Endometrial Carcinoma

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)

Endometrial hyperplasia with atypia Drugs: Tamoxifen

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

Transvaginal ultrasonography demonstrating an enlarged endometrial stripe

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

Five year survival

Stage 1 83 % Stage 2 - 71% Stage 3 39% Stage 4 27%

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

CLSSIFICATION OF OVARIAN TUMOR

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%

MALIGNANT 90% PROPORTIO N AGE GROUP 20+ TYPES

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

1.Teratoma 2.Dysgermin oma 3.Endoderma l sinus tumor 4.Choriocarci noma

1.Granulosastroma cell tumor 2.Sertolileydig cell tumor 3.gynandrobla stoma

Uterus, fallopian tube, contralateral ovary, pelvic peritoneum Others: breast, GIT(stomach,

PATHOLOGY OF THE EPITHELIAL TUMOR

Early stage of disease : well differentiated epithelial carcinoma No difference in survival in different epithelial cell types.

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

Clear Cell Carcinoma (mesonephroid)

Definition Epithelial tumors of the ovary in which most or all of the cells have clear cytoplasm; most are malignant with rare benign and borderline variants. (least common of malignant epithelial tumor of ovary)

Clinical features & clinical findings

Usually no symptoms in early ovarian cancer. Abdominal discomfort and early satiety are common non-specific complaints often elicited retrospectively. Pelvic mass or big enough to mimic abdominal mass that can cause urinary frequency.

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

CF for Sertoli-Leydig cell tumour (androblastoma)

Defeminization of women atrophy of breast, amenorrhea and sterility. May progress to: -virilisation (hirsutism) -male distribution of hair -hypertrophy of clitoris -voice changes

Investigation
Serum CA 125 Pelvic US CT scan of pelvis

FIGO STAGING FOR PRIMARY OVARIAN CA

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

Laparotomy and staging

Lower midline incision-allow adequate exploration
To confirm diagnosis To stage the malignancy Remove all tumor deposits

Peritoneal washing/ascitic fluid cytology

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

6 monthly for 3 years

Annually

Prognosis
5 years survival rate

Stage I Stage II Stage III Stage IV

78-90% 66-80% 30-50% 13%

PAP SMEAR ( Papanicolaou )

=> 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.

What is the next step?

Normal smear - smear again 1 year later if this is the 1st pap smear. Inflammatory changes- do a vaginal swab TRO infection. Pap smear repeat after 6 months.

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

WHEN TO DO PAP SMEAR

> 20 y/o or 3 years after being sexually active or which one comes first (continue at a regular basis even after 65 y/o) Screening intervals: Annually. If first 2 consecutive annual pap smear results are negative screening every 3 years are recommended.

Cervical Intraepithelial Carcinoma

 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)

Natural history of Cervical Intraepithelial Neoplasia

SIL- squamous intraepithelial lesion CIS- carcinoma in situ

(Verschraegen et al, 2004)

 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

Diagnosis & Assessment

Clinically : Lesion seen at time of vaginal examination Per rectal examination Biopsy of abnormal area confirming cancer Following colposcopy : Changes suggestive of cancer Examination under anaesthesia essential for staging

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

Carcinoma in situ, CIN Carcinoma confined to cervix

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

No obvious parametrial involvement

Obvious parametrial involvement

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

Spread to distant organs

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%

Stage 11B Stage 111

Stage 1V

65% 42%
17%