Gynecologic Oncology Consult

Obstetrician-gynecologists play a unique role in screening women for various malignancies, including breast, colon, and cervical carcinoma. Although less common, genetic syndromes also can affect the female reproductive tract; therefore, knowledge of the screening guidelines for the most common genetic syndromes – hereditary breast and ovarian cancer syndrome, hereditary nonpolyposis colorectal cancer syndrome, and Cowden syndrome – is important.

Hereditary breast and ovarian cancer syndrome

Caused by autosomal-dominant deletions in the BRCA1/2 genes, the lifetime risk of ovarian cancer in patients with a BRCA1 and BRCA2 mutation is 39%-46% and 12%-20%, respectively. Although not proven to improve detection or survival, the American College of Obstetricians and Gynecologists (ACOG) and National Comprehensive Cancer Network (NCCN) guidelines recommend that women with BRCA1/2 mutations should undergo screening with transvaginal ultrasonography and CA125 every 6 months beginning between ages 30-35 years or 5-10 years prior to the age of the youngest affected family member. For patients who have not completed childbearing, a recent meta-analysis showed that use of oral contraceptives was associated with a decreased risk of ovarian cancer in patients with BRCA1/2 (J. Clin. Oncol. 2013;31:4188-98). Once childbearing has been completed or at the age of 40 years, a risk-reducing bilateral salpingo-oophorectomy (BSO) should be strongly considered (Gynecol. Oncol. 2009;113:6-11; Obstet. Gynecol. 2011;117:742-6).

In addition, patients with BRCA 1/2 mutations carry a 65%-74% lifetime risk of developing breast cancer (Gynecol. Oncol. 2009;113:6-11).ACOG recommends that these women begin screening for breast cancer at the age of 25 years through semiannual self-breast exams as well as annual mammography and breast MRI or sooner if a family member’s cancer was diagnosed prior to this age. Chemoprevention with tamoxifen also has been shown to reduce the risk of breast cancer in patients with BRCA2 disease, but is less effective for BRCA1 patients. Prophylactic mastectomy has the ability to reduce a woman’s risk of developing breast cancer by 90%-95%.

Hereditary nonpolyposis colorectal cancer syndrome

Another autosomal-dominant disorder, hereditary nonpolyposis colorectal cancer (HNPCC) syndrome arises as a result of a genetic defect in DNA mismatch repair mechanisms. Colon cancer is the most common malignancy associated with this syndrome, with a 70% risk by the age of 70 years (JAMA 2006;296:1507-17). Other associated cancers include those of the urinary tract, hepatobiliary tract, small intestine, skin, and brain, but strong supportive data are lacking. Beginning at age 20-25 years (or 10 years before the age of the youngest family member to develop colon cancer), a colonoscopy is recommended every 1-2 years. Annual urinalysis with cytology is advocated by some as a screening test for urinary tract cancers.

Patients with HNPCC have up to a 60% lifetime risk of endometrial cancer and a 10% risk of ovarian cancer (Int. J. Cancer 1999;81:214-8; Hum. Mol. Gene. 1997;6:105-10). The American Cancer Society recommends an endometrial biopsy and transvaginal ultrasonography annually between 30-35 years of age (JAMA 2006;296:1507-17). Schmeler et al. compared outcomes among 315 women with mismatch repair defects, 61 of whom underwent risk-reducing hysterectomy and BSO. With an average follow-up of greater than 7 years, none of the patients who underwent surgery developed cancer, while 33% of those who did not have surgery developed endometrial cancer and 5.5% developed ovarian cancer (N. Engl. J. Med. 2006;354:261-9). Because of these data, risk-reducing surgery at the age of 35 should be considered.

Cowden Syndrome

Cowden Syndrome, caused by an autosomal-dominant mutation in the PTEN gene, is associated with an up to 10% lifetime risk of endometrial cancer and a 50% risk of breast cancer (Obstet. Gynecol. Clin. N. Am. 2010;37:109-33). The NCCN notes that data are limited, but discussion of endometrial cancer symptoms should be encouraged (NCCN Guidelines Version 4, 2013). Annual endometrial sampling and ultrasound should be considered in woman aged 35-40 years or 10 years earlier than the youngest affected family member (Obstet. Gynecol. Clin. N. Am. 2010;37:109-33). Screening for breast cancer should include annual mammography and breast MRI starting between age 30-35 years or earlier depending on family history, per the NCCN guidelines.

It is important to note that additional genetic syndromes can have repercussions on the female genital tract, including the Li-Fraumeni (ovarian cancer), the Peutz-Jeghers (sex cord–stromal tumors of the ovary, granulosa cell tumors), and the Ollier (granulosa cell tumors) syndromes; unfortunately, screening guidelines for these rare syndromes have not been well studied (JAMA 2006;296:1507-17).

Dr. Schuler is a gynecologic oncologist at Good Samaritan Hospital in Cincinnati. Dr. Gehrig is professor and director of gynecologic oncology at the University of North Carolina at Chapel Hill. Dr. Gehrig and Dr. Schuler said they had no relevant financial disclosures.

Obstetrician-gynecologists play a unique role in screening women for various malignancies, including breast, colon, and cervical carcinoma. Although less common, genetic syndromes also can affect the female reproductive tract; therefore, knowledge of the screening guidelines for the most common genetic syndromes – hereditary breast and ovarian cancer syndrome, hereditary nonpolyposis colorectal cancer syndrome, and Cowden syndrome – is important.

Hereditary breast and ovarian cancer syndrome

Caused by autosomal-dominant deletions in the BRCA1/2 genes, the lifetime risk of ovarian cancer in patients with a BRCA1 and BRCA2 mutation is 39%-46% and 12%-20%, respectively. Although not proven to improve detection or survival, the American College of Obstetricians and Gynecologists (ACOG) and National Comprehensive Cancer Network (NCCN) guidelines recommend that women with BRCA1/2 mutations should undergo screening with transvaginal ultrasonography and CA125 every 6 months beginning between ages 30-35 years or 5-10 years prior to the age of the youngest affected family member. For patients who have not completed childbearing, a recent meta-analysis showed that use of oral contraceptives was associated with a decreased risk of ovarian cancer in patients with BRCA1/2 (J. Clin. Oncol. 2013;31:4188-98). Once childbearing has been completed or at the age of 40 years, a risk-reducing bilateral salpingo-oophorectomy (BSO) should be strongly considered (Gynecol. Oncol. 2009;113:6-11; Obstet. Gynecol. 2011;117:742-6).

In addition, patients with BRCA 1/2 mutations carry a 65%-74% lifetime risk of developing breast cancer (Gynecol. Oncol. 2009;113:6-11).ACOG recommends that these women begin screening for breast cancer at the age of 25 years through semiannual self-breast exams as well as annual mammography and breast MRI or sooner if a family member’s cancer was diagnosed prior to this age. Chemoprevention with tamoxifen also has been shown to reduce the risk of breast cancer in patients with BRCA2 disease, but is less effective for BRCA1 patients. Prophylactic mastectomy has the ability to reduce a woman’s risk of developing breast cancer by 90%-95%.

Hereditary nonpolyposis colorectal cancer syndrome

Another autosomal-dominant disorder, hereditary nonpolyposis colorectal cancer (HNPCC) syndrome arises as a result of a genetic defect in DNA mismatch repair mechanisms. Colon cancer is the most common malignancy associated with this syndrome, with a 70% risk by the age of 70 years (JAMA 2006;296:1507-17). Other associated cancers include those of the urinary tract, hepatobiliary tract, small intestine, skin, and brain, but strong supportive data are lacking. Beginning at age 20-25 years (or 10 years before the age of the youngest family member to develop colon cancer), a colonoscopy is recommended every 1-2 years. Annual urinalysis with cytology is advocated by some as a screening test for urinary tract cancers.

Patients with HNPCC have up to a 60% lifetime risk of endometrial cancer and a 10% risk of ovarian cancer (Int. J. Cancer 1999;81:214-8; Hum. Mol. Gene. 1997;6:105-10). The American Cancer Society recommends an endometrial biopsy and transvaginal ultrasonography annually between 30-35 years of age (JAMA 2006;296:1507-17). Schmeler et al. compared outcomes among 315 women with mismatch repair defects, 61 of whom underwent risk-reducing hysterectomy and BSO. With an average follow-up of greater than 7 years, none of the patients who underwent surgery developed cancer, while 33% of those who did not have surgery developed endometrial cancer and 5.5% developed ovarian cancer (N. Engl. J. Med. 2006;354:261-9). Because of these data, risk-reducing surgery at the age of 35 should be considered.

