Improving the Diagnosis of Endometrial Hyperplasia Using Computerized Analysis and Immunohistochemical Biomarkers.

Endometrial hyperplasia (EH) is a precursor lesion to endometrial carcinoma (EC). Risks for EC include genetic, hormonal and metabolic factors most notably those associated with obesity: rates are rising and there is concern that cases in pre-menopausal women may remain undetected. Making an accurate distinction between benign and pre-malignant disease is both a challenge for the pathologist and important to the gynecologist who wants to deliver the most appropriate care to meet the needs of the patient. Premalignant change may be recognized by histological changes of endometrial hyperplasia (which may occur with or without atypia) and endometrial intraepithelial neoplasia (EIN). In this study we created a tissue resource of EH samples diagnosed between 2004 and 2009 (n = 125) and used this to address key questions: 1. Are the EIN/WHO2014 diagnostic criteria able to consistently identify premalignant endometrium? 2. Can computer aided image analysis inform identification of EIN? 3. Can we improve diagnosis by incorporating analysis of protein expression using immunohistochemistry. Our findings confirmed the inclusion of EIN in diagnostic criteria resulted in a better agreement between expert pathologists compared with the previous WHO94 criteria used for the original diagnosis of our sample set. A computer model based on assessment of stromal:epithelial ratio appeared most accurate in classification of areas of tissue without EIN. From an extensive panel of putative endometrial protein tissue biomarkers a score based on assessment of HAND2, PTEN, and PAX2 was able to identify four clusters one of which appeared to be more likely to be benign. In summary, our study has highlighted new opportunities to improve diagnosis of pre-malignant disease in endometrium and provide a platform for further research on this important topic.

Reducing the radicality of surgery for vulvar cancer: are smaller margins safer?

INTRODUCTION: Vulvar cancer accounts for ~4% of all gynecological malignancies and the majority of tumors (>90%) are squamous cell (keratinizing, ~60% and warty/basaloid, ~30%). Surgical excision forms the foundation of treatment, with resection margin status being the single most influential factor when predicting clinical outcome. There has been a paradigm shift concerning surgical approaches and radicality when managing vulvar cancer within recent times, largely owing to a desire to preserve vulvar structure and function without compromising oncological outcome. As such the safety of the size of resection margin has been called into question. In this narrative review we consider the current literature on the safety of resection margins for vulvar cancer. EVIDENCE ACQUISITION: PubMed, Medline and the Cochrane Database were searched for original peer-reviewed primary and review articles, from January 2005 to January 2020. The following search terms were used vulvar cancer surgery, vulvar squamous cell carcinoma, excision margins, adjuvant radiation. EVIDENCE SYNTHESIS: A pathological tumor margin of <8 mm has been widely considered to indicate "close" margins. This measurement after fixation of the tumor is considered comparable to a surgical resection margin of around 1cm, following an estimated 20% tissue shrinkage after formalin fixation and a 1-2cm clinical surgical margin in order to achieve the 8 mm final pathological margin. CONCLUSIONS: A surgical resection margin of 2-3mm does not appear to be associated with a higher rate of local recurrence than the widely used limit of 8 mm. As such the traditional practice of re-excision or adjuvant radiotherapy based on "close" surgical margins alone needs to be closely evaluated, since the attendant morbidity associated with these procedures may not be outweighed by oncological benefit.

New concepts for an old problem: the diagnosis of endometrial hyperplasia.

BACKGROUND: Endometrial hyperplasia (EH) is a uterine pathology representing a spectrum of morphological endometrial alterations. It is predominantly characterized by an increase in the endometrial gland-to-stroma ratio when compared to normal proliferative endometrium. The clinical significance of EH lies in the associated risk of progression to endometrioid endometrial cancer (EC) and 'atypical' forms of EH are regarded as premalignant lesions. Traditional histopathological classification systems for EH exhibit wide and varying degrees of diagnostic reproducibility and, as a consequence, standardized patient management can be challenging. OBJECTIVE AND RATIONALE: EC is the most common gynaecological malignancy in developed countries. The incidence of EC is rising, with alarming increases described in the 40-44-year-old age group. This review appraises the current EH classification systems used to stratify women at risk of malignant progression to EC. In addition, we summarize the evidence base regarding the use of immunohistochemical biomarkers for EH and discuss an emerging role for genomic analysis. SEARCH METHODS: PubMed, Medline and the Cochrane Database were searched for original peer-reviewed primary and review articles, from January 2000 to January 2016. The following search terms were used: 'endometrial hyperplasia', 'endometrial intraepithelial neoplasia', 'atypical hyperplasia', 'complex atypical hyperplasia', 'biomarker', 'immunohistochemistry', 'progression', 'genomic', 'classification' and 'stratification'. OUTCOMES: Recent changes to EH classification reflect our current understanding of the genesis of endometrioid ECs. The concept of endometrial intraepithelial neoplasia (EIN) as a mutationally activated, monoclonal pre-malignancy represents a fundamental shift from the previously held notion that unopposed oestrogenic stimulation causes ever-increasing hyperplastic proliferation, with accumulating cytological atypia that imperceptibly leads to the development of endometrioid EC. Our review highlights several key biomarker candidates that have been described as both diagnostic tools for EH and markers of progression to EC. We propose that, moving forwards, a 'panel' approach of combinations of the immunohistochemical biomarkers described in this review may be more informative since no single candidate can currently fill the entire role. WIDER IMPLICATIONS: EC has historically been considered a predominantly postmenopausal disease. Owing in part to the current unprecedented rates of obesity, we are starting to see signs of a shift towards a rising incidence of EC amongst pre- and peri-menopausal woman. This creates unique challenges both diagnostically and therapeutically. Furthering our understanding of the premalignant stages of EC development will allow us to pursue earlier diagnosis and facilitate appropriate stratification of women at risk of developing EC, permitting timely and appropriate therapeutic interventions.