Morcellation of gynecologic surgical specimens became controversial after concerns arose about the potential for inadvertent spread of malignant cells throughout the abdomen and pelvis during tissue morcellation of suspected benign disease. In 2014, the US Food and Drug Administration (FDA) issued a warningagainst the use of laparoscopic power morcellation specifically for myomectomy or hysterectomy in the treatment of leiomyomas (fibroids) because of the risk of spreading undiagnosed malignancy throughout the abdomen and pelvis.¹ This warning was issued after a high-profile case occurred in Boston in which an occult uterine sarcoma was morcellated during a supracervical robot-assisted hysterectomy for suspected benign fibroids.

Recently, the American College of Obstetricians and Gynecologists (ACOG) published a committee opinion with updated recommendations for practice detailing the risks associated with morcellation and suggestions for patient counseling regarding morcellation.²

In this review, we summarize the techniques and risks of morcellation, the epidemiology of undiagnosed uterine malignancies, practice changes noted at our institution, and clinical recommendations moving forward. A case scenario illustrates keys steps in preoperative evaluation and counseling.

Morcellation uses—and risks

Morcellation is the surgical process of dividing a large tissue specimen into smaller pieces to facilitate their removal through the small incisions made in minimally invasive surgery. Morcellation may be performed with a power instrument or manually.

In power morcellation, an electromechanical instrument is used to cut or shave the specimen; in manual morcellation, the surgeon uses a knife to carve the specimen. Power morcellation is performed through a laparoscopic incision, while the manual technique is performed through a minilaparotomy or vaginally after hysterectomy (TABLE). Unlike uncontained morcellation, contained morcellation involves the use of a laparoscopic bag to hold the specimen and therefore prevent tissue dissemination in the abdomen and pelvis.

Morcellation has greatly expanded our ability to perform minimally invasive surgery—for example, in patients with specimens that cannot be extracted en bloc through the vagina after hysterectomy or, in the case of myomectomy or supracervical hysterectomy without a colpotomy, through small laparoscopic ports. Minimally invasive surgery improves patient care, as it is associated with lower rates of infection, blood loss, venous thromboembolism, wound and bowel complications, postoperative pain, and shorter overall recovery time and hospital stay versus traditional open surgery.^3,4 Furthermore, laparoscopic hysterectomy has a 3-fold lower risk of mortality compared with open hysterectomy.⁴ For these reasons, ACOG recommends choosing a minimally invasive approach for all benign hysterectomies whenever feasible.³

With abundant data supporting the use of a minimally invasive approach, laparoscopic morcellation allowed procedures involving larger tissue specimens to be accomplished without the addition of a minilaparotomy for tissue extraction. However, disseminating potentially malignant tissue throughout the abdomen and pelvis during the morcellation process remains a risk. While tissue spread can occur with either power or manual morcellation, the case that drew media attention to the controversy used power morcellation, and thus intense scrutiny focused on this technique. Morcellation has additional risks, including direct injury to surrounding organs, disruption of the pathologic specimen, and distribution of benign tissue throughout the abdomen and pelvis, such as fibroid, endometriosis, and adenomyosis implants.^5-7

Continue to: The challenge of leiomyosarcoma...

The challenge of leiomyosarcoma

The primary controversy surrounding morcellation of fibroid tissue specimens is the potential for undiagnosed malignancy, namely uterine leiomyosarcoma or endometrial stromal sarcoma. While other gynecologic malignancies, including cervical and endometrial cancers, are more common and potentially could be disseminated by morcellation, these cancers are more reliably diagnosed preoperatively with cervical and endometrial biopsies, and they do not tend to mimic benign diseases.

Epidemiology and risk factors. Uterine leiomyosarcoma is rare, with an estimated incidence of 0.36 per 100,000 woman-years.⁸ However, leiomyosarcoma can mimic the appearance and clinical course of benign fibroids, making preoperative diagnosis difficult. Risk factors for leiomyosarcoma include postmenopausal status, with a median age of 54 years at diagnosis, tamoxifen use longer than 5 years, black race, history of pelvic radiation, and certain hereditary cancer syndromes, such as Lynch syndrome.^9-11 Because of these risk factors, preoperative evaluation is crucial to determine the most appropriate surgical method for removal of a large, fibroid uterus (see “Employ shared decision making”).

Estimated incidence at benign hysterectomy. The incidence of leiomyosarcoma diagnosed at the time of benign hysterectomy or myomectomy has been studied extensively since the FDA’s 2014 warning was released, with varying rates identified.^11,12 The FDA’s analysis cited a risk of 1 in 498 for unsuspected leiomyosarcoma and 1 in 352 for uterine sarcoma.¹ Notably, this analysis excluded studies of women undergoing surgery for presumed fibroids in which no leiomyosarcoma was found on pathology, likely inflating the quoted prevalence. The FDA and other entities subsequently performed further analyses, but a systematic literature review and meta-analysis by the Agency for Healthcare Research and Quality (AHRQ) in 2017 is probably the most accurate. That review included 160 studies and reported a prevalence of less than 1 in 10,000 to 1 in 770, lower than the FDA-cited rate.¹³

Prognosis. The overall prognosis for women with leiomyosarcoma is poor. Studies indicate a 5-year survival rate of only 55.4%, even in stage 1 disease that is apparently confined to the uterus.⁹ Although evidence is limited linking morcellation to increased recurrence of leiomyosarcoma, data from small, single-center, retrospective studies cite a worse prognosis, higher risk of recurrence, and shorter progression-free survival after sarcoma morcellation compared with patients who underwent en bloc resection.^12,14 Of note, these studies evaluated patients who underwent uncontained morcellation of specimens with unsuspected leiomyosarcoma.

