Ebook Gynecologic oncology clinical practice and surgical atlas: Part 1

Part 1 book “Gynecologic oncology clinical practice and surgical atlas” has contents: Epidemiology of gynecologic cancers, clinical trials, and statistical considerations, genetics and biology of gynecologic cancers, diagnostic modalities, cervical cancer, endometrial hyperplasia and cancer, uterine sarcomas, gestational trophoblastic disease,… and other contents.

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This textbook and all of our professional accomplishments would not be possiblewithout the enduring support of our families We dedicate this effort to ourunderstanding spouses, Scott, Michelle, and Cathy; our high-spirited children,Matthew and Jocelyn Karlan, Jackson, Chloe, and Haley Bristow, Jason, Lucas,and Evan Li; and to our loving parents, Beverly and Stanley Young, Lynn andLonnie Bristow, and Chien and Marian Li, who raised us with passions forcaring and eternal learning Our many teachers and mentors provided us with theknowledge and skills to care for women with gynecologic cancers and motivated

us to continue pushing the therapeutic envelope until cures are within our grasp.Our colleagues—physicians, scientists, nurses, and other professionals—workshoulder to shoulder with us, and support, challenge, motivate, and make uslaugh when it is most needed And most importantly, this book is dedicated tothe legions of women with gynecologic cancer, both living and in our memories,who have taught us tenacity, selflessness, and courage We hope that this textwill educate future generations of clinicians and scientists whom we can enlist

on our journey to end cancer as a threat to women

David A Iglesias, Marilyn Huang, Pamela T Soliman, Bojana Djordjevic, and Karen H Lu

Columbus, Ohio

Chapter 24

Michael Frumovitz, MD, MPH

David A Iglesias, MD

Fellow

Department of Gynecologic Oncology and Reproductive Medicine University ofTexas M.D Anderson Cancer Center Houston, Texas

Director, Gynecologic Oncology Fellowship Division of Gynecologic OncologyMagee-Women’s Hospital of the University of Pittsburgh Medical CenterPittsburgh, Pennsylvania

Ursula A Matulonis, MD

Medical Director, Associate Professor of Medicine Harvard Medical SchoolMedical Director of Gynecologic Oncology

Leigh G Seamon, DO, MPH

Assistant Professor

Obstetrics and Gynecology

Angela J Ziebarth, MD

Fellow

Department of Gynecologic OncologyUniversity of Alabama at BirminghamBirmingham, Alabama

Chapter 5

Gynecologic oncology has experienced remarkable advances over the lastdecade Scientific discovery has unraveled many of the underpinnings andmolecular origins of reproductive tract cancers Clinical trials and meticulousdata analyses have elucidated the natural history and led to evidence-basedtherapeutic advances Targeted therapies, vaccines, and immunotherapies havebeen added to our armamentarium, and important roles for complementarymedicine and supportive care have been recognized Surgical innovation hasrevolutionized the approach to gynecologic cancers resulting in both smaller andlarger surgeries that can now be performed with improved outcomes under saferoperative conditions

With this backdrop, the time is right to take a fresh look at the practice ofgynecologic oncology This new reference presents fundamental and emerginginformation in a comprehensive and accessible format Recognized expertsaddress individual gynecologic cancers and other relevant topics Clinicalpractice guidelines are highlighted and the diagnosis, management, andtreatment of specific reproductive tract malignancies are emphasized.Acknowledging access to electronic databases, only the most relevant and recentreferences are highlighted, as well as a few classic articles A key component ofthis reference is the surgical atlas, which illustrates essential procedures ingynecologic oncology in a step-by-step fashion

The reference is organized into four sections Fundamental and overarchingtopics such as genetics, clinical trial design, and diagnostic modalities arecovered in the first section Specific reproductive tract disease sites andconditions are individually addressed next These chapters are presented in auniform format including epidemiology, pathology, diagnosis, staging, treatment,and outcomes The focus is on evidence-based practice guidelines and thecritical supporting data The clinical management topics in the third sectioninclude perioperative and critical care, as well as principles of chemotherapy,radiation therapy, and targeted and immunotherapies All the chapters includemany figures, tables, color photos, and other illustrations that highlightimportant concepts and conditions while improving comprehension and learning.The last quarter of the text is devoted to the step-by-step surgical atlas Ovarian,uterine, cervical, vulvar, and vaginal procedures are meticulously illustrated In

addition, minimally invasive surgical procedures, staging, and advancedcytoreductive procedures are described and illustrated in detail Thiscomprehensive treatment of gynecologic oncology positions this reference as thedefinitive resource in the field.

