SAN DIEGO – Endometrial pathology findings at 3 months predicted response to levonorgestrel-releasing IUD treatment for complex atypical hyperplasia or grade 1 endometrial cancer at the MD Anderson Cancer Center in Houston.

Twenty-nine of 32 women (91%) who responded by 12 months showed stromal, glandular, or other endometrial changes indicating an effect at 3 months, vs. only 3 of 9 nonresponders (33%) (P less than .001). There were no differences in responders versus nonresponders in median age (47 vs. 56 years, P = .2) or body mass index (45 vs. 55 kg/m², P = .16).

The finding addresses an “unmet need” for markers of response to levonorgestrel-releasing IUD therapy. “You can look at [early] pathology” and have an idea how patients will do, Dr. Shannon Westin, a study investigator who is with the department of gynecologic oncology at MD Anderson, said at the annual meeting of the Society of Gynecologic Oncology.

Twenty-seven of 29 women (93%) with complex atypical hyperplasia (CAH) responded completely to the IUD, meaning they had normal endometrium or hyperplasia without atypia at 12 months. The response rate for endometrial cancer was 67%; 7 of 12 women had a complete response, and an 8th was diagnosed at 12 months with CAH, indicating a partial response. The rest of the patients remained stable or progressed.

Endometrial biopsies were performed every 3 months; the team also did molecular testing on tumors from 20 patients. Baseline protein Ki67 – a marker of proliferation – was significantly higher in nonresponders. Expression of several estrogen-induced genes was higher in responders.

Patients opted for the IUD to retain fertility or because obesity or comorbidities precluded surgery. Exclusion criteria included prior treatment for CAH or endometrial cancer, evidence of extrauterine spread, or levonorgestrel IUD contraindications, such as uterine infection.

Adverse events – primarily irregular bleeding and cramping – were mild and tended to resolve by 12 months. Treatment had little effect on measures of social, mental, and physical function. About half of the patients were white, a third were Hispanic, and most of the remaining patients were black.

There was no external funding for the work. Dr. Westin is a consultant for AstraZeneca, Medivation, Roche, Ovation, and Vermillion, and reported receiving research funding from AstraZeneca, Critical Outcomes Technologies, and Novartis.

[email protected]

SAN DIEGO – Endometrial pathology findings at 3 months predicted response to levonorgestrel-releasing IUD treatment for complex atypical hyperplasia or grade 1 endometrial cancer at the MD Anderson Cancer Center in Houston.

Twenty-nine of 32 women (91%) who responded by 12 months showed stromal, glandular, or other endometrial changes indicating an effect at 3 months, vs. only 3 of 9 nonresponders (33%) (P less than .001). There were no differences in responders versus nonresponders in median age (47 vs. 56 years, P = .2) or body mass index (45 vs. 55 kg/m², P = .16).

The finding addresses an “unmet need” for markers of response to levonorgestrel-releasing IUD therapy. “You can look at [early] pathology” and have an idea how patients will do, Dr. Shannon Westin, a study investigator who is with the department of gynecologic oncology at MD Anderson, said at the annual meeting of the Society of Gynecologic Oncology.

Twenty-seven of 29 women (93%) with complex atypical hyperplasia (CAH) responded completely to the IUD, meaning they had normal endometrium or hyperplasia without atypia at 12 months. The response rate for endometrial cancer was 67%; 7 of 12 women had a complete response, and an 8th was diagnosed at 12 months with CAH, indicating a partial response. The rest of the patients remained stable or progressed.

Endometrial biopsies were performed every 3 months; the team also did molecular testing on tumors from 20 patients. Baseline protein Ki67 – a marker of proliferation – was significantly higher in nonresponders. Expression of several estrogen-induced genes was higher in responders.

Patients opted for the IUD to retain fertility or because obesity or comorbidities precluded surgery. Exclusion criteria included prior treatment for CAH or endometrial cancer, evidence of extrauterine spread, or levonorgestrel IUD contraindications, such as uterine infection.

Adverse events – primarily irregular bleeding and cramping – were mild and tended to resolve by 12 months. Treatment had little effect on measures of social, mental, and physical function. About half of the patients were white, a third were Hispanic, and most of the remaining patients were black.

There was no external funding for the work. Dr. Westin is a consultant for AstraZeneca, Medivation, Roche, Ovation, and Vermillion, and reported receiving research funding from AstraZeneca, Critical Outcomes Technologies, and Novartis.

[email protected]

SAN DIEGO – Endometrial pathology findings at 3 months predicted response to levonorgestrel-releasing IUD treatment for complex atypical hyperplasia or grade 1 endometrial cancer at the MD Anderson Cancer Center in Houston.

Twenty-nine of 32 women (91%) who responded by 12 months showed stromal, glandular, or other endometrial changes indicating an effect at 3 months, vs. only 3 of 9 nonresponders (33%) (P less than .001). There were no differences in responders versus nonresponders in median age (47 vs. 56 years, P = .2) or body mass index (45 vs. 55 kg/m², P = .16).

The finding addresses an “unmet need” for markers of response to levonorgestrel-releasing IUD therapy. “You can look at [early] pathology” and have an idea how patients will do, Dr. Shannon Westin, a study investigator who is with the department of gynecologic oncology at MD Anderson, said at the annual meeting of the Society of Gynecologic Oncology.

Twenty-seven of 29 women (93%) with complex atypical hyperplasia (CAH) responded completely to the IUD, meaning they had normal endometrium or hyperplasia without atypia at 12 months. The response rate for endometrial cancer was 67%; 7 of 12 women had a complete response, and an 8th was diagnosed at 12 months with CAH, indicating a partial response. The rest of the patients remained stable or progressed.

Endometrial biopsies were performed every 3 months; the team also did molecular testing on tumors from 20 patients. Baseline protein Ki67 – a marker of proliferation – was significantly higher in nonresponders. Expression of several estrogen-induced genes was higher in responders.

Patients opted for the IUD to retain fertility or because obesity or comorbidities precluded surgery. Exclusion criteria included prior treatment for CAH or endometrial cancer, evidence of extrauterine spread, or levonorgestrel IUD contraindications, such as uterine infection.

Adverse events – primarily irregular bleeding and cramping – were mild and tended to resolve by 12 months. Treatment had little effect on measures of social, mental, and physical function. About half of the patients were white, a third were Hispanic, and most of the remaining patients were black.

There was no external funding for the work. Dr. Westin is a consultant for AstraZeneca, Medivation, Roche, Ovation, and Vermillion, and reported receiving research funding from AstraZeneca, Critical Outcomes Technologies, and Novartis.

[email protected]

Women with suspected coronary artery disease had similar symptoms and more heart disease risk factors, compared with men, but were assessed as lower risk by their providers and on all standard risk scores, according to a secondary analysis of the PROMISE trial.

The results “highlight the need for sex-specific approaches to coronary artery disease evaluation and testing,” said Kshipra Hemal at Duke Clinical Research Institute in Durham, N.C., and her associates. The findings will be presented April 3 at the annual meeting of the American College of Cardiology and were published online March 23 in the Journal of the American College of Cardiology: Cardiovascular Imaging.

©Alexander Raths/Fotolia.com

The PROMISE (Prospective Multicenter Imaging Study for the Evaluation of Chest Pain) trial is one of the largest contemporary trials of symptomatic, nonacute suspected CAD. The study included 10,003 stable outpatients, nearly half of whom were women. The researchers calculated the 2008 Framingham score, 2013 Atherosclerotic Cardiovascular Disease score, 1979 Diamond and Forrester score, modified 2011 Diamond and Forrester score, and 2012 combined Diamond-Forrester and Coronary Artery Surgery Study scores for all patients. Patients also were randomly assigned to either anatomical testing with CT angiography or to functional testing with exercise electrocardiogram, stress nuclear imaging, or stress echocardiogram (J Am Coll Cardiol Img. 2016 Mar 23. doi: 10.1016/j.jcmg.2016.02.001).

Women in the study were an average of 3 years older than the men and were significantly more likely to be hypertensive (67% vs. 63%), dyslipidemic (69% vs. 66%), and to have a family history of premature CAD (35% vs. 29%; P less than .01 for all comparisons), the researchers reported. Nonetheless, all five risk scores characterized women as lower risk than men (P less than .001 for mean differences). Moreover, before testing, providers characterized 41% of women having a low (less than 30%) likelihood of CAD, compared with 34% of men (P less than .001).

Women were more likely than men to be referred for stress echocardiography or nuclear stress test, but only 9.7% had a positive noninvasive test, compared with 15% of men (P less than .001), the researchers also reported. “A number of characteristics predicted positive test results, and many characteristics were similar between the sexes,” they added. “However, in multivariable models, key predictors of test positivity were few and varied by sex.” Body mass index and Framingham risk score predicted a positive test for women, while both the Framingham and modified Diamond-Forrester risk scores predicted a positive test for men.

Chest pain was the most common primary symptom reported by nearly three-quarters of women and men and was described as “crushing/pressure/squeezing/tightness” 53% and 46% of the time, respectively (P less than .001). Dyspnea was the second most frequent primary symptom at 15% for both sexes. Women were more likely than men to describe back pain, neck or jaw pain, or palpitations, but only 0.6% to 2.7% of patients ranked these among their main symptoms.

“Further studies are warranted to examine the underlying pathophysiology and implications for clinical care of the sex-based clinical differences observed along the entire diagnostic pathway of suspected CAD, including risk factor burden, presenting symptoms, and testing results,” the researchers concluded.

The PROMISE study was funded by the National Heart, Lung, and Blood Institute. Ms. Hemal had no disclosures. Senior author Dr. Pamela S. Douglas disclosed grant support from HeartFlow and having served on a data and safety monitoring board for General Electric Healthcare. Two of the other 15 coinvestigators also disclosed relationships with industry; the rest had no disclosures.

Women with suspected coronary artery disease had similar symptoms and more heart disease risk factors, compared with men, but were assessed as lower risk by their providers and on all standard risk scores, according to a secondary analysis of the PROMISE trial.

The results “highlight the need for sex-specific approaches to coronary artery disease evaluation and testing,” said Kshipra Hemal at Duke Clinical Research Institute in Durham, N.C., and her associates. The findings will be presented April 3 at the annual meeting of the American College of Cardiology and were published online March 23 in the Journal of the American College of Cardiology: Cardiovascular Imaging.

©Alexander Raths/Fotolia.com

The PROMISE (Prospective Multicenter Imaging Study for the Evaluation of Chest Pain) trial is one of the largest contemporary trials of symptomatic, nonacute suspected CAD. The study included 10,003 stable outpatients, nearly half of whom were women. The researchers calculated the 2008 Framingham score, 2013 Atherosclerotic Cardiovascular Disease score, 1979 Diamond and Forrester score, modified 2011 Diamond and Forrester score, and 2012 combined Diamond-Forrester and Coronary Artery Surgery Study scores for all patients. Patients also were randomly assigned to either anatomical testing with CT angiography or to functional testing with exercise electrocardiogram, stress nuclear imaging, or stress echocardiogram (J Am Coll Cardiol Img. 2016 Mar 23. doi: 10.1016/j.jcmg.2016.02.001).

Women in the study were an average of 3 years older than the men and were significantly more likely to be hypertensive (67% vs. 63%), dyslipidemic (69% vs. 66%), and to have a family history of premature CAD (35% vs. 29%; P less than .01 for all comparisons), the researchers reported. Nonetheless, all five risk scores characterized women as lower risk than men (P less than .001 for mean differences). Moreover, before testing, providers characterized 41% of women having a low (less than 30%) likelihood of CAD, compared with 34% of men (P less than .001).

Women were more likely than men to be referred for stress echocardiography or nuclear stress test, but only 9.7% had a positive noninvasive test, compared with 15% of men (P less than .001), the researchers also reported. “A number of characteristics predicted positive test results, and many characteristics were similar between the sexes,” they added. “However, in multivariable models, key predictors of test positivity were few and varied by sex.” Body mass index and Framingham risk score predicted a positive test for women, while both the Framingham and modified Diamond-Forrester risk scores predicted a positive test for men.

Chest pain was the most common primary symptom reported by nearly three-quarters of women and men and was described as “crushing/pressure/squeezing/tightness” 53% and 46% of the time, respectively (P less than .001). Dyspnea was the second most frequent primary symptom at 15% for both sexes. Women were more likely than men to describe back pain, neck or jaw pain, or palpitations, but only 0.6% to 2.7% of patients ranked these among their main symptoms.

“Further studies are warranted to examine the underlying pathophysiology and implications for clinical care of the sex-based clinical differences observed along the entire diagnostic pathway of suspected CAD, including risk factor burden, presenting symptoms, and testing results,” the researchers concluded.

The PROMISE study was funded by the National Heart, Lung, and Blood Institute. Ms. Hemal had no disclosures. Senior author Dr. Pamela S. Douglas disclosed grant support from HeartFlow and having served on a data and safety monitoring board for General Electric Healthcare. Two of the other 15 coinvestigators also disclosed relationships with industry; the rest had no disclosures.

Women with suspected coronary artery disease had similar symptoms and more heart disease risk factors, compared with men, but were assessed as lower risk by their providers and on all standard risk scores, according to a secondary analysis of the PROMISE trial.

The results “highlight the need for sex-specific approaches to coronary artery disease evaluation and testing,” said Kshipra Hemal at Duke Clinical Research Institute in Durham, N.C., and her associates. The findings will be presented April 3 at the annual meeting of the American College of Cardiology and were published online March 23 in the Journal of the American College of Cardiology: Cardiovascular Imaging.

©Alexander Raths/Fotolia.com

The PROMISE (Prospective Multicenter Imaging Study for the Evaluation of Chest Pain) trial is one of the largest contemporary trials of symptomatic, nonacute suspected CAD. The study included 10,003 stable outpatients, nearly half of whom were women. The researchers calculated the 2008 Framingham score, 2013 Atherosclerotic Cardiovascular Disease score, 1979 Diamond and Forrester score, modified 2011 Diamond and Forrester score, and 2012 combined Diamond-Forrester and Coronary Artery Surgery Study scores for all patients. Patients also were randomly assigned to either anatomical testing with CT angiography or to functional testing with exercise electrocardiogram, stress nuclear imaging, or stress echocardiogram (J Am Coll Cardiol Img. 2016 Mar 23. doi: 10.1016/j.jcmg.2016.02.001).

Women in the study were an average of 3 years older than the men and were significantly more likely to be hypertensive (67% vs. 63%), dyslipidemic (69% vs. 66%), and to have a family history of premature CAD (35% vs. 29%; P less than .01 for all comparisons), the researchers reported. Nonetheless, all five risk scores characterized women as lower risk than men (P less than .001 for mean differences). Moreover, before testing, providers characterized 41% of women having a low (less than 30%) likelihood of CAD, compared with 34% of men (P less than .001).

Women were more likely than men to be referred for stress echocardiography or nuclear stress test, but only 9.7% had a positive noninvasive test, compared with 15% of men (P less than .001), the researchers also reported. “A number of characteristics predicted positive test results, and many characteristics were similar between the sexes,” they added. “However, in multivariable models, key predictors of test positivity were few and varied by sex.” Body mass index and Framingham risk score predicted a positive test for women, while both the Framingham and modified Diamond-Forrester risk scores predicted a positive test for men.

