosome 3q copy number. In particular, the gene coding for the RNA component of telomerase (TERC) at 3q26 has been implicated as a possible candidate gene. Since it is not known to date how these events are temporally related during cervical carcinogenesis, the aim of the present study was to assess the correlation between TERC gene copy number and the physical status of HPV during progression in cervical neoplasia. Solitary precursor lesions of the uterine cervix (CIN 2/3, n = 17), lesions associated with a micro-invasive carcinoma (CIN 3&mCA, n = 13), and advanced invasive carcinomas (invCA, n = 7) were analysed by fluorescence in situ hybridization (FISH) to determine the physical status of the virus and TERC gene copy number. The TERC gene was increasingly gained with progression of CIN 2/3 (3 of 17) through CIN 3&mCA (7 of 13) to invCA (5 of 7). In the lesions exhibiting gain of TERC, the virus was predominantly integrated. This was seen in eight of ten diploid lesions, indicating that these events can occur prior to aneuploidization and are strongly associated with the progression of CIN 3 to mCA and invCA (p < 0.001). With progression to carcinoma, a number of these lesions show polyploidization, resulting in aneuploidy and high TERC gene copy numbers. In conclusion, genomic integration of oncogenic HPV and gain of the human telomerase gene TERC appear to be important associated genetic events in the progression of uterine cervical dysplasia to invasive cancer.

Validation of the proposed International Society for Heart and Lung Transplantation grading system for primary graft dysfunction after lung transplantation.

BACKGROUND: A scoring system was recently proposed to grade the severity of primary graft dysfunction (PGD), a frequent early complication of lung transplantation. The purposes of this study are to: (1) validate the PGD grading system with respect to patient outcomes; and (2) compare the performance of criteria employing the arterial oxygenation to fraction of inspired oxygen (P/F) ratio to an alternative grading system employing the oxygenation index (OI). METHODS: We retrospectively reviewed the medical records of 402 patients having undergone lung transplantation at our institution from 1992 through 2004. The ISHLT PGD grading system was modified and grades were assigned up to 48 hours post-transplantation as follows: Grade 1 PGD, P/F > 300; Grade 2, P/F 200 to 300; and Grade 3, P/F < 200. A worst score T(0-48) was also assigned, which reflects the highest grade recorded between T0 and T48. RESULTS: The prevalence of severe PGD (P/F Grade 3) declined after transplant, from 25% at T0 to 15% at T48. Grouping patients by P/F grade at T48 demonstrated the clearest differentiation of 90-day death rates (Grade 1, 7%; Grade 2, 12%; Grade 3, 33%) (p = 0.0001). T48 OI grade also differentiates 90-day death rates. There was no difference in longer-term survival between patients with PGD Grades 1 and 2. OI grade at T0 qualitatively improved differential mortality between Grades 1 and 2; however, the differences did not reach statistical significance. Patients with a worst score T(0-48) of Grade 3 PGD did have significantly decreased long-term survival, as well as longer ICU and hospital stay, when compared with Grades 1 and 2 PGD. Significant risk factors for short- and long-term mortality in our multivariate model were P/F Grade 3 [worst score T(0-48) as well as T0 grade], single-lung transplant, use of cardiopulmonary bypass and high pre-operative mean pulmonary artery pressure. CONCLUSIONS: There is an increased risk of short- and long-term mortality and length of hospital stay associated with severe (Grade 3) PGD. The proposed ISHLT grading system can rapidly identify patients with poor outcomes who may benefit from early, aggressive treatment. Refinement of the scoring system may further improve patient risk stratification.

Villoglandular adenocarcinoma of the cervix: clarity is needed on the histological definition for this difficult diagnosis.

BACKGROUND: Villoglandular adenocarcinoma (VGA) of the cervix is reported as a variant of a cervical adenocarcinoma with a good prognosis. CASES: We present two cases histologically reported as a villoglandular adenocarcinoma of the cervix that have recurred and progressed rapidly since initial treatment. External histopathological review suggested both had a prominent villoglandular pattern but with an associated underlying well-differentiated adenocarcinoma. CONCLUSION: The diagnosis of VGA is difficult. Current literature is not entirely consistent in the presented definition, and further clarity is needed. Because of the rarity of VGA and the difficulty but importance of the diagnosis, we would feel that a central review of all cases of VGA is warranted. This would assist in diagnosis and also in obtaining accurate follow-up data.

Dual beam fibre trap for Raman micro-spectroscopy of single cells.

