Abstract
The development of guidelines recommendations is one of the core activities of the European Society for Medical Oncology (ESMO) and European Society of Gynaecologial Oncology (ESGO), as part ...of the mission of both societies to improve the quality of care for patients with cancer across Europe. ESMO and ESGO jointly developed clinically relevant and evidence-based recommendations in several selected areas in order to improve the quality of care for women with ovarian cancer. The ESMO–ESGO consensus conference on ovarian cancer was held on 12–14 April 2018 in Milan, Italy, and comprised a multidisciplinary panel of 40 leading experts in the management of ovarian cancer. Before the conference, the expert panel worked on five clinically relevant questions regarding ovarian cancer relating to each of the following four areas: pathology and molecular biology, early-stage and borderline tumours, advanced stage disease and recurrent disease. Relevant scientific literature, as identified using a systematic search, was reviewed in advance. During the consensus conference, the panel developed recommendations for each specific question and a consensus was reached. The recommendations presented here are thus based on the best available evidence and expert agreement. This article presents the recommendations of this ESMO–ESGO consensus conference, together with a summary of evidence supporting each recommendation.
Ovarian carcinomas of epithelial type comprise a heterogeneous group of neoplasms, each with a different underlying pathogenesis and natural behaviour. Accurate classification of ovarian carcinomas ...is important since each type may be associated with a different behaviour, natural history and outcome. Precise classification is also critical to determine whether alternative therapeutic strategies are appropriate for different tumour types. Previous studies have shown significant interobserver variation in the typing of ovarian carcinomas. There are several areas where there are particular difficulties; these include the distinction between high-grade serous and endometrioid adenocarcinomas and the distinction between a true clear cell carcinoma and clear cell areas within other adenocarcinomas. This review details my approach to the typing of ovarian carcinomas. Morphological assessment, which remains the mainstay in diagnosis, can be supplemented by immunohistochemistry which, for example, is useful in the distinction between serous carcinomas (WT1 positive) and other carcinomas (generally WT1 negative). In recent years, there has been emerging new information regarding the major underlying molecular events in several types of ovarian carcinoma. This has resulted in the acceptance that there are two distinct types of ovarian serous carcinoma. These are termed low-grade and high-grade serous carcinoma, but represent two distinct tumour types rather than low-grade and high-grade variants of the same neoplasm. The integration of clinical, morphological and molecular data has resulted in a more precise classification of ovarian carcinomas and has resulted in the proposal for a broad dualistic pathway of ovarian epithelial carcinogenesis with, in general, low-grade type 1 tumours evolving from benign and borderline neoplasms through a well-defined adenoma-carcinoma sequence, and high-grade type 2 neoplasms arising from an, as yet, undefined precursor lesion.
This review discusses recent developments in vulvovaginal pathology. A variety of morphologically bland mesenchymal lesions occur at this site with considerable histological and immunohistochemical ...overlap. Aggressive angiomyxoma exhibits HMGA2 immunoreactivity in approximately 50% of cases, and this nuclear transcription factor is emerging as a useful and relatively specific marker for aggressive angiomyxoma, although occasional vulvovaginal smooth muscle neoplasms are positive. HMGA2 is useful in the diagnosis of aggressive angiomyxoma and its distinction from mimics, in the evaluation of resection margins and in the assessment of the presence or absence of residual disease in re‐excisions. Aggressive angiomyxoma is almost invariably positive with oestrogen and progesterone receptors, and there have been several reports of a dramatic reduction in size following gonadotropin releasing hormone agonist therapy. Recent series of the relatively newly described entities cellular angiofibroma and superficial myofibroblastoma of the lower female genital tract have expanded upon the morphological spectrum of these neoplasms. Recently described mesenchymal lesions at this site include massive oedema and prepubertal vulval fibroma. Gastrointestinal stromal tumours have been described as primary neoplasms in the vagina, and rectovaginal septum and extragastrointestinal stromal tumour should be added to the differential diagnosis of a vulvovaginal mesenchymal lesion. Many mesenchymal lesions in the vulvovaginal region exhibit immunoreactivity with both CD34 and desmin, a somewhat unusual immunophenotype in mesenchymal lesions at other sites. It is now established that there are two distinct types of vulval intraepithelial neoplasia (VIN), most commonly termed classic and differentiated VIN, the former associated with human papillomavirus (HPV) infection. There are two corresponding types of vulval squamous carcinoma with HPV‐associated and non‐HPV‐associated variants, the latter often arising in a vulval dystrophy and associated with p53 mutation. However, in some cases there is clinicopathological overlap between HPV‐associated and non‐HPV‐associated squamous carcinomas, and immunohistochemistry with p16 is more reliable than morphology in predicting the presence of HPV. There have been new developments regarding Paget’s disease of the vulva with the identification of markers that are useful in diagnosis and evidence that the neoplastic cells represent a proliferation of adnexal stem cells residing in sebaceous units. The newly described entity vaginal tubulo‐squamous polyp typically exhibits immunopositivity with prostatic markers, possibly indicating derivation from displaced periurethral Skene’s glands.
