Pocket ObGyn – Cervical Cancer / Uterine Cancer
See Abbreviations
Epidemiology (CA Cancer J Clin 2011;61:212)
- 2nd most common cancer in women worldwide
- Mean age at dx: 40–59 y; bimodal distribution peaks 35–39 y & 60–64 y
- 60% women w/ cervical cancer in developed countries were never screened or were not screened in past 5 y
Pathology (J Clin Pathol 1998;51:96)
- Squamous cell carcinoma: 80% of invasive cervical cancer
- AdenoCa: 20–25% of invasive cervical In 15%, lesion not visible (located w/i endocervical canal)
Mucinous adenoCa: Most common type (well differentiated)
Endometrioid carcinoma: 30% of cervical adenocarcinomas
Clear cell carcinoma: 4% of adenocarcinomas. DES exposure risk
- Adenosquamous carcinoma: Benign & malig glandular & squamous elements. More aggressive than
- Small cell carcinoma: Neuroendocrine Clinically aggressive; propensity for metastases; a/w HPV18; CD56 marker often positive
Etiology (J Pathol 1999;189(1):1)
- Risk factors (Int J Cancer 2007;120:885)
Lack of cervical cancer screening. Cigarette smoking: 2–3 fold risk in current & former smokers. Multi sexual partners (more than 6 partners significantly risk). HPV infxn.
H/o STIs. Early age of sexual activity. parity. Long-term combined OCP use (higher hormone levels make cells vulnerable to mut). Immunosuppression (esp HIV). Low socioeconomic status. DES exposure in utero. No known racial predilection but mortality rate for black > white.
Role of HPV
- HPV detected in 99% of cervical cancer
- HPV types 16, 18, 31, 33, & 45 ® high-risk Most common HPV 16 & 18.
E1–E7 (early oncoproteins in cervical cancer) expressed in HPV positive cases (E1 & E2 ® viral replication; E6 & E7 ® viral transformation). E6 & E7 form complexes w/ p53 & pRB (tumor suppressor genes); E6 inactivates p53; E7 inactivates Rb.
- CIN: Precursor Cervical cancer may take >10 y.
CIN 1: 57% spontaneously regress; 1% progress to carcinoma
CIN 2: 43% spontaneously regress; 5% progress to carcinoma
CIN 3: 30% spontaneously regress; 12% progress to carcinoma
Clinical Manifestations (J Clin Pathol 1998;51:96)
- Abn uterine bleeding or postcoital bleeding.Vaginal discharge (serosanguinous or yellow, foul smelling). Hematometra: Pelvic pain, difficulty w/ urination or Metastatic dz: Back pain, leg swelling (usually unilateral), & neuropathic pain.
- Exam: Firm barrel-shaped cervix; necrotic or friable lesion on cervix, poss extension into parametrium, vagina pelvic sidewall, & uterosacral ligament
Diagnostic Workup and Staging (see Table)
- Cervical Cytology Screening Guidelines (American Society for Colposcopy and Cervical Pathology (ASCCP), American Cancer Society (ACS), and S. Preventive Services Task Force (USPSTF)). See Ch. 1.
- Clinically Advanced imaging does not influence staging dx.
- Inspection, palpation, CXR, colposcopy, cystoscopy, proctoscopy, IVP, bx of exophytic cervical lesions; cervical conization
- Preoperative imaging may guide PET superior to CT & MRI for imaging of nodal dz: PET sens = 84%.
Treatment (see Table) (Gynecol Oncol 1980;9:90; Gynecol Oncol 1980;32:135)
- Surg: An option for stages IIA or less
- Chemo & RT: An option for stages IA2–IVB
- Recurrent cervical carcinoma: Evaluated w/ PET scan to exclude distant metastases
Localized recurrence after Surg ® RT or chemoradiation or Surg
Central recurrences after definitive Surg or adjuvant RT: Pelvic exenteration. Rpt RT considered in selected pts.
• Fertility sparing Surg:
Radical trachelectomy (pts w/ up to stage IB1; tumor size <2 cm) similar recurrence rates to radical hysterectomy in carefully selected pts.