Chest pain was the most common primary symptom reported by nearly three-quarters of women and men and was described as “crushing/pressure/squeezing/tightness” 53% and 46% of the time, respectively (P less than .001). Dyspnea was the second most frequent primary symptom at 15% for both sexes. Women were more likely than men to describe back pain, neck or jaw pain, or palpitations, but only 0.6% to 2.7% of patients ranked these among their main symptoms.

“Further studies are warranted to examine the underlying pathophysiology and implications for clinical care of the sex-based clinical differences observed along the entire diagnostic pathway of suspected CAD, including risk factor burden, presenting symptoms, and testing results,” the researchers concluded.

The PROMISE study was funded by the National Heart, Lung, and Blood Institute. Ms. Hemal had no disclosures. Senior author Dr. Pamela S. Douglas disclosed grant support from HeartFlow and having served on a data and safety monitoring board for General Electric Healthcare. Two of the other 15 coinvestigators also disclosed relationships with industry; the rest had no disclosures.

WASHINGTON – Practices and clinics should implement cultural humility training and gender protocols for dealing with transgender youth because many of these youth and their parents find health care experiences to be difficult when procedures for treating and interacting with transgender youth are confusing or nonexistent.

The study is part of an ongoing effort to “provide high-quality, respectful health care for transgender youth [because] these youth are at greatly increased risk of issues including substance abuse, depression, anxiety, homelessness, and suicide,” explained Julia M. Crouch of Seattle Children’s Research Institute.

“A growing body of evidence shows improved health outcomes for transgender youth who received support from family, schools, and providers, and there are now an increasing number of multidisciplinary gender clinics throughout the country [that] have been demonstrated to be a feasible and effective way to provide coordinated care to this population,” Ms. Crouch said at the annual meeting of the Society for Adolescent Health and Medicine.

Ms. Crouch and her coinvestigators recruited transgender youth between the ages of 14 and 22 years, along with parents of transgender youth, all of whom were evaluated and enrolled from the Seattle metropolitan area. Both parents and youth were given the option of participating in either a semistructured interview or a focus group discussion, during which investigators learned about the concerns and experiences of both youth and parents when visiting their health care clinics (J Adolesc Health. 2011 Apr;48[4]:351-7; J Adolesc Health. 2011 Apr;48(4):351-7)..

In total, 13 youth and 16 parents – the latter of whom were not made up of 8 pairs of parents, but rather 16 individual parents of transgender youth who were not necessarily the same 13 youth recruited for the study – were eventually selected for inclusion. The parents split evenly between opting for interviews and focus groups, while four of the youth chose interviews and the remaining nine chose focus groups. Seven youth identified themselves as male, three identified as female, and the remaining three identified as “genderqueer or gender fluid.”

Analysis of interview and focus group conversations identified six key “barriers to care” that Ms. Crouch and her coauthors call necessary to rectify in order to improve the quality of health care provided to transgender youth. These are:

• The dearth of health care providers with sufficient knowledge and interest in working with transgender youth.

• The lack of access to pubertal blockers and cross-sex hormones.

• Doctors and their staff who are unable or unwilling to use the names and pronouns that youths prefer to go by.

• Patients being made to feel uncomfortable or “not normal” by health care providers,

• The lack of a set protocol or treatment methodology for dealing with transgender youth.

• The lack of coordination between health care providers and specialties on treating transgender youth – specifically, a lack of cohesive care between mental and medical health care.

“ ‘It was hard enough to find providers who were accepting new patients, worked with adolescents and my insurance, [and] on top of it, finding someone who was transfriendly made it all but impossible,’ ” Ms. Crouch recalled one transgender youth saying during the study.

Ms. Crouch also recounted that providers’ inability to consistently use the correct pronoun when talking about or to a transgender patient was harmful, and despite most instances being dismissed as unintentional, several were said to be intentional and malicious.

“For example, one parent told us [their] doctor said, ‘her, her, her,’ and [her] son, who was 10 years old, said, ‘him, him, him,’ and the doctor got mad, became dismissive and irritated, and kept saying ‘her,’ ” said Ms. Crouch.

The average age of the youth was 18 years, and of the parents was 49 years. The parents were 88% white and 75% female, with 44% holding at least a college degree. Most of the youth were white (69%), and 77% had either completed high school or some college. Youth and parents were recruited in 2015 from local clinics in the Seattle area, as well as through local and national listservs. Thirty-three percent of the parents were from outside the state of Washington.

The study was funded by the Center for Diversity and Health Equity, and the Clinical and Translational Research Faculty Research Support Fund, at Seattle Children’s Research Institute. Ms. Crouch did not report any relevant financial disclosures.

[email protected]

WASHINGTON – Practices and clinics should implement cultural humility training and gender protocols for dealing with transgender youth because many of these youth and their parents find health care experiences to be difficult when procedures for treating and interacting with transgender youth are confusing or nonexistent.

The study is part of an ongoing effort to “provide high-quality, respectful health care for transgender youth [because] these youth are at greatly increased risk of issues including substance abuse, depression, anxiety, homelessness, and suicide,” explained Julia M. Crouch of Seattle Children’s Research Institute.

“A growing body of evidence shows improved health outcomes for transgender youth who received support from family, schools, and providers, and there are now an increasing number of multidisciplinary gender clinics throughout the country [that] have been demonstrated to be a feasible and effective way to provide coordinated care to this population,” Ms. Crouch said at the annual meeting of the Society for Adolescent Health and Medicine.

Ms. Crouch and her coinvestigators recruited transgender youth between the ages of 14 and 22 years, along with parents of transgender youth, all of whom were evaluated and enrolled from the Seattle metropolitan area. Both parents and youth were given the option of participating in either a semistructured interview or a focus group discussion, during which investigators learned about the concerns and experiences of both youth and parents when visiting their health care clinics (J Adolesc Health. 2011 Apr;48[4]:351-7; J Adolesc Health. 2011 Apr;48(4):351-7)..

In total, 13 youth and 16 parents – the latter of whom were not made up of 8 pairs of parents, but rather 16 individual parents of transgender youth who were not necessarily the same 13 youth recruited for the study – were eventually selected for inclusion. The parents split evenly between opting for interviews and focus groups, while four of the youth chose interviews and the remaining nine chose focus groups. Seven youth identified themselves as male, three identified as female, and the remaining three identified as “genderqueer or gender fluid.”

Analysis of interview and focus group conversations identified six key “barriers to care” that Ms. Crouch and her coauthors call necessary to rectify in order to improve the quality of health care provided to transgender youth. These are:

• The dearth of health care providers with sufficient knowledge and interest in working with transgender youth.

• The lack of access to pubertal blockers and cross-sex hormones.

• Doctors and their staff who are unable or unwilling to use the names and pronouns that youths prefer to go by.

• Patients being made to feel uncomfortable or “not normal” by health care providers,

• The lack of a set protocol or treatment methodology for dealing with transgender youth.

• The lack of coordination between health care providers and specialties on treating transgender youth – specifically, a lack of cohesive care between mental and medical health care.

“ ‘It was hard enough to find providers who were accepting new patients, worked with adolescents and my insurance, [and] on top of it, finding someone who was transfriendly made it all but impossible,’ ” Ms. Crouch recalled one transgender youth saying during the study.

Ms. Crouch also recounted that providers’ inability to consistently use the correct pronoun when talking about or to a transgender patient was harmful, and despite most instances being dismissed as unintentional, several were said to be intentional and malicious.

“For example, one parent told us [their] doctor said, ‘her, her, her,’ and [her] son, who was 10 years old, said, ‘him, him, him,’ and the doctor got mad, became dismissive and irritated, and kept saying ‘her,’ ” said Ms. Crouch.

The average age of the youth was 18 years, and of the parents was 49 years. The parents were 88% white and 75% female, with 44% holding at least a college degree. Most of the youth were white (69%), and 77% had either completed high school or some college. Youth and parents were recruited in 2015 from local clinics in the Seattle area, as well as through local and national listservs. Thirty-three percent of the parents were from outside the state of Washington.

The study was funded by the Center for Diversity and Health Equity, and the Clinical and Translational Research Faculty Research Support Fund, at Seattle Children’s Research Institute. Ms. Crouch did not report any relevant financial disclosures.

[email protected]

WASHINGTON – Practices and clinics should implement cultural humility training and gender protocols for dealing with transgender youth because many of these youth and their parents find health care experiences to be difficult when procedures for treating and interacting with transgender youth are confusing or nonexistent.

The study is part of an ongoing effort to “provide high-quality, respectful health care for transgender youth [because] these youth are at greatly increased risk of issues including substance abuse, depression, anxiety, homelessness, and suicide,” explained Julia M. Crouch of Seattle Children’s Research Institute.

“A growing body of evidence shows improved health outcomes for transgender youth who received support from family, schools, and providers, and there are now an increasing number of multidisciplinary gender clinics throughout the country [that] have been demonstrated to be a feasible and effective way to provide coordinated care to this population,” Ms. Crouch said at the annual meeting of the Society for Adolescent Health and Medicine.

Ms. Crouch and her coinvestigators recruited transgender youth between the ages of 14 and 22 years, along with parents of transgender youth, all of whom were evaluated and enrolled from the Seattle metropolitan area. Both parents and youth were given the option of participating in either a semistructured interview or a focus group discussion, during which investigators learned about the concerns and experiences of both youth and parents when visiting their health care clinics (J Adolesc Health. 2011 Apr;48[4]:351-7; J Adolesc Health. 2011 Apr;48(4):351-7)..

In total, 13 youth and 16 parents – the latter of whom were not made up of 8 pairs of parents, but rather 16 individual parents of transgender youth who were not necessarily the same 13 youth recruited for the study – were eventually selected for inclusion. The parents split evenly between opting for interviews and focus groups, while four of the youth chose interviews and the remaining nine chose focus groups. Seven youth identified themselves as male, three identified as female, and the remaining three identified as “genderqueer or gender fluid.”

Analysis of interview and focus group conversations identified six key “barriers to care” that Ms. Crouch and her coauthors call necessary to rectify in order to improve the quality of health care provided to transgender youth. These are:

• The dearth of health care providers with sufficient knowledge and interest in working with transgender youth.

• The lack of access to pubertal blockers and cross-sex hormones.

• Doctors and their staff who are unable or unwilling to use the names and pronouns that youths prefer to go by.

• Patients being made to feel uncomfortable or “not normal” by health care providers,

• The lack of a set protocol or treatment methodology for dealing with transgender youth.

• The lack of coordination between health care providers and specialties on treating transgender youth – specifically, a lack of cohesive care between mental and medical health care.

“ ‘It was hard enough to find providers who were accepting new patients, worked with adolescents and my insurance, [and] on top of it, finding someone who was transfriendly made it all but impossible,’ ” Ms. Crouch recalled one transgender youth saying during the study.

Ms. Crouch also recounted that providers’ inability to consistently use the correct pronoun when talking about or to a transgender patient was harmful, and despite most instances being dismissed as unintentional, several were said to be intentional and malicious.

“For example, one parent told us [their] doctor said, ‘her, her, her,’ and [her] son, who was 10 years old, said, ‘him, him, him,’ and the doctor got mad, became dismissive and irritated, and kept saying ‘her,’ ” said Ms. Crouch.

The average age of the youth was 18 years, and of the parents was 49 years. The parents were 88% white and 75% female, with 44% holding at least a college degree. Most of the youth were white (69%), and 77% had either completed high school or some college. Youth and parents were recruited in 2015 from local clinics in the Seattle area, as well as through local and national listservs. Thirty-three percent of the parents were from outside the state of Washington.

The study was funded by the Center for Diversity and Health Equity, and the Clinical and Translational Research Faculty Research Support Fund, at Seattle Children’s Research Institute. Ms. Crouch did not report any relevant financial disclosures.

[email protected]

A lack of psychiatrists only partially accounted for substantial variations in rates of mental illness diagnosis and prescriptions for psychotropic medications in practices nationwide, a study has shown.

Although a lack of available specialty care was associated with significantly higher odds of a diagnosis or prescription, the colocation of mental health professionals or percentage of children in foster care treated in a practice did not fully explain the differences.

Among 294,748 children aged 4-18 years, seen one or more times in 43 primary care practices nationwide, 15% received a mental health diagnosis between Jan. 1, 2009, and June 30, 2014. Psychotropic medications were prescribed to 14%, reported lead researcher Stephanie L. Mayne of the center for pediatric clinical effectiveness at the the Children’s Hospital of Philadelphia (Pediatrics. 2016 doi: 10.1542/peds.2015-2974).

The most common diagnosis was attention-deficit/hyperactivity disorder at a rate of between 1% and 16%. Differences in other diagnoses “were smaller, but still meaningful” at ranges of 1%-8% for anxiety, 0%-5% for depression, 0.2%-3% for autism, 0%-3% for conduct disorder, and 0%-2% for oppositional-defiant disorder. Bipolar disorder was “uncommon” at less than 1%, Ms. Mayne and her associates reported.

The rate of children receiving any psychotropic medication was between 4% and 26%, while the proportion of patients receiving two or more medication classes ranged between 1% and 12%. Prescription rates for specific medication classes also varied at between 4% and 18% for stimulants, 1% and 12% for antidepressants, 0.1% and 8% for alpha-agonists, and 0.1% and 5% for second-generation antipsychotics.

“Primary care providers’ level of agreement with current guidelines, perceived self-efficacy in diagnosing or treating particular conditions, training, relationships with schools, and reimbursement from insurers might affect prescribing practices,” Ms. Mayne and her associates wrote.

“Even with colocation, barriers such as financial differences in reimbursement for medical and mental health services, difficulties with information sharing, differing expertise, and limited hours may impede integration,” they commented.

Dr. Alexander G. Fiks is an investigator for Pfizer; the other researchers said they had no relevant financial disclosures. This study was funded by the National Institutes of Health and the National Institute of Child Health and Human Development under the Best Pharmaceuticals for Children Act.

[email protected]

On Twitter @whitneymcknight

A lack of psychiatrists only partially accounted for substantial variations in rates of mental illness diagnosis and prescriptions for psychotropic medications in practices nationwide, a study has shown.

Although a lack of available specialty care was associated with significantly higher odds of a diagnosis or prescription, the colocation of mental health professionals or percentage of children in foster care treated in a practice did not fully explain the differences.

Among 294,748 children aged 4-18 years, seen one or more times in 43 primary care practices nationwide, 15% received a mental health diagnosis between Jan. 1, 2009, and June 30, 2014. Psychotropic medications were prescribed to 14%, reported lead researcher Stephanie L. Mayne of the center for pediatric clinical effectiveness at the the Children’s Hospital of Philadelphia (Pediatrics. 2016 doi: 10.1542/peds.2015-2974).

The most common diagnosis was attention-deficit/hyperactivity disorder at a rate of between 1% and 16%. Differences in other diagnoses “were smaller, but still meaningful” at ranges of 1%-8% for anxiety, 0%-5% for depression, 0.2%-3% for autism, 0%-3% for conduct disorder, and 0%-2% for oppositional-defiant disorder. Bipolar disorder was “uncommon” at less than 1%, Ms. Mayne and her associates reported.