Quality assurance and research in colposcopy and cervical pathology require standardized terminologies and reporting. However, clinical and histologic definitions of the cervical transformation zone ...(TZ) and squamocolumnar junction (SCJ) vary considerably. We aimed to identify areas of agreement and areas where work is required to standardize the definitions of the TZ and the SCJ. We conducted a survey among the board members of the European Federation of Colposcopy member societies and members of the International Society of Gynecological Pathologists. Overall, 22 expert colposcopists and 34 gynecologic pathologists responded. There was broad agreement that the TZ is the area where squamous metaplasia has occurred. There was consensus that the original SCJ can appear colposcopically indistinct in cases of maturation of the metaplastic squamous epithelium but can be identified histologically by the presence of the so-called last cervical gland. It was agreed that the border between the metaplastic squamous epithelium and the columnar epithelium on the surface of the cervix is called the new SCJ. Areas where work is required include the questions as to whether the cervical crypts lined by columnar epithelium in the field of squamous metaplasia are an integral part of the TZ or not and whether the individual microscopic borders between the metaplastic squamous epithelium of glandular crypts and the residual columnar epithelium of glandular crypts should be considered as part of the new SCJ or not. This paper is a step in an attempt to standardize colposcopic and histologic definitions among colposcopists and pathologists.
Uterine carcinosarcomas (malignant mixed Mullerian tumours) are highly aggressive and have traditionally been regarded as a subtype of uterine sarcoma. However, in recent years convincing evidence ...has suggested that most, but not all, are monoclonal in origin rather than true collision tumours. Data confirm that the carcinomatous element is the “driving force” and that the sarcomatous component is derived from the carcinoma or from a stem cell that undergoes divergent differentiation. Thus, uterine carcinosarcomas are best regarded as metaplastic carcinomas, although the designation carcinosarcoma is likely to remain. Adjuvant treatment for uterine carcinosarcoma should probably be similar to that directed against aggressive high grade endometrial carcinomas rather than being sarcoma based. Importantly, a small proportion of uterine carcinosarcomas are true collision tumours and should be recognised as such because, in some instances, the prognosis may be better than for a similar stage carcinosarcoma.
In this review, we sought to address 2 important issues in the diagnosis of endometrial carcinoma: how to grade endometrial endometrioid carcinomas and how to incorporate the 4 genomic subcategories ...of endometrial carcinoma, as identified through The Cancer Genome Atlas, into clinical practice. The current International Federation of Gynecology and Obstetrics grading scheme provides prognostic information that can be used to guide the extent of surgery and use of adjuvant chemotherapy or radiation therapy. We recommend moving toward a binary scheme to grade endometrial endometrioid carcinomas by considering International Federation of Gynecology and Obstetrics defined grades 1 and 2 tumors as "low grade" and grade 3 tumors as "high grade." The current evidence base does not support the use of a 3-tiered grading system, although this is considered standard by International Federation of Gynecology and Obstetrics, the American College of Obstetricians and Gynecologists, and the College of American Pathologists. As for the 4 genomic subtypes of endometrial carcinoma (copy number low/p53 wild-type, copy number high/p53 abnormal, polymerase E mutant, and mismatch repair deficient), which only recently have been identified, there is accumulating evidence showing these categories can be reproducibly diagnosed and accurately assessed based on biopsy/curettage specimens as well as hysterectomy specimens. Furthermore, this subclassification system can be adapted for current clinical practice and is of prognostic significance independent of conventional variables used for risk assessment in patients with endometrial carcinoma (eg, stage). It is too soon to recommend the routine use of genomic classification in this setting; however, with further evidence, this system may become the basis for the subclassification of all endometrial carcinomas, supplanting (partially or completely) histotype, and grade. These recommendations were developed from the International Society of Gynecological Pathologists Endometrial Carcinoma project.