Cervical conization in stage IA1 cancers
Posttreatment Surveillance
- Cancer detected w/i the 1st 6 mo after rx = persistent cancer
|
|||||||||||||
- F/u exam w/ pap q3mo ´ 2 y, then q6mo ´ 3 y, then annually
|
|||||||||||||
Cervical Carcinoma in Pregnancy (Best Pract Res Clin Obstet Gynaecol 2005;19:611)
- Stage IA1: Follow w/ colposcopy each trimester; surgical rx after vaginal deliv if invasion <3 mm & no Risk of hemorrhage at deliv . Or C-section + simple hysterectomy (stage IA1) if childbearing complete.
- Stage IA2 (Tumors >3–5-mm invasion): Can be followed until term; modified radical hysterectomy + pelvic lymphadenectomy at deliv or 6 w Vaginal deliv acceptable; C-section necessary for stage IB & above.
- Stages IB1–IIA dz: Delay of rx can impact survival; if dx made after 20 w, rx can be postponed® classical C-section; modified radical hysterectomy + pelvic/paraaortic RT is as effective as Surg.
- Invasive cancer: If at or near term, immediate deliv & definitive rx is At gestational age <20 w, termination of Preg & definitive rx is an option.
- Neoadjuvant chemo in Preg may be an option for stages IB2–IIB after appropriate counseling
Uterine Cancer
Epidemiology (Obstet Gynecol; 2005;104:65:413; J Natl Med Assoc 2006;98:1930; Cancer Control 2009;16:53)
- Most common gynecologic malig; 4th most common cancer in females
- 8th leading cause of cancer-related death among women in US
- Lifetime incid: 6%; White > Black > Hispanic > Asian. Mortality: Black > White.
- Median age at dx: 67 y (5% <40 y; 90% >50 y)
- Tumors confined to the uterus in 75% of cases
Endometrial Hyperplasia (EH) (Cancer 1985;56:403)
- Precursor lesion of endometrioid EC. From continuous estrogen stimulation & relative progestin Classification based on architecture (simple vs. complex) & cytologic features.
Simple EH (w/o atypia): gland proliferation; abundant stroma; no nuclear atypia Complex EH (w/o atypia): gland:stroma ratio; crowded irreg glands; no nuclear atypia Simple EH w/ atypia: gland:stroma ratio; simple appearing glands; glands lined
by atypical nuclei
Complex EH w/ atypia: Markedly gland:stroma ratio, severely crowded glands; nuclear atypia
- D&C req prior to rx to rule out occult 43% have EC diagnosed at the time of hysterectomy for hyperplasia (Cancer 2006;106:1012)
| Outcomes by type of endometrial hyperplasia | |||
|
Pathology |
Progression to
cancer (%) |
Regression (%) |
Persistence (%) |
| Simple EH, w/o atypia | 1 | 80 | 19 |
| Complex EH, w/o atypia | 3 | 80 | 17 |
| Simple EH w/ atypia | 8 | 69 | 23 |
| Complex EH w/ atypia | 29 | 57 | 14 |
| From Cancer. 1985;56:403; Hum Reprod. 1999;14:479. | |||
• Rx of EH w/o atypia:
Progestins (cyclic or continuous); eg, MDPA 10 mg/d for 12–14 d for 3–6 mo or local progestogen (LNG IUD) or OCPs. Postmenopausal women: MDPA; D&C for f/u
F/u: Rpt endometrial sampling if abn bleeding recurs
• Rx of EH w/ atypia:
Hysterectomy. For fertility preservation or poor surgical candidates: LNG IUD or continuous progestins: Megestrol acetate (40–60 mg 2–4 times/d for 6 mo) ® 94% regression rate. F/u: Endometrial bx or D&C q3mo for at least 1 y; if regression does not occur, progesterone dosage should be increased or hysterectomy considered.
