[Show abstract][Hide abstract] ABSTRACT: Background and aims:
Although most ovarian cancers express estrogen (ER), progesterone (PR), and androgen (AR) receptors, they are currently not applied in clinical decision making. We explored the prognostic impact of sex steroid hormone receptor protein and mRNA expression on survival in epithelial ovarian cancer.
Immunohistochemical stainings for ERα, ERβ, PR, and AR were assessed in relation to survival in 118 serous and endometrioid ovarian cancers. Expression of the genes encoding the four receptors was studied in relation to prognosis in the molecular subtypes of ovarian cancer in an independent data set, hypothesizing that the expression levels and prognostic impact may differ between the subtypes.
Expression of PR or AR protein was associated with improved 5-year progression-free (P=.001 for both) and overall survival (P<.001 for both, log-rank test). ERα and ERβ did not provide prognostic information. Patients whose tumors coexpressed PR and AR had the most favorable prognosis, and this effect was retained in multivariable analyses. Analyses of the corresponding genes using an independent data set revealed differences among the molecular subtypes, but no clear relationship between high coexpression of PGR and AR and prognosis.
A favorable outcome was seen for patients whose tumors coexpressed PR and AR. Gene expression data suggested variable effects in the different molecular subtypes. These findings demonstrate a prognostic role for PR and AR in ovarian cancer and support that tumors should be stratified based on molecular as well as histological subtypes in future studies investigating the role of endocrine treatment in ovarian cancer.
[Show abstract][Hide abstract] ABSTRACT: In early-stage endometrial carcinoma, there is controversy regarding the prognostic value of the flow cytometric variables DNA ploidy (diploid vs. aneuploid) and S-phase fraction. In Sweden, the former is included in national guidelines despite poor scientific support and the latter is not used clinically. This study investigates the prognostic properties of these variables, together with classical histopathological variables, in multivariate analysis in a stringently stratified material.
A consecutive, population-based patient material restricted to FIGO 2009 stage I endometroid endometrial carcinoma (n=1140) was retrospectively collected from routinely reported data from medical records. Data on age, FIGO stage, degree of differentiation, S-phase fraction, DNA ploidy status, and adjuvant treatment were included in the study. Cumulative incidence curves with other causes of death as a competing risk were used for univariable analysis for the primary endpoint endometrial cancer death. Cox proportional hazards regression analysis was used for multivariate modeling of all endpoints, and for univariable analysis for the secondary endpoints overall survival and time to progression.
An S-phase fraction value of > 5.5% was associated with worse outcome (for endometrial cancer death: hazard ratio = 2.25; 95% CI 1.38-3.67; p = 0.001, adjusted) and DNA ploidy status was not, for all endpoints tested.
In FIGO stage I endometroid endometrial carcinoma, DNA ploidy status had no prognostic value, while S-phase fraction may be used to identify those with a higher risk of adverse clinical outcome. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Objective
Transcriptional profiling of epithelial ovarian cancer has revealed molecular subtypes correlating to biological and clinical features. We aimed to determine gene expression differences between malignant, benign and borderline serous ovarian tumors, and investigate similarities with the well-established intrinsic molecular subtypes of breast cancer.
Global gene expression profiling using Illumina's HT12 Bead Arrays was applied to 59 fresh-frozen serous ovarian malignant, benign and borderline tumors. Nearest centroid classification was performed applying previously published gene profiles for the ovarian and breast cancer subtypes. Correlations to gene expression modules representing key biological breast cancer features were also sought. Validation was performed using an independent, publicly available dataset.
5,944 genes were significantly differentially expressed between benign and malignant serous ovarian tumors, with cell cycle processes enriched in the malignant subgroup. Borderline tumors were split between the two clusters. Significant correlations between the malignant serous tumors and the highly aggressive ovarian cancer signatures, and the basal-like breast cancer subtype were found. The benign and borderline serous tumors together were significantly correlated to the normal-like breast cancer subtype and the ovarian cancer signature derived from borderline tumors. The borderline tumors in the study dataset, in addition, also correlated significantly to the luminal A breast cancer subtype. These findings remained when analyzed in an independent dataset, supporting links between the molecular subtypes of ovarian cancer and breast cancer beyond those recently acknowledged.