Gynecologic Oncology: Clinical Practice and Surgical Atlas will be useful to

all physicians involved in the diagnosis and management of gynecologiccancers Reproductive tract malignancies remain a significant aspect in the dailyclinical practice of obstetrician-gynecologists and other providers of women’shealth care Our goal is to become the authoritative resource for gynecologiconcology and to impact women’s health care

Epidemiology of Gynecologic Cancers, Clinical Trials, and Statistical Considerations

Uterine Corpus Cancer

Endometrial cancer is the most common gynecologic cancer and the fourth mostcommon cancer of women in the United States; 43,470 new cases diagnosed arepredicted for 2010, with 7950 deaths.2 A 50-year old woman in the United Stateshas a 1.3% probability of being diagnosed with endometrial cancer before age 70years

Eighty-seven percent of all endometrial cancers are of endometrioid histology.The most common nonendometrioid histology is papillary serous (10%),followed by clear cell (2%-4%), mucinous (0.6%-5%), and squamous cell(0.1%-0.5%) Some nonendometrioid endometrial carcinomas behave moreaggressively than the endometrioid cancers such that even women with clinical

stage I disease often have extrauterine metastasis at the time of surgicalevaluation.3 Features of type 1 (endometrioid) carcinoma include increasedexposure to estrogen (nulliparity, early menarche, chronic anovulation, andunopposed exogenous estrogen), obesity, and responsiveness to progesteronetherapy Patients more often are white, younger in age, present with a low-gradecancer, and have a better prognosis The precursor to this malignancy isendometrial hyperplasia Type 1 endome-trial cancers often have a phosphatase

and tensin homolog (PTEN) mutation and a higher incidence of microsatellite

instability In contrast, type 2 endometrial cancers are unrelated to estrogenexposure and occur in older, thinner women The most common forms of type 2endometrial cancer include uterine papillary serous carcinoma and clear cellcarcinoma Uterine papillary serous cancers are aggressive, with an increased

incidence of p53 and HER-2/neu overexpression.

Risk factors for endometrial cancer include diabetes, obesity, hypertension,nulliparity, polycystic ovarian syndrome, unopposed estrogen therapy, tamoxifenusage, infertility or failure to ovulate, and late meno-pause.4 A number of studieshave reported a positive association between diabetes and incidence of mortalityfrom endometrial cancer.5 Diabetes mellitus (both types 1 and 2) has beenassociated with up to a 2-fold increased risk of endometrial cancer

Adult overweight/obesity is one of the strongest risk factors for endometrialcancer In affluent societies, adult obesity accounts for approximately 40% of theendometrial cancer incidence.6 In postmenopausal women, adiposity is thought

to enhance endometrial cancer risk through the mitogenic effects of excessendogenous estrogens that are produced in the adipose tissue througharomatization of androgens In addition, obesity is accompanied by increasedbioavailable estrogen as a result of decreased sex hormone–binding globulinconcentration.6 Although obesity increases endometrial cancer risk independent

of other factors, it is not associated with stage or grade of disease.7

Tamoxifen citrate is an antiestrogen agent that binds to estrogen receptors butacts as a weak estrogen agonist in postmenopausal endometrial tissue Aspectrum of endometrial abnormalities is associated with its use (includingpolyps and hyperplasia) Endometrial carcinoma is also associated with long-term tamoxifen treatment.8

Endometrial Hyperplasia

In a nested case-control retrospective review of predominantly white participantsfrom Kaiser Permanente Northwest, in the northwest of the United States, the

average age at the time of diagnosis of endometrial hyperplasia was 52 years.The endometrial carcinoma risk among women with non-atypical endometrialhyperplasia—who represent the majority of all endometrial hyperplasiadiagnoses—is 3 times higher than that of the average population The risk ofendometrial cancer among women with atypical hyperplasia (27.5%) is 21 timeshigher than the average population risk The absolute and cumulative risk ofprogression are represented in Figures 1-1 and 1-2 Cumulative 20-yearprogression risk among women who remain at risk for at least 1 year is less than5% for non-atypical endometrial hyperplasia but is 28% for atypicalhyperplasia.9 A Gynecologic Oncology Group (GOG) prospective cohort studydesigned to estimate the prevalence of concurrent carcinoma in patients whohave a biopsy diagnosis of atypical endometrial hyperplasia found that theprevalence of carcinoma in hysterectomy specimens was 42.6%.10

