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Definition
Carcinoma arising from the endometrial tissue
Epidemiology
25% of all gynaecological malignancy Second most common gynaecological cancer ( after cervical cancer in Malaysia) 75-80%occurs in postmenopausal women, with 5% under the age 40 years.
Risk Factor
Age- occurring predominantly in post menopausal women Family history or previous history of breast cancer Hereditary- Pre menopausal women can develop endometrial carcinoma if has history of hereditary non-polyposis colerectal cancer (HNPCC- which is auutosomol dominant)
Risk factor
Unopposed oestrogen:
exogenous :Unopposed oestrogen replacement therapy. Endogenous: prolonged exposure ( early menarche, late menopause, nulliparity, chronic anovulation e.g PCOS, obesity) elevated oestrogen as in ovarian tumor, secreting oestrogen (granulosa-thecal tumours)
Clinical Features
Postmenopausal bleeding Postmenopausal discharge , particularly blood stain discharge In premenopausal period:intermestrual bleeding, heavy periods Concomintant obesity, diabetes, hypertension.
Investigations
1. Transvaginal pelvic ultrasound scan determine endometrial thickness > 5mm in post menopausal women 2. Pipelle sampling sampling of the endometrium 3. Hysteroscopy directed biopsy accurate in cases of adenomatous hyperplasia early carcinoma
#able to locate other cause of bleeding and take biopsy #can provide info either cervical region is involved
Pipelle sampling
Hysteroscopy
Pathology
Commonest subtype of endometrial adenocarcinoma endometriod (resembles the normal proliferative endometrium) Adenocarcinoma with squamous differentiation Aggressive forms
Clear cell carcinoma microscopic appearance significant for clear cells or hobnail cells Papillary serous carcinoma accounts for 50% of all relapses in stage 1 tumor
Typical histologic pattern, specifically cribriform glandular appearance, of endometrioid adenocarcinoma of the endometrium. Increased nuclear atypia and mitotic figures are present
Staging
Surgical pathological stage the patient during surgery (FIGO Staging) Stage 1 carcinoma confined to the corpus Stage 2 carcinoma has involved the corpus and the cervix but has not extended outside the uterus Stage 3 extended outside the uterus but not outside the true pelvis Stage 4 extended outside the true pelvis or has obviously involved the mucosa of the bladder or rectum
Prognosis
Poor prognostics variable
Advanced surgical stage include grade of disease, myometrial invasion and lymph node involvement Older age Histologic type: clear cell and papillary serous Peritoneal cytology for cancer cells Increased tumor size
Management
(1)Surgery Stage l TAHBSO with peritoneal washing for cytology (+/- nodes sampling if suspicious) Stage ll Wertheim type radical hysterectomy with bilateral pelvic lymphadenectomy (+/- selective aortic dissection)
Stage lll Surgical debulking if operable. Otherwise radiotherapy first surgery if resectable. Stage lV Systemic chemotherapy / hormonal. Local irradiation beneficial for local control.
(2) Adjuvant radiotherapyIndications: - Nodes involvement (restaged lllc) - Involve cervix from pathological specimen (restaged ll) - Invasion >50% myometrium (stage lC) - Grade 3 (poorly differentiated)
(3) Hormones - Progestogen - For recurrent disease or infit for surgery/radiotherapy (4) Chemotherapy - Reserved for recurrent or metastatic disease - Carboplatin, cisplatin or docitaxol
Follow up
1. Physical examination every 3-6 months for 2 years 6 monthly / annually 2. Vaginal cytology 6 monthly for 2 years annually 3. CXR annually 4. CA125 (if initially elevated) at each visit
Recurrence
- 35% recur within 2 years most localized to vault or vagina
OVARIAN CANCER
INTRODUCTION
~23% of gynaecological cancers Responsible for almost half of death from cancer of female genital tract. 80% benign Age: rare in < 35 y/o. Incidence increase with age. Peak at 50-70y/o age group Most are epithelial origin.
Aetiology
1) Incessant Ovulation Theory Nulliparity Early menarchy
Late age of menopause Ovulation induction: Clomiphene use > 1 year increase risk by 10 fold. This suggest continous ovulation is important factor.