The rate of children receiving any psychotropic medication was between 4% and 26%, while the proportion of patients receiving two or more medication classes ranged between 1% and 12%. Prescription rates for specific medication classes also varied at between 4% and 18% for stimulants, 1% and 12% for antidepressants, 0.1% and 8% for alpha-agonists, and 0.1% and 5% for second-generation antipsychotics.

“Primary care providers’ level of agreement with current guidelines, perceived self-efficacy in diagnosing or treating particular conditions, training, relationships with schools, and reimbursement from insurers might affect prescribing practices,” Ms. Mayne and her associates wrote.

“Even with colocation, barriers such as financial differences in reimbursement for medical and mental health services, difficulties with information sharing, differing expertise, and limited hours may impede integration,” they commented.

Dr. Alexander G. Fiks is an investigator for Pfizer; the other researchers said they had no relevant financial disclosures. This study was funded by the National Institutes of Health and the National Institute of Child Health and Human Development under the Best Pharmaceuticals for Children Act.

[email protected]

On Twitter @whitneymcknight

A lack of psychiatrists only partially accounted for substantial variations in rates of mental illness diagnosis and prescriptions for psychotropic medications in practices nationwide, a study has shown.

Although a lack of available specialty care was associated with significantly higher odds of a diagnosis or prescription, the colocation of mental health professionals or percentage of children in foster care treated in a practice did not fully explain the differences.

Among 294,748 children aged 4-18 years, seen one or more times in 43 primary care practices nationwide, 15% received a mental health diagnosis between Jan. 1, 2009, and June 30, 2014. Psychotropic medications were prescribed to 14%, reported lead researcher Stephanie L. Mayne of the center for pediatric clinical effectiveness at the the Children’s Hospital of Philadelphia (Pediatrics. 2016 doi: 10.1542/peds.2015-2974).

The most common diagnosis was attention-deficit/hyperactivity disorder at a rate of between 1% and 16%. Differences in other diagnoses “were smaller, but still meaningful” at ranges of 1%-8% for anxiety, 0%-5% for depression, 0.2%-3% for autism, 0%-3% for conduct disorder, and 0%-2% for oppositional-defiant disorder. Bipolar disorder was “uncommon” at less than 1%, Ms. Mayne and her associates reported.

The rate of children receiving any psychotropic medication was between 4% and 26%, while the proportion of patients receiving two or more medication classes ranged between 1% and 12%. Prescription rates for specific medication classes also varied at between 4% and 18% for stimulants, 1% and 12% for antidepressants, 0.1% and 8% for alpha-agonists, and 0.1% and 5% for second-generation antipsychotics.

“Primary care providers’ level of agreement with current guidelines, perceived self-efficacy in diagnosing or treating particular conditions, training, relationships with schools, and reimbursement from insurers might affect prescribing practices,” Ms. Mayne and her associates wrote.

“Even with colocation, barriers such as financial differences in reimbursement for medical and mental health services, difficulties with information sharing, differing expertise, and limited hours may impede integration,” they commented.

Dr. Alexander G. Fiks is an investigator for Pfizer; the other researchers said they had no relevant financial disclosures. This study was funded by the National Institutes of Health and the National Institute of Child Health and Human Development under the Best Pharmaceuticals for Children Act.

[email protected]

On Twitter @whitneymcknight

PRACTICE CHANGER
Do not prescribe tamsulosin or nifedipine for stone expulsion in patients with ureteral stones that are ≤ 10 mm.¹

Strength of recommendation
A: Based on a high-quality randomized controlled trial (RCT).¹

Bob Z, age 48, presents to the emergency department (ED) with unspecified groin pain. CT of the kidney, ureter, and bladder (CT KUB) finds evidence of a single ureteral stone measuring 8 mm. He’s prescribed medication for the pain and discharged. The day after his ED visit, he comes to your office to discuss further treatment options. Should you prescribe tamsulosin or nifedipine to help him pass the stone?

The most recent National Health and Nutrition Examination Survey found kidney stones affect 8.8% of the population.² Outpatient therapy is indicated for patients with ureteric colic secondary to stones ≤ 10 mm who do not have uncontrolled pain, impaired kidney function, or severe infection. Routine out­patient care includes oral hydration, antiemetics, and pain medications.

Medical expulsive therapy (MET) is also used to facilitate stone passage. MET is increasingly becoming part of routine care; use of MET in kidney stone patients in the United States has grown from 14% in 2009 to 64% in 2012.^3,4

The joint European Association of Urology/American Urological Association Nephrolithiasis Guideline Panel supports the use of MET.⁵ Meta-analyses of multiple RCTs suggest that an α-blocker (tamsulosin) or a calcium channel blocker (nifedipine) can reduce pain and lead to quicker stone passage and a higher rate of eventual stone passage when compared to placebo or observation.^6,7 However, these reviews included small, heterogeneous studies with a high or unclear risk for bias.

Continue for the study summary >>

STUDY SUMMARY
MET doesn’t increase the rate of stone passage
The SUSPEND (Spontaneous Urinary Stone Passage ENabled by Drugs) trial¹ was a multicenter RCT designed to determine the effectiveness of tamsulosin or nifedipine as MET for patients ages 18 to 65 with a single ureteric stone measuring ≤ 10 mm on CT KUB, which has 98% diagnostic accuracy.⁸ (Stones > 10 mm typically require surgery or lithotripsy.)

In this RCT, 1,167 adults were randomized to take tamsulosin (0.4 mg/d), nifedipine (30 mg/d), or placebo for four weeks or until the stone spontaneously passed, whichever came first. The participants, clinicians, and research staff were blinded to treatment assignment. The primary outcome was the proportion of participants who spontaneously passed their stone, as indicated in patient self-reported questionnaires and case-report forms completed by researchers. Secondary outcomes were time to stone passage and pain as assessed by analgesic use and a visual analogue scale (VAS).

At four weeks, 1,136 (97%) of the randomized participants had data available for analysis. The proportion of participants who passed their stone did not differ between MET and placebo; 80% of the placebo group (303 of 379 participants) passed the stone, compared with 81% (307 of 378) of the tamsulosin group and 80% (304 of 379) of the nifedipine group. The odds ratio (OR) for MET vs placebo was 1.04 (95% confidence interval [CI], 0.77 to 1.43) and the OR for tamsulosin vs nifedipine was 1.07 (95% CI, 0.74 to 1.53). These findings did not change with further subgroup analysis, including by sex, stone size (≤ 5 mm vs > 5 mm), or stone location.

There were no differences between groups in time to stone passage as measured by clinical report and confirmed by imaging. Time to passage of stone was available for 237 (21% of) participants. The mean days to stone passage was 15.9 (n = 84) for placebo, 16.5 (n = 79) for tamsulosin, and 16.2 (n = 74) for nifedipine, with a MET vs placebo difference of 0.5 days (95% CI, –2.9 to 3.9; P = .78). Sensitivity analysis accounting for bias from missing data did not change this outcome.

No differences in analgesic use or pain. Self-reported use of pain medication during the first four weeks was similar between groups: 59% (placebo patients), 56% (tamsulosin), and 56% (nifedipine). The mean days of pain medication use was 10.5 for placebo, 11.6 for tamsulosin, and 10.7 for nifedipine, with a MET vs placebo difference of 0.6 days (95% CI, –1.6 to 2.8; P = .45).

There was no difference between groups in the VAS pain score at four weeks. The MET vs placebo difference was 0.0 (95% CI, –0.4 to 0.4; P = .96) and the mean VAS pain score was 1.2 for placebo, 1.0 for tamsulosin, and 1.3 for nifedipine.

WHAT’S NEW
This large RCT contradicts results from previous meta-analyses
The SUSPEND study is the first large, multicenter RCT of MET with tamsulosin or nifedipine for kidney stones that used patient-oriented outcomes to find no benefit for stone expulsion, analgesic use, or reported pain compared to placebo. The discrepancy with prior meta-analyses is not unusual. Up to one-third of meta-analyses that show positive outcomes of a therapy are subsequently altered by the inclusion of results from a single, large, well-designed, multicenter RCT.⁹

Continue for caveats >>

CAVEATS
This trial included fewer women than previous studies
The SUSPEND study included a smaller proportion of women than previously published case series due to a need for a diagnostic CT KUB, which excluded more women than men due to radiation concerns. However, the proportion of women was balanced across all groups in this trial, and there was no evidence that sex impacted the efficacy of treatment for the primary outcome.¹

CHALLENGES TO IMPLEMENTATION
We see no challenges to the implementation of this recommendation.

References
1. Pickard R, Starr K, MacLennan G, et al. Medical expulsive therapy in adults with ureteric colic: a multicentre, randomised, placebo-controlled trial. Lancet. 2015;386:341-349.
2. Scales CD Jr, Smith AC, Hanley JM, et al. Prevalence of kidney stones in the United States. Eur Urol. 2012;62:160-165.
3. Fwu CW, Eggers PW, Kimmel PL, et al. Emergency department visits, use of imaging, and drugs for urolithiasis have increased in the United States. Kidney Int. 2013;89:479-486.
4. Bagga H, Appa A, Wang R, et al. 2257 medical expulsion therapy is underutilized in women presenting to an emergency department with acute urinary stone disease. J Urol. 2013; 189:e925-e926.
5. Preminger GM, Tiselius HG, Assimos DG, et al; American Urological Association Education and Research, Inc; European Association of Urology. 2007 Guideline for the management of ureteral calculi. Eur Urol. 2007;52:1610-1631.
6. Campschroer T, Zhu Y, Duijvesz D, et al. Alpha-blockers as medical expulsive therapy for ureteral stones. Cochrane Database Syst Rev. 2014;4:CD008509.
7. Seitz C, Liatsikos E, Porpiglia F, et al. Medical therapy to facilitate the passage of stones: what is the evidence? Eur Urol. 2009;56:455-471.
8. Worster A, Preyra I, Weaver B, et al. The accuracy of noncontrast helical computed tomography versus intravenous pyelography in the diagnosis of suspected acute urolithiasis: a meta-analysis. Ann Emerg Med. 2002;40: 280-286.
9. LeLorier J, Gregoire G, Benhaddad A, et al. Discrepancies between meta-analyses and subsequent large randomized, controlled trials. N Engl J Med. 1997;337:536-542.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2016. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2016;65(2):118-120.

PRACTICE CHANGER
Do not prescribe tamsulosin or nifedipine for stone expulsion in patients with ureteral stones that are ≤ 10 mm.¹

Strength of recommendation
A: Based on a high-quality randomized controlled trial (RCT).¹

Bob Z, age 48, presents to the emergency department (ED) with unspecified groin pain. CT of the kidney, ureter, and bladder (CT KUB) finds evidence of a single ureteral stone measuring 8 mm. He’s prescribed medication for the pain and discharged. The day after his ED visit, he comes to your office to discuss further treatment options. Should you prescribe tamsulosin or nifedipine to help him pass the stone?

The most recent National Health and Nutrition Examination Survey found kidney stones affect 8.8% of the population.² Outpatient therapy is indicated for patients with ureteric colic secondary to stones ≤ 10 mm who do not have uncontrolled pain, impaired kidney function, or severe infection. Routine out­patient care includes oral hydration, antiemetics, and pain medications.

Medical expulsive therapy (MET) is also used to facilitate stone passage. MET is increasingly becoming part of routine care; use of MET in kidney stone patients in the United States has grown from 14% in 2009 to 64% in 2012.^3,4

The joint European Association of Urology/American Urological Association Nephrolithiasis Guideline Panel supports the use of MET.⁵ Meta-analyses of multiple RCTs suggest that an α-blocker (tamsulosin) or a calcium channel blocker (nifedipine) can reduce pain and lead to quicker stone passage and a higher rate of eventual stone passage when compared to placebo or observation.^6,7 However, these reviews included small, heterogeneous studies with a high or unclear risk for bias.

Continue for the study summary >>

STUDY SUMMARY
MET doesn’t increase the rate of stone passage
The SUSPEND (Spontaneous Urinary Stone Passage ENabled by Drugs) trial¹ was a multicenter RCT designed to determine the effectiveness of tamsulosin or nifedipine as MET for patients ages 18 to 65 with a single ureteric stone measuring ≤ 10 mm on CT KUB, which has 98% diagnostic accuracy.⁸ (Stones > 10 mm typically require surgery or lithotripsy.)

In this RCT, 1,167 adults were randomized to take tamsulosin (0.4 mg/d), nifedipine (30 mg/d), or placebo for four weeks or until the stone spontaneously passed, whichever came first. The participants, clinicians, and research staff were blinded to treatment assignment. The primary outcome was the proportion of participants who spontaneously passed their stone, as indicated in patient self-reported questionnaires and case-report forms completed by researchers. Secondary outcomes were time to stone passage and pain as assessed by analgesic use and a visual analogue scale (VAS).

At four weeks, 1,136 (97%) of the randomized participants had data available for analysis. The proportion of participants who passed their stone did not differ between MET and placebo; 80% of the placebo group (303 of 379 participants) passed the stone, compared with 81% (307 of 378) of the tamsulosin group and 80% (304 of 379) of the nifedipine group. The odds ratio (OR) for MET vs placebo was 1.04 (95% confidence interval [CI], 0.77 to 1.43) and the OR for tamsulosin vs nifedipine was 1.07 (95% CI, 0.74 to 1.53). These findings did not change with further subgroup analysis, including by sex, stone size (≤ 5 mm vs > 5 mm), or stone location.

There were no differences between groups in time to stone passage as measured by clinical report and confirmed by imaging. Time to passage of stone was available for 237 (21% of) participants. The mean days to stone passage was 15.9 (n = 84) for placebo, 16.5 (n = 79) for tamsulosin, and 16.2 (n = 74) for nifedipine, with a MET vs placebo difference of 0.5 days (95% CI, –2.9 to 3.9; P = .78). Sensitivity analysis accounting for bias from missing data did not change this outcome.

No differences in analgesic use or pain. Self-reported use of pain medication during the first four weeks was similar between groups: 59% (placebo patients), 56% (tamsulosin), and 56% (nifedipine). The mean days of pain medication use was 10.5 for placebo, 11.6 for tamsulosin, and 10.7 for nifedipine, with a MET vs placebo difference of 0.6 days (95% CI, –1.6 to 2.8; P = .45).

There was no difference between groups in the VAS pain score at four weeks. The MET vs placebo difference was 0.0 (95% CI, –0.4 to 0.4; P = .96) and the mean VAS pain score was 1.2 for placebo, 1.0 for tamsulosin, and 1.3 for nifedipine.

WHAT’S NEW
This large RCT contradicts results from previous meta-analyses
The SUSPEND study is the first large, multicenter RCT of MET with tamsulosin or nifedipine for kidney stones that used patient-oriented outcomes to find no benefit for stone expulsion, analgesic use, or reported pain compared to placebo. The discrepancy with prior meta-analyses is not unusual. Up to one-third of meta-analyses that show positive outcomes of a therapy are subsequently altered by the inclusion of results from a single, large, well-designed, multicenter RCT.⁹

Continue for caveats >>

CAVEATS
This trial included fewer women than previous studies
The SUSPEND study included a smaller proportion of women than previously published case series due to a need for a diagnostic CT KUB, which excluded more women than men due to radiation concerns. However, the proportion of women was balanced across all groups in this trial, and there was no evidence that sex impacted the efficacy of treatment for the primary outcome.¹

CHALLENGES TO IMPLEMENTATION
We see no challenges to the implementation of this recommendation.