These data link the transcriptional profiles of serous ovarian cancer to the intrinsic molecular subtypes of breast cancer, in line with the shared clinical and molecular features between high-grade serous ovarian cancer and basal-like breast cancer, and suggest that biomarkers and targeted therapies may overlap between these tumor subsets. The link between benign and borderline ovarian cancer and luminal breast cancer may indicate endocrine responsiveness in a subset of ovarian cancers.
PLoS ONE 09/2014; 9(9):e107643. DOI:10.1371/journal.pone.0107643 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Ovarian cancer linked to Lynch syndrome represents a rare subset that typically presents at young age as early-stage tumors with an overrepresentation of endometrioid and clear cell histologies. We investigated the molecular profiles of Lynch syndrome-associated and sporadic ovarian cancer with the aim to identify key discriminators and central tumorigenic mechanisms in hereditary ovarian cancer. Global gene expression profiling using whole-genome c-DNA-mediated Annealing, Selection, extension, and Ligation was applied to 48 histopathologically matched Lynch syndrome-associated and sporadic ovarian cancers. Lynch syndrome-associated and sporadic ovarian cancers differed by 349 significantly deregulated genes, including PTPRH, BIRC3, SHH and TNFRSF6B. The genes involved were predominantly linked to cell growth, proliferation, and cell-to-cell signaling and interaction. When stratified for histologic subtype, hierarchical clustering confirmed distinct differences related to heredity in the endometrioid and serous subtypes. Furthermore, separate clustering was achieved in an independent, publically available data set. The distinct genetic signatures in Lynch syndrome-associated and sporadic ovarian cancers point to alternative preferred tumorigenic routes and suggest that genetic discriminators may be relevant for molecular diagnostics and targeted therapeutics.
Electronic supplementary material
The online version of this article (doi:10.1007/s10689-014-9728-1) contains supplementary material, which is available to authorized users.
Familial Cancer 05/2014; 13(4). DOI:10.1007/s10689-014-9728-1 · 1.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To assess the variation in ovarian carcinoma type diagnosis among gynaecological pathologists from Nordic countries, and whether a rationally designed panel of immunohistochemical markers could improve diagnostic reproducibility.
Eight pathologists from four countries (Sweden, Denmark, Norway and Finland) received an educational lecture on diagnosis of ovarian carcinoma type. All tumour-containing slides from 54 ovarian carcinoma cases were independently reviewed by the participants, who 1) determined type based purely on histology, 2) indicated whether they would apply immunohistochemistry in their routine practice, and 3) determined type after reviewing the staining results. The results for 6 markers (WT1, TP53, P16, HNF-1beta, ARID1A and PR) were determined for all 54 cases, by staining a tissue microarray. The median concordance with central review diagnosis was 86%, significantly improving to 90% with incorporation of immunostaining results (p=0.0002). The median interobserver agreement was 78%, significantly improving to 85% with incorporation of immunostaining results. (p=0.0002).
Use of the immunostaining results significantly improved both diagnostic accuracy and interobserver agreement. These results indicate that ovarian carcinoma type can be reliably diagnosed by pathologists from different countries, and further demonstrates that immunohistochemistry has an important role in improving diagnostic accuracy and agreement between pathologists. This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Objective:
To compare the diagnostic accuracy of ultrasound (US) and magnetic resonance imaging (MRI) in the preoperative assessment of early-stage cervical cancer using pathologic findings as the reference standard.
Patients and methods:
Prospective multi-center trial enrolling 209 consecutive women with early-stage cervical cancer (FIGO IA2-IIA) scheduled for surgery. The following parameters were assessed on US and MRI and compared to pathology: remaining tumor, size, tumor stromal invasion<2/3 (superficial) or ≥2/3 (deep), and parametrial invasion.