Cowden Syndrome

Cowden Syndrome, caused by an autosomal-dominant mutation in the PTEN gene, is associated with an up to 10% lifetime risk of endometrial cancer and a 50% risk of breast cancer (Obstet. Gynecol. Clin. N. Am. 2010;37:109-33). The NCCN notes that data are limited, but discussion of endometrial cancer symptoms should be encouraged (NCCN Guidelines Version 4, 2013). Annual endometrial sampling and ultrasound should be considered in woman aged 35-40 years or 10 years earlier than the youngest affected family member (Obstet. Gynecol. Clin. N. Am. 2010;37:109-33). Screening for breast cancer should include annual mammography and breast MRI starting between age 30-35 years or earlier depending on family history, per the NCCN guidelines.

It is important to note that additional genetic syndromes can have repercussions on the female genital tract, including the Li-Fraumeni (ovarian cancer), the Peutz-Jeghers (sex cord–stromal tumors of the ovary, granulosa cell tumors), and the Ollier (granulosa cell tumors) syndromes; unfortunately, screening guidelines for these rare syndromes have not been well studied (JAMA 2006;296:1507-17).

Dr. Schuler is a gynecologic oncologist at Good Samaritan Hospital in Cincinnati. Dr. Gehrig is professor and director of gynecologic oncology at the University of North Carolina at Chapel Hill. Dr. Gehrig and Dr. Schuler said they had no relevant financial disclosures.

Obstetrician-gynecologists play a unique role in screening women for various malignancies, including breast, colon, and cervical carcinoma. Although less common, genetic syndromes also can affect the female reproductive tract; therefore, knowledge of the screening guidelines for the most common genetic syndromes – hereditary breast and ovarian cancer syndrome, hereditary nonpolyposis colorectal cancer syndrome, and Cowden syndrome – is important.

Hereditary breast and ovarian cancer syndrome

Caused by autosomal-dominant deletions in the BRCA1/2 genes, the lifetime risk of ovarian cancer in patients with a BRCA1 and BRCA2 mutation is 39%-46% and 12%-20%, respectively. Although not proven to improve detection or survival, the American College of Obstetricians and Gynecologists (ACOG) and National Comprehensive Cancer Network (NCCN) guidelines recommend that women with BRCA1/2 mutations should undergo screening with transvaginal ultrasonography and CA125 every 6 months beginning between ages 30-35 years or 5-10 years prior to the age of the youngest affected family member. For patients who have not completed childbearing, a recent meta-analysis showed that use of oral contraceptives was associated with a decreased risk of ovarian cancer in patients with BRCA1/2 (J. Clin. Oncol. 2013;31:4188-98). Once childbearing has been completed or at the age of 40 years, a risk-reducing bilateral salpingo-oophorectomy (BSO) should be strongly considered (Gynecol. Oncol. 2009;113:6-11; Obstet. Gynecol. 2011;117:742-6).

In addition, patients with BRCA 1/2 mutations carry a 65%-74% lifetime risk of developing breast cancer (Gynecol. Oncol. 2009;113:6-11).ACOG recommends that these women begin screening for breast cancer at the age of 25 years through semiannual self-breast exams as well as annual mammography and breast MRI or sooner if a family member’s cancer was diagnosed prior to this age. Chemoprevention with tamoxifen also has been shown to reduce the risk of breast cancer in patients with BRCA2 disease, but is less effective for BRCA1 patients. Prophylactic mastectomy has the ability to reduce a woman’s risk of developing breast cancer by 90%-95%.

Hereditary nonpolyposis colorectal cancer syndrome

Another autosomal-dominant disorder, hereditary nonpolyposis colorectal cancer (HNPCC) syndrome arises as a result of a genetic defect in DNA mismatch repair mechanisms. Colon cancer is the most common malignancy associated with this syndrome, with a 70% risk by the age of 70 years (JAMA 2006;296:1507-17). Other associated cancers include those of the urinary tract, hepatobiliary tract, small intestine, skin, and brain, but strong supportive data are lacking. Beginning at age 20-25 years (or 10 years before the age of the youngest family member to develop colon cancer), a colonoscopy is recommended every 1-2 years. Annual urinalysis with cytology is advocated by some as a screening test for urinary tract cancers.

Patients with HNPCC have up to a 60% lifetime risk of endometrial cancer and a 10% risk of ovarian cancer (Int. J. Cancer 1999;81:214-8; Hum. Mol. Gene. 1997;6:105-10). The American Cancer Society recommends an endometrial biopsy and transvaginal ultrasonography annually between 30-35 years of age (JAMA 2006;296:1507-17). Schmeler et al. compared outcomes among 315 women with mismatch repair defects, 61 of whom underwent risk-reducing hysterectomy and BSO. With an average follow-up of greater than 7 years, none of the patients who underwent surgery developed cancer, while 33% of those who did not have surgery developed endometrial cancer and 5.5% developed ovarian cancer (N. Engl. J. Med. 2006;354:261-9). Because of these data, risk-reducing surgery at the age of 35 should be considered.

Cowden Syndrome

Cowden Syndrome, caused by an autosomal-dominant mutation in the PTEN gene, is associated with an up to 10% lifetime risk of endometrial cancer and a 50% risk of breast cancer (Obstet. Gynecol. Clin. N. Am. 2010;37:109-33). The NCCN notes that data are limited, but discussion of endometrial cancer symptoms should be encouraged (NCCN Guidelines Version 4, 2013). Annual endometrial sampling and ultrasound should be considered in woman aged 35-40 years or 10 years earlier than the youngest affected family member (Obstet. Gynecol. Clin. N. Am. 2010;37:109-33). Screening for breast cancer should include annual mammography and breast MRI starting between age 30-35 years or earlier depending on family history, per the NCCN guidelines.

It is important to note that additional genetic syndromes can have repercussions on the female genital tract, including the Li-Fraumeni (ovarian cancer), the Peutz-Jeghers (sex cord–stromal tumors of the ovary, granulosa cell tumors), and the Ollier (granulosa cell tumors) syndromes; unfortunately, screening guidelines for these rare syndromes have not been well studied (JAMA 2006;296:1507-17).

Dr. Schuler is a gynecologic oncologist at Good Samaritan Hospital in Cincinnati. Dr. Gehrig is professor and director of gynecologic oncology at the University of North Carolina at Chapel Hill. Dr. Gehrig and Dr. Schuler said they had no relevant financial disclosures.

Numerous screening methods for cervical cancer have been proposed internationally by various professional societies, including Pap cytology alone, cytology with human papillomavirus testing as triage (HPV testing for atypical squamous cells of unknown significance [ASCUS] on cytology), cytology with HPV cotesting (cytology and HPV testing obtained together), HPV testing alone, or HPV testing followed by Pap cytology triage (cytology in patients who are positive for high-risk oncogenic subtypes of HPV). Recommendations for use of cervical cytology and HPV testing continue to vary among professional societies, with variable adoption of these guidelines by providers as well. (Am. J. Prev. Med. 2013;45:175-81).

In 2012, updated cervical cancer screening recommendations were published by ASCCP (the American Society for Colposcopy and Cervical Pathology) (Am. J. Clin. Pathol. 2012;137:516-42); the USPSTF (U.S. Preventive Services Task Force ); and ACOG (the American College of Obstetricians and Gynecologists) (Obstet. Gynecol. 2009;114:1409-20).

These most recent guidelines show a greater degree of harmony across these governing bodies than did prior guidelines. All three professional societies recommend initiating screening at age 21 years and ceasing screening at age 65 years with an adequate screening history. All groups recommend against HPV cotesting in women under 30 years of age; however, after age 30 years, ASCCP and ACOG recommend HPV cotesting every 5 years as the preferred method of cervical cancer screening, while USPSTF suggests this only as an "option." Primary HPV testing without concurrent cytology for cervical cancer screening is not currently recommended by ASCCP and USPSTF and is not addressed by ACOG.