2) Family history (Familial Ovarian Cancer) Rare, 5-10% At least two 1st degree relatives with ovarian, breast or colorectal Ca Case usually diagnosed before age of 50 Defective gene: BRCA-1, BRCA-2 Risk of ovarian Ca (40%) in this families is less than risk of breast Ca (80%)
Reduced risk:
oral contraceptive use reduce the risk by fourfold Pregnancy lactation
CELL ORIGIN OF OVARIAN TUMOR SEX CORD METASTASIS ORIGIN SURFACE GERM CELLS
EPITHELIAL CELLS OVERALL FREQUENC Y 65-70% 15-20% MESENCHYM AL 5-10% TO OVARIES 5%
3-5%
2-3%
5%
0-25+
All age
Variable
1.Serous tumor 2.Mucinous tumor 3.Endometriod tumor 4.Clear cell tumor 5.Brenner tumor
Uterus, fallopian tube, contralateral ovary, pelvic peritoneum Others: breast, GIT(stomach,
SEROUS CARCINOMA
30% of all ovarian tumor is serous tumor (most common) 75% benign & borderline malignancy (2050 yrs) 25% malignant (later in life) Have solid & cystic (mainly) Well defferentiated tumors- hv papillary pattern w stromal invasion. +psammoma bodies
Mucinous Tumor
25% of ovarian neoplasm Middle adult life (50s) 80% (benign or borderline), 15%(malignant) Mucinous carcinoma: o Usually multilocular, thin-walled cyst with smooth external surface contained mucinous fluid o Amongst the largest tumor
Endometriod Carcinoma
Definition Ovarian tumors that are composed of epithelial cells with pattern of growth that is similar to common hyperplastic and neoplastic proliferations of the endometrium and can be divided in benign, borderline and malignant variants. 1025% of all primary ovarian carcinomas Coexistent endometriosis in 1020% of case
Cont
Loss of appetite Loss of weight Late weakness, cachexia, ascites metastasis signs and symptoms to regional lymph nodes, lungs, liver or GIT. PE in advanced disease : tense abdomen with ascites, immobile pelvic mass
Investigation
Serum CA 125 Pelvic US CT scan of pelvis
Prevention
Screening (CA 125 + US) not been shown to reliably detect early disease or decrease mortality Chemoprevention oral contraceptive use decreases the incidence of ovarian ca. Surgical prophylaxis women at high risk (BRCA 1 mutation carrier) may be offered bilateral salphingoophorectomy (BSO). However, patients remain at risk for primary peritoneal carcinoma. Genetic counseling (with family history)
MANAGEMENT
CHEMOTHER APY RADIOTHERA PY
SURGERY
Surgery
Remove encapsulated mass Stage Ia:unilateral salpingo-oophorectomy (if to reserve fertility) All stages(including Stage I if completed family): TAHBSO+omentectomy+ appendectomy
Chemotherapy
Adjuvant to surgery To prolong remission and survival, for palliation in advanced disease Stage Ic, II, III, IV 5-6 cycles at 3-4 weeks interval As single or combination therapy Eg:cisplatin, carboplatinum, Taxol, cyclophosphomide, adriamycin
Radiotherapy
Palliation only
Follow-up
Every 2-4 months for 2 year
Annually
Prognosis
5 years survival rate
=> Cervical cytology screening/ conventional cytology Screening method for cervical cancers Can detect pre-cancerous and cancerous cells in the cervix Efficacy depends on: 1. Quality of specimen ( adequate no. of cells, good fixation & well stained ) 2. Accuracy of cytologic interpretation
PREREQUISITE
Not menstruating ( best time done at middle of menstrual cycle or btw 10 & 20 days after onset of last menstruation) 2 days before, avoid douching or using vaginal medicines or spermicidal agentsmay wash away or hide abnormal cells
TECHNIQUE
1. Exposed the cervix adequately with a speculum 2. Using an Ayers wooden spatula ( or a small cytobrush in some settings), rotate 360 and take cells sample from Squamo-columnar junction ( transformation zone)- pinkish area around the region of external os. 3. Using a cotton swab, rotate 360 and scrape the endocervical canal for endocervical cells.