Pathology (J Clin Oncol 2006;24:4783; Am J Surg Pathol 1994;18:687)
- Grading: Based degree of solid components, nuclear features, & architectural pattern
Grade 1: 5% or less nonsquamous or nonmorular solid growth pattern Grade 2: 6–50% nonsquamous or nonmorular solid growth pattern Grade 3: >50% nonsquamous or nonmorular solid growth pattern
• Epithelial tumors
Endometrioid adenoCa: 75–80% of EC; most common
UPSC: 10% of EC; closely resembles tumors of the ovary and fallopian tube. More than 50% of pts w/ stage I UPSC have extrauterine dz. Poor prog; high risk of recurrence. EIC: Poss precursor of UPSC.
Clear cell: 3–4% of EC. Poor prog; 20–65% 5-y survival
Others: Mucinous, secretory, squamous
- Mesenchymal tumors (sarcomas): 2–5% of EC
| Epithelial endometrial cancer types | |
| Type I (90%) | Type II (10%) |
| Low-grade nuclei | High-grade nuclei |
| Endometrioid histology; background of EH | Papillary serous & clear cell histology |
| Estrogen-associated | Atrophic background/polyps |
| Good prog, younger age | Worse prog, early metastasis |
| PTEN, K-ras, DNA mismatch repair mutations | P53 mutations |
| From Bokhman JV. Two pathogenetic types of endometrial carcinoma. Gynecol Oncol. 1983;15(1):10–17. | |
Etiology (Obstet Gynecol 2005;104:413)
- unopposed estrogen ® EH ® EC
- Microsatellite instability: Germ-line mut in DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2) ® Lynch II syn: 25–30% of all EC; 40–60% lifetime risk of EC
- Risk factors for EC: Prolonged unopposed estrogen (RR 10); chronic anovulation (eg, PCOS); BMI >30 (RR 2–5); diabetes & HTN (independent risk factors); Tamoxifen (RR 3–7); older age (RR 2–3); nulliparity (RR 3); early menarche, late menopause (1.5–3)
- Protective factors for EC: Smoking (RR 5); OCPs: ¯ EC risk by 40% up to 15 y after discontinuation; 12 y of use ¯ risk by 72%
Clinical Manifestations and Physical Exam (Obstet Gynecol 2005;106:413)
- Presentation: Abn uterine bleeding (10% postmenopausal bleeding is EC); chronic anovulation; abn pap smear 30–50%; asymptomatic 5%; leukorrhea 10%; hematometra due to cervical stenosis
- Ddx: Atropic vaginitis, fibroids, endometrial polyps, cervical carcinoma, CIN
Diagnostic Workup
- Office endometrial sampling: Least invasive approach
- Pelvic US (not diagnostic but may help triage pts): ET <5 mm = 99% NPV (NEJM
1997;227:1792)
- Fractional D&C: Office endometrial bx results correlate well w/ uterine curettage & ET up to 6 mm (Acta Obst Gynecol Scand 2001;80:959)
- Cervical conization if cervical involvement suspected to rule out primary cervical carcinoma
- CA125: Elevated in women w/ advanced stage dz & Not routinely performed.
