2023 Female Reproductive Tract Pathology 3 - Endometrial cancer.pptx

Pathology of the Female Reproductive Tract Tony Williams Consultant Histopathologist Brighton and Sussex University Hospitals 2023 Module 203 • Microscopic anatomy of the female reproductive tract and terminology of neoplasia + endometriosis • Cervical intra epithelial neoplasia (CIN) and carcinom...

Pathology of the Female Reproductive Tract Tony Williams Consultant Histopathologist Brighton and Sussex University Hospitals 2023 Module 203 • Microscopic anatomy of the female reproductive tract and terminology of neoplasia + endometriosis • Cervical intra epithelial neoplasia (CIN) and carcinoma • Endometrial carcinoma – Virtual microscopy: Cervix & cervical carcinoma – Virtual microscopy: Endo/myometrium & endometrial carcinoma • The testis and spermatogenesis – Semen analysis Endometrial carcinoma • Risk factors in endometrial cancer • Morphologic and molecular subtypes • Tumour grading and staging Learning outcomes To recognize that cancers arising at particular sites include subtypes defined by appearance or molecular profile and that these have discrete biological features; to understand the evaluation of parameters which predict behaviour. Age standardised incidence rates of endometrial cancer (UK 1993-2016) body of the uterus Over 80% of women with endometrial cancer present with post menopausal bleeding • What is endometrial cancer? • Is endometrial cancer one disease or several? • Can we recognize a preinvasive dysplastic lesion? • Risk factors for endometrial cancer • What factors inform behaviour of the disease? What is endometrial cancer? body of the uterus endometrium Composed of glands in a specialised stroma with a specialised blood supply Growth, maturation and regression of all three components is coordinated during each menstrual cycle endometrium Endometrial Cancer • The predominant endometrial cancer arises from the glands of the endometrium • Malignant neoplasm of glandular epithelium = adenocarcinoma Compare normal endometrium and adenocarcinoma Adenocarcinoma • Adenocarcinomas arising at different sites in the body have different risk factors, pathogenesis, appearances, genetic abnormalities, behaviour, prognosis and treatment. • Among adenocarcinomas arising at a single site there are multiple subtypes, initially divided by different appearances and increasingly supplemented by understanding molecular genetic pathogenesis. Subtypes of endometrial adenocarcinoma by morphology* • • • • • • Endometrioid Serous Clear cell Mixed (components of the previous 3) Undifferentiated / Dedifferentiated Carcinosarcomas *morphology means microscopic appearance Endometrioid Adenocarcinoma Named for the resemblance of malignant glands (left) to normal endometrial glands (right) Why the adenocarcinoma subtypes are named endometrioid, serous, clear cell Endometrioid cancers show differentiation that resembles endometrial glands Serous cancers were thought to resemble Fallopian tube epithelium Clear cell cancers have clear cytoplasm • Adenocarcinoma subtypes with similar appearance and the same names occur at other sites • eg there are clear cell carcinomas of the ovary and of the kidney • They are NOT the same disease • If a tumour has spread to other sites it can be very difficult to work out which is the site of origin and which is the site of metastasis • We know that there are different microscopic morphologic types of endometrial adenocarcinoma. • Does the appearance of the tumours reflect any biological difference in their cause and behaviour? Molecular Pathology • The cancer genome atlas (TCGA) published an integrated genomic classification of endometrial cancer in 4 groups • Based on integrated genomic, transcriptomic and proteomic characterisation of c370 endometrial carcinomas TCGA Endometrial Cancers 1. Ultramutated cancers (DNA pol epsilon mutations) 7% 2. Hypermutated cancers (defective mismatch repair and microsatelite instability) 28% 3. Endometrial cancers with low frequency of DNA copy number alterations 39% 4. Endometrial cancers with high frequency of DNA copy number alterations (p53 mutation) 26% Review: Dysplasia in the cervix • the precursor lesion • We detect and treat to invasive squamous CIN by – screening for HR HPV cell carcinoma is infection, Cervical Intra– looking for abnormal Epithelial Neoplasia (dyskaryotic) cells (CIN) – examining the cervix • the precursor lesion by colposcopy to adenocarcionoma – treating eg by LLETZ is Cervical Glandular Intra-Epithelial Neoplasia (CGIN) We know less about precursor lesions in the endometrium • It is assumed that the common (endometrioid) form of endometrial carcinoma has its origin in a lesion called atypical hyperplasia • This is supported by temporal, genetic and morphologic