3. Cells spread on a glass slide 4. Rapidly fixed with alcohol 5. Send to the lab for examination under microscope.
TECHNIQUE
RESULT of smear
1. 2. 3. Negative smear does not mean its normal But abnormal smear = definite abnormality Types of smear results: Normal Inflammatory changes ( atrophic vaginitis/cervicitis/specific infections like Candida) Atypical squamous cells of uncertain significance ( ASCUS) Favours benign? Favours dysplasia? Low grade squamous intraepithelial lesion ( LGSIL) High grade squamous intraepithelial lesion ( HGSIL)
4. 5.
ASCUS depends. For favours benign, most physicians repeat pap smear in 3-4 months. For favours dysplasia, most will proceed with colposcopy.
LGSIL and HGSIL - proceed with colposcopy! If colposcopy shows abnormalities Cervical biopsy
Endocervical cells are also assessed. The glandular cells are similarly range like squamous cells: A) Atypical glandular cells of uncertain significance ( AGUS ) B) Endocervical adenocarcinoma in situ C) Endocervical carcinoma
Bethesda 2001 Pap Smear Classification System -The most recent proposed classification in reporting a pap smear-
Unsatisfactory for evaluation reason will be specified as to why it is unsatisfactory Negative for intraepithelial lesion or malignancy vaginal organisms may be mentioned such as trichomonas, yeast, shift in vaginal flora, actinomyces, herpes simplex other non-neoplastic findings such as reactive changes associated with inflammation, radiation, or intrauterine device, glandular cells status post hysterectomy, or atrophy other changes such as endometrial cells in a woman over age 40
Epithelial cell abnormality SQUAMOUS CELL Atypical squamous cells atypical squamous cell changes of undetermined significance ASCUS cannot exclude high grade intraepithelial lesion ASC-H LGSIL - low-grade squamous intraepithelial dysplasia encompassing: HPV/mild dysplasia/CIN1 HGSIL - high-grade squamous intraepithelial dysplasia encompassing: moderate or severe dysplasia, CIS/CIN-2,CIN3 -with features suspicious for invasion (if invasion suspected) Squamous cell carcinoma
GLANDULAR CELL Atypical - endocervical cells - endometrial cells - glandular cells Atypical - endocervical cells, favor neoplastic - glandular cells, favor neoplastic Endocervical adenocarcinoma in situ Adenocarcinoma - endocervical - endometrial - extrauterine - not otherwise specified
Other malignant neoplasms/cancer
aka cervical dyplasia presence of atypical cells within squamous epithelium atypical cell- dyskaryotic, large nuclei, frequent mitoses Grading - CIN I (mild dysplasia) - CIN II (moderate dysplasia) - CIN III (severe dysplasia)
If untreated - CIN II/III will develop cervical cancer over next 10 years - CIN I least malignant potential - CIN I can progress to CIN II/III but commonly regress spontaneously
Expression of E6/E7 oncogenes increases with the severity of the lesion. In cervical carcinoma the virus is integrated into the host cell chromosomes, this leads to further deregulation of E6/E7 expression (Agnes et al, 2008)
Principle of management
- Ex:i) ablation technique - destroying the abnormal epithelium (cold coagulation, cryotherapy, laser vapourazation) ii) excisional technique complete removal of abnormal epithelium Loop excision of transformation zone(LLETZ)
HPV vaccination
- 2 principle i) prevention vaccine direct against capsular antigen ii) therapeutic vaccine utilize nuclear antigen (E6, E7)
Prevention Vaccine
- 3 major prevention vaccines
HPV 16 Monovalent HPV Quadrivalent ( HPV 6, 11, 16, 18) HPV 16, 18 Bivalent
- are made up of virus-like particles (VLP) similar to HPV outer capsid protein - recombinant proteins produced in yeast and purified - administered in 3 doses
Therapeutic vaccination