CASE Woman with enlarged, irregular uterus and heavy bleeding

A 40-year-old woman (G2P2) with a history of 2 uncomplicated vaginal deliveries presents for evaluation of heavy uterine bleeding. She has regular periods, every 28 days, and she bleeds for 7 days, saturating 6 pads per day. She is currently taking only oral iron therapy as recommended by her primary care physician. Over the last 1 to 2 years she has felt that her abdomen has been getting larger and that her pants do not fit as well. She is otherwise in excellent health, exercises regularly, and has a full-time job. She has not been sexually active in several months.

The patient’s vitals are within normal limits and her body mass index (BMI) is 35 kg/m2.Pelvic examination reveals that she has an enlarged, irregular uterus with the fundus at the level of the umbilicus. The exam is otherwise unremarkable. On further questioning, the patient does not desire future fertility.

What next steps would you include in this patient’s workup, including imaging studies or lab tests? What surgical options would you give her? How would your management differ if this patient were 70 years old (postmenopausal)?

Continue to: Perform a thorough preoperative evaluation to optimize outcomes...

Perform a thorough preoperative evaluation to optimize outcomes

Women like this case patient who present with symptoms that may lead to treatment with myomectomy or hysterectomy should undergo appropriate preoperative testing to evaluate for malignancy.

According to ACOG guidance, patients should undergo a preoperative endometrial biopsy if they¹⁵:

• are older than 45 years with abnormal uterine bleeding
• are younger than 45 years with unopposed estrogen exposure (including obesity or polycystic ovary syndrome)
• have persistent bleeding, or
• failed medical management.

Our case patient is younger than 45 but is obese (BMI, 35) and therefore is a candidate for endometrial biopsy. Additionally, all patients should have up-to-date cervical cancer screening. ACOG also recommends appropriate use of imaging with ultrasonography or magnetic resonance imaging (MRI), although imaging is not recommended solely to evaluate for malignancy, as it cannot rule out the diagnosis of many gynecologic malignancies, including leiomyosarcoma.²

Currently, no tests are available to completely exclude a preoperative diagnosis of leiomyosarcoma. While studies have evaluated the use of MRI combined with lactate dehydrogenase isoenzyme testing, the evidence is weak, and this method is not recommended. Sarcoma is detected by endometrial sampling only 30% to 60% of the time, but it should be performed if the patient meets criteria for sampling or if she has other risk factors for malignancy.¹⁶ There are no data to support biopsy of presumed benign fibroids prior to surgical intervention. Patients should be evaluated with a careful history and physical examination for other uterine sarcoma risk factors.

Employ shared decision making

Clinicians should use shared decision making with patients to facilitate decisions on morcellation use in gynecologic surgeries for suspected benign fibroids. Informed consent must be obtained after thorough discussion and counseling regarding the literature on morcellation.¹⁷ For all patients, including the case patient described, this discussion should include alternative treatment options, surgical approach with associated risks, the use of morcellation, the incidence of leiomyosarcoma with presumed benign fibroids, leiomyosarcoma prognosis, and the risk of disseminating benign or undiagnosed cancerous tissue throughout the abdomen and pelvis.

Some would argue that the risks of laparotomy outweigh the possible risks associated with morcellation during a minimally invasive myomectomy or hysterectomy. However, this risk analysis is not uniform across all patients, and it is likely that in older women, because they have an a priori increased risk of malignancy in general, including leiomyosarcoma, the risks of power morcellation may outweigh the risks of open surgery.¹⁸ Younger women have a much lower risk of leiomyosarcoma, and thus discussion and consideration of the patient’s age should be a part of counseling. If the case patient described was 70 years of age, power morcellation might not be recommended, but these decisions require an in-depth discussion with the patient to make an informed decision and ensure patient autonomy.

The contained morcellation approach

Many surgeons who perform minimally invasive procedures use contained morcellation. In this approach, specimens are placed in a containment bag and morcellated with either power instruments or manually to ensure no dissemination of tissue. Manual contained morcellation can be done through a minilaparotomy or the vagina, depending on the procedure performed, while power contained morcellation is performed through a 15-mm laparoscopic incision.

Continue to: Currently, one containment bag has been...

Currently, one containment bag has been FDA approved for use in laparoscopic contained power morcellation.¹⁹ Use of a containment bag increases operative time by approximately 20 minutes, due to the additional steps required to accomplish the procedure.²⁰ Its use, however, suggests a decrease in the risk of possible disease spread and it is feasible with appropriate surgeon training.

One study demonstrated the safety and feasibility of power morcellation within an insufflated containment bag, and subsequent follow-up revealed negative intraperitoneal washings.^21,22 In another study evaluating tissue dissemination with contained morcellation of tissue stained with dye, the authors noted actual spillage of tissue fragments in only one case.²³ Although more information is needed to confirm prevention of tissue dissemination and the safety of contained tissue morcellation, these studies provide promising data supporting the use of tissue morcellation in appropriate cases in order to perform minimally invasive surgery with larger specimens.

