ONCOLOGIC CONCERNS IN WOMEN
| HUMAN PAPILLOMAVIRUS AND CERVICAL CANCER —Anita L. Nelson, MD, Professor of Obstetrics and Gynecology,
David Geffen School of Medicine at the University of California, Los Angeles, and Harbor UCLA Medical Center,
Torrance, CA, and Program Director, Women’s Health Care Teams, Coastal County Health Centers, Los Angeles County
Department of Health Services
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| Introduction: >10,000 new cases of cervical cancer anticipated this year in United States; incidence reduced by Papanicolaou
(Pap) testing; second most common malignancy worldwide (≈500,000 cases/yr; 240,000 deaths)
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| Approaches to reducing cervical cancer: cessation of tobacco smoking increases 5-yr survival by 5% to 15%; chemotherapy
during irradiation for more advanced disease; early detection (new liquid-preparation screening helpful); primary
prevention (eg, safer sex practices, male condoms, vaccine)
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| Human papillomavirus (HPV) and cervical cancer: cervical cancer first cancer to be recognized as virally induced;
HPV infection alone does not cause cancer (cancer caused by persistence of infection and other conditions that
prevent clearance of virus and increase susceptibility [eg, tobacco smoking, immunocompromise]); high-risk viral
types found in nearly all cervical cancers; association between HPV and cervical cancer stronger than that between tobacco
smoking and lung cancer; ≈40 viral subtypes have affinity for anogenital area; 12 viral subtypes have high oncogenic
potential (eg, HPV types 16 [HPV-16] and 18 [HPV-18]); HPV sexually transmitted and preferentially infects
rapidly dividing cells (affects where viral infections manifested and acquired; vulnerability higher in younger
women); HPV infections common; not all persons infected with HPV develop antibodies (in past, all treatments for
external genital warts and cervical dysplasia dependent on cellular immunity); no good markers for measuring antibodies
to determine exposure; estimated lifetime exposure in sexually active people, ≤90%; 1% to 2% of those with
HPV develop external genital warts; 2% to 5% of women have Pap test results suggestive of condylomatous changes;
time from initial exposure to development of first lesion, 1 to 8 mo; infection can be suppressed for years; time from
development of first cervical dysplasia to time patient progresses “long”; do not perform Pap testing on women for
first 3 yr after sexual debut; regional infection (virus may ascend into cervix without vaginal penetration by, eg, genital-to-genital
contact)
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| Screening: perform initial Pap testing 3 yr after sexual debut; in adolescents with atypical squamous cells of undetermined
significance (ASCUS) or low-grade squamous intraepithelial lesion (LSIL), “don’t do anything”; in young
women with LSIL, repeat high-grade HPV test in 1 yr; once Pap testing initiated, perform every year (or every 2 yr with
liquid-based Pap testing; this less frequent testing not yet advocated by American Academy of Family Physicians); after
age 30 yr—after 3 consecutive normal results, perform testing every 2 to 3 yr; woman 30 yr of age who acquired infection
“should have suppressed it by now”; test for high-risk virus and perform Pap testing (if both negative, Pap
testing not needed for 3-5 yr, but annual pelvic examinations necessary); after age 70 yr (or age 65 yr, according to
United States Preventive Services Task Force)—Pap testing can be discontinued if woman had ≥3 documented adequate
specimens with normal results in last 10 yr or after total hysterectomy for benign disease (with subtotal hysterectomy,
however, cervix remains, and continued Pap testing necessary)
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| New recommendations: ASCUS and positive results for high-risk HPV—send adults for immediate colposcopy; repeat
HPV testing in adolescents after 1 yr; ASCUS and negative results for high-risk HPV—continue routine testing;
LSIL—colposcopy for adults; test adolescents for high-risk HPV; high-grade squamous intraepithelial lesion
(HSIL)—colposcopy; atypical glandular cells—further detailed testing required; Pap testing poor; cervical intraepithelial
neoplasia grade I (CIN I)—mild dysplasia; not precancerous; if colposcopy satisfactory and endocervical curettage
(ECC) negative, repeat high-risk HPV testing after 12 mo; CIN grade II (CIN II) considered precancerous (be
aggressive in adults)
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| Women ≥30 yr of age: individualize therapy; chronologic age may not be same as exposure age (eg, woman 30 yr of
age with sexual debut at age 29 yr should be treated as younger woman); Pap test negative and high-risk HPV test
negative—repeat both tests in 3 yr; ASCUS and high-risk HPV test negative—repeat screening routinely; Pap test
negative and high-risk HPV test positive—repeat testing in 4 mo
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| Quadrivalent HPV recombinant vaccine (Gardasil): unusual for woman ≤26 yr of age to have exposure to ≥1