References
1. Pickard R, Starr K, MacLennan G, et al. Medical expulsive therapy in adults with ureteric colic: a multicentre, randomised, placebo-controlled trial. Lancet. 2015;386:341-349.
2. Scales CD Jr, Smith AC, Hanley JM, et al. Prevalence of kidney stones in the United States. Eur Urol. 2012;62:160-165.
3. Fwu CW, Eggers PW, Kimmel PL, et al. Emergency department visits, use of imaging, and drugs for urolithiasis have increased in the United States. Kidney Int. 2013;89:479-486.
4. Bagga H, Appa A, Wang R, et al. 2257 medical expulsion therapy is underutilized in women presenting to an emergency department with acute urinary stone disease. J Urol. 2013; 189:e925-e926.
5. Preminger GM, Tiselius HG, Assimos DG, et al; American Urological Association Education and Research, Inc; European Association of Urology. 2007 Guideline for the management of ureteral calculi. Eur Urol. 2007;52:1610-1631.
6. Campschroer T, Zhu Y, Duijvesz D, et al. Alpha-blockers as medical expulsive therapy for ureteral stones. Cochrane Database Syst Rev. 2014;4:CD008509.
7. Seitz C, Liatsikos E, Porpiglia F, et al. Medical therapy to facilitate the passage of stones: what is the evidence? Eur Urol. 2009;56:455-471.
8. Worster A, Preyra I, Weaver B, et al. The accuracy of noncontrast helical computed tomography versus intravenous pyelography in the diagnosis of suspected acute urolithiasis: a meta-analysis. Ann Emerg Med. 2002;40: 280-286.
9. LeLorier J, Gregoire G, Benhaddad A, et al. Discrepancies between meta-analyses and subsequent large randomized, controlled trials. N Engl J Med. 1997;337:536-542.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2016. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2016;65(2):118-120.

PRACTICE CHANGER
Do not prescribe tamsulosin or nifedipine for stone expulsion in patients with ureteral stones that are ≤ 10 mm.¹

Strength of recommendation
A: Based on a high-quality randomized controlled trial (RCT).¹

Bob Z, age 48, presents to the emergency department (ED) with unspecified groin pain. CT of the kidney, ureter, and bladder (CT KUB) finds evidence of a single ureteral stone measuring 8 mm. He’s prescribed medication for the pain and discharged. The day after his ED visit, he comes to your office to discuss further treatment options. Should you prescribe tamsulosin or nifedipine to help him pass the stone?

The most recent National Health and Nutrition Examination Survey found kidney stones affect 8.8% of the population.² Outpatient therapy is indicated for patients with ureteric colic secondary to stones ≤ 10 mm who do not have uncontrolled pain, impaired kidney function, or severe infection. Routine out­patient care includes oral hydration, antiemetics, and pain medications.

Medical expulsive therapy (MET) is also used to facilitate stone passage. MET is increasingly becoming part of routine care; use of MET in kidney stone patients in the United States has grown from 14% in 2009 to 64% in 2012.^3,4

The joint European Association of Urology/American Urological Association Nephrolithiasis Guideline Panel supports the use of MET.⁵ Meta-analyses of multiple RCTs suggest that an α-blocker (tamsulosin) or a calcium channel blocker (nifedipine) can reduce pain and lead to quicker stone passage and a higher rate of eventual stone passage when compared to placebo or observation.^6,7 However, these reviews included small, heterogeneous studies with a high or unclear risk for bias.

Continue for the study summary >>

STUDY SUMMARY
MET doesn’t increase the rate of stone passage
The SUSPEND (Spontaneous Urinary Stone Passage ENabled by Drugs) trial¹ was a multicenter RCT designed to determine the effectiveness of tamsulosin or nifedipine as MET for patients ages 18 to 65 with a single ureteric stone measuring ≤ 10 mm on CT KUB, which has 98% diagnostic accuracy.⁸ (Stones > 10 mm typically require surgery or lithotripsy.)

In this RCT, 1,167 adults were randomized to take tamsulosin (0.4 mg/d), nifedipine (30 mg/d), or placebo for four weeks or until the stone spontaneously passed, whichever came first. The participants, clinicians, and research staff were blinded to treatment assignment. The primary outcome was the proportion of participants who spontaneously passed their stone, as indicated in patient self-reported questionnaires and case-report forms completed by researchers. Secondary outcomes were time to stone passage and pain as assessed by analgesic use and a visual analogue scale (VAS).

At four weeks, 1,136 (97%) of the randomized participants had data available for analysis. The proportion of participants who passed their stone did not differ between MET and placebo; 80% of the placebo group (303 of 379 participants) passed the stone, compared with 81% (307 of 378) of the tamsulosin group and 80% (304 of 379) of the nifedipine group. The odds ratio (OR) for MET vs placebo was 1.04 (95% confidence interval [CI], 0.77 to 1.43) and the OR for tamsulosin vs nifedipine was 1.07 (95% CI, 0.74 to 1.53). These findings did not change with further subgroup analysis, including by sex, stone size (≤ 5 mm vs > 5 mm), or stone location.

There were no differences between groups in time to stone passage as measured by clinical report and confirmed by imaging. Time to passage of stone was available for 237 (21% of) participants. The mean days to stone passage was 15.9 (n = 84) for placebo, 16.5 (n = 79) for tamsulosin, and 16.2 (n = 74) for nifedipine, with a MET vs placebo difference of 0.5 days (95% CI, –2.9 to 3.9; P = .78). Sensitivity analysis accounting for bias from missing data did not change this outcome.

No differences in analgesic use or pain. Self-reported use of pain medication during the first four weeks was similar between groups: 59% (placebo patients), 56% (tamsulosin), and 56% (nifedipine). The mean days of pain medication use was 10.5 for placebo, 11.6 for tamsulosin, and 10.7 for nifedipine, with a MET vs placebo difference of 0.6 days (95% CI, –1.6 to 2.8; P = .45).

There was no difference between groups in the VAS pain score at four weeks. The MET vs placebo difference was 0.0 (95% CI, –0.4 to 0.4; P = .96) and the mean VAS pain score was 1.2 for placebo, 1.0 for tamsulosin, and 1.3 for nifedipine.

WHAT’S NEW
This large RCT contradicts results from previous meta-analyses
The SUSPEND study is the first large, multicenter RCT of MET with tamsulosin or nifedipine for kidney stones that used patient-oriented outcomes to find no benefit for stone expulsion, analgesic use, or reported pain compared to placebo. The discrepancy with prior meta-analyses is not unusual. Up to one-third of meta-analyses that show positive outcomes of a therapy are subsequently altered by the inclusion of results from a single, large, well-designed, multicenter RCT.⁹

Continue for caveats >>

CAVEATS
This trial included fewer women than previous studies
The SUSPEND study included a smaller proportion of women than previously published case series due to a need for a diagnostic CT KUB, which excluded more women than men due to radiation concerns. However, the proportion of women was balanced across all groups in this trial, and there was no evidence that sex impacted the efficacy of treatment for the primary outcome.¹

CHALLENGES TO IMPLEMENTATION
We see no challenges to the implementation of this recommendation.

References
1. Pickard R, Starr K, MacLennan G, et al. Medical expulsive therapy in adults with ureteric colic: a multicentre, randomised, placebo-controlled trial. Lancet. 2015;386:341-349.
2. Scales CD Jr, Smith AC, Hanley JM, et al. Prevalence of kidney stones in the United States. Eur Urol. 2012;62:160-165.
3. Fwu CW, Eggers PW, Kimmel PL, et al. Emergency department visits, use of imaging, and drugs for urolithiasis have increased in the United States. Kidney Int. 2013;89:479-486.
4. Bagga H, Appa A, Wang R, et al. 2257 medical expulsion therapy is underutilized in women presenting to an emergency department with acute urinary stone disease. J Urol. 2013; 189:e925-e926.
5. Preminger GM, Tiselius HG, Assimos DG, et al; American Urological Association Education and Research, Inc; European Association of Urology. 2007 Guideline for the management of ureteral calculi. Eur Urol. 2007;52:1610-1631.
6. Campschroer T, Zhu Y, Duijvesz D, et al. Alpha-blockers as medical expulsive therapy for ureteral stones. Cochrane Database Syst Rev. 2014;4:CD008509.
7. Seitz C, Liatsikos E, Porpiglia F, et al. Medical therapy to facilitate the passage of stones: what is the evidence? Eur Urol. 2009;56:455-471.
8. Worster A, Preyra I, Weaver B, et al. The accuracy of noncontrast helical computed tomography versus intravenous pyelography in the diagnosis of suspected acute urolithiasis: a meta-analysis. Ann Emerg Med. 2002;40: 280-286.
9. LeLorier J, Gregoire G, Benhaddad A, et al. Discrepancies between meta-analyses and subsequent large randomized, controlled trials. N Engl J Med. 1997;337:536-542.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2016. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2016;65(2):118-120.

Endometriosis is a common condition, occurring in this country in 1 of 10 women of reproductive age. An association between endometriosis and subsequent ovarian carcinoma has been reported for decades, yet it is only recently that our knowledge has deepened enough to support more rational methods for preventing the malignancy.

Each year, approximately 22,000 new cases of ovarian cancer are diagnosed. The lifetime risk of developing this malignancy is low, but it is the deadliest of the gynecologic malignancies, with diagnosis usually made in advanced stages when prognosis is poor.

Endometriosis shows some characteristics of malignancy, such as the development of local and distant foci, and attachment to and invasion of other tissues with subsequent damage to these tissues. Endometriosis also is characterized by recurrent, unregulated cell proliferation and estrogen-dependent growth.

Our attempts during the past 2 decades to detect ovarian carcinoma at the early stages through a combined screening modality involving transvaginal ultrasound and a test for the serum level of cancer antigen 125 have failed to provide any survival benefit or even any measurable reduction in morbidity. Today, early-stage ovarian carcinoma, which has a 5-year survival rate of more than 90%, is diagnosed in only a minority of women.

There is good news, however. In recent years our insight into the pathophysiology of ovarian cancer has deepened, providing us with a new paradigm for ovarian cancer pathogenesis that divides ovarian epithelial carcinoma into two distinct types with distinct molecular profiles – one which originates largely in the distal portion of the fallopian tube and the other which traces back to endometriosis.

This new paradigm strengthens and helps to explain the reported association between endometriosis and ovarian cancer. It also has important clinical implications for current practice. While we have much more to learn about the etiology of endometriosis and the causes of malignant transformation, our current knowledge provides a strong rationale for identification and close monitoring of some patients with endometriosis deemed at risk for ovarian cancer, risk-reducing medical management, earlier and more meticulous surgical treatment, and close monitoring.

By combining this new approach to endometriosis with consideration of salpingectomy after completion of childbearing, we have an unprecedented opportunity to reduce the incidence of epithelial ovarian cancer.

Dual pathogenesis

The majority of ovarian cancers are of epithelial origin and fall into four histologic categories: serous, endometrioid, clear cell, and mucinous. In recent years, we have gained a deeper understanding of the pathogenesis of ovarian carcinoma, with an array of epidemiologic, histologic, and molecular data showing us that epithelial ovarian cancers are also of two distinct types (Am J Obstet Gynecol. 2015 Sep;213[3]:262-7).

One of these types, a high-grade serous carcinoma, appears to arise in many cases in the epithelium of the fallopian tube. The other type of tumor is a low-grade carcinoma – particularly of the endometrioid and clear cell histologic subtypes – that originates largely from ovarian endometriotic lesions or from borderline serous tumors in the case of serous histology.

The majority of diagnosed stage 1 ovarian cancers are carcinomas of this low-grade type and not high-grade serous carcinomas. In a study of 76 consecutive stage 1 carcinomas, investigators found that ovarian endometriosis was present in 40 of the 76 cases. More than two-thirds of the 76 cases (71%) were nonserous cancers, and almost all of these cases were associated with endometriosis based on histologic examination (Fertil Steril. 2007 Oct;88[4]:906-10).

This study was among the first to show that the majority of stage 1 ovarian carcinomas are not high-grade serous carcinomas, but rather nonserous, primarily endometrioid and clear cell, cancers. The research demonstrated that endometriosis should be viewed as a potential precursor lesion to specific subtypes of ovarian cancer.

The malignant transformation of endometriosis was first suggested by Dr. J. A. Sampson in 1925, and a number of studies – in addition to the 2007 landmark study – have since described ovarian cancer arising from endometriosis, based on the frequent co-occurrence in surgical specimens.

Most recently, a study from the Ovarian Cancer Association Consortium (OCAC) found that women who reported a history of endometriosis had a significantly higher risk of developing ovarian cancer than the general population (odds ratio, 1.46).

Investigators of this critical study pooled data from 13 ovarian cancer case-control studies involving more than 13,226 controls and 7,911 women with invasive epithelial ovarian cancer – 818 (6.2%) and 738 (9.3%) of whom, respectively, reported a history of endometriosis. Specifically, they determined that self-reported endometriosis was associated with a 3.05-fold increased risk for clear cell invasive ovarian cancer and a 2.04-fold increased risk of endometrioid ovarian cancer.

Moreover, a significant association between preexisting endometriosis and low-grade serous invasive ovarian cancer (OR, 2.11) was demonstrated, while no association was found between endometriosis and the risk of high-grade serous invasive ovarian cancer (Lancet Oncol. 2012 Apr;13[4]:385-94).

A second recently published report – a meta-analysis of 20 case-control and 15 cohort studies published between 1990 and 2012 and involving more than 444,000 patients – found that endometriosis increased cancer risk in case-control or two-arm cohort studies by 27% (relative risk, 1.265) and by approximately 80% in single-arm cohort studies (standard incidence ratio, 1.797). Endometrioid and clear cell carcinomas were more common in endometriosis-associated ovarian cancer, while serous carcinoma was less frequent (Br J Cancer. 2014 Apr 2;110[7]:1878-90).

Findings of both of these large studies have served to clarify the association between endometriosis and specific histologic subtypes and suggested that there are important differences in the pathogenesis of low-grade and high-grade serous ovarian carcinomas.

Clinical implications

It is not clear what causes malignant transformation or what predisposes some patients with endometriosis to develop ovarian cancer, but the risk likely involves genetic and epigenetic influences as well as immunologic, inflammatory, and hormonal factors.

The molecular profiles of the main two types of ovarian cancer are different: While the majority of high-grade serous ovarian tumors are characterized by TP53 mutations, the low-grade carcinomas are characterized by a variety of mutations, including KRAS, BRAF, ERBB2, CTNNB1, and BCL2 mutations.

There currently are not enough data to recommend genetic screening tests in patients with endometriosis, but our hope is that we eventually will be able to screen for “high-risk” endometriotic lesions by testing for genes specific to various histologic subtypes of low-grade ovarian cancer, or by finding and utilizing other biomarkers.