Raman spectroscopy permits acquisition of molecular signatures from both cellular and sub-cellular samples. When combined with optical trapping we may interrogate an isolated cell reducing extraneous signals from the local environment. To date, experimental configurations have employed combinations of the single beam optical tweezers trap and Raman spectroscopy, using either the same beam or separate beams for Raman interrogation and trapping. A key problem in optical tweezers is the ability to hold and manoeuvre large cells. In this paper, we use a dual beam fibre trap to hold and manoeuvre cells combined with an orthogonally placed objective to record Raman spectra. The dual beam trap, due to its divergent light fields, offers an as yet unexploited ability to hold and move large cellular objects with reduced prospects of photodamage. We additionally show how this system permits us to move large primary human keratinocytes (approximately 30 microns in diameter), such that we may record Raman spectra from local parts of a trapped cell with ease. Finally, we develop a rudimentary microfluidic system used to generate a flow of cells. Using our dual beam trap, combined with this flow system, we hold and acquire Raman spectra from individual cells chosen from a sample of HL60 human promyelocytic leukemia cells.

Effect of preoperative pulmonary artery pressure on early survival after lung transplantation for idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is the second largest indication for lung transplantation worldwide. Average 90-day mortality rates for this procedure are 22%. It is unclear what factors predispose patients with IPF to this increased early posttransplant mortality. Pulmonary hypertension may increase the risk of development of early posttransplant complications through several mechanisms. We examined the effect of secondary pulmonary hypertension on 90-day mortality after lung transplantation for IPF. METHODS: An International Society for Heart and Lung Transplant Registry cohort study of 830 patients with IPF transplanted from January 1995 to June 2002 was undertaken. Risk factors were assessed individually and adjusted for confounding by a multivariable logistic regression model. RESULTS: In the univariate analysis, pulmonary hypertension and bilateral-lung transplantation were significant risk factors for increased 90-day mortality. Multivariate analysis confirmed that mean pulmonary artery pressure and bilateral procedure remain independent risk factors after adjustment for potential confounders. Recipient age, ischemia time, cytomegalovirus status mismatch, and donor age were not independent risk factors for early mortality. CONCLUSIONS: Bilateral-lung transplantation carries a greater risk of early mortality than single-lung transplantation for IPF. Increasing pulmonary artery pressure is a risk factor for death after single-lung transplantation in IPF. Mean pulmonary artery pressure should be included in the overall risk assessment of patients with IPF evaluated for lung transplantation.

The pathology and management of endocervical glandular neoplasia.

The incidence of cervical glandular intraepithelial neoplasia and adenocarcinoma is rising, and our limited knowledge about these lesions presents the gynecologist with a management dilemma. Recently, pathologists have paid increasing attention to the diagnosis and pathogenesis of adenocarcinoma of the cervix. Although there is no uniformity in the management of these lesions, nonradical surgery appears to give satisfactory results especially in young women who want to preserve their fertility. This review focuses on the issues surrounding the histologic diagnosis of endocervical glandular abnormalities, including their classification, and discusses the management of cervical preinvasive glandular disease, including follow-up after treatment.

Upregulation of heat shock protein 27 in metaplastic and neoplastic lesions of the endocervix.

Heat shock proteins (hsps) are molecular chaperones that are known to play a pivotal role in regulating intracellular homeostasis. hsp27 may have diagnostic and prognostic values for different gynecological malignancies. A cross-sectional analytical study was conducted at the Department of Pathology, The University of Liverpool, Liverpool, UK. Included in the study were 80 cervical glandular lesions of various histologic types, representing tuboendometrial metaplasia/endometriosis (n = 19), cervical glandular intraepithelial neoplasia (n = 33), and invasive adenocarcinoma (n = 28). Paraffin-embedded sections were stained using a commercial mouse monoclonal anti-hsp27 antibody with prior pressure-cooking for antigen retrieval. Sections of 11 normal cervices were used as controls. The median percentage of cells expressing hsp27 in each group was calculated. Normal cervical glands showed minimal expression of hsp27 (median: 10%, interquartile ranges [IQ]: 5-15). Expression was significantly more widespread in tuboendometrial metaplasia/endometriosis (median: 35%, IQ: 15-80), cervical glandular intraepithelial neoplasia (median: 60%, IQ: 32-80), and invasive adenocarcinoma (median: 40%, IQ: 25-80) when compared with normal endocervix (P = 0.007, < 0.001, and 0.001, respectively). However, no significant difference in hsp27 protein expression was found between cervical glandular intraepithelial neoplasia and invasive adenocarcinoma. In invasive adenocarcinoma, hsp27 showed no correlation with tumor grade, lymph node involvement, and lymphovascular space invasion. Our data highlight early dysregulation of hsp27 expression in both metaplastic and neoplastic lesions of the cervix.