Efficacy of screening modalities

The rationale behind these screening recommendations depends on the efficacy of both cervical cytology and HPV testing to identify preinvasive cases or invasive cervical cancer. Multiple studies have addressed the sensitivity and specificity of cytology in cervical cancer screening. Overall, the sensitivity of Pap cytology is low at approximately 51%, while specificity is high at 96%-98% (Ann. Intern. Med. 2000;132:810-9; Vaccine 2008;26 Suppl. 10:K29-41). Since the initiation of cervical cytology for cancer screening, serial annual screening has compensated for the overall poor sensitivity of the test. Two consecutive annual Pap tests can increase overall sensitivity for detection of cervical cancer to 76%, and three consecutive annual Pap tests can increase overall sensitivity to 88%.

Unlike Pap cytology, HPV testing has a high sensitivity, ranging from 81%-97% in detection of cervical cancer (N. Engl. J. Med. 2007;357:1579-88). As a result, HPV testing does not rely on serial testing for accuracy and has a high negative predictive value, making negative results very reassuring. However, HPV testing has a slightly lower specificity of 94%, which results in a higher number of false positives. Furthermore, many patients who screen positive for high-risk HPV subtypes may have transient HPV infections, which are not clinically significant, and may not cause invasive cervical cancer.

Several randomized studies have compared Pap cytology to HPV testing for use in cervical cancer screening. A Canadian study randomized more than 10,000 women to either Pap cytology or HPV testing to detect cervical intraepithelial neoplasia (CIN) 2 or higher grade cervical lesions (Int. J. Cancer. 2006;119:615-23). Findings showed a sensitivity of 55.4% for Pap cytology vs. 94.6% for HPV testing. Pap cytology had a specificity of 96.8% while HPV testing had a specificity of 94.1%. The negative predictive value of HPV testing was 100%.

Swedescreen, a Swedish study of more 12,000 women (J. Med. Virol. 2007;79:1169-75), and POBASCAM, a large Dutch study of more than 18,000 women (Lancet 2007;370:1764-72), both compared HPV testing combined with Pap cytology (cotesting) to cytology alone. Both studies found that patients screened with Pap cytology alone had more CIN2 or greater lesions in follow-up than did patients screened with cytology in combination with HPV testing (relative risk, 0.53-0.58 for CIN 2+ and RR 0.45-0.53 for CIN 3+) (J. Natl. Cancer Inst. 2009;101:88-99).

Because of the higher sensitivity of HPV testing compared with Pap cytology, some have advocated the use of HPV testing as primary screening with cytology triage rather than the reverse (cytology with HPV triage), which is more commonly used today. A Finnish study showed that primary HPV testing with cytology performed only in patients who screened positive for high risk oncogenic subtypes of HPV was more sensitive than was conventional cytology in identifying cervical dysplasia and cancer. Additionally, in women over age 35 years, HPV testing combined with Pap cytology triage was more specific than cytology alone, and decreased colposcopy referrals and follow-up tests, making this screening option cost effective (J. Natl. Cancer Inst. 2009;101:1612-23). Nowhere else in medicine is a more specific test used prior to a more sensitive test when screening for disease; the screening test is typically the more sensitive, while the confirmatory test is the more specific.

HPV vaccination and effects on screening

Currently, given that the HPV vaccines available do not protect women from all oncogenic HPV types, the ASCCP, USPSTF, and ACOG all recommend screening vaccinated women in an identical fashion to unvaccinated women. Increasing vaccination rates will likely have an impact on the efficacy of the various cervical cancer screening modalities. Vaccination will result in a reduction in the prevalence of cytologic abnormalities. As disease prevalence decreases and screening intervals increase based on current guidelines, the positive predictive value of Pap cytology also will decline, resulting in more false-positive diagnoses and possibly unnecessary procedures and patient stress (Vaccine 2013;31:5495-9). As prevalence of disease decreases, Pap cytology has the potential to become less reliable. While the positive predictive value of HPV testing also declines with decreasing disease prevalence, HPV testing is more reproducible than interpretation of Pap cytology, so the extent of increasing false-positive results may be less (Vaccine 2006;24 Suppl 3:S3/171-7).

Future directions

HPV testing as primary screening for cervical cancer is not currently recommended. However, in the post-HPV vaccination era, this may become an increasingly reasonable approach, particularly in conjunction with Pap cytology used to triage patients who test positive for high-risk HPV subtypes. HPV testing has much greater sensitivity than Pap cytology does and can better identify patients who are likely to have a cytologic abnormality. In this group of patients with greater disease prevalence, the slightly higher specificity of Pap cytology can then be used to identify precancerous lesions and guide treatment. Once this group of patients with higher lesion prevalence than the general population has been identified through HPV testing, Pap cytology can then be used and will perform better than in a lower prevalence population.

The importance of Pap cytology and HPV testing in cervical cancer screening continues to evolve, particularly in the current era of HPV vaccination. The combination of HPV testing followed by Pap cytology has potential for becoming a highly effective screening strategy; however, the optimal administration of these tests is yet to be determined. As current screening modalities improve and new technologies emerge, ongoing work is needed to identify the most effective screening method for cervical cancer.

Dr. Wysham is currently a fellow in the department of gynecologic oncology at the University of North Carolina at Chapel Hill. Dr. Kim is the department of gynecologic oncology at UNC-Chapel Hill. Dr. Gehrig is professor and director of gynecologic oncology at UNC-Chapel Hill.

Numerous screening methods for cervical cancer have been proposed internationally by various professional societies, including Pap cytology alone, cytology with human papillomavirus testing as triage (HPV testing for atypical squamous cells of unknown significance [ASCUS] on cytology), cytology with HPV cotesting (cytology and HPV testing obtained together), HPV testing alone, or HPV testing followed by Pap cytology triage (cytology in patients who are positive for high-risk oncogenic subtypes of HPV). Recommendations for use of cervical cytology and HPV testing continue to vary among professional societies, with variable adoption of these guidelines by providers as well. (Am. J. Prev. Med. 2013;45:175-81).

In 2012, updated cervical cancer screening recommendations were published by ASCCP (the American Society for Colposcopy and Cervical Pathology) (Am. J. Clin. Pathol. 2012;137:516-42); the USPSTF (U.S. Preventive Services Task Force ); and ACOG (the American College of Obstetricians and Gynecologists) (Obstet. Gynecol. 2009;114:1409-20).

These most recent guidelines show a greater degree of harmony across these governing bodies than did prior guidelines. All three professional societies recommend initiating screening at age 21 years and ceasing screening at age 65 years with an adequate screening history. All groups recommend against HPV cotesting in women under 30 years of age; however, after age 30 years, ASCCP and ACOG recommend HPV cotesting every 5 years as the preferred method of cervical cancer screening, while USPSTF suggests this only as an "option." Primary HPV testing without concurrent cytology for cervical cancer screening is not currently recommended by ASCCP and USPSTF and is not addressed by ACOG.

Efficacy of screening modalities

The rationale behind these screening recommendations depends on the efficacy of both cervical cytology and HPV testing to identify preinvasive cases or invasive cervical cancer. Multiple studies have addressed the sensitivity and specificity of cytology in cervical cancer screening. Overall, the sensitivity of Pap cytology is low at approximately 51%, while specificity is high at 96%-98% (Ann. Intern. Med. 2000;132:810-9; Vaccine 2008;26 Suppl. 10:K29-41). Since the initiation of cervical cytology for cancer screening, serial annual screening has compensated for the overall poor sensitivity of the test. Two consecutive annual Pap tests can increase overall sensitivity for detection of cervical cancer to 76%, and three consecutive annual Pap tests can increase overall sensitivity to 88%.

Unlike Pap cytology, HPV testing has a high sensitivity, ranging from 81%-97% in detection of cervical cancer (N. Engl. J. Med. 2007;357:1579-88). As a result, HPV testing does not rely on serial testing for accuracy and has a high negative predictive value, making negative results very reassuring. However, HPV testing has a slightly lower specificity of 94%, which results in a higher number of false positives. Furthermore, many patients who screen positive for high-risk HPV subtypes may have transient HPV infections, which are not clinically significant, and may not cause invasive cervical cancer.

