Cancer in Pregnancy

Jeffrey L. Stern, M.D.

Physician Reaction

• Ob/Gyn: Oh No! She has cancer!

• Med Onc: Oh No! She’s pregnant!

• Surgeon/Primary Care: Oh No! She’s pregnant and has cancer!

• Get a Gyn/Onc involved!

Incidence• 1/1000 – 1/1500 term pregnancies• Incidence increasing: delayed childbearing

Frequency by Cell Type Frequency in Reproductive Age Group

Breast Cancer 30%

Lymphoma 10%

Leukemia 23%

Melanoma 30%

Cervix 35%

Ovary 15%

Bone/soft tissue tumors 25%

Thyroid 50%

What’s Different About Pregnancy?

• Hormones• Metabolic Changes• Hemodynamics• Immunology• Increased vascularity• Age• Few cases – anecdotal experience• Inherent bias – breast, ovarian cancer

General Considerations

• Pregnancy does not have a proven negative effect on any cancer

• Maintaining pregnancy after diagnosis– Delay of treatment (assume delivery at 34th week)

• First trimester diagnosis: up to 28 week delay• Second trimester diagnosis: up to 22 week delay• Third trimester diagnosis: up to 10 week delay

General Considerations

• Surgery– Wait until 16-18 weeks for abdominal surgery:

Spontaneous Abortion: 40% 3%– Don’t remove corpus luteum if possible until

14th week (progesterone supp. 50mg BID)– Deliver at maturity (at around 34 weeks)– No proven teratogenic effects of anesthesia

General Considerations

• Chemotherapy– First trimester (organogenesis ends at 12th week)

• Increase incidence of anomalies and abortion; drug dependent i.e. antimetabolites (MTX)

• IUGR and preterm labor are common

– Second and Third trimester• Delay chemotherapy if possible until 16th week

– end of the rapid growth phase

• No increase in incidence of abortion• IUGR and preterm labor are common • Delay chemotherapy if possible until 16th week

– end of the rapid growth phase

General Considerations

– Chemotherapy and Breastfeeding• Generally not recommended

– Long-term effects of chemotherapy on children exposed in utero• Aviles, et.al. 43 cases with f/u for 3-19 yrs.

Normal: PhysicallyNeurologicallyIntelligencePsychologicallySexual DevelopmentHemotologicallyBone Marrow Cytogenics

General Considerations

• Radiation Exposure– Diagnostic Radiation

• Avoid “unnecessary” diagnostic pelvic x-rays

• Use MRI when possible• CXR/Mammogram – little risk

with shielding

– Therapeutic Radiation• High incidence of abortion and

anomalies

-Dose and trimester dependent

Dose to Fetus

KUB 200 millicentigray

B.E. 450-900

CXR 1

CT Scan 900

IVP 600

L/S Scan 275-725

Lung Scan 370

Pelvic X-ray

210

UGI Series 170-330

General Considerations

• Obstetrical Considerations– First trimester SONO: if dates?– Level 2 SONO at 20 weeks– Chromosome analysis

• Amnio: 15 weeks• CVS: Transcervical (except cervix ca)

or transabdominal at 10-12 weeks– Deliver when mature

• L/S ratio at 34 weeks• Betamethasone

Epidemiology of Genital HPV/SIL/Cancer in Pregnancy

• Up to 40% of reproductive age women have HPV• 2.0-6.5% cases of CIN/SIL occur in pregnant women• 13,500 cases of cervical cancer & 4,000 deaths/ year

in U.S.• 25% of women with cervical cancer are < 36 years old• 1-13 cases of cervical cancer for every 10,000

pregnancy• 1.9% of microinvasive cervical ca. occurs in pregnancy• Stage for stage – prognosis is not effected by

pregnancy

Screening for Cervical Cancer/SIL

• Symptoms of cancer similar to physiologic changes of pregnancy

• Often a delay in diagnosis (fear of biopsies)• Pap smear at registration and 8 weeks postpartum

– Ectocervical scrape– Endocervical swab / brush – risky– Reflex HPV typing

• Pap less accurate in pregnancy: – increased false negative rate

• Blood, inflammation• Failure to sample SCJ• Concern about bleeding• Difficult to see cervix: put CONDOM over speculum• Absence of endocervical cells

Absence of Endocervical Cells

Conventional PAP Liquid PAP

Non-pregnant 20% 10%

Pregnant 40% 20%

Post partum 30% 15%

Post menopause 70% 35%

Diagnosis of SIL and Cervical Cancer

• Careful palpation of cervix: no induration or enlargement• Biopsy all suspicious lesions: even if Pap/HPV are neg.• Abnormal Pap:

– ASCUS/LSIL and HPV negative – repeat post partum– ASCUS/LSIL and HPV positive: colposcopy– ASCH: Colposcopy- HSIL: Colposcopy

• Don’t defer biopsy because of fear of bleeding or preterm labor. First trimester easiest.