A retrospective clinical audit of cervical smears reported as 'glandular neoplasia'.

The aims of this study were to review the diagnostic pathway of women with smears reported as 'glandular neoplasia' and to outline the management, colposcopy findings, treatment and final histological diagnosis in these women. The design was a retrospective review. A total of 114 women were identified over a 5-year period from the cytology database at the Royal Liverpool University Hospital Cytology Department, whose hospital case notes were available for review. Methods included a review of the case notes for the demographic details, indication for smear, colposcopic findings, investigation and/or treatment procedures, histology, final diagnosis and current disease status. Of 114 smears reported as 'glandular neoplasia', 67 were reported as consistent with cervical glandular intra-epithelial neoplasia (CGIN), six with endocervical adenocarcinoma, 36 with endometrial adenocarcinoma and five with other glandular neoplastic abnormalities. The average age was 46.5 years. 79 (69.3%) smears were routine call/recall and 36 (30.7%) women were symptomatic. The positive predictive value (PPV) for a significant histological abnormality in the CGIN smear group was 80.6% (23.9% invasive carcinomas, 43.3% CGIN and 13.4% CIN) and the PPV of an 'endometrial adenocarcinoma' smear was 86.1%. Smears indicating glandular neoplasia are associated with a high probability of clinically significant lesions, the PPV of a CGIN smear being over 80%. Immediate referral for colposcopy and assessment by an experienced colposcopist is recommended.

Medium-term results of extracorporeal membrane oxygenation for severe acute lung injury after lung transplantation.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) has been used successfully for early, severe reperfusion injury after lung transplantation. The purposes of this study are to: (1) document the medium-term survival of patients treated with ECMO; and (2) assess the extent of recovery of their pulmonary function. METHODS: We retrospectively reviewed charts of 172 patients having lung transplants at our institution from 1997 through 2002. The group included 16 patients (9% of total; 10 bilateral, 5 single, 1 living lobar) treated with ECMO for primary allograft failure after single or bilateral single-lung transplantation. Survival and bronchiolitis obliterans syndrome (BOS)-free survival rates were calculated. Pulmonary function was assessed at 2 months, 1 year and 2 years post-transplant. RESULTS: Median hospital stay was 48 days for the ECMO group and 16 days for the overall group (p < 0.05). The 90-day survival was 60% in the ECMO group, and 90% in the overall group. The 2-year survival was 46% in the ECMO group, and 69% in the overall group. Mean forced expiratory volume in 1 second (FEV(1)) in the ECMO group at 1 year was 59 +/- 13% of predicted, and at 2 years 60 +/- 15% of predicted; it was not significantly different for the overall group. CONCLUSIONS: Patients treated with ECMO for primary allograft failure after lung transplantation showed acceptable medium-term survival and pulmonary function.

Induction of tetrasomy by human papillomavirus type 16 E7 protein is independent of pRb binding and disruption of differentiation.

We have demonstrated previously that high-risk human papillomaviruses (HPVs) induce tetrasomy in low-grade squamous intraepithelial lesions of the cervix. In this study we show that the E6 and E7 genes of high-risk HPV-16, but not those of low-risk HPV-6, are independently able to induce tetrasomy when constitutively expressed in proliferating monolayer cultures of primary human keratinocytes. Of seven HPV-16 E7 mutants analysed (H2P, Delta6-10, Delta21-24, C24G, S31G/S32G, A50S and S71I), five were severely impaired in their ability to induce tetrasomy in monolayer and raft culture. Only mutant C24G induced tetrasomy to levels comparable with wild-type E7 in monolayer and raft culture. This mutant shows strongly reduced binding to the retinoblastoma gene product pRb. The casein kinase II phosphorylation defective mutant S31G/S32G induced tetrasomy to levels comparable with wild-type E7 in raft culture, but not in monolayer culture, and induction of tetrasomy did not correlate with raft morphology. These results indicate that pRb protein binding is not required for HPV-16 E7 associated tetrasomy and that tetrasomy is not directly related to the ability of this protein to disrupt keratinocyte differentiation.

Use of the nested reverse transcription-polymerase chain reaction for the detection of human papillomavirus 16 E6 transcriptional activity in cervical cancer: a technical perspective.