Aims : It has been suggested that WT‐1 is helpful in distinguishing a primary ovarian serous carcinoma (OSC) from a primary uterine serous carcinoma (USC). Since both neoplasms are often disseminated ...at diagnosis and since USC often spreads to the ovary and vice versa, it may be difficult to ascertain the primary site. This is important, since adjuvant therapies for OSC and USC may differ. WT‐1 staining patterns also differ between OSC and ovarian endometrioid carcinoma and so it is possible that WT‐1 may assist in the distinction of these two neoplasms, which is sometimes problematic, especially with poorly differentiated tumours. This study aims to document the value of WT‐1 in these settings. Cases of ovarian borderline serous tumour, primary peritoneal serous carcinoma (PPSC) and uterine endometrioid carcinoma were also studied.
Methods and results : Cases of OSC (n = 38), USC (n = 25) (in five of these cases there was also a component of endometrioid adenocarcinoma), ovarian endometrioid carcinoma (n = 13), uterine endometrioid carcinoma (n = 7), ovarian borderline serous tumour (n = 16) and PPSC (n = 6) were stained with WT‐1. Cases were scored on a scale of 0–3, depending on the percentage of positive cells. The intensity of staining was scored as weak, moderate or strong. There was positive nuclear stainingof 36 of 38 (94.7%) OSC with WT‐1. In most OSC (68.4%), >50% of cells stained positively and staining was usually strong. Five of 25 (20%) USC were positive with only two cases exhibiting staining of >50% of cells. All primary ovarian and uterine endometrioid carcinomas were negative. All PPSC were positive, usually with diffuse strong immunoreactivity. Fourteen of 16 borderline serous tumours exhibited positivity with WT‐1.
Conclusions : WT‐1 is useful in distinguishing OSC (characteristically diffuse strong nuclear positivity) from USC (characteristically negative). However, rarely OSC is negative and occasional cases of USC are positive. WT‐1 may also be helpful in differentiating poorly differentiated OSC from poorly differentiated ovarian endometrioid carcinoma.
Non-epithelial gonadal tumours largely comprise sex cord-stromal tumours (SCSTs) and germ cell tumours (GCTs). Specific somatic mutations in DICER1, a microRNA maturation pathway gene, have been ...identified in these tumours. We conducted a study that aimed to confirm, refine and extend the previous observations.
We used Sanger sequencing to sequence the RNase IIIa and IIIb domains of DICER1 in 154 gonadal tumours from 135 females and 19 males, as well as 43 extra-gonadal GCTs from 26 females and 17 males.
We identified heterozygous non-synonymous mutations in the RNase IIIb domain of DICER1 in 14/197 non-epithelial tumours (7.1%). Mutations were found in 9/28 SCSTs (32%), 5/118 gonadal GCTs (4.2%), 0/43 extra-gonadal GCTs and 0/8 miscellaneous tumours. The 14 mutations affected only five residues: E1705, D1709, E1788, D1810 and E1813. In all five patients where matched and constitutional DNA was available, the mutations were only somatic. There were no mutations found in the RNase IIIa domain.
More than half (8/15) of Sertoli-Leydig cell tumours (SLCTs) harbour DICER1 mutations in the RNase IIIb domain, while mutations are rarely found in GCTs. Genetic alterations in SLCTs may aid in classification and provide new approaches to therapy.
A major proportion of the workload in many histopathology laboratories is accounted for by endometrial biopsies, either curettage specimens or outpatient biopsy specimens. The increasing use of ...pipelle and other methods of biopsy not necessitating general anaesthesia has resulted in greater numbers of specimens with scant tissue, resulting in problems in assessing adequacy and in interpreting artefactual changes, some of which appear more common with outpatient biopsies. In this review, the criteria for adequacy and common artefacts in endometrial biopsies, as well as the interpretation of endometrial biopsies in general, are discussed, concentrating on areas that cause problems for pathologists. An adequate clinical history, including knowledge of the age, menstrual history and menopausal status, and information on the use of exogenous hormones and tamoxifen, is necessary for the pathologist to critically evaluate endometrial biopsies. Topics such as endometritis, endometrial polyps, changes that are induced by hormones and tamoxifen within the endometrium, endometrial metaplasias and hyperplasias, atypical polypoid adenomyoma, adenofibroma, adenosarcoma, histological types of endometrial carcinoma and grading of endometrial carcinomas are discussed with regard to endometrial biopsy specimens rather than hysterectomy specimens. The value of ancillary techniques, especially immunohistochemistry, is discussed where appropriate.
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