viral type; explain to patients and parents that vaccine does not cause infection; efficacy—study of women with history
of <5 sex partners and no history of abnormal Pap test; 1 case of CIN II or CIN grade III (CIN III) related to HPV-16 or
HPV-18 or adenocarcinoma in situ (AIS), compared to 81 cases in placebo group (98.8% reduction); vaccine did not increase
risk in women positive for HPV-16 at time of entering study; vaccine “does not protect you from viruses you already
have”; 39% reduction in general population; 69% reduction in development of warts; after 4 yr, women who
received vaccine did not acquire new viruses; side effects—pain at injection site; fever; pregnancy—discontinue vaccine
series during pregnancy; continue series (ie, do not restart series) after patient gives birth and finishes breast-feeding;
indications—girls and women 9 to 26 yr of age; contraindicated in hypersensitive women; does not substitute for
routine cervical cancer screening; may not result in protection for everybody; not intended for treatment
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| Questions and answers: woman with infection already established—because woman has demonstrated susceptibility
(ie, inability to clear infection), vaccine recommended to prevent new infections (but will not clear established infection);
women 30 to 65 yr of age who never had abnormal Pap tests undergoing Pap testing every 3 yr—require
annual pelvic and breast examinations and other well-woman care for reproductive health; Pap testing for women >21
yr of age with no history of intercourse—recommended, due to varying degrees of sexual activity; patient may be suppressing
sexual abuse or assault; inclusion of nonhigh-risk HPV types 6 (HPV-6) and 11 (HPV-11) in vaccine—
vectors used to help eradicate virus; vaccination of girls 11 to 12 yr of age—antibody response robust; suggested that
immunity lasts until sexual debut (at, eg, age 21 yr); use of Gardasil in woman >26 yr of age with multiple sex
partners—not contraindicated; pregnant woman with HSIL and acetowhite changes on colposcopy—if suspicious
for cancer, perform biopsy and treat appropriately; otherwise, repeat colposcopy every 4 to 6 wk during pregnancy to rule
out invasive carcinoma
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| BREAST LUMPS AND MASSES —Armando E. Guiliano, MD, Clinical Professor of Surgery, David Geffen School of
Medicine at the University of California, Los Angeles, and Chief of Science and Medicine, John Wayne Cancer Institute at
Saint John’s Health Center, Santa Monica, CA
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| Introduction: failure to diagnose breast cancer most common cause of malpractice lawsuits in United States; breast
composed primarily of fat; major ducts open to nipple and branch out; breast cancer begins in intermediate and terminal
ductal lobular units; lumps can occur in any breast structure (eg, fat, connective tissue, epithelium); always be concerned
about possibility of cancer; cancers may appear as infections or feel benign
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| Risk factors: genetic mutations (BRCA1 and BRCA2); positive family history; personal history of breast cancer; proliferative
breast disease; fibrocystic disease with hyperplasia (fibrocystic disease alone not risk factor); hormone replacement
therapy (HRT); length of reproductive window (ie, time from menarche to menopause; longer time increases risk);
age at first live birth (greater protection at younger age)
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| Epidemiology: decrease in incidence of breast cancer may be due to diminished use of HRT; ≈250,000 new cases of
breast cancer in United States annually; 1 in 8 women develops breast cancer; decrease in death rate in past few years
may be due to earlier detection and improvements in adjuvant systemic therapy
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| Clinical assessment of breast mass: history—how long breast mass present; ask about changes (with, eg, menstrual
cycle), tenderness, pain, and risk factors; physical examination—while patient seated, look for symmetry; look for skin
changes and retraction of nipple (ask patient to elevate arms over head to move pectoralis muscles); look for dimpling
and edema; presentation of breast cancer—mass; swelling; pain; nipple retraction; nipple discharge (bloody discharge
concerning); abnormal mammography with no palpable lump; most located in upper outer quadrant; can be located from
clavicle to costal margin; skin puckering when patient flexes pectoralis; palpation—supraclavicular lymph node; axilla;
tail of Spence; bimanual palpation of large breasts; patients better than doctors at feeling breast masses (repeat examination
in 1-2 mo); palpate breasts while patient lying down (place pillow under patients with large breasts)
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| Parenchymal characteristics: postmenopausal woman not on HRT—breast primarily composed of fat; soft with
mild or no nodularity; premenopausal woman or postmenopausal woman on HRT—diffuse nodularity; areas of increased