• Control bleeding with:– Pressure, Monsell’s solution (Ferric subsulfate), Silver nitrate

Management of Cervical SIL On Biopsy

• Satisfactory Colposcopy

– LSIL / HPV+/- :• Re-evaluate 6-8 weeks postpartum• 50% regress postpartum: delivery route seems

to matter

– HSIL / HPV+/- : • Follow up depends on trimester• 30% regress postpartum• Vaginal delivery OK

Management of Cervical SIL

• Cone biopsy in pregnancy– Indications

• Unsatisfactory colposcopy/ Pap: SCC• Adenocarcinoma in situ• Microinvasive SCC

– Perform at 16-18 weeks– Risks

• Abortion: 5%• Hermorrhage: immediate: 9%, delayed: 4%

– Technique

• Local wedge resection• Shallow cone• LEEP• Circumferential figure 8 sutures at cervical-vaginal junction• Vasopressin/ local anesthetic with epinephrine

Management of Cervical SIL

HSIL/ HPV positive: No Lesion Visible on Colposcopy– Reinspect: Vulva, Vagina, Anus and Cervix– Lugol’s: Vagina and Cervix– Review Cytology– Consider Random Biopsies: 6 and 12:00– Careful Follow-up: Pap and Colpo

Vulvar/ Vaginal Condylomata or SIL in Pregnancy

• Warts and SIL often enlarge rapidly in pregnancy• No treatment unless symptomatic• Often regresses dramatically postpartum• Treat if symptomatic or interferes with vaginal delivery -

disease on perineal body or posterior fourchette• Treatment options:

– Trichloroacetic Acid– Podophyllin– Aldara– 5-FU cream– Laser– Excision: scalpel; LEEP– Cryotherapy

Cervical Cancer in Pregnancy

• Work-up– MRI of pelvis/abdomen– Chest X-ray– Carcinoembryonic Antigen (CEA)– CBC, BUN, Creatine, LFT’s

• Advanced disease– Urine cytology/ cystoscopy– Stool for occult blood/ sigmoidoscopy

Cervical Cancer in Pregnancy: Treatment by Stage

• Stage IA1 - <3mm invasion; < 7mm wide – 1.2% positive nodes– Cone biopsy: no further treatment necessary – Vaginal delivery at term– Simple hysterectomy post-partum or Cesarian

hysterectomy at term

Cervical Cancer in Pregnancy: Treatment by Stage

• Stage IA2 (3-5mm invasion, no vascular inv.): – 6.3% positive nodes

• Stage IB – Disease confined to cervix• Stage IIA – vaginal extension

– Vaginal delivery: increased risk of hemorrhage and cervical laceration

– Depends on desire for pregnancy• First trimester: delay of up to 28 weeks – degree of risk

unknown• Radical hyst. and pelvic LND at diagnosis• “Radical” cone biopsy/ trachelectomy/ cerclage and

extraperitoneal pelvic and aortic LND at 16-18 weeks• C-Section and Radical hyst. and pelvic LND when mature

Cervical Cancer in Pregnancy: Treatment by Stage

• Stage IA2, IB, IIA– Second trimester: delay of up to 22 weeks

• Depends on desire for pregnancy– Can probably safely wait until maturity

– Third trimester: delay of up to 10 weeks• C-section, Radical hysterectomy and pelvic

Lymph node dissection at maturity

Cervical Cancer in Pregnancy: Treatment by Stage

• Stage IB (bulky) or Stages IIb-IV– First trimester – delay of up to 28 weeks

• Depends on desire for pregnancy– Unwanted

» Whole pelvic radiation therapy/ chemotherapy» If SAB occurs before XRT is finished – proceed with

cesium insertions (about 35 days)» Occasionally will need hysterotomy and pelvic LND if

no SAB and then cesium insertions; or a “small” radical hyst. & pelvic LND if small residual cervical disease

– Wanted» Consider chemotherapy until maturity at 34 weeks

Cervical Cancer in Pregnancy: Treatment by Stage

• Stage IB (bulky) or Stages IIb-IV– Second trimester – delay of up to 22 weeks

• Unwanted: pregnancy – Radiation therapy as above – Spontaneous abortion at 35 days