- Patients affected with cervix cancer are immunocompromised and usually lack T-cellmediated immunoresponsiveness - downregulation of HLA class 1 molecules which may be peptide-mediated - because of HPV infection, E6 and E7 HPV genes are retained in cervical cancer cells, become a target of therapeutic vaccination
Peptide-based vaccines of cervical carcinoma use small peptides derived from cervical cancer cells that theoretically are recognized by antigen presenting cells, and stimulate the production of T cells and NK cells Specific dendritic cell stimulation is used to increase the immunity of the patient Vaccination with vectors encoding for HPV (E6, E7) may build an immune reaction against the cancer cells
- For example, a TA-HPV (therapeutic antigen-human papilloma
virus), developed by Xenova, has an antigenic property that activates HPV-specific cytotoxic T-cells to attack tumor cells containing the viral antigen
C. F. Verschraegen, L. A. Padilla-Paz & H. O. Smith : New Strategies In The Prevention And Treatment Of Cervical Cancer . The Internet Journal of Oncology. 2004 Volume 2 Number 1 Agnes Kathrine Lie, Gunnar Kristensen : Human Papillomavirus E6/E7 mRNA Testing as a Predictive Marker for Cervical Carcinoma. Expert Rev iew Molecular Diagnosis. 2008;8(4):405-415
CERVICAL CARCINOMA
Risk factors:
1. Early onset of sexual activity 2. Multiple sexual partners 3. Male partner with multiple sexual partners 4. Male partner who has had a partner with cervical carcinoma 5. HPV types 16 & 18 infection 6. Smoking 7. Use of COCP 8. Immunocompromise (body immune system does not recognize and destroyed HPV infected cells)
Types: squamous (90%), adenocarcinoma (10%) Pathophysiology: transformation zone @ squamocolumnar junction (metaplasia) dysplasia (CIN) carcinoma
Clinical presentation
Early/ microinvasive : asymptomatic Clinically detected disease: postcoital bleeding, intermenstrual bleeding, postmenopausal bleeding, dyspareunia, profuse, offensive, blood stained vaginal discharge Advanced stage disease: backache, leg pain/oedema, hematuria, bowel changes, malaise and weight loss
Investigations
Chest X-ray Urea & Electrolyte Liver function test CT/MRI IV Urogram/Cystoscopy/Sigmoidoscopy (when indicated)
Staging
Staging : Clinical + Radiological + Histological FIGO Staging
0 1
Stage 1
1a 1a1 1a2 1b 1b1 1b2 Microscopic cancer < 3mm depth, < 7mm width > 3mm but < 5mm depth, <7mm width Clinical lesions < 4cm size > 4cm size
Stage 2
Cancer extending beyond cervix and involving the vagina ( not the lower third)
11a
11b
Stage 3
Disease extending to pelvic side wall or to lower 1/3 of vagina 111a 111b Extension to lower 1/3 vagina not to pelvic side wall Extension to pelvic side wall +/hydronephrosis or non-functioning kidney
Stage 4
Disease has extended beyond true pelvis, or has involved mucosa of bladder or rectum 1Va Spread to adjacent organs
1Vb
Treatment
Stage 1a Stage 1b 11a Stage 11b 1V Knife cone biopsy Wertheims Hysterectomy Chemo-radiation therapy Chemo-radiotherapy
Surgery
Simple hysterectomy Wertheims hysterectomy ( cervix, uterus, parametrium, vagina cuff + pelvic node dissection)
Advantages Can conserve ovaries Better staging d/2 LN biopsy Avoid cx of radiotherapy esp vaginal stenosis Major abdominal surgery with associated risks of bleeding, infection, surrounding organ damage
Disadvantages
Radiotherapy/ Chemotherapy
For stages 1b-1Va S/e: acute gastrointestinal sx (proctitisdiarrhea), urinary sx (cystitis, hematuria),ovarian failure (radiation menopause), vaginal stenosis, fistula formation Chemotherapy (cisplatinum) + radiotherapy a/w longer ds free period and reduction in cancer progression in advanced ds
Prognosis
Overall 5 years survival
Stage 1A Stage 1B Stage 11A 98% 83% 70%
65% 42%
17%