nodularity predominantly in upper outer quadrant; subareolar nodularity; dense parenchyma; look for something
different (eg, hardness); normal structures—nodularity; prominent fat lobule; prominent rib; intramammary lymph
nodes usually not palpable, but normal in upper outer quadrant; edge of previous biopsy site; accessory breast in axilla
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| Breast masses: nonneoplastic—fibrocystic disease (solid or cystic component); galactocele; stromal fibrosis (proliferation
of stromal connective tissue); inflammation (eg, mastitis, abscess); fat necrosis (from, eg, trauma); granuloma;
Mondor’s disease (superficial thrombophlebitis); skin mass (eg, sebaceous cyst); benign tumors—fibroadenoma; papilloma;
lipoma; granular cell myoblastoma; feel indistinguishable from carcinoma; intermediate tumors—cystosarcoma
phyllodes; recur locally; usually do not metastasize; often confused with fibroadenoma; malignant tumors—carcinoma
due to infiltrating ductal cancer or lobular carcinoma; cystosarcoma phyllodes can be malignant (rare); lymphoma; sarcoma;
metastases from other site; peau d’orange—orange skin; sign that lymphatics obstructed; classic sign of advanced
breast cancer, usually with metastases to subdermal lymphatics or lymphatics of axilla; concerning sign in
patients with no history of lumpectomy and irradiation; grade 4 Paget’s disease—eczema-like rash (small patch on nipple);
follow until resolution; consider steroid cream; if no resolution in 2 to 3 wk, refer for biopsy; associated with early
cancer; breast infections—seen in lactating women; almost always due to Staphylococcus aureus; if patient not lactating,
consider inflammatory carcinoma (lethal form of breast cancer; causes immune inflammation, destruction of subdermal
lymphatics, and early metastases); if infection suspected, prescribe antibiotics, and perform biopsy in 1 wk if no
resolution
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| Screening: mammography and ultrasonography (US) to rule out intracystic tumor; computed tomography (CT) rarely
used; magnetic resonance imaging (MRI); mammography—used as annual screening tool in asymptomatic women ≥40
yr of age; used as diagnostic tool in women with breast mass; American Cancer Society guidelines suggest starting clinical
breast examinations at age 20 yr in patients at average risk; breast self-examination (BSE); evidence supports decrease
in breast cancer mortality with screening mammography; yearly MRI screening not recommended for women at
average risk (recommended for women with BRCA1 and BRCA2); in women at increased risk (15%-20%, eg, strong
family history, genetic mutation), perform yearly mammography and screening MRI 6 mo later; survival rates of stage I
breast cancer >90% (early detection important)
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| Mammographic findings: benign mass—round with smooth margins; fibrous breast tissue intact; coarse calcifications;
symmetry; stable; malignant mass—irregular; spiculated; breast architecture distorted; microcalcifications; asymmetry;
new; 5% incidence of bilaterality in initial diagnosis of breast cancer (and patient with 1 breast cancer has 1%-2%
chance of having breast cancer in other breast; bilateral mammography recommended); skin thickening; nipple retraction;
breast edema; peau d’orange; asymmetry in breast tissue; breast appears more dense; benign calcifications—
scattered; solitary; large; monomorphic; malignant calcifications—multiple (>5); clustered; tiny; branched; polymorphic
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| Biopsy: fine-needle—if mass suspected to be cyst, fluid not bloody, and mass resolves, reexamine patient in 3 to 4 wk;
test for blood with hemoccult test (test nipple discharge); relies on cytology; core-needle—highly accurate; definitive;
surgical—incisional (rare) for large tumors; excisional more common and removes entire lesion; definitive; nonsurgical
biopsy—technique of choice; fine-needle cytology easy way to make diagnosis
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| Magnetic resonance imaging: cross-sectional anatomy; no radiation; sensitivity high; problems include high cost and
low specificity; indications—implant rupture (order MRI implant or silicone study for better evaluation of intracapsular
leaks than mammography); abnormal mammographic findings; to determine extent of disease; to evaluate scar or recurrence
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| Methoxyisobutyl isonitrile (MIBI) imaging: MIBI taken up like thallium in tumors; used to prioritize surgery; detects
large tumors; “worthless; don’t ever order one”
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| Work-up of breast mass: postmenopausal woman—1) presents with fixed palpable mass that appears malignant;
proceed with mammography and US; fine-needle or core-needle biopsy; evaluation and counseling; definitive procedure;
2) presents with palpable mass (not fixed); not obviously malignant; mammography and US; biopsy; any mass in
postmenopausal woman must be considered suspicious for malignancy and ultimately must undergo biopsy; “pretty
