ESGO-ESMO-ESP consensus conference recommendations on ovarian cancer: pathology and molecular biology and early, advanced and recurrent disease.

The European Society of Gynaecological Oncology, the European Society for Medical Oncology (ESMO) and the European Society of Pathology held a consensus conference (CC) on ovarian cancer on 15-16 June 2022 in Valencia, Spain. The CC panel included 44 experts in the management of ovarian cancer and pathology, an ESMO scientific advisor and a methodologist. The aim was to discuss new or contentious topics and develop recommendations to improve and harmonise the management of patients with ovarian cancer. Eighteen questions were identified for discussion under four main topics: (i) pathology and molecular biology, (ii) early-stage disease and pelvic mass in pregnancy, (iii) advanced stage (including older/frail patients) and (iv) recurrent disease. The panel was divided into four working groups (WGs) to each address questions relating to one of the four topics outlined above, based on their expertise. Relevant scientific literature was reviewed in advance. Recommendations were developed by the WGs and then presented to the entire panel for further discussion and amendment before voting. This manuscript focuses on the recommendation statements that reached a consensus, their voting results and a summary of evidence supporting each recommendation.

ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease†.

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.

ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease.

The development of guidelines 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 April 12-14, 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.

Defining the Cervical Transformation Zone and Squamocolumnar Junction: Can We Reach a Common Colposcopic and Histologic Definition?

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.

Gastric-type adenocarcinoma of the cervix in a patient with Lynch syndrome: A case report.

•Lynch syndrome (LS) is an uncommon, genetic disorder which predisposes affected individuals to colorectal, endometrial and ovarian malignancies.•We report a case of cervical gastric-type adenocarcinoma in a patient with LS.•Immunohistochemistry for mismatch repair proteins is a useful screening tool in tumours suspected to be associated with LS.

DICER1 hotspot mutations in non-epithelial gonadal tumours.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Bone marrow micrometastases in esophageal carcinoma: a 10-year follow-up study.

Detection of bone marrow micrometastases (BMMs) in patients with esophageal carcinoma may indicate a metastatic phenotype. We assessed if the presence of BMMs had adverse prognostic significance in a 10-year follow-up study. Patients undergoing surgery for esophageal cancer were prospectively recruited between February 1999 and August 2000. Bone marrow aspirates were obtained from the iliac crest of patients under general anesthesia at the time of surgery. Immunocytochemical analysis using anticytokeratin antibodies CAM 5.2 and AE1/AE3 was undertaken to determine the presence of BMMs. Union International Contre le Cancer staging was recorded for all patients. Patient follow-up was completed over a 10-year period through analysis of the Northern Ireland Cancer Registry. Forty-two patients (male = 35) were included, with a mean age of 67.2 years (range 39-83). BMMs were detected in 19 patients (45.2%). International Contre le Cancer tumor staging was stage I = 6, stage II = 10, stage III = 24, and stage IV = 2. BMMs were associated with lymphovascular invasion (P= 0.02) and advanced T stage (P= 0.02). Overall, 10-year survival was 21.4% (n= 9), with a median follow-up of 877.5 days (interquartile range 391.5-2546.3). There was no statistically significant difference between the survival of patients with or without BMMs (1451.4 vs. 1431.6 days, P= 0.99). Univariate analysis demonstrated a trend toward decreased survival for patients with positive lymph nodes (P= 0.07), an increased T stage (P= 0.06), and lymphovascular invasion (P= 0.07). Multivariate analysis demonstrated that none of the variables were significant predictors of mortality. Although the presence of BMMs correlates with recognized adverse tumor characteristics in patients with esophageal cancer, micrometastases detected in the bone marrow at time of surgery does not influence long-term survival.

Enterobious vermicularis (pinworm) infestation of the vulva: report of 2 cases of a pseudoneoplastic lesion mimicking squamous carcinoma.