CASE Next steps and treatment outcome

The patient has up-to-date and negative cervical cancer screening. The complete blood count is notable for a hemoglobin level of 11.0 g/dL (normal range, 12.1 to 15.1 g/dL). You perform an endometrial biopsy; results are negative for malignancy. You order pelvic ultrasonography to better characterize the location and size of the fibroids. It shows multiple leiomyomas throughout the myometrium, with the 2 largest fibroids (measuring 5 and 7 cm) located in the left anterior and right posterolateral aspects of the uterus, respectively. Several 3- to 4-cm fibroids appear to be disrupting the endometrial canal, and there is no evidence of an endometrial polyp. There do not appear to be any cervical or lower uterine segment fibroids, which may have further complicated the proposed surgery.

You discuss treatment options for abnormal uterine bleeding with the patient, including initiation of combined oral contraceptive pills, placement of a levonorgestrel-containing intrauterine device, endometrial ablation, uterine artery embolization, and hysterectomy. You discuss the risks and benefits of each approach, keeping in mind the fibroids that are disrupting the contour of the endometrial canal and causing her bulk symptoms.

The patient ultimately decides to undergo a hysterectomy and would like it to be performed with a minimally invasive procedure, if possible. Because of the size of her uterus, you discuss the use of contained power morcellation, including the risks and benefits. You have a thorough discussion about the risk of occult malignancy, although she is at lower risk because of her age, and she consents.

The patient undergoes an uncomplicated total laparoscopic hysterectomy with bilateral salpingectomy. The specimen is removed using contained power morcellation through the umbilical port site. She has an unremarkable immediate postoperative course and is discharged on postoperative Day 1.

You see the patient in the clinic 2 weeks later. She reports minimal pain or discomfort and has no other complaints. Her abdominal incisions are healing well. You review the final pathology report with her, which showed no evidence of malignancy.

Society guidance on clinical applications

In current clinical practice, many surgeons have converted to exclusively performing contained morcellation in appropriate patients with a low risk of uterine leiomyosarcoma. At our institution, uncontained morcellation has not been performed since the FDA’s 2014 warning.

ACOG and AAGL (formerly the American Association of Gynecologic Laparoscopists) recommend use of containment bags as a solution to continue minimally invasive surgery for large specimens without the risk of possible tissue dissemination, although more in-depth surgeon training is likely required for accurate technique.^2,24 The Society of Gynecologic Oncology (SGO) states that power morcellation or any other techniques that divide the uterus in the abdomen are contraindicated in patients with documented or highly suspected malignancy.²⁵

With the presented data of risks associated with uncontained morcellation and agreement of the ACOG, AAGL, and SGO professional societies, we recommend that all morcellation be performed in a contained fashion to prevent the dissemination of benign or undiagnosed malignant tissue throughout the abdomen and pelvis. Shared decision making and counseling on the risks, benefits, and alternatives are paramount for patients to make informed decisions about their medical care. Continued exploration of techniques and methods for safe tissue extraction is still needed to improve minimally invasive surgical options for all women.

Morcellation of gynecologic surgical specimens became controversial after concerns arose about the potential for inadvertent spread of malignant cells throughout the abdomen and pelvis during tissue morcellation of suspected benign disease. In 2014, the US Food and Drug Administration (FDA) issued a warningagainst the use of laparoscopic power morcellation specifically for myomectomy or hysterectomy in the treatment of leiomyomas (fibroids) because of the risk of spreading undiagnosed malignancy throughout the abdomen and pelvis.¹ This warning was issued after a high-profile case occurred in Boston in which an occult uterine sarcoma was morcellated during a supracervical robot-assisted hysterectomy for suspected benign fibroids.

Recently, the American College of Obstetricians and Gynecologists (ACOG) published a committee opinion with updated recommendations for practice detailing the risks associated with morcellation and suggestions for patient counseling regarding morcellation.²

In this review, we summarize the techniques and risks of morcellation, the epidemiology of undiagnosed uterine malignancies, practice changes noted at our institution, and clinical recommendations moving forward. A case scenario illustrates keys steps in preoperative evaluation and counseling.

Morcellation uses—and risks

Morcellation is the surgical process of dividing a large tissue specimen into smaller pieces to facilitate their removal through the small incisions made in minimally invasive surgery. Morcellation may be performed with a power instrument or manually.

In power morcellation, an electromechanical instrument is used to cut or shave the specimen; in manual morcellation, the surgeon uses a knife to carve the specimen. Power morcellation is performed through a laparoscopic incision, while the manual technique is performed through a minilaparotomy or vaginally after hysterectomy (TABLE). Unlike uncontained morcellation, contained morcellation involves the use of a laparoscopic bag to hold the specimen and therefore prevent tissue dissemination in the abdomen and pelvis.

Morcellation has greatly expanded our ability to perform minimally invasive surgery—for example, in patients with specimens that cannot be extracted en bloc through the vagina after hysterectomy or, in the case of myomectomy or supracervical hysterectomy without a colpotomy, through small laparoscopic ports. Minimally invasive surgery improves patient care, as it is associated with lower rates of infection, blood loss, venous thromboembolism, wound and bowel complications, postoperative pain, and shorter overall recovery time and hospital stay versus traditional open surgery.^3,4 Furthermore, laparoscopic hysterectomy has a 3-fold lower risk of mortality compared with open hysterectomy.⁴ For these reasons, ACOG recommends choosing a minimally invasive approach for all benign hysterectomies whenever feasible.³

With abundant data supporting the use of a minimally invasive approach, laparoscopic morcellation allowed procedures involving larger tissue specimens to be accomplished without the addition of a minilaparotomy for tissue extraction. However, disseminating potentially malignant tissue throughout the abdomen and pelvis during the morcellation process remains a risk. While tissue spread can occur with either power or manual morcellation, the case that drew media attention to the controversy used power morcellation, and thus intense scrutiny focused on this technique. Morcellation has additional risks, including direct injury to surrounding organs, disruption of the pathologic specimen, and distribution of benign tissue throughout the abdomen and pelvis, such as fibroid, endometriosis, and adenomyosis implants.^5-7

Continue to: The challenge of leiomyosarcoma...

