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Endometrial Carcinoma Final Presentation

Details presentation on Endometrial carcinoma

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ENDOMETRIAL CARCINOMA
Introduction •Endometrial cancer is the sixth most common cancer, with 4,17 000 new cases and 97,000 deaths in 2020. •Third cancer malignancy of female genital tract in India next to cervical and ovarian malignancy. •The Incidence of endometrial cancer is rising alongside the growing obesity. •Most women with endometrial cancer are diagnosed at an early stage and have highly curable disease, reflected in excellent 5-year survival rates. •Patients presenting with adverse clinicopathological characteristics have biologically aggressive endometrial cancer phenotypes with poor prognosis. •The diagnosis and management of endometrial cancer is challenging and complex, requires the expertise team who are familiar with all aspects of its evaluation and treatment. Sung H et al,.2021
Incidence •Most frequently diagnosed cancer in females with the greatest incidence in high-income countries. •In developing countries including India, endometrial cancer is seen in 1.8 per 100,000 population. The peak incidence of endometrial cancer is at 55-70 years, 20-25 % occur in Peri menopausal women Only 5% develop in women below the age of 45 years (when they are well differentiated and have good survival). Crosbie E, Morrison J. The emerging epidemic of endometrial cancer: Time to take action. Cochrane Database Syst Rev. 2014 Dec 22;12(ED000095
Risk factors • Most of the risk factors are related to prolonged, unopposed estrogen stimulation of endometrium. • Nulliparity • Late menopause • Obesity • Diabetes mellitus • Unopposed estrogen therapy • Tamoxifen therapy • Atypical endometrial hyperplasia • LYNCH II syndrome (Hereditary non polyposis colorectal cancer syndrome)-Mutation in mismatch repair gene MLH1,MSH2,MSH6 Novak 16th edition
Clinical features Symptoms •About 90% of women with endometrial carcinoma have abnormal perimenopausal or postmenopausal vaginal bleeding or discharge as their only presenting symptoms. •May be asymptomatic (7-10 %) cases. •Obesity and hypertension are associated constitutional factors. Signs • Pelvic examination- may reveal a normal looking healthy cervix and blood or purulent discharge from external os. • Bimanual examination-may reveal either atrophic, normal or enlarged uterus.
Etiology •Most of the endometrial cancer begins with uninterrupted endometrial proliferation, hormonally stimulated by endogenous or exogenous estrogen unopposed by progesterone or progestins, progressing through states of simple to complex forms of endometrial hyperplasia (EH). •Endometrial intraepithelial neoplasia (EIN), may transform to endometrioid carcinoma by-  Stromal and/or myometrial invasion, PTEN mutations, and KRAS2 mutations, Microsatellite instability caused by mismatch repair (MMR) defects. • The hormonal etiology of EIN and endometrial endometrioid carcinomas usually express estrogen and progesterone receptors (ER and PR) •Most endometrial endometrioid carcinomas are lower grade cancers Mahdy H et al.,2022
Histopathological Classification • Endometroid adenocarcinoma (about 80%) • Mucinous carcinoma (5%) • Papillary carcinoma • Clear cell carcinoma(<5%) • Squamous carcinoma(rare) • Undifferentiated carcinoma • Mixed carcinoma
Clinicopathological Types TYPE 1 TYPE 2 Risk factors Unopposed estrogen Age Age Perimenopause Postmenopause Endometrial hyperplasia present absent Tissue differentiation well Poor Myometrial invasion minimal deep Histology Endometrioid Serous, clear
TYPE 1 TYPE 2 Ploidy Polyploid Aneuploid HER2/neu Overexpression No Yes P-53 No Yes PTEN mutation Yes No Prognosis Favorable Not favorable Molecular Characters
FIGO Grading Staging of EC is based on the FIGO 2018 (International Federation of Gynecology and Obstetrics) staging system. GRADE 1- <5 % non-squamous or non-morular growth pattern GRADE 2- 6-50% non-squamous or non-morular growth pattern GRADE 3- >50% non-squamous or non-morular growth pattern