Enterobious Vermicularis (pinworm) infestation outside the gastrointestinal tract is rare. We report 2 patients with vulval involvement, one of whom presented with a clinically suspicious, rapidly growing mass. The histology of both lesions showed similar features of epidermal proliferation in the form of hyperkeratosis, acanthosis, and papillomatosis; this pseudoepitheliomatous hyperplasia raised the possibility of a well-differentiated squamous carcinoma. There was associated inflammation in both cases, including large numbers of eosinophils in 1 case. On the surface or within the keratin layer, structures with the morphology of enterobious vermicularis eggs were identified. In reporting this unusual pseudoneoplastic phenomenon, we stress the necessity for the pathologist to consider and look for parasites in proliferative squamous lesions of the vulva, especially when there is an associated inflammatory infiltrate rich in eosinophils.

Diffusely infiltrating endometrial carcinomas with no stromal response: report of a series, including cases with cervical and ovarian involvement and emphasis on the potential for misdiagnosis.

Endometrial carcinomas, particularly of endometrioid type, can invade the myometrium or cervix without eliciting a stromal desmoplastic or inflammatory response and have been referred to as diffusely infiltrating endometrial carcinomas. This study describes a series of 14 endometrial carcinomas infiltrating as single "naked" glands without a stromal response. The neoplasms consisted of 12 endometrioid carcinomas, 1 mixed endometrioid and clear cell carcinoma, and 1 serous carcinoma. In all cases, there was myometrial invasion without stromal response. Seven cases exhibited cervical stromal involvement and in 2 there was involvement of both ovaries in a similar pattern. Several of the cases were seen in consultation and the pattern of infiltration raised a number of differential diagnoses, both benign and malignant, depending on the site of tumor involvement, including adenomyosis, adenomyoma, primary endocervical glandular lesions, cervical mesonephric remnants, endometriosis or tuboendometrioid metaplasia, and ovarian cortical inclusion cysts. Although this pattern of invasion has been reported previously, it continues to present diagnostic difficulties.

Combined actinomycotic and pseudoactinomycotic radiate granules in the female genital tract: description of a series of cases.

BACKGROUND: Both actinomycotic granules and pseudoactinomycotic radiate granules (PAMRAGs) occur in the female genital tract, most commonly in the endometrium. It is important to distinguish between these since the former may result in pelvic inflammatory disease and require antibiotic treatment while the latter is non-infectious and does not require specific treatment. AIMS: To investigate the coexistence of actinomyces-like organisms and PAMRAGs in the same granules, and describe the presence of PAMRAGs in the cervix and the vulva. METHODS: Six cases with actinomyces-like organisms and PAMRAGs in the same granules (four in the endometrium, one in a tubo-ovarian abscess, and one in both the endometrium and a tubo-ovarian abscess) are reported as well as seven examples of PAMRAGs in the cervix and one in a vulval abscess. RESULTS: The combined granules consisted of central basophilic Gram and silver positive filamentous organisms consistent with actinomyces surrounded by radiating eosinophilic club-like formations which were Gram and silver negative, the latter consistent with PAMRAGs. The PAMRAGs in the cervix and vulva consisted entirely of Gram and silver negative radiating eosinophilic club-like formations. CONCLUSIONS: Although actinomycotic granules and PAMRAGs are distinct lesions which should be distinguished for patient management, they may coexist in the same granules. It is likely in such cases that the PAMRAGs form around the bacterial colonies which act as a nidus. The presence of radiating eosinophilic club-like formations characteristic of PAMRAGs does not preclude the presence of actinomyces. Careful morphological examination plus supportive Gram and silver stains, if necessary, allows the diagnosis of these combined granules. PAMRAGs also occur in the cervix, where it is likely that they form secondary to encrustation of inspissated mucus, and in the vulva.

Clinical and immunohistochemical assessment of vulval intraepithelial neoplasia following photodynamic therapy using a novel bioadhesive patch-type system loaded with 5-aminolevulinic acid.