continuity with endometrioid endometrial adenocarcinoma Atypical hyperplasia in the endometrium Risk factors for endometrial adenocarcinoma • Most common invasive cancer of the female genital tract in UK • Fourth most common cancer in women in the UK (breast, lung, colorectum) • Lifetime risk of 1 in 46 • Usually arises in postmenopausal women • Peak incidence in the 55-65 y/o age group • Most common presenting feature is postmenopausal bleeding (c80%) Endometrial carcinoma by age Risk factors for endometrial cancer • Endogenous hormones and reproductive factors • Excess body weight • Diabetes mellitus and insulin • Exogenous hormones & modulators • Ethnicity • Familial (Lynch syndrome, Cowden’s syndrome) Endogenous hormones • Excess exposure to estrogen unopposed by progestogens • Overweight increases estrogen levels in post menopausal women • Overweight can disrupt ovulation and progestogen production in pre menopausal women • Polycystic ovarian disease • Some rare ovarian neoplasms can produce estrogens Reproduction • Pregnancy and parity reduce the risk of endometrial cancer • Mechanism includes the break from unopposed oestrogen during pregnancy and the removal of abnormal cells at delivery • Early menarche and late menopause increase risk Excess body weight • c 34 % endometrial cancers are linked to excess body weight • 2-3 times increased risk in overweight women • Increased risk begins with a moderately elevated BMI • Central adiposity (waist circumference and waist:hip ratios) may be more important than BMI Diabetes mellitus and insulin • Women with diabetes mellitus have a twofold increased risk of endometrial cancer • Hard to separate effect of insulin from excess body weight but a probably direct effect • Insulin and insulin-like growth factors may increase the effects of estrogen on the endometrium Exogenous hormones & modulators • Hormone replacement therapy - Unopposed estrogen (RR 6.0) • Tamoxifen (RR 2.0) Ethnicity • US studies show endometrial carcinoma is less common in African American women – 13 per 105 in African-American women – 23 per 105 in white • BUT this group has higher mortality (x4) • Many variables involved – Later stage at diagnosis – Unfavourable tumour type – Sociodemographic factors and treatment – Comorbidities Evaluation of parameters informing behaviour and treatment There are three tumour-specific parameters • Tumour type ✔ • Tumour grade • Tumour stage Grading of Neoplasms Grading reflects how much a tumour resembles its parent tissue Has to be done on tissue under a microscope Many use a three-point system Well differentiated Grade 1 Moderately differentiated Grade 2 Poorly differentiated Grade 3 Grading of endometrial carcinoma ormal endometrial epithelium matures to form glands denocarcinomas also form glands he fraction of the tumour forming glands is estimated as a percentage hen divided into three groups also taking nuclear features into account) umour grade affects prognosis Evaluation of parameters informing behaviour and treatment There are three tumour-specific parameters • Tumour type ✔ • Tumour grade ✔ • Tumour stage Staging systems For all neoplasms a T N M system exists T for tumour: local spread N for nodes: lymph node deposits M for metastasis: metastatic deposits For gynaecological tumours a different system called FIGO is usually used FIGO Staging of Endometrial Carcinoma • Stage 1: Confined to corpus • Stage 2: Involving cervix • Stage 3: Serosa/Adnexa/Vagina/Lymph Nodes • Stage 4: Bladder, Bowel, Distant Metastasis Key facts • Over 80% of women with endometrial cancer present with post menopausal bleeding • Most ‘endometrial cancers’ arise from endometrial glands and are adenocarcinomas • There are several different types of adenocarcinoma – the most common is called endometrioid because it resembles endometrial glands Key facts • Other types of endometrial adenocarcinoma can be recognized microscopically • These may have distinct molecular abnormalities and behaviour • Recognizing different types of adenocarcinoma benefits patients since it informs likely prognosis and treatment Key facts • Endometrioid cancer has a precursor lesion called atypical hyperplasia • Tumour grading estimates the degree to which the neoplasm matures and informs prognosis and treatment • Tumour staging demonstrates the extent to which a neoplasm has spread and informs prognosis and treatment Key facts • Incidence of endometrial cancer has been increasing in the last ten years • Risk factors include – – – – – – Endogenous hormones and reproductive factors Excess body weight Diabetes mellitus and insulin Exogenous hormones & modulators Ethnicity Familial (Lynch syndrome; Cowden’s syndrome) • Mortality from endometrial cancer has been falling however, except for women over the age of 85