• Wanted: pregnancy – consider chemotherapy until maturity

– Third trimester – delay of up to 10 weeks• C-Section at maturity/ staging lap; transpose ovaries• Start radiation therapy 2 weeks postpartum• Consider chemotherapy until maturity

Juvenile Laryngeal HPV

• 3.5 million deliveries in U.S./year

• Prevalence of HPV: 10-40%

• Infected pregnant women: 350k - 1.5 million

• 120 cases annually

• Risk to infant (1:2,900 – 1:12,500)

• VAGINAL DELIVERY

Ovarian Masses in Pregancy

• Overall incidence– 1:500 pregnancies– Increased incidence secondary to sonography

• Incidence of true neoplasms– 1:1,000 pregancies

• Incidence of ovarian cancer– 1:10,000 – 1:25,000 pregancies

• Unexpected adnexal mass at C-Section– 1:700 pregnancies

Ovarian Masses in Pregnancy Frequency by Type

• Non-neoplastic – 33%– Corpus luteum cyst– Follicular cyst

• Neoplastic – Benign – 63%– Dermoid (36%)– Serous cystadenoma (17%)– Mucinous cystadenoma (8%)– Others (2%)

• Neoplastic – Malignant – 5%– Low malignant potential (3%)– Adenocarcinoma (1%)– Germ cell / Stromal tumor (1%)

Management of Ovarian Masses in Pregnancy

• Generalizations– Symptoms– Ultrasound/ MRI appearance– Size– Gestational age– Tumor markers

• B-HCG, AFP, CA-125 all increased in pregnancy• CA-125 should be normal after 1st trimester

– Fear of missing cancer or development of complications

• Corpus luteum resolves by 14th week• Ovarian cysts “benign” by Ultrasound or MRI, < 6 cm,

that do not change over time, do not require surgery• Cysts greater than 6-8 cm or inc. in size: “usually” operated on• Cysts which persist after 18th week are “usually” operated on

– Usually operate at 18 weeks to minimize fetal loss

Complications of Ovarian Masses in Pregnancy: 10% Total

• Severe pain: 25%• Obstruction of labor: 15% – C-Section• Torsion: 10% of cases

– Sudden pain, Nausea & Vomiting etc.– Most common at:

• 8-16 week – rapid uterine growth (60%)• Postpartum – involution (40%)

• Hemorrhage: 10% of cases– Ruptured corpus luteum– Germ cell tumor

Complications of Ovarian Masses in Pregnancy

• Rupture/ tumor dissemination (10%)• Anemia• Malpresentations• Necrosis• Infection• Ascites• Masculinization of female fetus

– Hilar cell tumor– Luteoma of pregnancy – Sertoli-Leydig cell tumor

Work-up of Ovarian Cancer

• Pelvic ultrasound• MRI pelvis/ abdomen• Chest X-ray• CA-125: elevated in normal pregnancy, should

normalize after 12 weeks• AFP, B-HCG, LDH – predominantly solid mass• Liver FunctionTests, BUN, Creatinine• GI studies only if clinically indicated

Management of Ovarian Cancer

• Prognosis not affected by pregnancy• Tumors of Low Malignant Potential – all stages (20%)• Adenocarcinoma Stage I, grade 1 or 2 (10%)• Germ cell tumors (5%) – may require chemotherapy• Gonadal stromal tumors (15%)• Surgery at 16-18 weeks if possible• Frozen section: beware of inaccuracies• Conservative ovarian surgery

– Adnexectomy/ Oophorectomy/ Cystectomy

• Hysterectomy not indicated• Thorough staging:

– Pelvic/ aortic node disection/ Omentectomy/ peritoneal biopsies

Management of Ovarian Cancer

• Epithelial Ovarian Cancer Stage IC – IV– Try to delay chemotherapy until 12-16 weeks of

pregnancy– Try to delay removal of corpus luteum until 14 weeks– First trimester

• TAB followed by appropriate surgery and chemotherapy• Chemotherapy after FNA:

– C-Section and appropriate management at maturity

– Second and Third Trimester• Chemotherapy first

– C-Section and appropriate surgical management at maturity

Malignant Germ Cell Tumors

• Dysgerminoma– 30% of Ovarian malignant neoplasms in pregnancy– Most stage IA– Average 25cm; solid– Therapy

• Surgery: USO, wedge biopsy of opposite ovary, surgically stage– 25% are bilateral

• Stage IA & IB: No further treatment• Advance stages

– Hysterectomy not required– Chemotherapy

Malignant Germ Cell Tumors

• Endodermal sinus tumor

• Grade 2-3 malignant teratoma

• Choriocarcinoma (non-gestational)