Courtesy of Dr. Farr Nezhat

In the meantime, we believe it is important to more thoroughly treat endometriosis and to identify and follow women with a history of the condition, especially those with a long-standing history, those with a history of endometriosis associated with infertility, and those with ovarian endometrioma. Each of these factors predisposes patients to a higher risk of malignant transformation.

Complete surgical resection of all visible endometriosis is the most effective treatment and will afford the best cancer prevention, even in women who are asymptomatic. In a recent Swedish national registry case-control study, women who underwent radical surgical excision of all visible endometriosis were significantly less likely (OR, 0.30) to develop ovarian cancer (Acta Obstet Gynecol Scand. 2013 May;92[5]:546-54).

Suppressive hormonal therapy is another treatment option for patients with no interest in conceiving. Most large endometriomas are functional ovarian cysts that have been invaded by cortical ovarian endometriosis or by small primary endometriomas (J Reprod Med. 1992 Sep;37[9]:771-6).

While hormonal therapy will not always result in complete regression of endometriotic lesions, it will decrease the recurrence rate of endometriomas and can be considered for long-term prevention of potentially premalignant lesions. It is most effective when it follows surgical excision of endometriomas and associated endometriosis.

A patient who has completed childbearing at the time of surgical resection may be offered bilateral salpingectomy, regardless of menopausal status. Salpingectomy in both average and high-risk populations (e.g., BRCA 1/2 carriers) not only prevents high-grade serous carcinoma by eliminating the site of origin, but also may decrease the risk of endometrioid and clear cell carcinoma by blocking the passageway that enables the flow of endometrium and factors that induce inflammation. It is estimated that the procedure reduces the risk of ovarian cancer by 40%.

Interestingly, tubal ligation has historically been shown to decrease the risk of ovarian cancer, and recent data have shown that the risk of endometrioid and clear cell carcinoma is cut even more than the risk of high-grade serous carcinoma (Int J Epidemiol. 2013 Apr;42[2]:579-89).

Courtesy Dr. Farr Nezhat

The Society of Gynecologic Oncology recommends that risk-reducing salpingectomy be considered at the time of hysterectomy or other abdominal or pelvic surgery, and in lieu of tubal ligation. The American College of Obstetricians and Gynecologists similarly has stated that prophylactic salpingectomy may offer clinicians the opportunity to prevent ovarian cancer in their patients. Salpingectomy is an important option for all patients, but is especially important when the fallopian tubes are found to be damaged by endometriosis and/or pelvic inflammatory disease. When imaging studies show that endometriomas are present and resection is not performed, pelvic ultrasound should become part of the patient’s routine examination.

Most endometriomas have a homogeneous appearance; any significant increase in size or a change in the homogeneous cystic characteristics to a more heterogeneous appearance with mural components should raise suspicion about malignant change.

It can be difficult to detect relatively small endocystic components with ultrasound, so if there is any doubt about whether there is some heterogeneous consistency, an MRI should be performed. MRI is showing more promise in detecting malignant change. Hyperdense mural nodules within the ovary and rapid growth of an endometrioma have both been associated with malignant transformation and can be seen on these images.

In a cohort study comparing MRI findings of 10 patients with ovarian adenocarcinoma to 10 patients with benign endometriomas, investigators found mural nodules in all 10 malignancies but in only three of the benign cases (AJR Am J Roentgenol. 2000 Nov;175[5]:1423-30).

Long-term follow-up is necessary to understand the timeline of transformation in patients with mural nodules. This together with increasing knowledge of molecular events underpinning evolution of endometriosis will lead to better screening and preventive strategies.

Dr. Nezhat is the director of minimally invasive gynecologic surgery and robotics at Winthrop University Hospital in Mineola, N.Y., and an adjunct professor of obstetrics, gynecology, and reproductive medicine at the State University of New York at Stony Brook. He reported having no financial disclosures.

Endometriosis is a common condition, occurring in this country in 1 of 10 women of reproductive age. An association between endometriosis and subsequent ovarian carcinoma has been reported for decades, yet it is only recently that our knowledge has deepened enough to support more rational methods for preventing the malignancy.

Each year, approximately 22,000 new cases of ovarian cancer are diagnosed. The lifetime risk of developing this malignancy is low, but it is the deadliest of the gynecologic malignancies, with diagnosis usually made in advanced stages when prognosis is poor.

Endometriosis shows some characteristics of malignancy, such as the development of local and distant foci, and attachment to and invasion of other tissues with subsequent damage to these tissues. Endometriosis also is characterized by recurrent, unregulated cell proliferation and estrogen-dependent growth.

Our attempts during the past 2 decades to detect ovarian carcinoma at the early stages through a combined screening modality involving transvaginal ultrasound and a test for the serum level of cancer antigen 125 have failed to provide any survival benefit or even any measurable reduction in morbidity. Today, early-stage ovarian carcinoma, which has a 5-year survival rate of more than 90%, is diagnosed in only a minority of women.

There is good news, however. In recent years our insight into the pathophysiology of ovarian cancer has deepened, providing us with a new paradigm for ovarian cancer pathogenesis that divides ovarian epithelial carcinoma into two distinct types with distinct molecular profiles – one which originates largely in the distal portion of the fallopian tube and the other which traces back to endometriosis.

This new paradigm strengthens and helps to explain the reported association between endometriosis and ovarian cancer. It also has important clinical implications for current practice. While we have much more to learn about the etiology of endometriosis and the causes of malignant transformation, our current knowledge provides a strong rationale for identification and close monitoring of some patients with endometriosis deemed at risk for ovarian cancer, risk-reducing medical management, earlier and more meticulous surgical treatment, and close monitoring.

By combining this new approach to endometriosis with consideration of salpingectomy after completion of childbearing, we have an unprecedented opportunity to reduce the incidence of epithelial ovarian cancer.

Dual pathogenesis

The majority of ovarian cancers are of epithelial origin and fall into four histologic categories: serous, endometrioid, clear cell, and mucinous. In recent years, we have gained a deeper understanding of the pathogenesis of ovarian carcinoma, with an array of epidemiologic, histologic, and molecular data showing us that epithelial ovarian cancers are also of two distinct types (Am J Obstet Gynecol. 2015 Sep;213[3]:262-7).

One of these types, a high-grade serous carcinoma, appears to arise in many cases in the epithelium of the fallopian tube. The other type of tumor is a low-grade carcinoma – particularly of the endometrioid and clear cell histologic subtypes – that originates largely from ovarian endometriotic lesions or from borderline serous tumors in the case of serous histology.

The majority of diagnosed stage 1 ovarian cancers are carcinomas of this low-grade type and not high-grade serous carcinomas. In a study of 76 consecutive stage 1 carcinomas, investigators found that ovarian endometriosis was present in 40 of the 76 cases. More than two-thirds of the 76 cases (71%) were nonserous cancers, and almost all of these cases were associated with endometriosis based on histologic examination (Fertil Steril. 2007 Oct;88[4]:906-10).

This study was among the first to show that the majority of stage 1 ovarian carcinomas are not high-grade serous carcinomas, but rather nonserous, primarily endometrioid and clear cell, cancers. The research demonstrated that endometriosis should be viewed as a potential precursor lesion to specific subtypes of ovarian cancer.

The malignant transformation of endometriosis was first suggested by Dr. J. A. Sampson in 1925, and a number of studies – in addition to the 2007 landmark study – have since described ovarian cancer arising from endometriosis, based on the frequent co-occurrence in surgical specimens.

Most recently, a study from the Ovarian Cancer Association Consortium (OCAC) found that women who reported a history of endometriosis had a significantly higher risk of developing ovarian cancer than the general population (odds ratio, 1.46).

Investigators of this critical study pooled data from 13 ovarian cancer case-control studies involving more than 13,226 controls and 7,911 women with invasive epithelial ovarian cancer – 818 (6.2%) and 738 (9.3%) of whom, respectively, reported a history of endometriosis. Specifically, they determined that self-reported endometriosis was associated with a 3.05-fold increased risk for clear cell invasive ovarian cancer and a 2.04-fold increased risk of endometrioid ovarian cancer.

Moreover, a significant association between preexisting endometriosis and low-grade serous invasive ovarian cancer (OR, 2.11) was demonstrated, while no association was found between endometriosis and the risk of high-grade serous invasive ovarian cancer (Lancet Oncol. 2012 Apr;13[4]:385-94).

A second recently published report – a meta-analysis of 20 case-control and 15 cohort studies published between 1990 and 2012 and involving more than 444,000 patients – found that endometriosis increased cancer risk in case-control or two-arm cohort studies by 27% (relative risk, 1.265) and by approximately 80% in single-arm cohort studies (standard incidence ratio, 1.797). Endometrioid and clear cell carcinomas were more common in endometriosis-associated ovarian cancer, while serous carcinoma was less frequent (Br J Cancer. 2014 Apr 2;110[7]:1878-90).

Findings of both of these large studies have served to clarify the association between endometriosis and specific histologic subtypes and suggested that there are important differences in the pathogenesis of low-grade and high-grade serous ovarian carcinomas.

Clinical implications

It is not clear what causes malignant transformation or what predisposes some patients with endometriosis to develop ovarian cancer, but the risk likely involves genetic and epigenetic influences as well as immunologic, inflammatory, and hormonal factors.

The molecular profiles of the main two types of ovarian cancer are different: While the majority of high-grade serous ovarian tumors are characterized by TP53 mutations, the low-grade carcinomas are characterized by a variety of mutations, including KRAS, BRAF, ERBB2, CTNNB1, and BCL2 mutations.

There currently are not enough data to recommend genetic screening tests in patients with endometriosis, but our hope is that we eventually will be able to screen for “high-risk” endometriotic lesions by testing for genes specific to various histologic subtypes of low-grade ovarian cancer, or by finding and utilizing other biomarkers.

Courtesy of Dr. Farr Nezhat

In the meantime, we believe it is important to more thoroughly treat endometriosis and to identify and follow women with a history of the condition, especially those with a long-standing history, those with a history of endometriosis associated with infertility, and those with ovarian endometrioma. Each of these factors predisposes patients to a higher risk of malignant transformation.

Complete surgical resection of all visible endometriosis is the most effective treatment and will afford the best cancer prevention, even in women who are asymptomatic. In a recent Swedish national registry case-control study, women who underwent radical surgical excision of all visible endometriosis were significantly less likely (OR, 0.30) to develop ovarian cancer (Acta Obstet Gynecol Scand. 2013 May;92[5]:546-54).

Suppressive hormonal therapy is another treatment option for patients with no interest in conceiving. Most large endometriomas are functional ovarian cysts that have been invaded by cortical ovarian endometriosis or by small primary endometriomas (J Reprod Med. 1992 Sep;37[9]:771-6).

While hormonal therapy will not always result in complete regression of endometriotic lesions, it will decrease the recurrence rate of endometriomas and can be considered for long-term prevention of potentially premalignant lesions. It is most effective when it follows surgical excision of endometriomas and associated endometriosis.

A patient who has completed childbearing at the time of surgical resection may be offered bilateral salpingectomy, regardless of menopausal status. Salpingectomy in both average and high-risk populations (e.g., BRCA 1/2 carriers) not only prevents high-grade serous carcinoma by eliminating the site of origin, but also may decrease the risk of endometrioid and clear cell carcinoma by blocking the passageway that enables the flow of endometrium and factors that induce inflammation. It is estimated that the procedure reduces the risk of ovarian cancer by 40%.

Interestingly, tubal ligation has historically been shown to decrease the risk of ovarian cancer, and recent data have shown that the risk of endometrioid and clear cell carcinoma is cut even more than the risk of high-grade serous carcinoma (Int J Epidemiol. 2013 Apr;42[2]:579-89).

Courtesy Dr. Farr Nezhat

The Society of Gynecologic Oncology recommends that risk-reducing salpingectomy be considered at the time of hysterectomy or other abdominal or pelvic surgery, and in lieu of tubal ligation. The American College of Obstetricians and Gynecologists similarly has stated that prophylactic salpingectomy may offer clinicians the opportunity to prevent ovarian cancer in their patients. Salpingectomy is an important option for all patients, but is especially important when the fallopian tubes are found to be damaged by endometriosis and/or pelvic inflammatory disease. When imaging studies show that endometriomas are present and resection is not performed, pelvic ultrasound should become part of the patient’s routine examination.

Most endometriomas have a homogeneous appearance; any significant increase in size or a change in the homogeneous cystic characteristics to a more heterogeneous appearance with mural components should raise suspicion about malignant change.

It can be difficult to detect relatively small endocystic components with ultrasound, so if there is any doubt about whether there is some heterogeneous consistency, an MRI should be performed. MRI is showing more promise in detecting malignant change. Hyperdense mural nodules within the ovary and rapid growth of an endometrioma have both been associated with malignant transformation and can be seen on these images.

In a cohort study comparing MRI findings of 10 patients with ovarian adenocarcinoma to 10 patients with benign endometriomas, investigators found mural nodules in all 10 malignancies but in only three of the benign cases (AJR Am J Roentgenol. 2000 Nov;175[5]:1423-30).

Long-term follow-up is necessary to understand the timeline of transformation in patients with mural nodules. This together with increasing knowledge of molecular events underpinning evolution of endometriosis will lead to better screening and preventive strategies.

Dr. Nezhat is the director of minimally invasive gynecologic surgery and robotics at Winthrop University Hospital in Mineola, N.Y., and an adjunct professor of obstetrics, gynecology, and reproductive medicine at the State University of New York at Stony Brook. He reported having no financial disclosures.

Endometriosis is a common condition, occurring in this country in 1 of 10 women of reproductive age. An association between endometriosis and subsequent ovarian carcinoma has been reported for decades, yet it is only recently that our knowledge has deepened enough to support more rational methods for preventing the malignancy.

Each year, approximately 22,000 new cases of ovarian cancer are diagnosed. The lifetime risk of developing this malignancy is low, but it is the deadliest of the gynecologic malignancies, with diagnosis usually made in advanced stages when prognosis is poor.

Endometriosis shows some characteristics of malignancy, such as the development of local and distant foci, and attachment to and invasion of other tissues with subsequent damage to these tissues. Endometriosis also is characterized by recurrent, unregulated cell proliferation and estrogen-dependent growth.

Our attempts during the past 2 decades to detect ovarian carcinoma at the early stages through a combined screening modality involving transvaginal ultrasound and a test for the serum level of cancer antigen 125 have failed to provide any survival benefit or even any measurable reduction in morbidity. Today, early-stage ovarian carcinoma, which has a 5-year survival rate of more than 90%, is diagnosed in only a minority of women.

There is good news, however. In recent years our insight into the pathophysiology of ovarian cancer has deepened, providing us with a new paradigm for ovarian cancer pathogenesis that divides ovarian epithelial carcinoma into two distinct types with distinct molecular profiles – one which originates largely in the distal portion of the fallopian tube and the other which traces back to endometriosis.

This new paradigm strengthens and helps to explain the reported association between endometriosis and ovarian cancer. It also has important clinical implications for current practice. While we have much more to learn about the etiology of endometriosis and the causes of malignant transformation, our current knowledge provides a strong rationale for identification and close monitoring of some patients with endometriosis deemed at risk for ovarian cancer, risk-reducing medical management, earlier and more meticulous surgical treatment, and close monitoring.