The challenge of leiomyosarcoma

The primary controversy surrounding morcellation of fibroid tissue specimens is the potential for undiagnosed malignancy, namely uterine leiomyosarcoma or endometrial stromal sarcoma. While other gynecologic malignancies, including cervical and endometrial cancers, are more common and potentially could be disseminated by morcellation, these cancers are more reliably diagnosed preoperatively with cervical and endometrial biopsies, and they do not tend to mimic benign diseases.

Epidemiology and risk factors. Uterine leiomyosarcoma is rare, with an estimated incidence of 0.36 per 100,000 woman-years.⁸ However, leiomyosarcoma can mimic the appearance and clinical course of benign fibroids, making preoperative diagnosis difficult. Risk factors for leiomyosarcoma include postmenopausal status, with a median age of 54 years at diagnosis, tamoxifen use longer than 5 years, black race, history of pelvic radiation, and certain hereditary cancer syndromes, such as Lynch syndrome.^9-11 Because of these risk factors, preoperative evaluation is crucial to determine the most appropriate surgical method for removal of a large, fibroid uterus (see “Employ shared decision making”).

Estimated incidence at benign hysterectomy. The incidence of leiomyosarcoma diagnosed at the time of benign hysterectomy or myomectomy has been studied extensively since the FDA’s 2014 warning was released, with varying rates identified.^11,12 The FDA’s analysis cited a risk of 1 in 498 for unsuspected leiomyosarcoma and 1 in 352 for uterine sarcoma.¹ Notably, this analysis excluded studies of women undergoing surgery for presumed fibroids in which no leiomyosarcoma was found on pathology, likely inflating the quoted prevalence. The FDA and other entities subsequently performed further analyses, but a systematic literature review and meta-analysis by the Agency for Healthcare Research and Quality (AHRQ) in 2017 is probably the most accurate. That review included 160 studies and reported a prevalence of less than 1 in 10,000 to 1 in 770, lower than the FDA-cited rate.¹³

Prognosis. The overall prognosis for women with leiomyosarcoma is poor. Studies indicate a 5-year survival rate of only 55.4%, even in stage 1 disease that is apparently confined to the uterus.⁹ Although evidence is limited linking morcellation to increased recurrence of leiomyosarcoma, data from small, single-center, retrospective studies cite a worse prognosis, higher risk of recurrence, and shorter progression-free survival after sarcoma morcellation compared with patients who underwent en bloc resection.^12,14 Of note, these studies evaluated patients who underwent uncontained morcellation of specimens with unsuspected leiomyosarcoma.

CASE Woman with enlarged, irregular uterus and heavy bleeding

A 40-year-old woman (G2P2) with a history of 2 uncomplicated vaginal deliveries presents for evaluation of heavy uterine bleeding. She has regular periods, every 28 days, and she bleeds for 7 days, saturating 6 pads per day. She is currently taking only oral iron therapy as recommended by her primary care physician. Over the last 1 to 2 years she has felt that her abdomen has been getting larger and that her pants do not fit as well. She is otherwise in excellent health, exercises regularly, and has a full-time job. She has not been sexually active in several months.

The patient’s vitals are within normal limits and her body mass index (BMI) is 35 kg/m2.Pelvic examination reveals that she has an enlarged, irregular uterus with the fundus at the level of the umbilicus. The exam is otherwise unremarkable. On further questioning, the patient does not desire future fertility.

What next steps would you include in this patient’s workup, including imaging studies or lab tests? What surgical options would you give her? How would your management differ if this patient were 70 years old (postmenopausal)?

Continue to: Perform a thorough preoperative evaluation to optimize outcomes...

Perform a thorough preoperative evaluation to optimize outcomes

Women like this case patient who present with symptoms that may lead to treatment with myomectomy or hysterectomy should undergo appropriate preoperative testing to evaluate for malignancy.

According to ACOG guidance, patients should undergo a preoperative endometrial biopsy if they¹⁵:

• are older than 45 years with abnormal uterine bleeding
• are younger than 45 years with unopposed estrogen exposure (including obesity or polycystic ovary syndrome)
• have persistent bleeding, or
• failed medical management.

Our case patient is younger than 45 but is obese (BMI, 35) and therefore is a candidate for endometrial biopsy. Additionally, all patients should have up-to-date cervical cancer screening. ACOG also recommends appropriate use of imaging with ultrasonography or magnetic resonance imaging (MRI), although imaging is not recommended solely to evaluate for malignancy, as it cannot rule out the diagnosis of many gynecologic malignancies, including leiomyosarcoma.²

Currently, no tests are available to completely exclude a preoperative diagnosis of leiomyosarcoma. While studies have evaluated the use of MRI combined with lactate dehydrogenase isoenzyme testing, the evidence is weak, and this method is not recommended. Sarcoma is detected by endometrial sampling only 30% to 60% of the time, but it should be performed if the patient meets criteria for sampling or if she has other risk factors for malignancy.¹⁶ There are no data to support biopsy of presumed benign fibroids prior to surgical intervention. Patients should be evaluated with a careful history and physical examination for other uterine sarcoma risk factors.