Several randomized studies have compared Pap cytology to HPV testing for use in cervical cancer screening. A Canadian study randomized more than 10,000 women to either Pap cytology or HPV testing to detect cervical intraepithelial neoplasia (CIN) 2 or higher grade cervical lesions (Int. J. Cancer. 2006;119:615-23). Findings showed a sensitivity of 55.4% for Pap cytology vs. 94.6% for HPV testing. Pap cytology had a specificity of 96.8% while HPV testing had a specificity of 94.1%. The negative predictive value of HPV testing was 100%.

Swedescreen, a Swedish study of more 12,000 women (J. Med. Virol. 2007;79:1169-75), and POBASCAM, a large Dutch study of more than 18,000 women (Lancet 2007;370:1764-72), both compared HPV testing combined with Pap cytology (cotesting) to cytology alone. Both studies found that patients screened with Pap cytology alone had more CIN2 or greater lesions in follow-up than did patients screened with cytology in combination with HPV testing (relative risk, 0.53-0.58 for CIN 2+ and RR 0.45-0.53 for CIN 3+) (J. Natl. Cancer Inst. 2009;101:88-99).

Because of the higher sensitivity of HPV testing compared with Pap cytology, some have advocated the use of HPV testing as primary screening with cytology triage rather than the reverse (cytology with HPV triage), which is more commonly used today. A Finnish study showed that primary HPV testing with cytology performed only in patients who screened positive for high risk oncogenic subtypes of HPV was more sensitive than was conventional cytology in identifying cervical dysplasia and cancer. Additionally, in women over age 35 years, HPV testing combined with Pap cytology triage was more specific than cytology alone, and decreased colposcopy referrals and follow-up tests, making this screening option cost effective (J. Natl. Cancer Inst. 2009;101:1612-23). Nowhere else in medicine is a more specific test used prior to a more sensitive test when screening for disease; the screening test is typically the more sensitive, while the confirmatory test is the more specific.

HPV vaccination and effects on screening

Currently, given that the HPV vaccines available do not protect women from all oncogenic HPV types, the ASCCP, USPSTF, and ACOG all recommend screening vaccinated women in an identical fashion to unvaccinated women. Increasing vaccination rates will likely have an impact on the efficacy of the various cervical cancer screening modalities. Vaccination will result in a reduction in the prevalence of cytologic abnormalities. As disease prevalence decreases and screening intervals increase based on current guidelines, the positive predictive value of Pap cytology also will decline, resulting in more false-positive diagnoses and possibly unnecessary procedures and patient stress (Vaccine 2013;31:5495-9). As prevalence of disease decreases, Pap cytology has the potential to become less reliable. While the positive predictive value of HPV testing also declines with decreasing disease prevalence, HPV testing is more reproducible than interpretation of Pap cytology, so the extent of increasing false-positive results may be less (Vaccine 2006;24 Suppl 3:S3/171-7).

Future directions

HPV testing as primary screening for cervical cancer is not currently recommended. However, in the post-HPV vaccination era, this may become an increasingly reasonable approach, particularly in conjunction with Pap cytology used to triage patients who test positive for high-risk HPV subtypes. HPV testing has much greater sensitivity than Pap cytology does and can better identify patients who are likely to have a cytologic abnormality. In this group of patients with greater disease prevalence, the slightly higher specificity of Pap cytology can then be used to identify precancerous lesions and guide treatment. Once this group of patients with higher lesion prevalence than the general population has been identified through HPV testing, Pap cytology can then be used and will perform better than in a lower prevalence population.

The importance of Pap cytology and HPV testing in cervical cancer screening continues to evolve, particularly in the current era of HPV vaccination. The combination of HPV testing followed by Pap cytology has potential for becoming a highly effective screening strategy; however, the optimal administration of these tests is yet to be determined. As current screening modalities improve and new technologies emerge, ongoing work is needed to identify the most effective screening method for cervical cancer.

Dr. Wysham is currently a fellow in the department of gynecologic oncology at the University of North Carolina at Chapel Hill. Dr. Kim is the department of gynecologic oncology at UNC-Chapel Hill. Dr. Gehrig is professor and director of gynecologic oncology at UNC-Chapel Hill.

Numerous screening methods for cervical cancer have been proposed internationally by various professional societies, including Pap cytology alone, cytology with human papillomavirus testing as triage (HPV testing for atypical squamous cells of unknown significance [ASCUS] on cytology), cytology with HPV cotesting (cytology and HPV testing obtained together), HPV testing alone, or HPV testing followed by Pap cytology triage (cytology in patients who are positive for high-risk oncogenic subtypes of HPV). Recommendations for use of cervical cytology and HPV testing continue to vary among professional societies, with variable adoption of these guidelines by providers as well. (Am. J. Prev. Med. 2013;45:175-81).

In 2012, updated cervical cancer screening recommendations were published by ASCCP (the American Society for Colposcopy and Cervical Pathology) (Am. J. Clin. Pathol. 2012;137:516-42); the USPSTF (U.S. Preventive Services Task Force ); and ACOG (the American College of Obstetricians and Gynecologists) (Obstet. Gynecol. 2009;114:1409-20).

These most recent guidelines show a greater degree of harmony across these governing bodies than did prior guidelines. All three professional societies recommend initiating screening at age 21 years and ceasing screening at age 65 years with an adequate screening history. All groups recommend against HPV cotesting in women under 30 years of age; however, after age 30 years, ASCCP and ACOG recommend HPV cotesting every 5 years as the preferred method of cervical cancer screening, while USPSTF suggests this only as an "option." Primary HPV testing without concurrent cytology for cervical cancer screening is not currently recommended by ASCCP and USPSTF and is not addressed by ACOG.

Efficacy of screening modalities

The rationale behind these screening recommendations depends on the efficacy of both cervical cytology and HPV testing to identify preinvasive cases or invasive cervical cancer. Multiple studies have addressed the sensitivity and specificity of cytology in cervical cancer screening. Overall, the sensitivity of Pap cytology is low at approximately 51%, while specificity is high at 96%-98% (Ann. Intern. Med. 2000;132:810-9; Vaccine 2008;26 Suppl. 10:K29-41). Since the initiation of cervical cytology for cancer screening, serial annual screening has compensated for the overall poor sensitivity of the test. Two consecutive annual Pap tests can increase overall sensitivity for detection of cervical cancer to 76%, and three consecutive annual Pap tests can increase overall sensitivity to 88%.

Unlike Pap cytology, HPV testing has a high sensitivity, ranging from 81%-97% in detection of cervical cancer (N. Engl. J. Med. 2007;357:1579-88). As a result, HPV testing does not rely on serial testing for accuracy and has a high negative predictive value, making negative results very reassuring. However, HPV testing has a slightly lower specificity of 94%, which results in a higher number of false positives. Furthermore, many patients who screen positive for high-risk HPV subtypes may have transient HPV infections, which are not clinically significant, and may not cause invasive cervical cancer.

Several randomized studies have compared Pap cytology to HPV testing for use in cervical cancer screening. A Canadian study randomized more than 10,000 women to either Pap cytology or HPV testing to detect cervical intraepithelial neoplasia (CIN) 2 or higher grade cervical lesions (Int. J. Cancer. 2006;119:615-23). Findings showed a sensitivity of 55.4% for Pap cytology vs. 94.6% for HPV testing. Pap cytology had a specificity of 96.8% while HPV testing had a specificity of 94.1%. The negative predictive value of HPV testing was 100%.

Swedescreen, a Swedish study of more 12,000 women (J. Med. Virol. 2007;79:1169-75), and POBASCAM, a large Dutch study of more than 18,000 women (Lancet 2007;370:1764-72), both compared HPV testing combined with Pap cytology (cotesting) to cytology alone. Both studies found that patients screened with Pap cytology alone had more CIN2 or greater lesions in follow-up than did patients screened with cytology in combination with HPV testing (relative risk, 0.53-0.58 for CIN 2+ and RR 0.45-0.53 for CIN 3+) (J. Natl. Cancer Inst. 2009;101:88-99).