By combining this new approach to endometriosis with consideration of salpingectomy after completion of childbearing, we have an unprecedented opportunity to reduce the incidence of epithelial ovarian cancer.

Dual pathogenesis

The majority of ovarian cancers are of epithelial origin and fall into four histologic categories: serous, endometrioid, clear cell, and mucinous. In recent years, we have gained a deeper understanding of the pathogenesis of ovarian carcinoma, with an array of epidemiologic, histologic, and molecular data showing us that epithelial ovarian cancers are also of two distinct types (Am J Obstet Gynecol. 2015 Sep;213[3]:262-7).

One of these types, a high-grade serous carcinoma, appears to arise in many cases in the epithelium of the fallopian tube. The other type of tumor is a low-grade carcinoma – particularly of the endometrioid and clear cell histologic subtypes – that originates largely from ovarian endometriotic lesions or from borderline serous tumors in the case of serous histology.

The majority of diagnosed stage 1 ovarian cancers are carcinomas of this low-grade type and not high-grade serous carcinomas. In a study of 76 consecutive stage 1 carcinomas, investigators found that ovarian endometriosis was present in 40 of the 76 cases. More than two-thirds of the 76 cases (71%) were nonserous cancers, and almost all of these cases were associated with endometriosis based on histologic examination (Fertil Steril. 2007 Oct;88[4]:906-10).

This study was among the first to show that the majority of stage 1 ovarian carcinomas are not high-grade serous carcinomas, but rather nonserous, primarily endometrioid and clear cell, cancers. The research demonstrated that endometriosis should be viewed as a potential precursor lesion to specific subtypes of ovarian cancer.

The malignant transformation of endometriosis was first suggested by Dr. J. A. Sampson in 1925, and a number of studies – in addition to the 2007 landmark study – have since described ovarian cancer arising from endometriosis, based on the frequent co-occurrence in surgical specimens.

Most recently, a study from the Ovarian Cancer Association Consortium (OCAC) found that women who reported a history of endometriosis had a significantly higher risk of developing ovarian cancer than the general population (odds ratio, 1.46).

Investigators of this critical study pooled data from 13 ovarian cancer case-control studies involving more than 13,226 controls and 7,911 women with invasive epithelial ovarian cancer – 818 (6.2%) and 738 (9.3%) of whom, respectively, reported a history of endometriosis. Specifically, they determined that self-reported endometriosis was associated with a 3.05-fold increased risk for clear cell invasive ovarian cancer and a 2.04-fold increased risk of endometrioid ovarian cancer.

Moreover, a significant association between preexisting endometriosis and low-grade serous invasive ovarian cancer (OR, 2.11) was demonstrated, while no association was found between endometriosis and the risk of high-grade serous invasive ovarian cancer (Lancet Oncol. 2012 Apr;13[4]:385-94).

A second recently published report – a meta-analysis of 20 case-control and 15 cohort studies published between 1990 and 2012 and involving more than 444,000 patients – found that endometriosis increased cancer risk in case-control or two-arm cohort studies by 27% (relative risk, 1.265) and by approximately 80% in single-arm cohort studies (standard incidence ratio, 1.797). Endometrioid and clear cell carcinomas were more common in endometriosis-associated ovarian cancer, while serous carcinoma was less frequent (Br J Cancer. 2014 Apr 2;110[7]:1878-90).

Findings of both of these large studies have served to clarify the association between endometriosis and specific histologic subtypes and suggested that there are important differences in the pathogenesis of low-grade and high-grade serous ovarian carcinomas.

Clinical implications

It is not clear what causes malignant transformation or what predisposes some patients with endometriosis to develop ovarian cancer, but the risk likely involves genetic and epigenetic influences as well as immunologic, inflammatory, and hormonal factors.

The molecular profiles of the main two types of ovarian cancer are different: While the majority of high-grade serous ovarian tumors are characterized by TP53 mutations, the low-grade carcinomas are characterized by a variety of mutations, including KRAS, BRAF, ERBB2, CTNNB1, and BCL2 mutations.

There currently are not enough data to recommend genetic screening tests in patients with endometriosis, but our hope is that we eventually will be able to screen for “high-risk” endometriotic lesions by testing for genes specific to various histologic subtypes of low-grade ovarian cancer, or by finding and utilizing other biomarkers.

Courtesy of Dr. Farr Nezhat

In the meantime, we believe it is important to more thoroughly treat endometriosis and to identify and follow women with a history of the condition, especially those with a long-standing history, those with a history of endometriosis associated with infertility, and those with ovarian endometrioma. Each of these factors predisposes patients to a higher risk of malignant transformation.

Complete surgical resection of all visible endometriosis is the most effective treatment and will afford the best cancer prevention, even in women who are asymptomatic. In a recent Swedish national registry case-control study, women who underwent radical surgical excision of all visible endometriosis were significantly less likely (OR, 0.30) to develop ovarian cancer (Acta Obstet Gynecol Scand. 2013 May;92[5]:546-54).

Suppressive hormonal therapy is another treatment option for patients with no interest in conceiving. Most large endometriomas are functional ovarian cysts that have been invaded by cortical ovarian endometriosis or by small primary endometriomas (J Reprod Med. 1992 Sep;37[9]:771-6).

While hormonal therapy will not always result in complete regression of endometriotic lesions, it will decrease the recurrence rate of endometriomas and can be considered for long-term prevention of potentially premalignant lesions. It is most effective when it follows surgical excision of endometriomas and associated endometriosis.

A patient who has completed childbearing at the time of surgical resection may be offered bilateral salpingectomy, regardless of menopausal status. Salpingectomy in both average and high-risk populations (e.g., BRCA 1/2 carriers) not only prevents high-grade serous carcinoma by eliminating the site of origin, but also may decrease the risk of endometrioid and clear cell carcinoma by blocking the passageway that enables the flow of endometrium and factors that induce inflammation. It is estimated that the procedure reduces the risk of ovarian cancer by 40%.

Interestingly, tubal ligation has historically been shown to decrease the risk of ovarian cancer, and recent data have shown that the risk of endometrioid and clear cell carcinoma is cut even more than the risk of high-grade serous carcinoma (Int J Epidemiol. 2013 Apr;42[2]:579-89).

Courtesy Dr. Farr Nezhat

The Society of Gynecologic Oncology recommends that risk-reducing salpingectomy be considered at the time of hysterectomy or other abdominal or pelvic surgery, and in lieu of tubal ligation. The American College of Obstetricians and Gynecologists similarly has stated that prophylactic salpingectomy may offer clinicians the opportunity to prevent ovarian cancer in their patients. Salpingectomy is an important option for all patients, but is especially important when the fallopian tubes are found to be damaged by endometriosis and/or pelvic inflammatory disease. When imaging studies show that endometriomas are present and resection is not performed, pelvic ultrasound should become part of the patient’s routine examination.

Most endometriomas have a homogeneous appearance; any significant increase in size or a change in the homogeneous cystic characteristics to a more heterogeneous appearance with mural components should raise suspicion about malignant change.

It can be difficult to detect relatively small endocystic components with ultrasound, so if there is any doubt about whether there is some heterogeneous consistency, an MRI should be performed. MRI is showing more promise in detecting malignant change. Hyperdense mural nodules within the ovary and rapid growth of an endometrioma have both been associated with malignant transformation and can be seen on these images.

In a cohort study comparing MRI findings of 10 patients with ovarian adenocarcinoma to 10 patients with benign endometriomas, investigators found mural nodules in all 10 malignancies but in only three of the benign cases (AJR Am J Roentgenol. 2000 Nov;175[5]:1423-30).

Long-term follow-up is necessary to understand the timeline of transformation in patients with mural nodules. This together with increasing knowledge of molecular events underpinning evolution of endometriosis will lead to better screening and preventive strategies.

Dr. Nezhat is the director of minimally invasive gynecologic surgery and robotics at Winthrop University Hospital in Mineola, N.Y., and an adjunct professor of obstetrics, gynecology, and reproductive medicine at the State University of New York at Stony Brook. He reported having no financial disclosures.

During an ob.gyn. rotation, a medical student quickly learns the risks related to endometriosis; that is, pelvic pain, abnormal uterine bleeding, and infertility. With more experience, the young practitioner realizes the concern of unopposed estrogen therapy in patients with a history of endometriosis (i.e., cancer).

Now, in this excellent discussion by Dr. Farr Nezhat, for the current edition of the Master Class in Gynecologic Surgery, he describes the risk of endometriosis and ovarian cancer. Not only does Dr. Nezhat present data revealing the increased association between ovarian cancer and endometriosis, but he goes on to describe the usual type of epithelial ovarian cancer that is noted in the patient with endometriosis.

Dr. Nezhat describes women who appear to be predisposed to malignant transformation and provides current recommendations to lower the risk of malignancy in patients with endometriosis. This includes complete surgical resection of endometriosis, routine ultrasound/MRI if endometriosis is not resected, suppressive hormonal therapy, and bilateral salpingectomy. Moreover, Dr. Nezhat looks to the future and the possibility of genetic screening tests.

Dr. Nezhat is board certified in gynecologic oncology and is world renowned for his work with advanced laparoscopic and robotic surgery for the treatment of gynecologic cancers and complex benign conditions. He is the director of minimally invasive gynecologic surgery and robotics at Winthrop University Hospital in Mineola, N.Y., and an adjunct professor of obstetrics, gynecology, and reproductive medicine at State University of New York at Stony Brook.

His main areas of interest and research include early detection and treatment of early and advanced ovarian cancer, as well as cancer arising in endometriosis. Dr. Nezhat has authored and coauthored more than 200 medical and scientific manuscripts and book chapters.

Dr. Miller is a clinical associate professor at the University of Illinois at Chicago, and a past president of the AAGL and the International Society for Gynecologic Endoscopy (ISGE). He is a reproductive endocrinologist and minimally invasive gynecologic surgeon in private practice in Naperville and Schaumburg, Ill.; director of minimally invasive gynecologic surgery and the director of the AAGL/Society of Reproductive Surgery fellowship in minimally invasive gynecologic surgery at Advocate Lutheran General Hospital, Park Ridge, Ill.; and the medical editor of this column, Master Class. Dr. Miller reported having no financial disclosures relevant to this column.

During an ob.gyn. rotation, a medical student quickly learns the risks related to endometriosis; that is, pelvic pain, abnormal uterine bleeding, and infertility. With more experience, the young practitioner realizes the concern of unopposed estrogen therapy in patients with a history of endometriosis (i.e., cancer).

Now, in this excellent discussion by Dr. Farr Nezhat, for the current edition of the Master Class in Gynecologic Surgery, he describes the risk of endometriosis and ovarian cancer. Not only does Dr. Nezhat present data revealing the increased association between ovarian cancer and endometriosis, but he goes on to describe the usual type of epithelial ovarian cancer that is noted in the patient with endometriosis.

Dr. Nezhat describes women who appear to be predisposed to malignant transformation and provides current recommendations to lower the risk of malignancy in patients with endometriosis. This includes complete surgical resection of endometriosis, routine ultrasound/MRI if endometriosis is not resected, suppressive hormonal therapy, and bilateral salpingectomy. Moreover, Dr. Nezhat looks to the future and the possibility of genetic screening tests.

Dr. Nezhat is board certified in gynecologic oncology and is world renowned for his work with advanced laparoscopic and robotic surgery for the treatment of gynecologic cancers and complex benign conditions. He is the director of minimally invasive gynecologic surgery and robotics at Winthrop University Hospital in Mineola, N.Y., and an adjunct professor of obstetrics, gynecology, and reproductive medicine at State University of New York at Stony Brook.

His main areas of interest and research include early detection and treatment of early and advanced ovarian cancer, as well as cancer arising in endometriosis. Dr. Nezhat has authored and coauthored more than 200 medical and scientific manuscripts and book chapters.

Dr. Miller is a clinical associate professor at the University of Illinois at Chicago, and a past president of the AAGL and the International Society for Gynecologic Endoscopy (ISGE). He is a reproductive endocrinologist and minimally invasive gynecologic surgeon in private practice in Naperville and Schaumburg, Ill.; director of minimally invasive gynecologic surgery and the director of the AAGL/Society of Reproductive Surgery fellowship in minimally invasive gynecologic surgery at Advocate Lutheran General Hospital, Park Ridge, Ill.; and the medical editor of this column, Master Class. Dr. Miller reported having no financial disclosures relevant to this column.

During an ob.gyn. rotation, a medical student quickly learns the risks related to endometriosis; that is, pelvic pain, abnormal uterine bleeding, and infertility. With more experience, the young practitioner realizes the concern of unopposed estrogen therapy in patients with a history of endometriosis (i.e., cancer).

Now, in this excellent discussion by Dr. Farr Nezhat, for the current edition of the Master Class in Gynecologic Surgery, he describes the risk of endometriosis and ovarian cancer. Not only does Dr. Nezhat present data revealing the increased association between ovarian cancer and endometriosis, but he goes on to describe the usual type of epithelial ovarian cancer that is noted in the patient with endometriosis.

Dr. Nezhat describes women who appear to be predisposed to malignant transformation and provides current recommendations to lower the risk of malignancy in patients with endometriosis. This includes complete surgical resection of endometriosis, routine ultrasound/MRI if endometriosis is not resected, suppressive hormonal therapy, and bilateral salpingectomy. Moreover, Dr. Nezhat looks to the future and the possibility of genetic screening tests.

Dr. Nezhat is board certified in gynecologic oncology and is world renowned for his work with advanced laparoscopic and robotic surgery for the treatment of gynecologic cancers and complex benign conditions. He is the director of minimally invasive gynecologic surgery and robotics at Winthrop University Hospital in Mineola, N.Y., and an adjunct professor of obstetrics, gynecology, and reproductive medicine at State University of New York at Stony Brook.

His main areas of interest and research include early detection and treatment of early and advanced ovarian cancer, as well as cancer arising in endometriosis. Dr. Nezhat has authored and coauthored more than 200 medical and scientific manuscripts and book chapters.

Dr. Miller is a clinical associate professor at the University of Illinois at Chicago, and a past president of the AAGL and the International Society for Gynecologic Endoscopy (ISGE). He is a reproductive endocrinologist and minimally invasive gynecologic surgeon in private practice in Naperville and Schaumburg, Ill.; director of minimally invasive gynecologic surgery and the director of the AAGL/Society of Reproductive Surgery fellowship in minimally invasive gynecologic surgery at Advocate Lutheran General Hospital, Park Ridge, Ill.; and the medical editor of this column, Master Class. Dr. Miller reported having no financial disclosures relevant to this column.

Cervical intraepithelial neoplasia (CIN) describes a precancerous lesion of the squamous epithelium of the ectocervix. The cervical cancer screening paradigm in the United States begins with collection of cervical cytology with a Pap smear, frequently in conjunction with human papillomavirus testing. Abnormalities will frequently lead to colposcopy with directed biopsy, which can result in a diagnosis of CIN. There are different grades of severity within CIN, which aids in making treatment recommendations.

Pregnancy is a convenient time to capture women for cervical cancer screening, given the increased contact with health care providers. Routine guidelines should be followed for screening women who are pregnant, as collection of cervical cytology and human papillomavirus (HPV) cotesting is safe.