Employ shared decision making

Clinicians should use shared decision making with patients to facilitate decisions on morcellation use in gynecologic surgeries for suspected benign fibroids. Informed consent must be obtained after thorough discussion and counseling regarding the literature on morcellation.¹⁷ For all patients, including the case patient described, this discussion should include alternative treatment options, surgical approach with associated risks, the use of morcellation, the incidence of leiomyosarcoma with presumed benign fibroids, leiomyosarcoma prognosis, and the risk of disseminating benign or undiagnosed cancerous tissue throughout the abdomen and pelvis.

Some would argue that the risks of laparotomy outweigh the possible risks associated with morcellation during a minimally invasive myomectomy or hysterectomy. However, this risk analysis is not uniform across all patients, and it is likely that in older women, because they have an a priori increased risk of malignancy in general, including leiomyosarcoma, the risks of power morcellation may outweigh the risks of open surgery.¹⁸ Younger women have a much lower risk of leiomyosarcoma, and thus discussion and consideration of the patient’s age should be a part of counseling. If the case patient described was 70 years of age, power morcellation might not be recommended, but these decisions require an in-depth discussion with the patient to make an informed decision and ensure patient autonomy.

The contained morcellation approach

Many surgeons who perform minimally invasive procedures use contained morcellation. In this approach, specimens are placed in a containment bag and morcellated with either power instruments or manually to ensure no dissemination of tissue. Manual contained morcellation can be done through a minilaparotomy or the vagina, depending on the procedure performed, while power contained morcellation is performed through a 15-mm laparoscopic incision.

Continue to: Currently, one containment bag has been...

Currently, one containment bag has been FDA approved for use in laparoscopic contained power morcellation.¹⁹ Use of a containment bag increases operative time by approximately 20 minutes, due to the additional steps required to accomplish the procedure.²⁰ Its use, however, suggests a decrease in the risk of possible disease spread and it is feasible with appropriate surgeon training.

One study demonstrated the safety and feasibility of power morcellation within an insufflated containment bag, and subsequent follow-up revealed negative intraperitoneal washings.^21,22 In another study evaluating tissue dissemination with contained morcellation of tissue stained with dye, the authors noted actual spillage of tissue fragments in only one case.²³ Although more information is needed to confirm prevention of tissue dissemination and the safety of contained tissue morcellation, these studies provide promising data supporting the use of tissue morcellation in appropriate cases in order to perform minimally invasive surgery with larger specimens.

CASE Next steps and treatment outcome

The patient has up-to-date and negative cervical cancer screening. The complete blood count is notable for a hemoglobin level of 11.0 g/dL (normal range, 12.1 to 15.1 g/dL). You perform an endometrial biopsy; results are negative for malignancy. You order pelvic ultrasonography to better characterize the location and size of the fibroids. It shows multiple leiomyomas throughout the myometrium, with the 2 largest fibroids (measuring 5 and 7 cm) located in the left anterior and right posterolateral aspects of the uterus, respectively. Several 3- to 4-cm fibroids appear to be disrupting the endometrial canal, and there is no evidence of an endometrial polyp. There do not appear to be any cervical or lower uterine segment fibroids, which may have further complicated the proposed surgery.

You discuss treatment options for abnormal uterine bleeding with the patient, including initiation of combined oral contraceptive pills, placement of a levonorgestrel-containing intrauterine device, endometrial ablation, uterine artery embolization, and hysterectomy. You discuss the risks and benefits of each approach, keeping in mind the fibroids that are disrupting the contour of the endometrial canal and causing her bulk symptoms.

The patient ultimately decides to undergo a hysterectomy and would like it to be performed with a minimally invasive procedure, if possible. Because of the size of her uterus, you discuss the use of contained power morcellation, including the risks and benefits. You have a thorough discussion about the risk of occult malignancy, although she is at lower risk because of her age, and she consents.

The patient undergoes an uncomplicated total laparoscopic hysterectomy with bilateral salpingectomy. The specimen is removed using contained power morcellation through the umbilical port site. She has an unremarkable immediate postoperative course and is discharged on postoperative Day 1.

You see the patient in the clinic 2 weeks later. She reports minimal pain or discomfort and has no other complaints. Her abdominal incisions are healing well. You review the final pathology report with her, which showed no evidence of malignancy.

Society guidance on clinical applications

In current clinical practice, many surgeons have converted to exclusively performing contained morcellation in appropriate patients with a low risk of uterine leiomyosarcoma. At our institution, uncontained morcellation has not been performed since the FDA’s 2014 warning.

ACOG and AAGL (formerly the American Association of Gynecologic Laparoscopists) recommend use of containment bags as a solution to continue minimally invasive surgery for large specimens without the risk of possible tissue dissemination, although more in-depth surgeon training is likely required for accurate technique.^2,24 The Society of Gynecologic Oncology (SGO) states that power morcellation or any other techniques that divide the uterus in the abdomen are contraindicated in patients with documented or highly suspected malignancy.²⁵

With the presented data of risks associated with uncontained morcellation and agreement of the ACOG, AAGL, and SGO professional societies, we recommend that all morcellation be performed in a contained fashion to prevent the dissemination of benign or undiagnosed malignant tissue throughout the abdomen and pelvis. Shared decision making and counseling on the risks, benefits, and alternatives are paramount for patients to make informed decisions about their medical care. Continued exploration of techniques and methods for safe tissue extraction is still needed to improve minimally invasive surgical options for all women.