FIGURE 1-1 Absolute risk of subsequent endometrial carcinoma by

endometrial hyperplasia (EH) type at index biopsy over intervals of 1 to 4, 5

to 9, and 10 to 19 years Vertical bars indicate 95% CIs Data points are plotted

at the mean time to diagnosis within each time interval Size of data points isproportional to the number of case patients diagnosed with endometrial

FIGURE 1-2 Cumulative risk of subsequent endometrial carcinoma by endometrial hyperplasia (EH) type at index biopsy Vertical bars indicate

95% CIs Data points are plotted at the mean time to diagnosis within each timeinterval Size of data points is proportional to the number of case patients

diagnosed with endometrial carcinoma during that time interval AH, atypicalhyperplasia; DPEM, disordered proliferative endometrium (Reproduced, withpermission, from Lacey JV Jr, Sherman ME, Rush BB, et al Absolute risk ofendometrial carcinoma during 20-year follow-up among women with

endometrial hyperplasia J Clin Oncol 2010;28(5):788-792.)

Hormonal Therapy

Menopausal estrogen therapy (ET) increases the risk of endometrial cancer inpostmenopausal women; however, the risk of endometrial cancer varies with theduration, dose, and type of estrogen used It is generally believed that daily use

of low-dose progestin opposes the effect of exogenous and endogenous estrogen

on the endometrium, resulting in a lower risk of endometrial cancer TheCalifornia Teachers Study cohort analyzed the association between long-termhormonal therapy use and endometrial cancer risk and the modifying effect ofbody mass index (BMI) in a case-control study Long-term (≥10 years) use of

ET, sequential estrogen–progesterone therapy (with < 10 days per month ofprogestin), and continuous combined estrogen and progesterone therapy (≥25

days/month of progestin) were all associated with an elevated risk ofendometrial cancer (odds ratio [OR], 4.5; 95% confidence interval [CI], 2.5-8.1;

OR, 4.4; 95% CI, 1.7-11.2; and OR, 2.1; 95% CI, 1.3-3.3, respectively) The riskassociated with short-term use was elevated only for ET preparations Theassociation for continuous combined estrogen–progesterone therapy wasconfined to thinner women Among heavier women

, use of continuous combined estrogen–progesterone therapywas associated with a nonsignificant reduction in risk These findings confirmthat long-term use of ET, sequential estrogen–progesterone therapy, orcontinuous combined estrogen–progesterone therapy among normal-weightwomen is associated with increased risk of endometrial cancer.11

Genetics of Endometrial Cancer

A somatic mutation or deletion of the PTEN tumor suppressor gene has been

reported in approximately 40% and 40% to 76%, respectively, of endometrialadenocarcinomas.12 It is well established that estrogen increases endometrial

cancer risk, whereas progesterone opposes the estrogen effects PTEN regulates

proliferation, growth, and apoptosis in a phosphatidylinositol-3-OH kinase(PI3K)–dependent pathway Genetic variation in the progesterone receptor generegion is associated with endometrial cancer risk.13

Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer)

Individuals with Lynch syndrome, also called hereditary nonpolyposis colorectalcancer (HNPCC), are at an increased risk for colorectal cancer, endometrialcancer, and other associated cancers such as gastric cancer, ovarian cancer,urothelial cancer, hepatobiliary tract cancer, brain cancer, cancer of the smallintestine, pancreatic cancer, and particular skin cancers HNPCC-associatedcancers are caused by defects in DNA mismatch repair genes Lynch syndrome

is primarily due to germline mutations in one of the DNA mismatch repair genes,mainly hMLH1 or hMSH2 and less frequently hMSH6 and rarely hPMS2.14These genetic defects in the DNA mismatch repair system result in microsatelliteinstability and the absence of protein expression in the tumor Currently, thediagnosis of Lynch syndrome is based on either clinical (revised Amsterdamcriteria) or molecular criteria The Bethesda Guidelines were revised in 2004 toinclude extra-colonic tumors to improve the sensitivity of detecting families with