STAGE CHARACTERISTICS Stage I Stage IA Stage IB Tumor confined to corpus uteri No or less than half invasion Invasion equal to or more than half of the myometrium Stage II Tumor invade cervical stroma, but does not extend beyond uterus Stage III Stage III A Stage III B Stage III C 1 III C 2 III C Local and /or regional spread of tumor Tumor invades the serosa of corpus uteri and /or adnexae Vaginal and /or parametrial involvement Metastasis to pelvic and /or paraaortic lymph nodes Positive pelvic lymph node Positive para-aortic lymph nodes with or without positive pelvic lymph nodes Stage IV Stage IV A Stage IV B Tumor invades bladder and/or bowel mucosa, and/or distant metastasis Tumor invades bladder and/ or bowel mucosa Distant metastasis including intra-abdominal and/or inguinal lymph node metastasis
Prognostic Variables Poor prognostic factors Good Prognostic Factors Increasing Age Hormone receptor positive status Nonendometriod histological subtypes Grade 2 or 3 tumors Tumor size > 2cm Increasing depth of myometrial invasion Lymph –vascular space invasion Isthmus and cervical extension Positive peritoneal cytology in association with other poor prognostic factors Aneuploid and high proliferative index of tumor
Pathophysiology • Endometrial carcinomas begin as preinvasive intraepithelial lesions, progress to full-blown invasive cancers then penetrating ever more deeply into the myometrium to engage lymphatic capillaries that carry the malignancy to regional lymph nodes. • Tumorous involvement of the uterine cervix and stroma probably is mostly through lymphatic channels • Lymphatic capillaries also may carry endometrial carcinoma cells to the adnexa. Mahdy H et al.,2022
• Locally advancing endometrial cancers may penetrate fully through the myometrium and uterine serosa to involve surrounding peritoneum, supporting tissues and other pelvic organs. • Low-grade, type 1 endometrioid carcinomas tend to remain confined to the uterus and are characterized by rather a favorable prognosis. • High-grade, type 2 endometrioid and non-endometrioid carcinomas with TP53 mutations often metastasize via the lymphatic system or transit through the fallopian lumens to disseminate throughout the pelvis and abdomen, manifesting at advanced stage and portending grave prognoses.
Screening • Screening is not recommended in general population & not very cost effective • For high risk group (eg: Lynch syndrome) screening can be done with TVS & aspiration biopsy ( start at 35yrs , annually until hysterectomy)
DIAGNOSIS • Transvaginal sonography - Endometrial Thickness is assessed as per menopausal status. A cutoff value of 4 mm is taken foe menopausal women and 16 mm for premenopausal women. Any intracavitary growth irregular endometrium is also considered suspicious. • Endometrial biopsy - Office endometrial aspiration biopsy is the first step in diagnosing endometrial carcinoma with 90-98% accuracy. Hysteroscopy guided biopsy should be done in patients with focal endometrial growth or thickening, irregular endometrium, cervical stenosis, recurrent bleeding after negative endometrial biopsy or if specimen obtained is inadequate on EA. • Liquid based cytology (LBC) and endocervical curettage (ECC) may be performed to rule out coexisting cervical pathology. • MRI abdomen and pelvis is useful for detecting invasion into the myometrium and lymph node metastasis. • Chest Xray is added for lung metastasis.
Pre-treatment Evaluation • History & physical examination • TVS, a first effective test with high negative predictive value (ET< 5mm) • Office endometrial biopsy &/or hysteroscopy & D&C • Full biochemistry (KFT & LFT) & CBC • Chest X-ray • Contrast enhanced MRI ( for clinical staging or resectability of tumor) • Serum CA-125 (not always necessary)
Treatment
 Surgery is the mainstay of treatment for endometrial cancer and is decided as per the preoperative assessment of stage of disease based on clinical examination and imaging.  Stage IA GI or II, endometroid histology - Extrafascial Total Abdominal Hysterectomy with Bilateral Salpingo Oophorectomy (TAH with BSO).  Stage IB or IA GIII or non-endometroid histology or tumor >2 cm or stage II - TAH with BSO with pelvic and para-aortic lymphadenectomy  Serous histology- TAH BSO with omentectomy and peritoneal biopsy  Stage III - Debulking surgery- TAH with BSO with omentectomy, removal of abdominopelvic metastasis and enlarged nodes.  Stage IV: Neoadjuvant chemotherapy f/b cytoreductive Sx. Vaginal bleeding/pain from local tumor/leg edema: pelvic radiotherapy.