Morcellation of gynecologic surgical specimens became controversial after concerns arose about the potential for inadvertent spread of malignant cells throughout the abdomen and pelvis during tissue morcellation of suspected benign disease. In 2014, the US Food and Drug Administration (FDA) issued a warningagainst the use of laparoscopic power morcellation specifically for myomectomy or hysterectomy in the treatment of leiomyomas (fibroids) because of the risk of spreading undiagnosed malignancy throughout the abdomen and pelvis.¹ This warning was issued after a high-profile case occurred in Boston in which an occult uterine sarcoma was morcellated during a supracervical robot-assisted hysterectomy for suspected benign fibroids.

Recently, the American College of Obstetricians and Gynecologists (ACOG) published a committee opinion with updated recommendations for practice detailing the risks associated with morcellation and suggestions for patient counseling regarding morcellation.²

In this review, we summarize the techniques and risks of morcellation, the epidemiology of undiagnosed uterine malignancies, practice changes noted at our institution, and clinical recommendations moving forward. A case scenario illustrates keys steps in preoperative evaluation and counseling.

Morcellation uses—and risks

Morcellation is the surgical process of dividing a large tissue specimen into smaller pieces to facilitate their removal through the small incisions made in minimally invasive surgery. Morcellation may be performed with a power instrument or manually.

In power morcellation, an electromechanical instrument is used to cut or shave the specimen; in manual morcellation, the surgeon uses a knife to carve the specimen. Power morcellation is performed through a laparoscopic incision, while the manual technique is performed through a minilaparotomy or vaginally after hysterectomy (TABLE). Unlike uncontained morcellation, contained morcellation involves the use of a laparoscopic bag to hold the specimen and therefore prevent tissue dissemination in the abdomen and pelvis.

Morcellation has greatly expanded our ability to perform minimally invasive surgery—for example, in patients with specimens that cannot be extracted en bloc through the vagina after hysterectomy or, in the case of myomectomy or supracervical hysterectomy without a colpotomy, through small laparoscopic ports. Minimally invasive surgery improves patient care, as it is associated with lower rates of infection, blood loss, venous thromboembolism, wound and bowel complications, postoperative pain, and shorter overall recovery time and hospital stay versus traditional open surgery.^3,4 Furthermore, laparoscopic hysterectomy has a 3-fold lower risk of mortality compared with open hysterectomy.⁴ For these reasons, ACOG recommends choosing a minimally invasive approach for all benign hysterectomies whenever feasible.³

With abundant data supporting the use of a minimally invasive approach, laparoscopic morcellation allowed procedures involving larger tissue specimens to be accomplished without the addition of a minilaparotomy for tissue extraction. However, disseminating potentially malignant tissue throughout the abdomen and pelvis during the morcellation process remains a risk. While tissue spread can occur with either power or manual morcellation, the case that drew media attention to the controversy used power morcellation, and thus intense scrutiny focused on this technique. Morcellation has additional risks, including direct injury to surrounding organs, disruption of the pathologic specimen, and distribution of benign tissue throughout the abdomen and pelvis, such as fibroid, endometriosis, and adenomyosis implants.^5-7

Continue to: The challenge of leiomyosarcoma...

The challenge of leiomyosarcoma

The primary controversy surrounding morcellation of fibroid tissue specimens is the potential for undiagnosed malignancy, namely uterine leiomyosarcoma or endometrial stromal sarcoma. While other gynecologic malignancies, including cervical and endometrial cancers, are more common and potentially could be disseminated by morcellation, these cancers are more reliably diagnosed preoperatively with cervical and endometrial biopsies, and they do not tend to mimic benign diseases.

Epidemiology and risk factors. Uterine leiomyosarcoma is rare, with an estimated incidence of 0.36 per 100,000 woman-years.⁸ However, leiomyosarcoma can mimic the appearance and clinical course of benign fibroids, making preoperative diagnosis difficult. Risk factors for leiomyosarcoma include postmenopausal status, with a median age of 54 years at diagnosis, tamoxifen use longer than 5 years, black race, history of pelvic radiation, and certain hereditary cancer syndromes, such as Lynch syndrome.^9-11 Because of these risk factors, preoperative evaluation is crucial to determine the most appropriate surgical method for removal of a large, fibroid uterus (see “Employ shared decision making”).

Estimated incidence at benign hysterectomy. The incidence of leiomyosarcoma diagnosed at the time of benign hysterectomy or myomectomy has been studied extensively since the FDA’s 2014 warning was released, with varying rates identified.^11,12 The FDA’s analysis cited a risk of 1 in 498 for unsuspected leiomyosarcoma and 1 in 352 for uterine sarcoma.¹ Notably, this analysis excluded studies of women undergoing surgery for presumed fibroids in which no leiomyosarcoma was found on pathology, likely inflating the quoted prevalence. The FDA and other entities subsequently performed further analyses, but a systematic literature review and meta-analysis by the Agency for Healthcare Research and Quality (AHRQ) in 2017 is probably the most accurate. That review included 160 studies and reported a prevalence of less than 1 in 10,000 to 1 in 770, lower than the FDA-cited rate.¹³

Prognosis. The overall prognosis for women with leiomyosarcoma is poor. Studies indicate a 5-year survival rate of only 55.4%, even in stage 1 disease that is apparently confined to the uterus.⁹ Although evidence is limited linking morcellation to increased recurrence of leiomyosarcoma, data from small, single-center, retrospective studies cite a worse prognosis, higher risk of recurrence, and shorter progression-free survival after sarcoma morcellation compared with patients who underwent en bloc resection.^12,14 Of note, these studies evaluated patients who underwent uncontained morcellation of specimens with unsuspected leiomyosarcoma.