much” no new benign masses in postmenopausal woman; premenopausal woman or postmenopausal woman on
HRT—1) presents with fixed palpable mass that appears malignant; mammography and US; core-needle biopsy; if benign,
consider excision; if malignant, preoperative evaluation and counseling; definitive procedure; 2) presents with
palpable mass, not clinically malignant; mammography and US; if mass appears malignant on imaging studies, perform
biopsy; if “solid, but not obviously malignant,” consider fibroadenoma (perform biopsy or reexamine patient in 1-2 mo
[perform biopsy if mass persists for 1-2 mo]); follow up in 6 mo; 3) presents with palpable mass; mammography and
US; if cystic, aspirate mass; reexamine if fluid not bloody and mass resolves; mass benign if it resolves with no recurrence;
if mass recurs, perform biopsy; large cysts may recur 2 to 3 wk after aspiration (repeat and send fluid for cytologic
study; consider intracystic carcinoma)
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Suggested Reading
No authors listed: Symptoms and signs of operable breast cancer 1976-1981. Br J Surg 70:350, 1983; Branca M et
al: Assessment of risk factors and human papillomavirus (HPV) related pathogenetic mechanisms of CIN in HIV-positive
and HIV-negative women. Study design and baseline data of the HPV-Pathogen ISS study. Eur J Gynaecol Oncol25:689,
2004; Castle PE et al: Human papillomavirus type 16 infections and 2-year absolute risk of cervical precancer in women
with equivocal or mild cytologic abnormalities. J Natl Cancer Inst 97:1066, 2005; Jones RW et al: Human papilloma
virus vaccines and their role in cancer prevention. N Z Med J 120:U2829, 2007; Nemec CF et al: How should we screen
for breast cancer? Mammography, ultrasonography, MRI. Cleve Clin J Med 74:897, 2007; Orel S: Who should have
breast magnetic resonance imaging evaluation? J Clin Oncol 26:703, 2008; Rodriguez R et al: Longitudinal cytological
follow-up of patients with a Papanicolaou test interpretation of "atypical squamous cells of undetermined significance"
that was followed by a negative reflex test for high-risk human papillomavirus types. Int J Gynecol Pathol 27:108, 2008;
Sherman ME et al: Baseline cytology, human papillomavirus testing, and risk for cervical neoplasia: a 10-year cohort
analysis. J Natl Cancer Inst 95:46, 2003; Shetty MK et al: Sonographically occult screen detected breast masses: a retrospective
analysis of cases undergoing biopsy. Clin Imaging 32:28, 2008; Skinner SR et al: Human papillomavirus
vaccination for the prevention of cervical neoplasia: is it appropriate to vaccinate women older than 26? Med J Aust
188:238, 2008; Spitzer M: Screening and management of women and girls with human papillomavirus infection. Gynecol
Oncol 107:S14, 2007; Verguts J et al: Prediction of recurrence after treatment for high-grade cervical intraepithelial
neoplasia: the role of human papillomavirus testing and age at conisation. BJOG 113:1303, 2006; Warner E et al:
Surveillance of BRCA1 and BRCA2 mutation carriers with magnetic resonance imaging, ultrasound, mammography, and
clinical breast examination. JAMA 292:1317, 2004; Yasmeen S et al: Frequency and predictive value of a mammographic
recommendation for short-interval follow-up. J Natl Cancer Inst 95:429, 2003.
Educational Objectives
| The goal of this program is to improve detection and management of human papillomavirus (HPV) infection, cervical cancer,
and breast cancer. After hearing and assimilating this program, the clinician will be better able to:
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 | 1. Counsel patients about HPV infection and susceptibility.
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| 2. Review recommendations for HPV screening and follow-up.
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| 3. Discuss efficacy of HPV recombinant vaccine.
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| 4. Identify types of breast masses and other conditions that may be associated with early cancer.
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| 5. Describe screening and diagnostic tools for breast cancer.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and planning committee
members to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of
interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and
not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Nelson is on the
Speakers’ Bureau and has received honoraria from Merck, and has attended speaker training for Digene. Dr. Giuliano and
the planning committee reported nothing to disclose.
Acknowledgements
Dr. Nelson spoke in San Diego, CA, at the 50th Annual Postgraduate Symposium Family Medicine Update 2007, presented
August 3-5, 2007, by the San Diego Academy of Family Physicians. Dr. Giuliano was recorded in Los Angeles, CA, at
the 34th Annual UCLA Family Practice Refresher Course, presented May 29 to June 2, 2007, by the David Geffen School
of Medicine at the University of California, Los Angeles. The Audio-Digest Foundation thanks the speakers and the sponsors
for their cooperation in the production of this program.
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