Because of the higher sensitivity of HPV testing compared with Pap cytology, some have advocated the use of HPV testing as primary screening with cytology triage rather than the reverse (cytology with HPV triage), which is more commonly used today. A Finnish study showed that primary HPV testing with cytology performed only in patients who screened positive for high risk oncogenic subtypes of HPV was more sensitive than was conventional cytology in identifying cervical dysplasia and cancer. Additionally, in women over age 35 years, HPV testing combined with Pap cytology triage was more specific than cytology alone, and decreased colposcopy referrals and follow-up tests, making this screening option cost effective (J. Natl. Cancer Inst. 2009;101:1612-23). Nowhere else in medicine is a more specific test used prior to a more sensitive test when screening for disease; the screening test is typically the more sensitive, while the confirmatory test is the more specific.

HPV vaccination and effects on screening

Currently, given that the HPV vaccines available do not protect women from all oncogenic HPV types, the ASCCP, USPSTF, and ACOG all recommend screening vaccinated women in an identical fashion to unvaccinated women. Increasing vaccination rates will likely have an impact on the efficacy of the various cervical cancer screening modalities. Vaccination will result in a reduction in the prevalence of cytologic abnormalities. As disease prevalence decreases and screening intervals increase based on current guidelines, the positive predictive value of Pap cytology also will decline, resulting in more false-positive diagnoses and possibly unnecessary procedures and patient stress (Vaccine 2013;31:5495-9). As prevalence of disease decreases, Pap cytology has the potential to become less reliable. While the positive predictive value of HPV testing also declines with decreasing disease prevalence, HPV testing is more reproducible than interpretation of Pap cytology, so the extent of increasing false-positive results may be less (Vaccine 2006;24 Suppl 3:S3/171-7).

Future directions

HPV testing as primary screening for cervical cancer is not currently recommended. However, in the post-HPV vaccination era, this may become an increasingly reasonable approach, particularly in conjunction with Pap cytology used to triage patients who test positive for high-risk HPV subtypes. HPV testing has much greater sensitivity than Pap cytology does and can better identify patients who are likely to have a cytologic abnormality. In this group of patients with greater disease prevalence, the slightly higher specificity of Pap cytology can then be used to identify precancerous lesions and guide treatment. Once this group of patients with higher lesion prevalence than the general population has been identified through HPV testing, Pap cytology can then be used and will perform better than in a lower prevalence population.

The importance of Pap cytology and HPV testing in cervical cancer screening continues to evolve, particularly in the current era of HPV vaccination. The combination of HPV testing followed by Pap cytology has potential for becoming a highly effective screening strategy; however, the optimal administration of these tests is yet to be determined. As current screening modalities improve and new technologies emerge, ongoing work is needed to identify the most effective screening method for cervical cancer.

Dr. Wysham is currently a fellow in the department of gynecologic oncology at the University of North Carolina at Chapel Hill. Dr. Kim is the department of gynecologic oncology at UNC-Chapel Hill. Dr. Gehrig is professor and director of gynecologic oncology at UNC-Chapel Hill.

An adnexal mass is a common gynecological presentation that can affect women of all ages. Typically, the mass is identified during an annual pelvic exam or incidentally when patients undergo pelvic imaging for evaluation of gastrointestinal or gynecological complaints.

The main goal of evaluating an adnexal mass in the nonacute setting is to rule out malignancy. A careful evaluation is needed to accurately distinguish benign from malignant masses, but often a definitive diagnosis only can be achieved with surgery. Hence, in the United States, women have a 5%-10% chance of undergoing surgery to evaluate a mass, but only 13%-21% of these patients are diagnosed with an ovarian cancer (Obstet. Gynecol. 2007;110:201-14).

We will review a stepwise approach for the evaluation of a newly diagnosed mass. As part of our review, we will discuss imaging findings that should prompt surgical evaluation or continued observation, as well as the correct use of the currently available serum biomarkers.

The majority of adnexal masses are benign and present most commonly in premenopausal women. However, in the outpatient setting, the evaluation approach should be aimed at ruling out malignancy regardless of age or reproductive status. The patient’s age should be considered clinically, as the suspicion for ovarian cancer should be heightened in postmenopausal women.

The evaluation should start with a detailed history because it may help in determining the etiology of the mass. Pelvic pain and pressure are very common but nonspecific symptoms in women with adnexal masses. However, if the pain is of sudden onset, urgent evaluation is warranted to rule out adnexal torsion or a ruptured hemorrhagic cyst. A history of dysmenorrhea and/or dyspareunia may suggest endometriosis and coexisting endometrioma, whereas a patient with fever and a vaginal discharge should be evaluated for a tubo-ovarian abscess.

Patients also should be asked about symptoms associated with ovarian cancer including early satiety, constipation, and bloating, as well as their duration. In addition, abnormal uterine bleeding or virilization may suggest the presence of estrogen- or testosterone-secreting tumors. Lastly, a detailed family history is important, as the presence of ovarian, breast, or colon cancer in the family would increase suspicion for hereditary ovarian cancer syndromes.

A thorough physical exam should include a speculum exam as well as bimanual and rectovaginal exams. The focus of the pelvic exam should be determining the size, mobility, and consistency of the mass, as well as other findings that may help discriminate benign versus malignant neoplasms. Malignant masses are usually solid, irregular in shape, and tend to be fixed. Nodularity in the posterior cul-de-sac also is associated with malignancy. The abdominal exam should focus on the presence or absence of ascites (fluid wave), an omental mass, or inguinal adenopathy. However, none of the findings on exam are specific for an ovarian or fallopian tube malignancy, and imaging should be obtained for further evaluation.

Ultrasound is the imaging study of choice for the evaluation of an adnexal mass because it is less expensive than and diagnostically equivalent to other imaging modalities. A pelvic ultrasound can help delineate the anatomic origin of the mass, but it also can detect characteristics of the mass that may help with the diagnosis, and the decision of whether or not to proceed to surgery. Endometriomas, mature teratomas (dermoid cysts), simple ovarian cysts, and hemorrhagic cysts have sonographic features that are highly predictive of the histology. Depending on whether or not the patient is symptomatic, the patient’s age, and comorbidities, these masses might be followed expectantly.

Ultrasound features that are suggestive of malignancy include solid components, septations greater than 2-3 mm, and vascular flow. The presence of ascites or peritoneal nodules detected at the time of ultrasound also is highly suspicious of malignancy in patients with a pelvic mass. If a pelvic ultrasound is equivocal, pelvic magnetic resonance imaging (MRI) is the second study of choice. Computed tomography (CT scan) should be used to evaluate for metastatic disease in patients with suspected ovarian carcinoma (ascites, adenopathy, peritoneal thickening or nodularity, omental thickening).

Serum biomarkers also may aid in the evaluation. The most well-studied and commonly used biomarker in the evaluation of an adnexal mass is CA-125. In general, the utility of CA-125 is limited mainly because of its low specificity, especially in premenopausal women. However, it can be used as adjunct when an ovarian malignancy is suspected based on the patient’s history, risk factors, and imaging findings. The American College of Obstetricians and Gynecologists (ACOG) and the Society of Gynecologic Oncologists (SGO) advise referral to a gynecologic oncologist for postmenopausal women with an elevated CA-125. Meanwhile, for premenopausal women, the recommendation is for referral of those with a "very elevated" CA-125. However, a specific value has not been established (Obstet. Gynecol. 2011;117:742-6).

CA-125 by itself should not be used to decide whether or not to take a patient to surgery. Nevertheless, once the decision to operate has been made, CA-125 can be used in conjunction with HE4 to calculate a Risk of Malignancy Algorithm (ROMA) score. The score is based on menopausal status, and if the calculated risk is elevated, patient referral to a gynecologic oncologist for her surgery should be strongly considered.

Similarly, the OVA1 test is currently approved by the Food and Drug Administration to assess the likelihood of malignancy in patients who are having surgery for an adnexal mass. The test is also based on menopausal status, and if elevated, a referral to a gynecologic oncologist is recommended. In young women with adnexal masses, germ cell tumor markers may be more helpful (lactate dehydrogenase [LDH], human chorionic gonadotropin [hCG], alpha-fetoprotein [AFP]), while in patients with signs or symptoms of estrogen or androgen excess, sex cord-stromal tumor markers (inhibin B, anti-Müllerian hormone [AMH], testosterone, dehydroepiandrosterone [DHEA], estradiol) would be appropriate to obtain. While no tumor marker is "diagnostic," the results may assist in the decision to perform surgery and consider referral to a gynecologic oncologist.