CASE Woman with enlarged, irregular uterus and heavy bleeding

A 40-year-old woman (G2P2) with a history of 2 uncomplicated vaginal deliveries presents for evaluation of heavy uterine bleeding. She has regular periods, every 28 days, and she bleeds for 7 days, saturating 6 pads per day. She is currently taking only oral iron therapy as recommended by her primary care physician. Over the last 1 to 2 years she has felt that her abdomen has been getting larger and that her pants do not fit as well. She is otherwise in excellent health, exercises regularly, and has a full-time job. She has not been sexually active in several months.

The patient’s vitals are within normal limits and her body mass index (BMI) is 35 kg/m2.Pelvic examination reveals that she has an enlarged, irregular uterus with the fundus at the level of the umbilicus. The exam is otherwise unremarkable. On further questioning, the patient does not desire future fertility.

What next steps would you include in this patient’s workup, including imaging studies or lab tests? What surgical options would you give her? How would your management differ if this patient were 70 years old (postmenopausal)?

Continue to: Perform a thorough preoperative evaluation to optimize outcomes...

Perform a thorough preoperative evaluation to optimize outcomes

Women like this case patient who present with symptoms that may lead to treatment with myomectomy or hysterectomy should undergo appropriate preoperative testing to evaluate for malignancy.

According to ACOG guidance, patients should undergo a preoperative endometrial biopsy if they¹⁵:

• are older than 45 years with abnormal uterine bleeding
• are younger than 45 years with unopposed estrogen exposure (including obesity or polycystic ovary syndrome)
• have persistent bleeding, or
• failed medical management.

Our case patient is younger than 45 but is obese (BMI, 35) and therefore is a candidate for endometrial biopsy. Additionally, all patients should have up-to-date cervical cancer screening. ACOG also recommends appropriate use of imaging with ultrasonography or magnetic resonance imaging (MRI), although imaging is not recommended solely to evaluate for malignancy, as it cannot rule out the diagnosis of many gynecologic malignancies, including leiomyosarcoma.²

Currently, no tests are available to completely exclude a preoperative diagnosis of leiomyosarcoma. While studies have evaluated the use of MRI combined with lactate dehydrogenase isoenzyme testing, the evidence is weak, and this method is not recommended. Sarcoma is detected by endometrial sampling only 30% to 60% of the time, but it should be performed if the patient meets criteria for sampling or if she has other risk factors for malignancy.¹⁶ There are no data to support biopsy of presumed benign fibroids prior to surgical intervention. Patients should be evaluated with a careful history and physical examination for other uterine sarcoma risk factors.

Employ shared decision making

Clinicians should use shared decision making with patients to facilitate decisions on morcellation use in gynecologic surgeries for suspected benign fibroids. Informed consent must be obtained after thorough discussion and counseling regarding the literature on morcellation.¹⁷ For all patients, including the case patient described, this discussion should include alternative treatment options, surgical approach with associated risks, the use of morcellation, the incidence of leiomyosarcoma with presumed benign fibroids, leiomyosarcoma prognosis, and the risk of disseminating benign or undiagnosed cancerous tissue throughout the abdomen and pelvis.

Some would argue that the risks of laparotomy outweigh the possible risks associated with morcellation during a minimally invasive myomectomy or hysterectomy. However, this risk analysis is not uniform across all patients, and it is likely that in older women, because they have an a priori increased risk of malignancy in general, including leiomyosarcoma, the risks of power morcellation may outweigh the risks of open surgery.¹⁸ Younger women have a much lower risk of leiomyosarcoma, and thus discussion and consideration of the patient’s age should be a part of counseling. If the case patient described was 70 years of age, power morcellation might not be recommended, but these decisions require an in-depth discussion with the patient to make an informed decision and ensure patient autonomy.

The contained morcellation approach

Many surgeons who perform minimally invasive procedures use contained morcellation. In this approach, specimens are placed in a containment bag and morcellated with either power instruments or manually to ensure no dissemination of tissue. Manual contained morcellation can be done through a minilaparotomy or the vagina, depending on the procedure performed, while power contained morcellation is performed through a 15-mm laparoscopic incision.

Continue to: Currently, one containment bag has been...

Currently, one containment bag has been FDA approved for use in laparoscopic contained power morcellation.¹⁹ Use of a containment bag increases operative time by approximately 20 minutes, due to the additional steps required to accomplish the procedure.²⁰ Its use, however, suggests a decrease in the risk of possible disease spread and it is feasible with appropriate surgeon training.