• USO and staging for early disease

• All require chemotherapy regardless of stage

Tumor like Ovarian Lesions Associated with Pregnancy

• All resolve spontaneously after delivery• Conservative surgical approach: frozen section +/-

oophorectomy– Luteoma of pregnancy - usually an incident. finding at C-Section

• Microscopic. -20cm – multiple nodules• Bilateral: 1/3 of cases• 25% have increased. testosterone• Maternal masculinization. – later ½ of pregnancy• Fetal virilization – 70% of female infants

– Hyperreactio Luteinalis - Bilateral multicystic theca lutein cysts– Large solitary luteinized follicular cyst of pregnancy– Hilar Cell Hyperplasia – masculinized fetus– Intrafollicular Granulosa cell proliferations– Ectopic Decidua

Breast Cancer in Pregnancy (2nd most common cancer in pregnancy)

• 20% of cases are in women <40 years old• 1-2% of cases are pregnant at time of diagnosis• One case/1500-3000 pregnancies• Often difficult to diagnose• Low dose mammogram with appropriate shielding of

fetus is “safe”• MRI – probably best• Diagnosis often delayed• Increase incidence of positive nodes (80%)• Termination of pregnancy & proph. castration is not

beneficial• No adverse effects on prognosis from subsequent

pregnancies

Treatment of Breast Cancer• Treatment same as non-pregnant• Lumpectomy• Sentinal node biopsy

– 2.5mCi technetium 99 – 4.3 mGy at worst. Usually contraindicated.– +/- radiation– Chemotherapy

• Modified radical mastectomy and nodes• Adjuvant chemotherapy after 16 weeks

– CAF better than CMF in 1st trimester• Axillary or localized chest wall RXT is probably safe after the first

trimester but can be difficult to shield fetus.• Prognosis:

5 Yr Disease Free Survival

Stage I 85%

Stage II 60%

Stage II 40%

Stage IV 5%

Leukemia in Pregnancy

• Most abort spontaneously• Average age is 28• Usually recommend termination of

pregnancy because of aggressive chemotherapy

• Prognosis – dependant on cell type

5 Yr Disease FreeSurvival

AML 10%

ALL 40-60%

CML 50%

CLL Excellent

Hodgkins Disease/Lymphoma in Pregnancy

• Gestational Age/ Stage– <20 weeks: TAB– >20 weeks: XRT

• Chest mantle first• Chemotherapy depending on stage• Abdominal XRT after delivery• 80% curable – depending on cell type

Melanoma in Pregnancy

• Incidence rising

• 30% occur in women of child bearing age

• 9% of cases occur in pregnancy

• Extremities most common site

• Pregnancy does not affect prognosis

Ovarian Function and Chemotherapy

• Dose and age related– Younger than 25: permanent amenorrhea uncommon– Older than 40: 50% permanent ovarian failure

• Birth control pills may prevent ovarian failure• Risk of birth defects in offspring not increased (4%)• Wait 2-3 years after therapy to become pregnant

– Allow for possible recurrent disease

Ovarian Function and Fertility and Radiation Therapy

• Age and dose related (<20 years old – better)– Ovaries outside radiation field (avg. dose 54 cGy):

• No failure– Ovaries at edge of radiation field (avg. dose 290 cGy):

• 25% failure• Start to lose function at 150 cGy

– Ovaries in radiation field: • At 500 cGy most women are amenorrheic

• Oophoropexy to the iliac fossa – Use clips to identify ovaries

Metastases to Fetus/Placenta

• Only 50 cases in literature

• Melanoma (50% of reported cases)

• Leukemia: 1/100 affected pregnancies

• Lymphoma

• Breast

Reference List

• Barber H.R.K., Brunschwig A: Am. J. OB/GYN, 85.156, 1963.• Baltzer J., Regenfrecht M., Kopche W., Carcinoma of the Cervix

and Pregnancy Int. J. Gyneco Obstet. 31:317, 1990.• Zemlickis D., Lishner M. Degendorfer P.et.el. Maternal and fetal

outcome after breast cancer pregnancy. Am.J. Obstet. Gynecol. 9: 1956, 1991.

• Karlen J.R. et.al. Dysgermenoma associated with pregnancy. OB/GYN 53:330, 1979.

• P.Struyk, P.S. Ovarian Masses in Pregnancy Acta.Scand. 63: 421, 1984.

• Aviles, A. et.al. Growth and Development of Children of Mothers Treated with Chemotherapy during pregnancy: Current status of 43 children. Am. J. Hematology 36: 243, 1991.

• Brodsky et.al. Am. J. Obstet, Gynecol. 138:1165, 1980.