Choice of Surgical Approach •RCTs show superiority of minimally invasive approaches. Considerations during MIS hysterectomy include use of uterine manipulator to facilitate exposure and avoidance of power morcellator to remove uterus should. •MIS may be difficult in cases with excessive uterine size, contraindication to trendelenburg position. •Sentinel lymph node biopsy can safely replace complete lymadenectomy where needed.
Adjuvant Therapy Low risk Stage IA, grade 1-2, endometroid, LVSI negative Staging laparotomy+ extrafascial hysterectomy+ BSO± omentectomy± sampling of pelvic and para-aortic lymph nodes No adjuvant therapy Intermediate risk Stage IB, grade 1-2, endometroid, LVSI negative Surgery as above+ Adjuvant brachytherapy High Intermediate risk Stage IA, grade 3, endometroid (regardless of LVSI); Stage IA/IB, Grade 1-2 endometroid with LVSI positive Nodes negative on nodal biopsy: Adjuvant brachytherapy Nodal staging not done but HPE shows grade 3 tumor with no LVSI: Adjuvant brachytherapy Nodal staging not done but HPE shows grade 3 tumor with LVSI: Adjuvant external beam radiation therapy (EBRT) High risk Stage IB grade3, II, III endometroid with no residual disease, non-endometroid histology Stage I: Adjuvant EBRT± adjuvant chemotherapy if nodal staging not done Stage II: Grade 1-2, LVSI negative: Vaginal brachytherapy Grade3/LVSI positive/nodal staging not done: Adjuvant EBRT± Vaginal boost± adjuvant chemotherapy Stage IIIA,IIIB,IIIC1: Chemotherapy + EBRT IIIC2: Chemotherapy + extended field EBRT Advanced Stage III residual disease, IVA Systemic therapy (chemotherapy or hormonal) Metastatic IVB Systemic therapy (chemotherapy or hormonal)
Special Consideration • Diagnosis post hysterectomy: If grade3 lesion, deep myometrial invasion, or LVSI – remove adnexa or adjuvant EBRT • Medically in operable patient: Most common reason is morbid obesity or severe cardiopulmonary dysfunction. • Primary radiotherapy is an option Well differentiated lesion, contraindication to general anesthesia, unsuitable for radiotherapy can be treated with high dose progestins or intrauterine hormone releasing device. • Diagnosis in young women: Uncommon, can be confused with severe atypical hyperplasia. • Fertility preservation only recommended in grde1 tumor with no myometrial invasion. • Progestins ( megestrol acetate 160-320mg/d or MPA 400-600 mg/d) may be given with LNG-IUS should be continued as long as disease is static or in remission. Hysterectomy is recommended once child bearing is complete
Targeted Therapy Includes drugs targeting molecular pathways vital to cancer survival. The drugs available are- Temsirolimus, Deforolimus, & Everolimus (mTOR inhibitors), Bevacizumab (Angiogenesis inhibitor) as single agent Paclitaxel & Carboplatin, Geftinib (tyrosine kinase inhbitor), Palbciclib (CDK4/6 inhibitor) & Rastuzumab ( Her2/neu receptor)
Follow-Up: •ACOG recommends follow-up every 3-4 months for 2-3yrs, then every 6 m0nth, annually after 5 yrs •Routine chest X-ray & vaginal cytology not recommended •Pelvic examination & symptoms directed examination is recommended •High risk for other cancer so life style modification advocated Recurrence: •Main stay of treatment is surgery, radiation therapy or both •Non localised tumor are treated with progestin therapy: MPA 50-100mg TDS or megesterol acetate 80mg BD or TDS •Platinum based chemotherapy (cisplatin & doxorubicin or carboplatin & paclitaxel) is recommended for patient with advanced or recurrent disease not amenable to cure by surgery and/or radiotherapy.
Summary • 3rd m/c malignancy of female genital tract in India • Women can be counseled about the risk factors such as obesity and increased body mass index. • Encouraged for lifestyle modification and weight loss which can lead to reduced endogenous production of estrogen. • Patients should be managed thoroughly by history examination and investigation for early detection of precursor of Endometrial cancer • Type 1 tumor is more common & have better prognosis • Staging is mainly surgical • No routine screening is recommended • Surgery is the main stay of treatment & MIS are better approach then conventional laparotomy • SLN mapping can safely replace conventional lymphadenectomy
Endometrial Carcinoma Final Presentation