In women who have been found to have abnormal cytology, CIN or malignancy has been identified in up to 19% of cases (Am J Obstet Gynecol. 2004 Jul;191[1]:105-13). High-grade lesions identified in pregnant women create a unique management dilemma.

Terminology

The Bethesda system describes colposcopic abnormalities as CIN and divides premalignant lesions into grades from 1 to 3 with the highest grade representing more worrisome lesions. CIN2 has been found to have poor reproducibility and likely represents a mix of low- and high-grade lesions. In addition, there is concern that HPV-associated lesions of the lower anogenital tract have incongruent terminology among different specialties that may not accurately represent the current understanding of HPV pathogenesis.

In 2012, the Lower Anogenital Squamous Terminology (LAST) project of the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology (ASCCP) advocated for consistent terminology across all lower anogenital tract lesions with HPV, including CIN (Int J Gynecol Pathol. 2013 Jan;32[1]:76-115).

With this new terminology, CIN1 is referred to as low-grade squamous intraepithelial lesion (LSIL). CIN2 is characterized by its p16 immunostaining; lesions that are p16 negative are considered LSIL, while those that are positive are considered HSIL (high-grade squamous intraepithelial lesion). While this staining is not universally performed, physicians will start seeing p16 staining results with increasing frequency on their cervical biopsies. CIN3 lesions are referred to as HSIL.

©monkeybusinessimages/Thinkstock

Given the current understanding of HPV-mediated disease, and a commitment to represent the most up-to-date information, the LAST project terminology of HSIL to represent previously identified CIN2 and CIN3 lesions will be used for the remainder of this text.

Diagnosis

There is little data on the natural history of HSIL diagnosed after colposcopy, as most women get some form of therapy. The information that is available suggests that in patients with untreated HSIL, the cumulative incidence of malignancy is as high as 30% at 30 years (Lancet Oncol. 2008 May;9[5]:425-34). Treatment recommendations for excision are aimed at addressing this alarming number; however, care must be individualized, especially in the setting of pregnancy.

If abnormal cervical cytology is obtained on routine screening, appropriate patients should be referred for colposcopic exam. Physicians performing colposcopy should be familiar with the physiologic effects of pregnancy that can obscure the exam, including the increased cervical mucus production, prominence of endocervical glands, and increased vascularity.

Colposcopic-directed ectocervical biopsies have been found to be safe in pregnancy, and these women should be provided the same care as those who are not pregnant (Obstet Gynecol. 1993 Jun;81[6]:915-8). Endocervical sampling and endometrial sampling should not be performed, however, and physicians should remain dedicated to checking pregnancy tests prior to colposcopy.

HSIL cytology should prompt a biopsy in pregnancy; a decision to skip the biopsy and perform an excisional procedure in this setting is not recommended regardless of patient or gestational age. If LSIL (CIN1) is noted on biopsy, reevaluation post partum should be strongly considered, unless a suspicious lesion was felt to be inadequately biopsied.

Management

Managing HSIL in pregnancy focuses on diagnosis and excluding malignancy, while treatment can be reserved for the postpartum period. When choosing a management option, consider individual patient factors such as colposcopic appearance of the lesion, gestational age, and access to health care.

If HSIL is noted on colposcopic-directed biopsy, consider one of several options. The most conservative approach is reevaluation with cytology and colposcopy 6 weeks post partum. This is an option for patients who do not have a colposcopic exam that was concerning for an invasive lesion, were able to be adequately biopsied, and will reliably return for follow-up. Many physicians feel more comfortable with repeat cytology and colposcopy in 3 months from the original biopsy. The most aggressive management would include an excisional procedure during pregnancy.

There are varying rates of regression of biopsy-proven HSIL in pregnancy ranging from 34% to 70% (Obstet Gynecol. 1999 Mar;93[3]:359-62; Acta Obstet Gynecol Scand. 2006;85[9]:1134-7; Reprod Sci. 2009 Nov;16[11]:1034-9). Out of more than 200 patients across these three studies, just two patients were diagnosed with an invasive lesion post partum. Given the low likelihood of progression during pregnancy and the high rate of regression, an excisional procedure should be considered only in cases where there is concern about invasive carcinoma.

In cases where an invasive lesion is suspected, consider an an excisional procedure. While there is some evidence that performing a laser excisional procedure early in pregnancy (18 weeks and earlier) can be safely done, that is not the most common management strategy in the United States (Tumori. 1998 Sep-Oct;84[5]:567-70; Int J Gynecol Cancer. 2007 Jan-Feb;17[1]:127-31). In this circumstance, referral to a gynecologic oncologist is warranted where consideration can be made for performing a cold knife conization. Physicians should be aware of the increased risk of bleeding with this procedure in pregnancy and the potential for preterm birth. There is little literature to guide counseling regarding these risks, and the decision to perform an excisional procedure should be made with a multidisciplinary team (Arch Gynecol Obstet. 2016 Jan 4. doi: 10.1007/s00404-015-3980-y).

The see-and-treat paradigm is not recommended in pregnancy. Those patients with poor follow-up should still undergo colposcopic-directed biopsies prior to any excisional procedure.

Treatment recommendations in pregnancy should be made on the basis of careful consideration of individual patient factors, with strong consideration of repeat testing with cytology and colposcopy prior to an excision procedure.

Dr. Sullivan is a fellow in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. Dr. Gehrig is professor and director of gynecologic oncology at the university. Dr. Sullivan and Dr. Gehrig reported having no relevant financial disclosures. Email them at [email protected].

Cervical intraepithelial neoplasia (CIN) describes a precancerous lesion of the squamous epithelium of the ectocervix. The cervical cancer screening paradigm in the United States begins with collection of cervical cytology with a Pap smear, frequently in conjunction with human papillomavirus testing. Abnormalities will frequently lead to colposcopy with directed biopsy, which can result in a diagnosis of CIN. There are different grades of severity within CIN, which aids in making treatment recommendations.

Pregnancy is a convenient time to capture women for cervical cancer screening, given the increased contact with health care providers. Routine guidelines should be followed for screening women who are pregnant, as collection of cervical cytology and human papillomavirus (HPV) cotesting is safe.

In women who have been found to have abnormal cytology, CIN or malignancy has been identified in up to 19% of cases (Am J Obstet Gynecol. 2004 Jul;191[1]:105-13). High-grade lesions identified in pregnant women create a unique management dilemma.

Terminology

The Bethesda system describes colposcopic abnormalities as CIN and divides premalignant lesions into grades from 1 to 3 with the highest grade representing more worrisome lesions. CIN2 has been found to have poor reproducibility and likely represents a mix of low- and high-grade lesions. In addition, there is concern that HPV-associated lesions of the lower anogenital tract have incongruent terminology among different specialties that may not accurately represent the current understanding of HPV pathogenesis.

In 2012, the Lower Anogenital Squamous Terminology (LAST) project of the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology (ASCCP) advocated for consistent terminology across all lower anogenital tract lesions with HPV, including CIN (Int J Gynecol Pathol. 2013 Jan;32[1]:76-115).

With this new terminology, CIN1 is referred to as low-grade squamous intraepithelial lesion (LSIL). CIN2 is characterized by its p16 immunostaining; lesions that are p16 negative are considered LSIL, while those that are positive are considered HSIL (high-grade squamous intraepithelial lesion). While this staining is not universally performed, physicians will start seeing p16 staining results with increasing frequency on their cervical biopsies. CIN3 lesions are referred to as HSIL.

©monkeybusinessimages/Thinkstock

Given the current understanding of HPV-mediated disease, and a commitment to represent the most up-to-date information, the LAST project terminology of HSIL to represent previously identified CIN2 and CIN3 lesions will be used for the remainder of this text.

Diagnosis

There is little data on the natural history of HSIL diagnosed after colposcopy, as most women get some form of therapy. The information that is available suggests that in patients with untreated HSIL, the cumulative incidence of malignancy is as high as 30% at 30 years (Lancet Oncol. 2008 May;9[5]:425-34). Treatment recommendations for excision are aimed at addressing this alarming number; however, care must be individualized, especially in the setting of pregnancy.

If abnormal cervical cytology is obtained on routine screening, appropriate patients should be referred for colposcopic exam. Physicians performing colposcopy should be familiar with the physiologic effects of pregnancy that can obscure the exam, including the increased cervical mucus production, prominence of endocervical glands, and increased vascularity.

Colposcopic-directed ectocervical biopsies have been found to be safe in pregnancy, and these women should be provided the same care as those who are not pregnant (Obstet Gynecol. 1993 Jun;81[6]:915-8). Endocervical sampling and endometrial sampling should not be performed, however, and physicians should remain dedicated to checking pregnancy tests prior to colposcopy.

HSIL cytology should prompt a biopsy in pregnancy; a decision to skip the biopsy and perform an excisional procedure in this setting is not recommended regardless of patient or gestational age. If LSIL (CIN1) is noted on biopsy, reevaluation post partum should be strongly considered, unless a suspicious lesion was felt to be inadequately biopsied.

Management

Managing HSIL in pregnancy focuses on diagnosis and excluding malignancy, while treatment can be reserved for the postpartum period. When choosing a management option, consider individual patient factors such as colposcopic appearance of the lesion, gestational age, and access to health care.

If HSIL is noted on colposcopic-directed biopsy, consider one of several options. The most conservative approach is reevaluation with cytology and colposcopy 6 weeks post partum. This is an option for patients who do not have a colposcopic exam that was concerning for an invasive lesion, were able to be adequately biopsied, and will reliably return for follow-up. Many physicians feel more comfortable with repeat cytology and colposcopy in 3 months from the original biopsy. The most aggressive management would include an excisional procedure during pregnancy.

There are varying rates of regression of biopsy-proven HSIL in pregnancy ranging from 34% to 70% (Obstet Gynecol. 1999 Mar;93[3]:359-62; Acta Obstet Gynecol Scand. 2006;85[9]:1134-7; Reprod Sci. 2009 Nov;16[11]:1034-9). Out of more than 200 patients across these three studies, just two patients were diagnosed with an invasive lesion post partum. Given the low likelihood of progression during pregnancy and the high rate of regression, an excisional procedure should be considered only in cases where there is concern about invasive carcinoma.

In cases where an invasive lesion is suspected, consider an an excisional procedure. While there is some evidence that performing a laser excisional procedure early in pregnancy (18 weeks and earlier) can be safely done, that is not the most common management strategy in the United States (Tumori. 1998 Sep-Oct;84[5]:567-70; Int J Gynecol Cancer. 2007 Jan-Feb;17[1]:127-31). In this circumstance, referral to a gynecologic oncologist is warranted where consideration can be made for performing a cold knife conization. Physicians should be aware of the increased risk of bleeding with this procedure in pregnancy and the potential for preterm birth. There is little literature to guide counseling regarding these risks, and the decision to perform an excisional procedure should be made with a multidisciplinary team (Arch Gynecol Obstet. 2016 Jan 4. doi: 10.1007/s00404-015-3980-y).

The see-and-treat paradigm is not recommended in pregnancy. Those patients with poor follow-up should still undergo colposcopic-directed biopsies prior to any excisional procedure.

Treatment recommendations in pregnancy should be made on the basis of careful consideration of individual patient factors, with strong consideration of repeat testing with cytology and colposcopy prior to an excision procedure.

Dr. Sullivan is a fellow in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. Dr. Gehrig is professor and director of gynecologic oncology at the university. Dr. Sullivan and Dr. Gehrig reported having no relevant financial disclosures. Email them at [email protected].

Cervical intraepithelial neoplasia (CIN) describes a precancerous lesion of the squamous epithelium of the ectocervix. The cervical cancer screening paradigm in the United States begins with collection of cervical cytology with a Pap smear, frequently in conjunction with human papillomavirus testing. Abnormalities will frequently lead to colposcopy with directed biopsy, which can result in a diagnosis of CIN. There are different grades of severity within CIN, which aids in making treatment recommendations.

Pregnancy is a convenient time to capture women for cervical cancer screening, given the increased contact with health care providers. Routine guidelines should be followed for screening women who are pregnant, as collection of cervical cytology and human papillomavirus (HPV) cotesting is safe.

In women who have been found to have abnormal cytology, CIN or malignancy has been identified in up to 19% of cases (Am J Obstet Gynecol. 2004 Jul;191[1]:105-13). High-grade lesions identified in pregnant women create a unique management dilemma.

Terminology

The Bethesda system describes colposcopic abnormalities as CIN and divides premalignant lesions into grades from 1 to 3 with the highest grade representing more worrisome lesions. CIN2 has been found to have poor reproducibility and likely represents a mix of low- and high-grade lesions. In addition, there is concern that HPV-associated lesions of the lower anogenital tract have incongruent terminology among different specialties that may not accurately represent the current understanding of HPV pathogenesis.

In 2012, the Lower Anogenital Squamous Terminology (LAST) project of the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology (ASCCP) advocated for consistent terminology across all lower anogenital tract lesions with HPV, including CIN (Int J Gynecol Pathol. 2013 Jan;32[1]:76-115).

With this new terminology, CIN1 is referred to as low-grade squamous intraepithelial lesion (LSIL). CIN2 is characterized by its p16 immunostaining; lesions that are p16 negative are considered LSIL, while those that are positive are considered HSIL (high-grade squamous intraepithelial lesion). While this staining is not universally performed, physicians will start seeing p16 staining results with increasing frequency on their cervical biopsies. CIN3 lesions are referred to as HSIL.

©monkeybusinessimages/Thinkstock

Given the current understanding of HPV-mediated disease, and a commitment to represent the most up-to-date information, the LAST project terminology of HSIL to represent previously identified CIN2 and CIN3 lesions will be used for the remainder of this text.

Diagnosis

There is little data on the natural history of HSIL diagnosed after colposcopy, as most women get some form of therapy. The information that is available suggests that in patients with untreated HSIL, the cumulative incidence of malignancy is as high as 30% at 30 years (Lancet Oncol. 2008 May;9[5]:425-34). Treatment recommendations for excision are aimed at addressing this alarming number; however, care must be individualized, especially in the setting of pregnancy.

If abnormal cervical cytology is obtained on routine screening, appropriate patients should be referred for colposcopic exam. Physicians performing colposcopy should be familiar with the physiologic effects of pregnancy that can obscure the exam, including the increased cervical mucus production, prominence of endocervical glands, and increased vascularity.

Colposcopic-directed ectocervical biopsies have been found to be safe in pregnancy, and these women should be provided the same care as those who are not pregnant (Obstet Gynecol. 1993 Jun;81[6]:915-8). Endocervical sampling and endometrial sampling should not be performed, however, and physicians should remain dedicated to checking pregnancy tests prior to colposcopy.

HSIL cytology should prompt a biopsy in pregnancy; a decision to skip the biopsy and perform an excisional procedure in this setting is not recommended regardless of patient or gestational age. If LSIL (CIN1) is noted on biopsy, reevaluation post partum should be strongly considered, unless a suspicious lesion was felt to be inadequately biopsied.

Management

Managing HSIL in pregnancy focuses on diagnosis and excluding malignancy, while treatment can be reserved for the postpartum period. When choosing a management option, consider individual patient factors such as colposcopic appearance of the lesion, gestational age, and access to health care.