BACKGROUND: The work in this study appraised photodynamic treatment (PDT) as a treatment method for vulval intraepithelial neoplasia (VIN) using a novel bioadhesive patch to deliver aminolevulinic acid. An analysis of changes in expression of apoptotic and cell cycle proteins (p53, p21, Mdm2, Blc-2, Bax, Ki-67) in response to PDT was evaluated. METHODS: PDT was performed using non-laser light, either as a one or two-cycle treatment, with clinical and pathological assessment following after 6 weeks. Twenty-three patients with 25 VIN lesions underwent 49 cycles of PDT. Patches were designed to conform to uneven vulval skin and contained 38 mg cm(-2) aminolevulinic acid. Assessment was carried out at 6 weeks post-treatment. Patient-based treatment assessment, along with clinical and pathological changes, were monitored. Immunohistochemical staining was used to elucidate a possible biomolecular basis for induced cellular changes. RESULTS: Most patients (52%) reported a symptomatic response, with normal pathology restored in 38% of lesions. The patch was easy to apply and remove, causing minimal discomfort. Fluorescence inspection confirmed protoporphyrin accumulation. Pain during implementation of PDT was problematic, necessitating some form of local analgesia. Changes in expression of cell cycle and apoptotic-related proteins suggested involvement of apoptotic pathways. Down regulation of p21 and inverse changes in Bcl-2 and Bax were key findings. CONCLUSION: Treatment of VIN lesions using a novel bioadhesive patch induced changes in cell cycle and apoptotic proteins in response to PDT with possible utilisation of apoptotic pathways. The efficacy of PDT in treating VIN could be improved by a better understanding of these apoptotic mechanisms, the influence of factors, such as HPV status, and of the need for effective pain management.

Peritoneal stromal endometriosis: a detailed morphological analysis of a large series of cases of a common and under-recognised form of endometriosis.

AIMS: It is generally considered that an unequivocal histological diagnosis of endometriosis requires the presence of endometrioid-type glands and endometrioid-type stroma. However, small nodules or plaques of endometrioid-type stroma without glands have been noticed by the authors in repeated peritoneal biopsies performed for suspected endometriosis. These are often, but not always, accompanied by typical endometriosis with glands. This form of endometriosis has been previously referred to as stromal or micronodular stromal endometriosis. However, there has been little reference to this condition in the literature. METHODS: In this study, there was a review of a large series (n = 274) of peritoneal biopsies with a diagnosis of endometriosis with a view to ascertaining the frequency of stromal endometriosis. RESULTS: Stromal endometriosis, characterised histologically by small microscopic nodules or plaques of endometrioid-type stroma, sometimes with a whorled pattern and prominent vascularity and erythrocyte extravasation, was identified in 44.9% of the biopsies. In 6.6% of the biopsies, stromal endometriosis occurred without typical endometriosis. The foci of stromal endometriosis usually had a superficial location just beneath the mesothelial surface or protruding above this. Associated histological features present in some cases included reactive mesothelial proliferation, inflammation, giant cell or granuloma formation, haemosiderin pigment deposition, microcalcification and decidualisation and myxoid change. CONCLUSIONS: Stromal endometriosis, usually in the form of superficial nodules or plaques, is a relatively common form of endometriosis which typically occurs in association with typical endometriosis but occasionally on its own. Pathologists should be aware of the existence of this form of endometriosis, the morphological features of which may be subtle. The typical location, intimately associated with surface mesothelium, may suggest that stromal endometriosis derives from mesothelial or submesothelial cells via a metaplastic process.

Recent developments in vulvovaginal pathology.

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.

Iatrogenic lesions and artefacts in gynaecological pathology.

Increasingly in the field of medicine, new therapeutic modalities, both surgical and non-surgical, are being introduced. Some of these may significantly alter the pathological appearance of normal and neoplastic tissue and result in problems for the pathologist. In this review, iatrogenic pathology within the female genital tract is described, especially concentrating on the recent literature. Pathological artefacts within the female genital tract are also reviewed. Topics covered include mechanical displacement of normal and neoplastic elements into vascular or tissue spaces and thermal artefacts. Recently described pathological findings in neoplastic and non-neoplastic tissue secondary to hormonal, chemotherapeutic and other medications are discussed. Changes associated with non-surgical management of uterine leiomyomas are also described. It behoves the pathologist to be aware of these iatrogenic lesions and artefacts in order to prevent diagnostic errors.

Morules in endometrioid proliferations of the uterus and ovary consistently express the intestinal transcription factor CDX2.