AIM: The aim of this study was to evaluate HPV 16 E6 expression using nested RT-PCR in cervical tumour tissue and compare this technique with standard RT-PCR in a group of patients using injectable contraceptive steroids. PATIENTS AND METHODS: Tumour DNA was analysed for the presence and type of HPV by polymerase chain reaction (PCR) from 120 cervical cancer samples. Ribonucleic acid (RNA) was extracted from cervical tissue samples and cell-lines. Reverse transcription was carried out on all samples using reverse transcriptase enzyme to form single-stranded cDNA. The GAPDH (glyceraldehyde-3-phosphate dehydrogenase) housekeeping gene was used. RESULTS: The majority of patients had squamous cell carcinoma. Of 120 cervical tissue samples, there were 111 samples with confirmed HPV 16 infection. RNA was extracted in only 86 samples. Of these, 23 samples contained genomic DNA. Of the remaining 63 patients, there were 53 patients who had expression of HPV-type 16. E6 full-length gene expression. In total there were 25 patients (40%) with expression of the HPV 16 E6*I gene and 30 patients with expression of the E6*II gene. The nested PCR method using S1/S2 primers detected 54 patients with the E6*I & E6*II transcripts in comparison to classical PCR which detected only 31 such transcripts. CONCLUSION: Nested RT-PCR is the method of choice to determine the role of different E6/E7 splice products in HPV-associated carcinogenesis.

The interaction between steroid hormones, human papillomavirus type 16, E6 oncogene expression, and cervical cancer.

Various risk factors have been implicated in the causation of cervical cancer including human papillomavirus (HPV), the early genes (E6 and E7 ) of which encode the main transforming proteins. Studies have suggested that steroid hormones may enhance the expression of these genes leading to loss of p53 gene-mediated cell apoptosis. A total of 120 cervical tissue samples were obtained from patients with proven cervical cancer. Patients who used depo-medroxyprogesterone acetate steroid contraception were recruited as part of the steroid arm. Only HPV DNA type 16 samples were used for the study. Controls included three cell lines (CaSki, SiHa, & C33A) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as an internal housekeeping gene. Of 120 patients, there were 111 patients with HPV type 16 identified. Of this number, RNA was present in 63 samples. There were 30 women (30/63) who used steroid contraception. In relation to patients who used contraception, HPV 16 E6 gene expression was present in 79% (n = 23) and 88% (n = 30) of steroid users compared to nonusers, respectively. In total there were 25 patients (40%) with expression of the HPV 16 E6*I gene and 30 patients with expression of the E6*II gene. There were 57% of steroid users (n = 17) who had expression of the E6*I/E6*II gene, compared to 52% (n = 17) of nonusers (P = 0.800). From a molecular level, this study does not confirm the role of injectable progesterones in cervical carcinogenesis.

CD10 and calretinin staining of endocervical glandular lesions, endocervical stroma and endometrioid adenocarcinomas of the uterine corpus: CD10 positivity is characteristic of, but not specific for, mesonephric lesions and is not specific for endometrial stroma.