Lynch syndrome and to determine which individuals should have microsatelliteinstability or immunohistochemical testing of their tumors (Table 1-1) LowBMI, age less than 50 years, and positive family history have all been identified

as risk factors in endometrial cancer patients who might benefit from HNPCCscreening.15

Table 1-1 Amsterdam Criteria II and Revised Bethesda Guidelines

Amsterdam Criteria II

There should be at least 3 relatives with colorectal cancer (CRC) or with a

Lynch syndrome–associated cancer: cancer of the endometrium, small bowel,ureter, or renal pelvis

3 CRC with MSI–H phenotype diagnosed in a patient aged < 60 years

4 Patient with CRC and a first–degree relative with a Lynch syndrome–relatedtumor,a with 1 of the cancers diagnosed at age < 50 years

5 Patient with CRC with ≥ 2 first–degree or second– degree relatives with aLynch syndrome–related tumor,a regardless of age

aLynch syndrome–related tumors include colorectal, endometrial, stomach,ovarian, pancreas, ureter, renal pelvis, biliary tract and brain tumors, sebaceousgland adenomas and keratoacanthomas, and carcinoma of the small bowel

Reproduced, with permission, from Vasen HF, Möslein G, Alonso A, et al.Guidelines for the clinical management of Lynch syndrome (hereditary non-

polyposis cancer) J Med Genet 2007;44(6):353-362.

Uterine Sarcomas

Uterine sarcomas are rare tumors of the uterus that comprise 4% to 9% of allinvasive uterine cancers and 1% of female genital tract malignancies.16Carcinosarcoma, previously referred to as malignant mixed mullerian tumor, is abiphasic neoplasm composed of distinctive and separate, but admixed,malignant-appearing epithelial and mesenchymal elements The sarcomatouscomponents are heterogeneous, and almost all are high grade The homologouscomponents of carcinosarcoma are usually spindle cell sarcoma without obviousdifferentiation; many resemble fibrosarcomas or pleomorphic sarcomas Themost common heterologous elements are malignant skeletal muscle or cartilageresembling either pleomorphic rhabdomyosarcoma or embryonalrhabdomyosarcoma Carcinosarcomas comprise almost half of all uterinesarcomas One-third of all cases are diagnosed at an advanced stage Up to 37%

of patients with carcinosarcomas have a history of pelvic irradiation Thesetumors tend to occur in younger women, often contain heterologous elements,and are found at advanced stage Carcinosarcomas are highly aggressive tumorsand are fatal in the vast majority of cases

After excluding carcinosarcoma, leiomyosarcoma is the second most commonsubtype of uterine sarcoma; however, it accounts for only 1% to 2% of uterinemalignancies Most occur in women over 40 years of age who usually presentwith abnormal vaginal bleeding (56%), palpable pelvic mass (54%), and pelvicpain (22%).16 The vast majority of uterine leiomyosarcomas are sporadic Theseare very aggressive tumors, even when diagnosed at an early stage Patients withgermline mutations in fumarate hydratase are believed to be at increased risk fordeveloping uterine leiomyosarcomas as well as uterine leiomyomas.17

The next common subset of uterine sarcomas, termed endometrial stromaltumors, are divided into 3 groups: endometrial stromal nodule, low-gradeendometrial stromal sarcoma, and undifferentiated endometrial sarcomas.Endometrial stromal nodules can occur in women at any age Patients withendometrial stromal nodules have an excellent prognosis and can be cured byhysterectomy.16 Endometrial stromal sarcomas are indolent tumors with afavorable prognosis They occur in women between 40 and 55 years of age.Some cases have been reported in patients with ovarian polycystic disease, afterestrogen use, or tamoxifen therapy In contrast, undifferentiated endometrialsarcomas have very poor prognosis Endometrial stromal tumors often containestrogen and progesterone receptors However, the prognostic implication ofthese findings is uncertain.18