Complete data were available for 182 patients. The agreement between US and pathology was excellent for detecting tumors, correctly classifying bulky tumors (>4cm), and detecting deep stromal invasion (kappa values 0.84, 0.82, and 0.81 respectively); and good for classifying small tumors (<2cm) and detecting parametrial invasion (kappa values 0.78 and 0.75, respectively). The agreement between MRI and histology was good for classifying tumors as <2cm, or >4cm, and detecting deep stromal invasion (kappa values 0.71, 0.76, and 0.77, respectively). It was moderately accurate in tumor detection, and in assessing parametrial invasion (kappa values 0.52 and 0.45, respectively). The agreement between histology and US was significantly better in assessing residual tumor (p<0.001) and parametrial invasion (p<0.001) than the results obtained by MRI. Imaging methods were not significantly influenced by previous cone biopsy.
US and MRI are highly accurate for the preoperative assessment of women with early-stage cervical cancer, although US may be more accurate in detecting residual tumors and assessing parametrial invasion.
[Show abstract][Hide abstract] ABSTRACT: Prospective cohort studies about cutaneous melanoma (CM) risk are still few. Host factor- and UVR exposure data were collected prospectively by questionnaire in this population-based cohort study including 40,000 Swedish born women, aged 25-64 years at enrolment (1990). Risk for CM (Cox regression and Stepwise Cox regression [SCR], hazard ratios [HRs] with 95% Confidence Intervals [CI]) in relation to risk factors, age groups (older or younger than 40 years) and primary site, were analyzed. In 29,520 women with complete follow-up through 2007, 155 invasive and 60 in situ CM were recorded. High numbers of nevi (HR, 2.9; 95% CI, 1.7-5.0) and heredity (HR, 3.7; 95% CI, 2.0-6.8) were associated with risk for CM. SCR analysis added red hair as a risk factor. Sunbed use >10 times/year increased risk for women <40 years (HR, 2.5; 95% CI, 1.0-6.2) and a trend for risk associated with sunbathing vacations (HR, 1.4; 95% CI, 1.0-2.0) was shown for women >40 years. Trunk melanoma showed correlations with high numbers of nevi (HR, 3.0; 95% CI, 1.2-7.3) and heredity (HR, 3.2; 95% CI, 1.1-9.4). Head/neck site was correlated to sunbathing vacations (HR, 2.5; 95% CI, 1.2-5.3) and heredity (HR, 7.6; 95% CI, 1.8-31.8). Our study supports divergent etiologic pathways to CM, with high numbers of nevi correlated to increased risk for trunk CM. Furthermore, it confirms that high numbers of nevi, red hair and heredity for CM are the most important risk factors and frequent sunbed use might be a risk factor for younger women.
International Journal of Cancer 08/2012; 131(3):706-15. DOI:10.1002/ijc.26408 · 5.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: For primary melanomas, tumor thickness, mitotic rate, and ulceration are well-laid cornerstones of prognostication. However, a molecular exposition of melanoma aggressiveness is critically missing. We recently uncovered a four-class structure in metastatic melanoma, which predicts outcome and informs biology. This raises the possibility that a molecular structure exists even in the early stages of melanoma and that molecular determinants could underlie histophenotype and eventual patient outcome.
We subjected 223 archival primary melanomas to a horizontally integrated analysis of RNA expression, oncogenic mutations at 238 lesions, histomorphometry, and survival data.
Our previously described four-class structure that was elucidated in metastatic lesions was evident within the expression space of primary melanomas. Because these subclasses converged into two larger prognostic and phenotypic groups, we used the metastatic lesions to develop a binary subtype-based signature capable of distinguishing between "high" and "low" grade forms of the disease. The two-grade signature was subsequently applied to the primary melanomas. Compared with low-grade tumors, high-grade primary melanomas were significantly associated with increased tumor thickness, mitotic rate, ulceration (all P < 0.01), and poorer relapse-free (HR = 4.94; 95% CI, 2.84-8.59), and overall (HR = 3.66; 95% CI, 2.40-5.58) survival. High-grade melanomas exhibited elevated levels of proliferation and BRCA1/DNA damage signaling genes, whereas low-grade lesions harbored higher expression of immune genes. Importantly, the molecular-grade signature was validated in two external gene expression data sets.