AIMS: In the female genital tract CD10 has been used to assist in the evaluation of mesenchymal tumours of the uterus and in determining whether endometrial stroma is present. CD10 positivity has also been shown in cervical mesonephric remnants and this antibody has been suggested as a useful immunohistochemical marker of mesonephric lesions in the female genital tract. Calretinin has also been shown to be positive in mesonephric lesions. In this study the specificity of these two antibodies in evaluating cervical and uterine glandular lesions and the value of CD10 in determining whether stroma is endometriotic or not were investigated. METHODS AND RESULTS: Cases of cervical tubo-endometrial metaplasia (TEM) (n = 11), microglandular hyperplasia (MGH) (n = 10), endometriosis (n = 8), mesonephric remnants/hyperplasia (n = 12), endocervical adenocarcinoma, usual type (n = 15), mucinous variant of minimal deviation adenocarcinoma (MDA) (n = 7) and mesonephric adenocarcinoma (n = 3) were stained with antibodies against CD10 and calretinin. Nine cases of endometrial adenocarcinoma of endometrioid type were also stained. In all the cervical cases normal endocervical glands were negative with both antibodies except for one case with strong positive luminal staining with CD10. All cases of TEM, MGH and endometriosis were negative with CD10 and calretinin except for focal staining with CD10 in one case each of MGH (cytoplasmic staining) and endometriosis (luminal staining). Most usual endocervical adenocarcinomas were negative with both antibodies, although one exhibited focal cytoplasmic staining with calretinin and five exhibited limited luminal positivity with CD10. All MDAs were negative with both antibodies. Ten of 12 mesonephric remnants/hyperplasia showed luminal positivity with CD10 and one exhibited cytoplasmic and nuclear staining with calretinin. Two of three mesonephric adenocarcinomas showed luminal positivity with CD10 and nuclear and cytoplasmic positivity with calretinin. Seven of nine endometrial adenocarcinomas were positive with CD10 (four cytoplasmic, two membranous and cytoplasmic, one luminal and cytoplasmic) and three with calretinin (two cytoplasmic, one nuclear and cytoplasmic). Positive staining of endometriotic stroma with CD10 was present in all endometriosis cases but normal cervical stroma was also strongly positive, especially around glands. Endometriotic stroma and cervical stroma were negative with calretinin. CONCLUSIONS: We conclude that most endocervical glandular lesions, including mesonephric remnants/ hyperplasia, are negative with calretinin. However, the focal nuclear and cytoplasmic positivity with calretinin in two of three mesonephric adenocarcinomas suggests that this may be a useful indicator of a mesonephric origin of a cervical adenocarcinoma. Most mesonephric remnants/hyperplasias exhibit luminal positivity with CD10, although this is not invariable and staining is usually focal. Positive luminal staining of a benign endocervical glandular lesion with CD10 may help confirm mesonephric remnants. Although positive staining with CD10 was found in two of three mesonephric adenocarcinomas, the observed immunoreactivity of several conventional cervical adenocarcinomas limits the diagnostic value of CD10 in confirming a mesonephric origin for an adenocarcinoma. Since all cervical MDAs were negative with CD10, positivity with this antibody may be of value in distinguishing mesonephric hyperplasia from MDA, although this distinction rarely necessitates immunohistochemistry. Most endometrial adenocarcinomas of endometrioid type stain with CD10 and thus positivity with this antibody is not specific for a mesonephric origin of an endometrial adenocarcinoma. Positivity of normal cervical stroma limits the value of CD10 staining in confirming a diagnosis of cervical endometriosis.

The role of steroid contraceptive hormones in the pathogenesis of invasive cervical cancer: a review.

Invasive cervical cancer remains a leading cause of morbidity and mortality, especially among women in the developing world where screening is either deficient or absent. Of all agents linked to the causation of this disease, high-risk human papillomavirus (HPV) appears to be the strongest factor. However, not all women with HPV develop cervical cancer. Steroid contraception has been postulated to be one mechanism whereby HPV exerts its tumorigenic effect on cervical tissue. Steroids are thought to bind to specific DNA sequences within transcriptional regulatory regions on the HPV DNA to either increase or suppress transcription of various genes. Although some earlier studies were reassuring as no increased incidence of cervical cancer was observed, subsequent research has shown a causative association, especially among long-term users. The role of steroids was further enhanced by the discovery of hormone receptors in cervical tissue. Some earlier studies of oral contraceptive steroids found no increased risk, even after controlling for other risk factors, including smoking and number of partners. However, prospective studies have shown a greater progression of dysplasia to carcinoma-in-situ with more than 6 years of oral steroid contraceptive use. Similar findings were also evident from other work, including the Royal College of General Practitioners Oral Contraception Study. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives showed a relative risk of 1.2 for invasive cancer in users of the long-acting progestational contraceptive, depo-medroxyprogesterone acetate. However, in users of more than 5 years duration, an estimate of 2.4 was reported. The upstream regulatory region (URR) of the HPV type 16 viral genome, mediates transcriptional control of the HPV genome and is thought to contain enhancer elements that are activated by steroid hormones. It has been shown that steroid hormones bind to specific glucorticoid-response elements within HPV-DNA. Experimental evidence has revealed that high-risk type HPV 16 are able to stimulate the development of vaginal and cervical squamous cell carcinomas in transgenic mice exposed to slow-release pellets of 17 beta-estradiol in the presence of human keratin-14 promoter. Squamous cell carcinomas developed in a multi-stage pathway only in transgenic mice and not in nontransgenic mice. The E6 oncoprotein of HPV 16 has been shown to bind to the p53 tumor suppressor gene and stimulate its degradation by a ubiquitin-dependent protease system. Steroid hormones are thought to increase the expression of the E6 and E7 HPV 16 oncogenes, which in turn bind to and degrade the p53 gene product, leading to apoptotic failure and carcinogenesis. However, the molecular basis of this remains to be proven.