Cervical Cancer

Cervical cancer is the second most frequent cancer in women worldwide and theprincipal cancer in most developing countries, where 80% of the cases occur.19During the years 1973 and 1997, cervical cancer rates decreased in most parts ofthe world Incidence rates are almost 2-fold higher in less-developed comparedwith more-developed countries (19.1 and 10.3 per 100,000 person-years,respectively) The incidence is highest in Africa and Central/South America(approximately 29 per 100,000 person-years) and lowest in Oceania and NorthAmerica (approximately 7.5 per 100,000 person-years).19 India, the second mostpopulous country in the world, accounts for 27% (77,100) of the total cervicalcancer deaths1 (Figure 1-3) In the United States, cervical cancer is the thirdmost common gynecologic cancer of women For 2010, 12,200 new cases and

4210 deaths were predicted.2

FIGURE 1-3 Age-standardized cervical cancer incidence and mortality rates by world area (Reproduced, with permission, from Jemal A, Bray F,

Center MM, Ferlay J, Ward E, Forman D Global cancer statistics CA Cancer J

Clin 2011;61(2):69-90.)

The search for an infectious etiology of cervical cancer dates back toobservations made centuries ago, when the Greeks and Romans observed thatgenital warts were associated with sexual promiscuity and regarded them asinfectious In 1842, Rigoni-Stern, an Italian physician in Verona, observed thehigher frequency of cervical cancer among married women, prostitutes, andwidows than among virgins or nuns Subsequently, the medical literaturedisplayed reports of rare malignant conversion of condylomata acuminate intosquamous cell carcinoma In 1976, 2 morphologically distinct human papilloma

virus (HPV) lesions were described in the uterine cervix, known currently as aflat and an inverted condyloma Koilocytes were identified These new HPVlesions were shown to be frequently associated with concomitant cervicalintraepithelial neoplasia (CIN) and carcinoma in situ (CIS) lesions andoccasionally with invasive cervical carcinomas as well Harald zur Hausenidentified HPV16 DNA in cervical cancers in 1983 and then identified HPV18 in

1984 by Southern blot hybridization He was awarded the Nobel Prize inMedicine in 2008 for his research on the role of the papilloma virus in cervicalcancer Cervix cancer is the result of the progression of a clone of persistentlyinfected cells from intraepithelial neoplasia to invasive disease

More than 200 genotypes of HPV have been identified, and approximately 30types of HPV specifically cause anogenital infections.20 HPV is classified intohigh-risk and low-risk virus types, depending on its ability to cause malignancy

in the infected epithelium The high-risk types (16, 18, 31, 33, 45, 51, 52, 58) areassociated with more than 90% of cervical cancers HPV16 accounts forapproximately half of all cervical cancers, whereas HPV18 is involved inanother 10% to 20%

Age-specific HPV prevalence in women over the age of 30 years generallydeclines from a peak at younger ages; however, the prevalence remainsconsistently above 20% in many low-resource regions In middle-aged women(age 35-50 years), maximum HPV prevalence differs across geographicalregions: Africa (approximately 20%), Asia/Australia (approximately 15%),Central and South America (approximately 20%), North America(approximately 20%), Southern Europe/Middle East (approximately 15%), andNorthern Europe (approximately 15%) Women aged 30 years and older who testnegative for carcinogenic HPV with cytologically normal Pap tests are at anextremely low risk for incipient precancer of the cervix over the next 10 years.21

In the United States, the prevalence of HPV in women 14 to 59 years isestimated to be 27%, with the highest prevalence (44.8%) among women aged

20 to 24 years The overall prevalence of HPV among females aged 14 to 24years is 33.8% This prevalence corresponds to 7.5 million females with HPVinfection22 (Figure 1-4) The acquisition of HPV occurs soon after sexualinitiation and typically resolves very quickly HPV acquisition is associated withnonpenetrative sexual activity, but much less frequently than with sexualintercourse Risk factors for HPV infection are primarily related to sexualbehavior, including the number of sex partners, introduction of new partners,lifetime history of sex partners, and partner’s sexual history23 (Figure 1-5)

FIGURE 1-4 Prevalence of human papilloma virus (HPV) types among females aged 14 to 59 years (Reproduced, with permission, from Dunne EF,

Unger ER, Sternberg M, et al Prevalence of HPV infection among females in

the United States JAMA 2007;297(8):813-819.)