We provide evidence for a molecular organization within melanomas, which is preserved across all stages of disease.
Clinical Cancer Research 06/2012; 18(15):4026-36. DOI:10.1158/1078-0432.CCR-12-0343 · 8.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To describe the gray-scale and vascular characteristics of endometrial cancer in relation to stage, grade and size using two-dimensional (2D)/three-dimensional (3D) transvaginal ultrasound.
This was a prospective multicenter study including 144 women with endometrial cancer undergoing transvaginal ultrasound before surgery. The sonographic characteristics assessed were echogenicity, endometrial/myometrial border, fibroids, vascular pattern, color score and tumor/uterus anteroposterior (AP) ratio. Histological assessment of tumor stage, grade, type and growth pattern was performed.
Hyperechoic or isoechoic tumors were more often seen in Stage IA cancer, whereas mixed or hypoechoic tumors were more often found in cancers of Stage IB or greater (P = 0.003). Hyperechogenicity was more common in Grade 1-2 tumors (i.e. well or moderately differentiated) (P = 0.02) and in tumors with a tumor/uterine AP ratio of < 50% (P = 0.002), whereas a non-hyperechoic appearance was more commonly found in Grade 3 tumors (i.e. poorly differentiated) and in tumors with a tumor/uterine AP ratio of ≥ 50%. Multiple global vessels were more often seen in tumors of Stage IB or greater than in Stage IA tumors (P = 0.02), in Grade 3 tumors than in Grade 1 and 2 tumors (P = 0.02) and in tumors with a tumor/uterine AP ratio of ≥ 50% (P < 0.001). A moderate/high color score was significantly more common in tumors of higher stage (P = 0.03) and larger size (P = 0.001).
The sonographic appearance of endometrial cancer is significantly associated with tumor stage, grade and size. More advanced tumors often have a mixed/hypoechoic echogenicity, a higher color score and multiple globally entering vessels, whereas less advanced tumors are more often hyperechoic and have no or a low color score.
Ultrasound in Obstetrics and Gynecology 11/2011; 38(5):586-93. DOI:10.1002/uog.9038 · 3.85 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The objective of this study was to describe the sonographic characteristics of squamous cell cancer (SCC) and adenocarcinoma (AC) of the cervix using transvaginal ultrasound.
Women with early stage cervical cancer undergoing transvaginal ultrasound examination before surgery were prospectively included. The sonographic characteristics were assessed with regard to tumor morphology, vascularization, size, extension and location. Histological assessment of tumor subtype, size, growth pattern, extension and location was performed. Both sonographic and histological assessments were carried out according to a standardized protocol.
Fifty-five women were recruited. Ten were excluded because no tumor was seen on ultrasound examination and five were excluded because radical surgery was aborted as a result of positive lymph nodes, detected using the sentinel node technique. Among the remaining 40 women, 20 had AC and 20 had SCC. At pathological examination, 34 women had tumors confined to the cervix, three had parametrial invasion and three had vaginal invasion. Hypoechogenicity was associated with SCC in 73% (11/15) of the women, while isoechogenicity indicated AC in 68% (13/19) of the women (P = 0.03). Mixed echogenicity (n = 4) showed a non-significant association with larger tumor volume (P = 0.23). Hyperechogenicity was found in two women, both of whom had the less malignant villoglandular AC. Color Doppler signals were found in all cases of AC and in 90% (18/20) of cases of SCC, compared with most normal cervical tissue in which virtually no detectable vascularization was found.
We found that the sonographic appearance of SCC and AC differs. This knowledge should be useful in the clinical evaluation of cervical tumors.