In summary, the workup for an adnexal mass should include a detailed medical and family history, a thorough physical exam, and imaging with pelvic ultrasound. For premenopausal women, there is a higher incidence of adnexal masses, and, in fact, most of them are benign. In these women, one must weigh the risk/benefit of close monitoring with pelvic ultrasound versus surgical intervention. A serum CA-125 can be helpful, but only if it is significantly elevated.

If uncertainty remains after a complete evaluation has been performed, it is appropriate to refer to a gynecologic oncologist. In postmenopausal women, serum biomarkers should be used in conjunction with the history, physical, and ultrasound because of the higher risk of malignancy. In addition, surgical intervention should be offered to these patients regardless of serum marker values in the setting of a complex mass. If there is high suspicion for malignancy by history and imaging or elevated ROMA or OVA1, referral to a gynecologic oncologist is prudent.

Dr. Clarke-Pearson is the chair and the Robert A. Ross Distinguished Professor of Obstetrics and Gynecology, and a professor in the division of gynecologic oncology at the University of North Carolina, Chapel Hill. Dr. Roque is a fellow in the gynecologic oncology program at the University of North Carolina. Neither Dr. Clarke-Pearson nor Dr. Roque has any relevant financial disclosures. E-mail them at obnews@frontlinemedcom.com.

An adnexal mass is a common gynecological presentation that can affect women of all ages. Typically, the mass is identified during an annual pelvic exam or incidentally when patients undergo pelvic imaging for evaluation of gastrointestinal or gynecological complaints.

The main goal of evaluating an adnexal mass in the nonacute setting is to rule out malignancy. A careful evaluation is needed to accurately distinguish benign from malignant masses, but often a definitive diagnosis only can be achieved with surgery. Hence, in the United States, women have a 5%-10% chance of undergoing surgery to evaluate a mass, but only 13%-21% of these patients are diagnosed with an ovarian cancer (Obstet. Gynecol. 2007;110:201-14).

We will review a stepwise approach for the evaluation of a newly diagnosed mass. As part of our review, we will discuss imaging findings that should prompt surgical evaluation or continued observation, as well as the correct use of the currently available serum biomarkers.

The majority of adnexal masses are benign and present most commonly in premenopausal women. However, in the outpatient setting, the evaluation approach should be aimed at ruling out malignancy regardless of age or reproductive status. The patient’s age should be considered clinically, as the suspicion for ovarian cancer should be heightened in postmenopausal women.

The evaluation should start with a detailed history because it may help in determining the etiology of the mass. Pelvic pain and pressure are very common but nonspecific symptoms in women with adnexal masses. However, if the pain is of sudden onset, urgent evaluation is warranted to rule out adnexal torsion or a ruptured hemorrhagic cyst. A history of dysmenorrhea and/or dyspareunia may suggest endometriosis and coexisting endometrioma, whereas a patient with fever and a vaginal discharge should be evaluated for a tubo-ovarian abscess.

Patients also should be asked about symptoms associated with ovarian cancer including early satiety, constipation, and bloating, as well as their duration. In addition, abnormal uterine bleeding or virilization may suggest the presence of estrogen- or testosterone-secreting tumors. Lastly, a detailed family history is important, as the presence of ovarian, breast, or colon cancer in the family would increase suspicion for hereditary ovarian cancer syndromes.

A thorough physical exam should include a speculum exam as well as bimanual and rectovaginal exams. The focus of the pelvic exam should be determining the size, mobility, and consistency of the mass, as well as other findings that may help discriminate benign versus malignant neoplasms. Malignant masses are usually solid, irregular in shape, and tend to be fixed. Nodularity in the posterior cul-de-sac also is associated with malignancy. The abdominal exam should focus on the presence or absence of ascites (fluid wave), an omental mass, or inguinal adenopathy. However, none of the findings on exam are specific for an ovarian or fallopian tube malignancy, and imaging should be obtained for further evaluation.

Ultrasound is the imaging study of choice for the evaluation of an adnexal mass because it is less expensive than and diagnostically equivalent to other imaging modalities. A pelvic ultrasound can help delineate the anatomic origin of the mass, but it also can detect characteristics of the mass that may help with the diagnosis, and the decision of whether or not to proceed to surgery. Endometriomas, mature teratomas (dermoid cysts), simple ovarian cysts, and hemorrhagic cysts have sonographic features that are highly predictive of the histology. Depending on whether or not the patient is symptomatic, the patient’s age, and comorbidities, these masses might be followed expectantly.

Ultrasound features that are suggestive of malignancy include solid components, septations greater than 2-3 mm, and vascular flow. The presence of ascites or peritoneal nodules detected at the time of ultrasound also is highly suspicious of malignancy in patients with a pelvic mass. If a pelvic ultrasound is equivocal, pelvic magnetic resonance imaging (MRI) is the second study of choice. Computed tomography (CT scan) should be used to evaluate for metastatic disease in patients with suspected ovarian carcinoma (ascites, adenopathy, peritoneal thickening or nodularity, omental thickening).

Serum biomarkers also may aid in the evaluation. The most well-studied and commonly used biomarker in the evaluation of an adnexal mass is CA-125. In general, the utility of CA-125 is limited mainly because of its low specificity, especially in premenopausal women. However, it can be used as adjunct when an ovarian malignancy is suspected based on the patient’s history, risk factors, and imaging findings. The American College of Obstetricians and Gynecologists (ACOG) and the Society of Gynecologic Oncologists (SGO) advise referral to a gynecologic oncologist for postmenopausal women with an elevated CA-125. Meanwhile, for premenopausal women, the recommendation is for referral of those with a "very elevated" CA-125. However, a specific value has not been established (Obstet. Gynecol. 2011;117:742-6).

CA-125 by itself should not be used to decide whether or not to take a patient to surgery. Nevertheless, once the decision to operate has been made, CA-125 can be used in conjunction with HE4 to calculate a Risk of Malignancy Algorithm (ROMA) score. The score is based on menopausal status, and if the calculated risk is elevated, patient referral to a gynecologic oncologist for her surgery should be strongly considered.

Similarly, the OVA1 test is currently approved by the Food and Drug Administration to assess the likelihood of malignancy in patients who are having surgery for an adnexal mass. The test is also based on menopausal status, and if elevated, a referral to a gynecologic oncologist is recommended. In young women with adnexal masses, germ cell tumor markers may be more helpful (lactate dehydrogenase [LDH], human chorionic gonadotropin [hCG], alpha-fetoprotein [AFP]), while in patients with signs or symptoms of estrogen or androgen excess, sex cord-stromal tumor markers (inhibin B, anti-Müllerian hormone [AMH], testosterone, dehydroepiandrosterone [DHEA], estradiol) would be appropriate to obtain. While no tumor marker is "diagnostic," the results may assist in the decision to perform surgery and consider referral to a gynecologic oncologist.

In summary, the workup for an adnexal mass should include a detailed medical and family history, a thorough physical exam, and imaging with pelvic ultrasound. For premenopausal women, there is a higher incidence of adnexal masses, and, in fact, most of them are benign. In these women, one must weigh the risk/benefit of close monitoring with pelvic ultrasound versus surgical intervention. A serum CA-125 can be helpful, but only if it is significantly elevated.

If uncertainty remains after a complete evaluation has been performed, it is appropriate to refer to a gynecologic oncologist. In postmenopausal women, serum biomarkers should be used in conjunction with the history, physical, and ultrasound because of the higher risk of malignancy. In addition, surgical intervention should be offered to these patients regardless of serum marker values in the setting of a complex mass. If there is high suspicion for malignancy by history and imaging or elevated ROMA or OVA1, referral to a gynecologic oncologist is prudent.

Dr. Clarke-Pearson is the chair and the Robert A. Ross Distinguished Professor of Obstetrics and Gynecology, and a professor in the division of gynecologic oncology at the University of North Carolina, Chapel Hill. Dr. Roque is a fellow in the gynecologic oncology program at the University of North Carolina. Neither Dr. Clarke-Pearson nor Dr. Roque has any relevant financial disclosures. E-mail them at obnews@frontlinemedcom.com.