- Chest radiograph, CT/MRI: If extrauterine dz suspected or CA125
| FIGO staging for endometrial cancer, 2009 | |||
| 2-y survival (%) | 5-y survival (%) | ||
| stage i
ia iB |
Tumor confined to uterus
No or <50% myometrial invasion ³50% myometrial invasion |
IA: 97 IB: 94–97 |
IA: 91 IB: 85–91 |
| stage ii | Tumor invades the cervical stroma | II: 85–93 | II: 74–83 |
| stage iii | Local &/or regional spread | ||
| iiia iiiB iiic
iiic1 iiic2 |
Invasion of uterine serosa ± adnexa Vaginal ± parametrial invasion Metastases to pelvic ± para-aortic
nodes Positive pelvic nodes Positive para-aortic nodes ± positive pelvic nodes |
IIIA: 80
IIIB: 62 IIIC: 75 |
IIIA: 66
IIIB: 50 IIIC: 57 |
| stage iv
iva ivB |
Tumor invades the bladder ± bowel
± distant metastases Invasion of bladder or bowel mucosa Distant metastases including intra- abdominal ± inguinal nodes |
IVA: 47 IVB: 37 |
IVA: 26 IVB: 20 |
| From Int J Gynecol Obstet. 2009;105:3; Int J Gynaecol Obstet. 2006;95:S105. | |||
Management (Obstet Gynecol 2005;106:413; Int J Gynaecol Obstet 2000;70:209)
- Surg depends on stage:
All stages: Hysterectomy & BSO (std rx)
All stages: LND (pelvic & para-aortic) & staging® allows assessment of the extent of dz to tailor adjuvant therapy.Therapeutic value in stage I dz is unk
(Obstet Gynecol 2012;120:383)
Stage II ® radical hysterectomy & lymphadenectomy + adjuvant therapy based on pathology
Stages III–IV ® optimal cytoreductive Surg Laparoscopic or robotic Surg not inferior to open Surg
• Radiation therapy (RT):
PORTEC trial ® pelvic radiation decreases local recurrence (4.2% vs. 13.7%) but overall survival unchanged
Vaginal brachytherapy ® for risk for recurrence or pts who have vaginal recurrence ® 60–75% survival
Whole pelvic (external beam) adjuvant radiation may prevent vaginal/local recurrence In poor surgical candidates, primary RT may be considered
Survival rate for pts treated w/ primary RT w/o Surg: 50% at 5 y
• Adjuvant chemo:
Rx of choice in pts w/ metastatic or recurrent endometrial cancer Combination chemo (carboplatin & paclitaxel) ® improved resp rate Serous & clear cell cancers: Carboplatin & paclitaxel = resp rate 60–70%
• Hormonal therapy:
Occ used in rx of stage I, grade 1 dz in women who wish to maintain fertility or in poor surgical candidates; resp rates 58–100%
In pts w/ recurrent dz, overall resp rate 25%
Regular histologic (eg, endometrial bx) monitoring necessary
Posttreatment Surveillance
- Exam q3–6mo ´ 2 y, then q6mo for 3 y, then If CA-125 elevated at the time of dx, it can be followed at each visit. Most recurrences diagnosed w/i the 1st 2 y; 10% recur >5 y after original dx. Routine chest radiographs or pap smears do NOT improve survival or outcome.
Uterine Sarcomas (Pathology 2007;39:55; Oncol 1993;50:105)
- Uncommon, arise from mesenchymal (stromal) component of uterus
Carcinosarcoma (previously called MMMT)
Present w/ postmenopausal bleeding; median age 65 y; h/o exposure to radiation; more common in AA women; lymphatic route of spread; potential for extrauterine metastasis
Adenosarcoma:
Variable in size. Locally invasive Endometrial stromal sarcoma
Abn uterine bleeding or asymptomatic uterine enlargement. Indolent course, may recur late. 70% are stage I or stage II at dx.
| FIGO staging for carcinosarcomas, 2009 | |
| stage i
ia iB |
Tumor confined to the uterus
Tumor 5 cm or less in greatest dimension Tumor more than 5 cm |
| stage ii
iia iiB |
Tumor extends beyond the uterus w/i the pelvis
Tumor invades adnexa Tumor involves other pelvic tissue |
| stage iii
iiia iiiB |
Tumor infiltrates abdominal tissues
1 site of involvement (abdominal) More than 1 site of involvement |
| stage iv
iva ivB |
Tumor invades bladder or rectum Distant metastasis |
| From Prat J. FIGO staging for uterine sarcomas. Int J Gynaecol Obstet. 2009;104(3):177–178. | |
Leiomyosarcoma
Median age at dx: 55 y. Menorrhagia & pelvic mass. Hematogenous route of spread. Primary sites of recurrence: Lung (41%), pelvis (13%).
• Rx of carcinosarcoma:
Surg – hysterectomy, BSO, removal of metastatic dz
LND preferred in carcinosarcomas, controversial in leiomyosarcomas & other sarcomas Adjuvant chemo & RT recommended