AIMS: To undertake an immunohistochemical analysis of squamous elements in endometrioid proliferations of the uterus and ovary and to compare the immunophenotype of typical squamous elements and so-called squamous morules. METHODS AND RESULTS: Cases of uterine or ovarian endometrioid glandular lesions with squamous elements were stained with CDX2, beta-catenin, oestrogen receptor (ER), CD10, p63 and high-molecular-weight cytokeratin LP34. Thirteen cases had typical squamous elements and 18 cases morules. Morules typically exhibited diffuse nuclear CDX2 and beta-catenin immunoreactivity and were positive for CD10 and LP34. They were usually ER- and p63-. In contrast, typical squamous elements were usually positive for ER, CD10, p63 and LP34. They were usually CDX2- or focally positive and exhibited no nuclear immunoreactivity for beta-catenin. Ten endometrioid carcinomas not exhibiting squamous differentiation were immunoreactive for CDX2; one was focally positive. Electron microscopy in two ovarian endometrioid adenocarcinomas with extensive morular differentiation showed that the morules exhibited epithelial features, but no overt evidence of squamous differentiation. CONCLUSIONS: Typical squamous elements and morules have an overlapping but differing immunophenotype. Morules exhibit no firm immunohistochemical or ultrastructural evidence of squamous differentiation, although immature squamous differentiation cannot be excluded. Nuclear beta-catenin positivity is in keeping with the observation that endometrioid glandular lesions with morules are often associated with beta-catenin gene mutation. The explanation for diffuse nuclear positivity with the intestinal transcription factor CDX2 in morules is not clear, but may be a result of overexpression of nuclear beta-catenin. We suggest that the term morular metaplasia is used instead of squamous morules.

Displaced granulosa cells in the fallopian tube mimicking small cell carcinoma.

A case is reported where displaced non-neoplastic ovarian granulosa cells within the fallopian tube mimicked a small cell carcinoma. This peculiar phenomenon of displaced granulosa cells has been described previously in the ovary as a rare diagnostic pitfall which may be misinterpreted as metastatic carcinoma. This is believed to be the first documentation of its occurrence in the fallopian tube. Awareness of this rare phenomenon and immunostaining for markers of sex cord differentiation assist in diagnosis and in preventing a false positive diagnosis of malignancy.

Signet ring cells of stromal derivation in the uterine cervix secondary to cauterisation: report of a previously undescribed phenomenon.

AIMS: To describe the occurrence of signet ring cells of stromal origin within the uterine cervix. METHODS: Following the identification of prominent signet ring cells in the stroma in a large loop excision of transformation zone (LLETZ) biopsy of cervix (the index case), a series of LLETZ specimens was prospectively examined for this phenomenon. RESULTS: Focal collections of identical signet ring cells in 15% of the specimens were found. The cells were characterised by bland eccentric round or crescentic nuclei with a single cytoplasmic vacuole. The signet ring cells in the index case were vimentin positive, and negative with cytokeratins, epithelial membrane antigen and CD68, in keeping with a stromal derivation. CONCLUSIONS: In all cases, the signet ring cells were in areas of thermal damage and they are believed to be an artefact of cauterisation; identical features have been described in transurethral resection of prostate specimens and also attributed to thermal damage. When the change is extensive in the cervix, there is potential for misdiagnosis as a signet ring carcinoma. Other cervical lesions with signet ring cells are discussed.

Application of immunohistochemistry to gynecologic pathology.

CONTEXT: A large variety of tumors and lesions arise in the female genital tract. Although the majority of these can be correctly recognized on routine hematoxylin-eosin-stained slides, occasional cases present a diagnostic challenge. Immunohistochemical stains are extremely useful in resolving many of these problematic cases. As the knowledge in this area is constantly expanding, it is useful to have this updated information in a review form for easy access. OBJECTIVE: To present our current knowledge of immunohistochemistry of the lesions of the female genital tract in a readily accessible form. DATA SOURCES: The review is based on previously published articles on this topic. CONCLUSIONS: Immunohistochemical stains help in reaching a conclusive diagnosis in a variety of problematic lesions seen in gynecologic pathology. As in any other system, immunohistochemical findings need to be interpreted in light of the clinical history and morphologic findings.