Ultrasound in Obstetrics and Gynecology 10/2010; 36(4):512-6. DOI:10.1002/uog.7638 · 3.85 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Disseminated melanoma is an aggressive disease with fatal outcome. Better understanding of the underlying biology is needed to find effective treatment. We applied microarray-based comparative genomic hybridization, gene expression and CpG island methylation analysis of primary tumors and multiple metastases from five melanoma patients with the aim of analyzing the molecular patterns of melanoma progression. Epigenetic profiling showed that the multiple metastases after a single primary melanoma share similar methylation patterns for many genes, although differences in methylation between the lesions were evident for several genes, example, PTEN, TFAP2C, and RARB. In addition, DNA copy number and global gene expression profiles of tumors from individual patients were highly similar, confirming common origin of metastases. Some of the identified genomic aberrations, for example, gain of chromosome 6p and loss of chromosomes 6q and 10, persisted during progression, indicating early changes highly important for melanoma development. Homozygous deletions at 3p26.1 and 6q23.2-q23.3 appeared in two consecutive metastases originating from the same primary tumor, respectively, in a mutually exclusive manner that provides evidence for two genetically different subclones. However, in another case, the similarity of the copy number aberrations in subsequent metastatic lesions suggests sequential metastatic development through the clonal evolution. These data are further corroborated by a switch in CDH1 and CDH2 expression between metastases from the same patient. In conclusion, our results provide evidence for different models of metastatic progression in melanoma.
Melanoma research 10/2010; 20(5):381-91. DOI:10.1097/CMR.0b013e32833b7c7c · 2.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Phenotypic characteristics were examined in melanoma-prone southern Swedish CDKN2A (p16-113insArg/p14ARF-128insSer) mutation families, in relation to the CDKN2A genotype, nevi, clinically atypical nevi (CAN) and melanoma. Individuals from eight melanoma-prone families, with index patients carrying the CDKN2A mutation, were offered skin examinations and genotyping (CDKN2A and MC1R). Ninety-three individuals above 18 years of age participated; 29 invasive melanomas in 16 patients were recorded, all in the 38 verified CDKN2A mutation carriers. Median age at diagnosis was 36 years. Several MC1R variants were observed. A significant correlation to CAN (P=0.01) and red hair colour (P=0.02) could be confirmed in melanoma patients. A positive mutation status (CDKN2A) was correlated to one or more CAN (P=0.007) but neither to blue eyes, red hair colour, heavy freckling nor high number of nevi. For mutation carriers, median total naevus count was 24 and interquartile range was 12-47 (mean 31); whereas for the whole cohort, median total naevus count was 12 and interquartile range was 5-25 (mean 22). No participant fulfilled the atypical mole syndrome phenotype criteria. Melanomas were diagnosed only in mutation carriers, and melanoma diagnosis was statistically correlated to the presence of one or more CAN and red hair colour, supporting the possible synergistic effect of a MC1R mutation on increased risk of melanoma in patients with a CDKN2A mutation. Family history, with verified tumour diagnoses, remains an important clinical tool for finding mutation carriers for referral to clinical geneticists and simultaneous presence of CAN in probable mutation carriers might strengthen this indication. The atypical mole syndrome phenotype was, however, not verified in the studied families and total naevus counts were low.
Melanoma research 08/2010; 20(4):266-72. DOI:10.1097/CMR.0b013e3283341339 · 2.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Databases with information on malignant tumors are of great value for epidemiologic studies. From the Regional South Swedish Tumour Registry, which is of documented high quality, 24 patients out of 8008 with reported melanoma diagnosis 1973-2003 were reported as having multiple (> or =3) primary, invasive cutaneous malignant melanomas (CMM). Of the 76 tumours identified in these patients, 7 (9%) were found not to be invasive melanomas. Additional cases could be put into question since the lesions could be interpreted as epidermotropic metastases, a diagnosis which can be difficult to establish reliably by microscopic examination. Among the 24 patients we could also identify 8 (10%) additional lesions representing invasive CMM, not included in the Tumour Registry database. Thorough information concerning an earlier melanoma diagnosis and its site of presentation is needed from the clinician and the pathologist for optimal assessment of the histology and the prognostication of the patient, as well as proper reporting to a tumour registry. Identifying multiple primary malignant melanomas is also of special importance for counselling patients belonging to families with hereditary disease. In this study it is shown that diagnosing and reporting multiple malignant melanomas can be problematic due to insufficient communication and to the rare and deceptive capability of cutaneous metastases to imitate primary tumours.