An adnexal mass is a common gynecological presentation that can affect women of all ages. Typically, the mass is identified during an annual pelvic exam or incidentally when patients undergo pelvic imaging for evaluation of gastrointestinal or gynecological complaints.

The main goal of evaluating an adnexal mass in the nonacute setting is to rule out malignancy. A careful evaluation is needed to accurately distinguish benign from malignant masses, but often a definitive diagnosis only can be achieved with surgery. Hence, in the United States, women have a 5%-10% chance of undergoing surgery to evaluate a mass, but only 13%-21% of these patients are diagnosed with an ovarian cancer (Obstet. Gynecol. 2007;110:201-14).

We will review a stepwise approach for the evaluation of a newly diagnosed mass. As part of our review, we will discuss imaging findings that should prompt surgical evaluation or continued observation, as well as the correct use of the currently available serum biomarkers.

The majority of adnexal masses are benign and present most commonly in premenopausal women. However, in the outpatient setting, the evaluation approach should be aimed at ruling out malignancy regardless of age or reproductive status. The patient’s age should be considered clinically, as the suspicion for ovarian cancer should be heightened in postmenopausal women.

The evaluation should start with a detailed history because it may help in determining the etiology of the mass. Pelvic pain and pressure are very common but nonspecific symptoms in women with adnexal masses. However, if the pain is of sudden onset, urgent evaluation is warranted to rule out adnexal torsion or a ruptured hemorrhagic cyst. A history of dysmenorrhea and/or dyspareunia may suggest endometriosis and coexisting endometrioma, whereas a patient with fever and a vaginal discharge should be evaluated for a tubo-ovarian abscess.

Patients also should be asked about symptoms associated with ovarian cancer including early satiety, constipation, and bloating, as well as their duration. In addition, abnormal uterine bleeding or virilization may suggest the presence of estrogen- or testosterone-secreting tumors. Lastly, a detailed family history is important, as the presence of ovarian, breast, or colon cancer in the family would increase suspicion for hereditary ovarian cancer syndromes.

A thorough physical exam should include a speculum exam as well as bimanual and rectovaginal exams. The focus of the pelvic exam should be determining the size, mobility, and consistency of the mass, as well as other findings that may help discriminate benign versus malignant neoplasms. Malignant masses are usually solid, irregular in shape, and tend to be fixed. Nodularity in the posterior cul-de-sac also is associated with malignancy. The abdominal exam should focus on the presence or absence of ascites (fluid wave), an omental mass, or inguinal adenopathy. However, none of the findings on exam are specific for an ovarian or fallopian tube malignancy, and imaging should be obtained for further evaluation.

Ultrasound is the imaging study of choice for the evaluation of an adnexal mass because it is less expensive than and diagnostically equivalent to other imaging modalities. A pelvic ultrasound can help delineate the anatomic origin of the mass, but it also can detect characteristics of the mass that may help with the diagnosis, and the decision of whether or not to proceed to surgery. Endometriomas, mature teratomas (dermoid cysts), simple ovarian cysts, and hemorrhagic cysts have sonographic features that are highly predictive of the histology. Depending on whether or not the patient is symptomatic, the patient’s age, and comorbidities, these masses might be followed expectantly.

Ultrasound features that are suggestive of malignancy include solid components, septations greater than 2-3 mm, and vascular flow. The presence of ascites or peritoneal nodules detected at the time of ultrasound also is highly suspicious of malignancy in patients with a pelvic mass. If a pelvic ultrasound is equivocal, pelvic magnetic resonance imaging (MRI) is the second study of choice. Computed tomography (CT scan) should be used to evaluate for metastatic disease in patients with suspected ovarian carcinoma (ascites, adenopathy, peritoneal thickening or nodularity, omental thickening).

Serum biomarkers also may aid in the evaluation. The most well-studied and commonly used biomarker in the evaluation of an adnexal mass is CA-125. In general, the utility of CA-125 is limited mainly because of its low specificity, especially in premenopausal women. However, it can be used as adjunct when an ovarian malignancy is suspected based on the patient’s history, risk factors, and imaging findings. The American College of Obstetricians and Gynecologists (ACOG) and the Society of Gynecologic Oncologists (SGO) advise referral to a gynecologic oncologist for postmenopausal women with an elevated CA-125. Meanwhile, for premenopausal women, the recommendation is for referral of those with a "very elevated" CA-125. However, a specific value has not been established (Obstet. Gynecol. 2011;117:742-6).

CA-125 by itself should not be used to decide whether or not to take a patient to surgery. Nevertheless, once the decision to operate has been made, CA-125 can be used in conjunction with HE4 to calculate a Risk of Malignancy Algorithm (ROMA) score. The score is based on menopausal status, and if the calculated risk is elevated, patient referral to a gynecologic oncologist for her surgery should be strongly considered.

Similarly, the OVA1 test is currently approved by the Food and Drug Administration to assess the likelihood of malignancy in patients who are having surgery for an adnexal mass. The test is also based on menopausal status, and if elevated, a referral to a gynecologic oncologist is recommended. In young women with adnexal masses, germ cell tumor markers may be more helpful (lactate dehydrogenase [LDH], human chorionic gonadotropin [hCG], alpha-fetoprotein [AFP]), while in patients with signs or symptoms of estrogen or androgen excess, sex cord-stromal tumor markers (inhibin B, anti-Müllerian hormone [AMH], testosterone, dehydroepiandrosterone [DHEA], estradiol) would be appropriate to obtain. While no tumor marker is "diagnostic," the results may assist in the decision to perform surgery and consider referral to a gynecologic oncologist.

In summary, the workup for an adnexal mass should include a detailed medical and family history, a thorough physical exam, and imaging with pelvic ultrasound. For premenopausal women, there is a higher incidence of adnexal masses, and, in fact, most of them are benign. In these women, one must weigh the risk/benefit of close monitoring with pelvic ultrasound versus surgical intervention. A serum CA-125 can be helpful, but only if it is significantly elevated.

If uncertainty remains after a complete evaluation has been performed, it is appropriate to refer to a gynecologic oncologist. In postmenopausal women, serum biomarkers should be used in conjunction with the history, physical, and ultrasound because of the higher risk of malignancy. In addition, surgical intervention should be offered to these patients regardless of serum marker values in the setting of a complex mass. If there is high suspicion for malignancy by history and imaging or elevated ROMA or OVA1, referral to a gynecologic oncologist is prudent.

Dr. Clarke-Pearson is the chair and the Robert A. Ross Distinguished Professor of Obstetrics and Gynecology, and a professor in the division of gynecologic oncology at the University of North Carolina, Chapel Hill. Dr. Roque is a fellow in the gynecologic oncology program at the University of North Carolina. Neither Dr. Clarke-Pearson nor Dr. Roque has any relevant financial disclosures. E-mail them at obnews@frontlinemedcom.com.

For the last decade, the obesity epidemic in the United States has been well recognized. In 2001, the surgeon general made a call to action to combat obesity. Despite this effort, obesity rates in the United States continued to rise, and in 2009-2010, more than one third (35.7%) of adults in the United States were classified as obese, according to the Centers for Disease Control and Prevention.

The definition of obesity relies on the body mass index. BMI is defined as a person’s weight in kilograms divided by the individual’s height in meters squared. Overweight is defined as a BMI of 25-29.9 kg/m² and obesity as a BMI of greater than 30 kg/m². Obesity has been further classified by the World Health Organization into class I (BMI, 30-34.9 kg/m²), class II (BMI, 35-39.9 kg/ m²), and class III (BMI, greater than 40 kg/ m²).

In the United States in 2013, there were approximately 50,000 new cases and more than 8,000 deaths from endometrial cancer (CA Cancer J. Clin. 2013;63:11-30). Rates of endometrial cancer have risen steadily along with the obesity epidemic. This is no surprise, as obesity has been linked to the development of endometrial cancer. It is believed that high levels of circulating estrogen created by adipose tissue convert androstenedione to estrone, and there is aromatization of androgens. For each 5-kg/m² increase in BMI, there is an increased risk of development of endometrial cancer (relative risk, 1.59) (Lancet 2008;371:569). While many physicians realize the link between obesity and the hyperestrogenic state associated with endometrial cancers, increased BMI is also associated with an increased risk of ovarian cancer (odds ratio, 1.3) (Eur. J. Cancer 2007;43:690).