If HSIL is noted on colposcopic-directed biopsy, consider one of several options. The most conservative approach is reevaluation with cytology and colposcopy 6 weeks post partum. This is an option for patients who do not have a colposcopic exam that was concerning for an invasive lesion, were able to be adequately biopsied, and will reliably return for follow-up. Many physicians feel more comfortable with repeat cytology and colposcopy in 3 months from the original biopsy. The most aggressive management would include an excisional procedure during pregnancy.

There are varying rates of regression of biopsy-proven HSIL in pregnancy ranging from 34% to 70% (Obstet Gynecol. 1999 Mar;93[3]:359-62; Acta Obstet Gynecol Scand. 2006;85[9]:1134-7; Reprod Sci. 2009 Nov;16[11]:1034-9). Out of more than 200 patients across these three studies, just two patients were diagnosed with an invasive lesion post partum. Given the low likelihood of progression during pregnancy and the high rate of regression, an excisional procedure should be considered only in cases where there is concern about invasive carcinoma.

In cases where an invasive lesion is suspected, consider an an excisional procedure. While there is some evidence that performing a laser excisional procedure early in pregnancy (18 weeks and earlier) can be safely done, that is not the most common management strategy in the United States (Tumori. 1998 Sep-Oct;84[5]:567-70; Int J Gynecol Cancer. 2007 Jan-Feb;17[1]:127-31). In this circumstance, referral to a gynecologic oncologist is warranted where consideration can be made for performing a cold knife conization. Physicians should be aware of the increased risk of bleeding with this procedure in pregnancy and the potential for preterm birth. There is little literature to guide counseling regarding these risks, and the decision to perform an excisional procedure should be made with a multidisciplinary team (Arch Gynecol Obstet. 2016 Jan 4. doi: 10.1007/s00404-015-3980-y).

The see-and-treat paradigm is not recommended in pregnancy. Those patients with poor follow-up should still undergo colposcopic-directed biopsies prior to any excisional procedure.

Treatment recommendations in pregnancy should be made on the basis of careful consideration of individual patient factors, with strong consideration of repeat testing with cytology and colposcopy prior to an excision procedure.

Dr. Sullivan is a fellow in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. Dr. Gehrig is professor and director of gynecologic oncology at the university. Dr. Sullivan and Dr. Gehrig reported having no relevant financial disclosures. Email them at [email protected].

Clinical question: Does AIMS65 risk stratification score predict inpatient mortality in patients with acute upper gastrointestinal bleed (UGIB)?

Background: Acute UGIB is associated with significant morbidity and mortality, which makes it crucial to identify high-risk patients early. Several prognostic algorithms such as Glasgow-Blatchford (GBS) and pre-endoscopy (pre-RS) and post-endoscopy (post-RS) Rockall scores are available to triage such patients. The goal of this study was to validate AIMS65 score as a predictor of inpatient mortality in patients with acute UGIB compared to these other prognostic scores.

Study Design: Retrospective, cohort study.

Setting: Tertiary-care center in Australia, January 2010 to June 2013.

Synopsis: Using ICD-10 diagnosis codes, investigators identified 424 patients with UGIB requiring endoscopy. All patients were risk-stratified using AIMS65, GBS, pre-RS, and post-RS. The AIMS65 score was found to be superior in predicting inpatient mortality compared to GBS and pre-RS scores and statistically superior to all other scores in predicting need for ICU admission.

In addition to being a single-center, retrospective study, other limitations include the use of ICD-10 codes to identify patients. Further prospective studies are needed to further validate the AIMS65 in acute UGIB.

Bottom line: AIMS65 is a simple and useful tool in predicting inpatient mortality in patients with acute UGIB. However, its applicability in making clinical decisions remains unclear.

Citation: Robertson M, Majumdar A, Boyapati R, et al. Risk stratification in acute upper GI bleeding: comparison of the AIMS65 score with the Glasgow-Blatchford and Rockall scoring systems [published online ahead of print October 16, 2015]. Gastrointest Endosc. doi:10.1016/j.gie.2015.10.021.

Clinical question: Does AIMS65 risk stratification score predict inpatient mortality in patients with acute upper gastrointestinal bleed (UGIB)?

Background: Acute UGIB is associated with significant morbidity and mortality, which makes it crucial to identify high-risk patients early. Several prognostic algorithms such as Glasgow-Blatchford (GBS) and pre-endoscopy (pre-RS) and post-endoscopy (post-RS) Rockall scores are available to triage such patients. The goal of this study was to validate AIMS65 score as a predictor of inpatient mortality in patients with acute UGIB compared to these other prognostic scores.

Study Design: Retrospective, cohort study.

Setting: Tertiary-care center in Australia, January 2010 to June 2013.

Synopsis: Using ICD-10 diagnosis codes, investigators identified 424 patients with UGIB requiring endoscopy. All patients were risk-stratified using AIMS65, GBS, pre-RS, and post-RS. The AIMS65 score was found to be superior in predicting inpatient mortality compared to GBS and pre-RS scores and statistically superior to all other scores in predicting need for ICU admission.

In addition to being a single-center, retrospective study, other limitations include the use of ICD-10 codes to identify patients. Further prospective studies are needed to further validate the AIMS65 in acute UGIB.

Bottom line: AIMS65 is a simple and useful tool in predicting inpatient mortality in patients with acute UGIB. However, its applicability in making clinical decisions remains unclear.

Citation: Robertson M, Majumdar A, Boyapati R, et al. Risk stratification in acute upper GI bleeding: comparison of the AIMS65 score with the Glasgow-Blatchford and Rockall scoring systems [published online ahead of print October 16, 2015]. Gastrointest Endosc. doi:10.1016/j.gie.2015.10.021.

Clinical question: Does AIMS65 risk stratification score predict inpatient mortality in patients with acute upper gastrointestinal bleed (UGIB)?

Background: Acute UGIB is associated with significant morbidity and mortality, which makes it crucial to identify high-risk patients early. Several prognostic algorithms such as Glasgow-Blatchford (GBS) and pre-endoscopy (pre-RS) and post-endoscopy (post-RS) Rockall scores are available to triage such patients. The goal of this study was to validate AIMS65 score as a predictor of inpatient mortality in patients with acute UGIB compared to these other prognostic scores.

Study Design: Retrospective, cohort study.

Setting: Tertiary-care center in Australia, January 2010 to June 2013.

Synopsis: Using ICD-10 diagnosis codes, investigators identified 424 patients with UGIB requiring endoscopy. All patients were risk-stratified using AIMS65, GBS, pre-RS, and post-RS. The AIMS65 score was found to be superior in predicting inpatient mortality compared to GBS and pre-RS scores and statistically superior to all other scores in predicting need for ICU admission.

In addition to being a single-center, retrospective study, other limitations include the use of ICD-10 codes to identify patients. Further prospective studies are needed to further validate the AIMS65 in acute UGIB.

Bottom line: AIMS65 is a simple and useful tool in predicting inpatient mortality in patients with acute UGIB. However, its applicability in making clinical decisions remains unclear.

Citation: Robertson M, Majumdar A, Boyapati R, et al. Risk stratification in acute upper GI bleeding: comparison of the AIMS65 score with the Glasgow-Blatchford and Rockall scoring systems [published online ahead of print October 16, 2015]. Gastrointest Endosc. doi:10.1016/j.gie.2015.10.021.

Thrombus

Image by Andre E.X. Brown

Results of a case-control study indicate that estrogen-only hormone therapy carries a lower risk of venous thromboembolism (VTE) than combined estrogen-progestogen therapy.

The study also suggests the type of progestogen a patient receives does not significantly impact the risk of VTE, but the route of administration for estrogen does.

Annica Bergendal, MD, PhD, of Karolinska Institutet in Stockholm, Sweden, and her colleagues reported these findings in Menopause.

The study was conducted in Sweden between 2003 and 2009. It included 838 women with VTE and 891 age-matched control subjects.

Analyses suggested the risk of VTE was almost 2-fold higher in women currently on hormone therapy than in those not taking hormones. The odds ratio (OR)—which was adjusted for smoking, body mass index, and immobilization—was 1.72 (95% CI 1.34-2.20).

Women who took combined estrogen-progestogen therapy had nearly 3 times the VTE risk of those who took no hormones (OR 2.85, 95% CI 2.08-3.90), but the risk was much lower for women who took estrogen alone (OR 1.31, 95% CI 0.78-2.21).

The risk of VTE with combined estrogen-progestogen treatment was about double that of estrogen alone (OR 2.18, 95% CI 1.21-3.92).

Researchers have wondered whether the type of progestogen used makes a difference in the risk of VTE, but this study didn’t show any significant difference in risk between 2 commonly used progestogens.

When oral estrogen was combined with progestogen, the risk of VTE was somewhat, but not significantly, higher among users of medroxyprogesterone acetate (OR 2.94, 95% CI 1.67-5.36) than among users of norethisterone acetate (OR 2.29, 95% CI 1.50-3.40).

On the other hand, the way estrogen was delivered appeared to impact the risk of VTE, with oral estrogen conferring the highest risk.

When the researchers used transdermal estrogen—given alone—as reference, they observed an increased risk of VTE associated with oral estrogen alone (OR 1.84, 95% CI 0.62-5.52).

And when the researchers used locally (vaginally) administered estrogen alone as reference, they saw an increased risk of VTE associated with oral estrogen alone (OR 2.64, 95% CI 1.30-5.38).

Among women using combined estrogen-progestogen treatment, with transdermal estrogen as a reference, there was an increase in VTE risk associated with oral estrogen (OR 2.21, 95% CI 0.88-5.60).

“This study adds to our knowledge that transdermal estrogen therapies are safer than oral, and that different estrogen or progestogen combinations may have different risks,” said JoAnn V. Pinkerton, MD, executive director of the North American Menopause Society, who was not involved in this study.

“The lack of blood clots with transdermal estrogen and with vaginal estrogen is very reassuring for women who need to continue taking hormones as they age, when risk of blood clots increases.”

Thrombus

Image by Andre E.X. Brown

Results of a case-control study indicate that estrogen-only hormone therapy carries a lower risk of venous thromboembolism (VTE) than combined estrogen-progestogen therapy.

The study also suggests the type of progestogen a patient receives does not significantly impact the risk of VTE, but the route of administration for estrogen does.

Annica Bergendal, MD, PhD, of Karolinska Institutet in Stockholm, Sweden, and her colleagues reported these findings in Menopause.

The study was conducted in Sweden between 2003 and 2009. It included 838 women with VTE and 891 age-matched control subjects.

Analyses suggested the risk of VTE was almost 2-fold higher in women currently on hormone therapy than in those not taking hormones. The odds ratio (OR)—which was adjusted for smoking, body mass index, and immobilization—was 1.72 (95% CI 1.34-2.20).

Women who took combined estrogen-progestogen therapy had nearly 3 times the VTE risk of those who took no hormones (OR 2.85, 95% CI 2.08-3.90), but the risk was much lower for women who took estrogen alone (OR 1.31, 95% CI 0.78-2.21).

The risk of VTE with combined estrogen-progestogen treatment was about double that of estrogen alone (OR 2.18, 95% CI 1.21-3.92).

Researchers have wondered whether the type of progestogen used makes a difference in the risk of VTE, but this study didn’t show any significant difference in risk between 2 commonly used progestogens.

When oral estrogen was combined with progestogen, the risk of VTE was somewhat, but not significantly, higher among users of medroxyprogesterone acetate (OR 2.94, 95% CI 1.67-5.36) than among users of norethisterone acetate (OR 2.29, 95% CI 1.50-3.40).

On the other hand, the way estrogen was delivered appeared to impact the risk of VTE, with oral estrogen conferring the highest risk.

When the researchers used transdermal estrogen—given alone—as reference, they observed an increased risk of VTE associated with oral estrogen alone (OR 1.84, 95% CI 0.62-5.52).

And when the researchers used locally (vaginally) administered estrogen alone as reference, they saw an increased risk of VTE associated with oral estrogen alone (OR 2.64, 95% CI 1.30-5.38).

Among women using combined estrogen-progestogen treatment, with transdermal estrogen as a reference, there was an increase in VTE risk associated with oral estrogen (OR 2.21, 95% CI 0.88-5.60).

“This study adds to our knowledge that transdermal estrogen therapies are safer than oral, and that different estrogen or progestogen combinations may have different risks,” said JoAnn V. Pinkerton, MD, executive director of the North American Menopause Society, who was not involved in this study.

“The lack of blood clots with transdermal estrogen and with vaginal estrogen is very reassuring for women who need to continue taking hormones as they age, when risk of blood clots increases.”

Thrombus

Image by Andre E.X. Brown

Results of a case-control study indicate that estrogen-only hormone therapy carries a lower risk of venous thromboembolism (VTE) than combined estrogen-progestogen therapy.

The study also suggests the type of progestogen a patient receives does not significantly impact the risk of VTE, but the route of administration for estrogen does.

Annica Bergendal, MD, PhD, of Karolinska Institutet in Stockholm, Sweden, and her colleagues reported these findings in Menopause.

The study was conducted in Sweden between 2003 and 2009. It included 838 women with VTE and 891 age-matched control subjects.

Analyses suggested the risk of VTE was almost 2-fold higher in women currently on hormone therapy than in those not taking hormones. The odds ratio (OR)—which was adjusted for smoking, body mass index, and immobilization—was 1.72 (95% CI 1.34-2.20).

Women who took combined estrogen-progestogen therapy had nearly 3 times the VTE risk of those who took no hormones (OR 2.85, 95% CI 2.08-3.90), but the risk was much lower for women who took estrogen alone (OR 1.31, 95% CI 0.78-2.21).

The risk of VTE with combined estrogen-progestogen treatment was about double that of estrogen alone (OR 2.18, 95% CI 1.21-3.92).

Researchers have wondered whether the type of progestogen used makes a difference in the risk of VTE, but this study didn’t show any significant difference in risk between 2 commonly used progestogens.

When oral estrogen was combined with progestogen, the risk of VTE was somewhat, but not significantly, higher among users of medroxyprogesterone acetate (OR 2.94, 95% CI 1.67-5.36) than among users of norethisterone acetate (OR 2.29, 95% CI 1.50-3.40).

On the other hand, the way estrogen was delivered appeared to impact the risk of VTE, with oral estrogen conferring the highest risk.

When the researchers used transdermal estrogen—given alone—as reference, they observed an increased risk of VTE associated with oral estrogen alone (OR 1.84, 95% CI 0.62-5.52).

And when the researchers used locally (vaginally) administered estrogen alone as reference, they saw an increased risk of VTE associated with oral estrogen alone (OR 2.64, 95% CI 1.30-5.38).

Among women using combined estrogen-progestogen treatment, with transdermal estrogen as a reference, there was an increase in VTE risk associated with oral estrogen (OR 2.21, 95% CI 0.88-5.60).

“This study adds to our knowledge that transdermal estrogen therapies are safer than oral, and that different estrogen or progestogen combinations may have different risks,” said JoAnn V. Pinkerton, MD, executive director of the North American Menopause Society, who was not involved in this study.

“The lack of blood clots with transdermal estrogen and with vaginal estrogen is very reassuring for women who need to continue taking hormones as they age, when risk of blood clots increases.”