In addition to increasing the risk of developing gynecologic cancers, obesity also increases the risk of death from all gynecologic malignancies. In the Cancer Prevention Study II, a large prospective cohort study, a BMI greater than 35 was associated with increased mortality compared with normal weight in ovarian (RR, 1.51), endometrial (RR, 2.77), and cervical cancer (RR, 3.20) (N. Engl. J. Med. 2003;348:1625). The same study found that those with a BMI greater than 40 with endometrial cancer had a relative risk of death of 6.25.

The increased mortality seen in obese endometrial cancer patients is particularly striking, given the fact that these women are more likely to have less-aggressive histologies and earlier-stage cancers (Gynecol. Oncol. 2009;90:150-7; Gynecol. Oncol. 2009;114:121-7). This highlights the importance of weight loss and healthy lifestyle choices in this population. The American Cancer Society recommends focusing on healthy lifestyles in cancer survivors. Key recommendations include the maintenance of healthy weight or weight loss for the overweight/obese, physical activity with at least 30 minutes of moderate activity on 5 or more days per week, a healthy diet with at least five servings of fruits and vegetables per day with limited processed foods and red meats, and limited alcohol intake (CA Cancer J. Clin. 2012;62:243).

Practicing gynecologists should appreciate the increasing rates of endometrial cancer and remain highly suspicious of abnormal uterine bleeding in their obese patients. Early detection of cancers and modification of lifestyle remain the mainstay of improving outcomes in obese patients.

Dr. Gehrig is professor and director of gynecologic oncology at the University of North Carolina at Chapel Hill. Dr. Clark is a chief resident in the department of obstetrics and gynecology at the university. Dr. Gehrig and Dr. Clark have no relevant conflicts of interest.*

* This story was updated 1/27/2014

For the last decade, the obesity epidemic in the United States has been well recognized. In 2001, the surgeon general made a call to action to combat obesity. Despite this effort, obesity rates in the United States continued to rise, and in 2009-2010, more than one third (35.7%) of adults in the United States were classified as obese, according to the Centers for Disease Control and Prevention.

The definition of obesity relies on the body mass index. BMI is defined as a person’s weight in kilograms divided by the individual’s height in meters squared. Overweight is defined as a BMI of 25-29.9 kg/m² and obesity as a BMI of greater than 30 kg/m². Obesity has been further classified by the World Health Organization into class I (BMI, 30-34.9 kg/m²), class II (BMI, 35-39.9 kg/ m²), and class III (BMI, greater than 40 kg/ m²).

In the United States in 2013, there were approximately 50,000 new cases and more than 8,000 deaths from endometrial cancer (CA Cancer J. Clin. 2013;63:11-30). Rates of endometrial cancer have risen steadily along with the obesity epidemic. This is no surprise, as obesity has been linked to the development of endometrial cancer. It is believed that high levels of circulating estrogen created by adipose tissue convert androstenedione to estrone, and there is aromatization of androgens. For each 5-kg/m² increase in BMI, there is an increased risk of development of endometrial cancer (relative risk, 1.59) (Lancet 2008;371:569). While many physicians realize the link between obesity and the hyperestrogenic state associated with endometrial cancers, increased BMI is also associated with an increased risk of ovarian cancer (odds ratio, 1.3) (Eur. J. Cancer 2007;43:690).

In addition to increasing the risk of developing gynecologic cancers, obesity also increases the risk of death from all gynecologic malignancies. In the Cancer Prevention Study II, a large prospective cohort study, a BMI greater than 35 was associated with increased mortality compared with normal weight in ovarian (RR, 1.51), endometrial (RR, 2.77), and cervical cancer (RR, 3.20) (N. Engl. J. Med. 2003;348:1625). The same study found that those with a BMI greater than 40 with endometrial cancer had a relative risk of death of 6.25.

The increased mortality seen in obese endometrial cancer patients is particularly striking, given the fact that these women are more likely to have less-aggressive histologies and earlier-stage cancers (Gynecol. Oncol. 2009;90:150-7; Gynecol. Oncol. 2009;114:121-7). This highlights the importance of weight loss and healthy lifestyle choices in this population. The American Cancer Society recommends focusing on healthy lifestyles in cancer survivors. Key recommendations include the maintenance of healthy weight or weight loss for the overweight/obese, physical activity with at least 30 minutes of moderate activity on 5 or more days per week, a healthy diet with at least five servings of fruits and vegetables per day with limited processed foods and red meats, and limited alcohol intake (CA Cancer J. Clin. 2012;62:243).

Practicing gynecologists should appreciate the increasing rates of endometrial cancer and remain highly suspicious of abnormal uterine bleeding in their obese patients. Early detection of cancers and modification of lifestyle remain the mainstay of improving outcomes in obese patients.

Dr. Gehrig is professor and director of gynecologic oncology at the University of North Carolina at Chapel Hill. Dr. Clark is a chief resident in the department of obstetrics and gynecology at the university. Dr. Gehrig and Dr. Clark have no relevant conflicts of interest.*

* This story was updated 1/27/2014

For the last decade, the obesity epidemic in the United States has been well recognized. In 2001, the surgeon general made a call to action to combat obesity. Despite this effort, obesity rates in the United States continued to rise, and in 2009-2010, more than one third (35.7%) of adults in the United States were classified as obese, according to the Centers for Disease Control and Prevention.

The definition of obesity relies on the body mass index. BMI is defined as a person’s weight in kilograms divided by the individual’s height in meters squared. Overweight is defined as a BMI of 25-29.9 kg/m² and obesity as a BMI of greater than 30 kg/m². Obesity has been further classified by the World Health Organization into class I (BMI, 30-34.9 kg/m²), class II (BMI, 35-39.9 kg/ m²), and class III (BMI, greater than 40 kg/ m²).

In the United States in 2013, there were approximately 50,000 new cases and more than 8,000 deaths from endometrial cancer (CA Cancer J. Clin. 2013;63:11-30). Rates of endometrial cancer have risen steadily along with the obesity epidemic. This is no surprise, as obesity has been linked to the development of endometrial cancer. It is believed that high levels of circulating estrogen created by adipose tissue convert androstenedione to estrone, and there is aromatization of androgens. For each 5-kg/m² increase in BMI, there is an increased risk of development of endometrial cancer (relative risk, 1.59) (Lancet 2008;371:569). While many physicians realize the link between obesity and the hyperestrogenic state associated with endometrial cancers, increased BMI is also associated with an increased risk of ovarian cancer (odds ratio, 1.3) (Eur. J. Cancer 2007;43:690).

In addition to increasing the risk of developing gynecologic cancers, obesity also increases the risk of death from all gynecologic malignancies. In the Cancer Prevention Study II, a large prospective cohort study, a BMI greater than 35 was associated with increased mortality compared with normal weight in ovarian (RR, 1.51), endometrial (RR, 2.77), and cervical cancer (RR, 3.20) (N. Engl. J. Med. 2003;348:1625). The same study found that those with a BMI greater than 40 with endometrial cancer had a relative risk of death of 6.25.

The increased mortality seen in obese endometrial cancer patients is particularly striking, given the fact that these women are more likely to have less-aggressive histologies and earlier-stage cancers (Gynecol. Oncol. 2009;90:150-7; Gynecol. Oncol. 2009;114:121-7). This highlights the importance of weight loss and healthy lifestyle choices in this population. The American Cancer Society recommends focusing on healthy lifestyles in cancer survivors. Key recommendations include the maintenance of healthy weight or weight loss for the overweight/obese, physical activity with at least 30 minutes of moderate activity on 5 or more days per week, a healthy diet with at least five servings of fruits and vegetables per day with limited processed foods and red meats, and limited alcohol intake (CA Cancer J. Clin. 2012;62:243).

Practicing gynecologists should appreciate the increasing rates of endometrial cancer and remain highly suspicious of abnormal uterine bleeding in their obese patients. Early detection of cancers and modification of lifestyle remain the mainstay of improving outcomes in obese patients.

Dr. Gehrig is professor and director of gynecologic oncology at the University of North Carolina at Chapel Hill. Dr. Clark is a chief resident in the department of obstetrics and gynecology at the university. Dr. Gehrig and Dr. Clark have no relevant conflicts of interest.*

* This story was updated 1/27/2014