One study demonstrated the safety and feasibility of power morcellation within an insufflated containment bag, and subsequent follow-up revealed negative intraperitoneal washings.^21,22 In another study evaluating tissue dissemination with contained morcellation of tissue stained with dye, the authors noted actual spillage of tissue fragments in only one case.²³ Although more information is needed to confirm prevention of tissue dissemination and the safety of contained tissue morcellation, these studies provide promising data supporting the use of tissue morcellation in appropriate cases in order to perform minimally invasive surgery with larger specimens.

CASE Next steps and treatment outcome

The patient has up-to-date and negative cervical cancer screening. The complete blood count is notable for a hemoglobin level of 11.0 g/dL (normal range, 12.1 to 15.1 g/dL). You perform an endometrial biopsy; results are negative for malignancy. You order pelvic ultrasonography to better characterize the location and size of the fibroids. It shows multiple leiomyomas throughout the myometrium, with the 2 largest fibroids (measuring 5 and 7 cm) located in the left anterior and right posterolateral aspects of the uterus, respectively. Several 3- to 4-cm fibroids appear to be disrupting the endometrial canal, and there is no evidence of an endometrial polyp. There do not appear to be any cervical or lower uterine segment fibroids, which may have further complicated the proposed surgery.

You discuss treatment options for abnormal uterine bleeding with the patient, including initiation of combined oral contraceptive pills, placement of a levonorgestrel-containing intrauterine device, endometrial ablation, uterine artery embolization, and hysterectomy. You discuss the risks and benefits of each approach, keeping in mind the fibroids that are disrupting the contour of the endometrial canal and causing her bulk symptoms.

The patient ultimately decides to undergo a hysterectomy and would like it to be performed with a minimally invasive procedure, if possible. Because of the size of her uterus, you discuss the use of contained power morcellation, including the risks and benefits. You have a thorough discussion about the risk of occult malignancy, although she is at lower risk because of her age, and she consents.

The patient undergoes an uncomplicated total laparoscopic hysterectomy with bilateral salpingectomy. The specimen is removed using contained power morcellation through the umbilical port site. She has an unremarkable immediate postoperative course and is discharged on postoperative Day 1.

You see the patient in the clinic 2 weeks later. She reports minimal pain or discomfort and has no other complaints. Her abdominal incisions are healing well. You review the final pathology report with her, which showed no evidence of malignancy.

Society guidance on clinical applications

In current clinical practice, many surgeons have converted to exclusively performing contained morcellation in appropriate patients with a low risk of uterine leiomyosarcoma. At our institution, uncontained morcellation has not been performed since the FDA’s 2014 warning.

ACOG and AAGL (formerly the American Association of Gynecologic Laparoscopists) recommend use of containment bags as a solution to continue minimally invasive surgery for large specimens without the risk of possible tissue dissemination, although more in-depth surgeon training is likely required for accurate technique.^2,24 The Society of Gynecologic Oncology (SGO) states that power morcellation or any other techniques that divide the uterus in the abdomen are contraindicated in patients with documented or highly suspected malignancy.²⁵

With the presented data of risks associated with uncontained morcellation and agreement of the ACOG, AAGL, and SGO professional societies, we recommend that all morcellation be performed in a contained fashion to prevent the dissemination of benign or undiagnosed malignant tissue throughout the abdomen and pelvis. Shared decision making and counseling on the risks, benefits, and alternatives are paramount for patients to make informed decisions about their medical care. Continued exploration of techniques and methods for safe tissue extraction is still needed to improve minimally invasive surgical options for all women.

It was a simple message in the body of an email: “A strong voice in and for psychiatry is now silent.”

That is how I shared the news of the passing of Carl Compton Bell, MD, with the leadership of the American Psychiatric Association and what I think Carl would have approved be shared. Although he was a member of APA, he was never interested in the trappings of leadership there or any other organizations of which he was a longtime member, really. He preferred to “do the work” and was known to not suffer fools who were in it to promote themselves. He was always ready, willing, and able to offer guidance or assistance in your work and never failed to have an opinion on what else you needed to do. Some of my favorite memories of Carl are the talks he initiated at the drop of a hat where he “dropped some knowledge” about what he was doing or what you should be doing.

Upon hearing of his death, I described him to someone as fearless, unapologetic, smart, and ready to advocate for black people at the drop of one of the many hats he wore over the years. In fact, his decades of wardrobes is one the other things many of us will remember – the CMHC baseball cap with the “Stop Black on Black” crime T-shirt, the Obama cap paired with an assortment of message T-shirts (depending on what issue he was focused on at the time), and, most recently, the longer hair sticking out from under the wide brim leather cowboy hat with the highway patrol polarized sunglasses.

Whether at the podium presenting or standing in the back of the room, he was a presence, an obvious powerful force in that room. And whether it was the Surgeon General or an audience at the Carter Center, the message was consistent and powerful. An international researcher, clinician, teacher, and author of more than 500 books, chapters, and articles, he spent most of his career directly addressing issues of violence and HIV prevention, misdiagnosis of psychiatric disorders in African Americans, and the psychological effects on children exposed to violence.

Honoring the legacy of Carl Bell is about more than how we can all follow in his footsteps and more about being like him – unapologetically fearless and focused on improving the health, mental health, and overall well-being of black people. He was very clear that his talents, his skills, his focus – whether it was clinical care, training, or research – would be on black people, and he was often amused at the response, mostly from white people, when he stated clearly that this was his focus. He was often challenged by them, and his response as I frequently heard him say was: “I care about black people; I want to help black people.” I think he basically felt that, if it was good for black people, it would also benefit everyone else.

So, there’s a lesson for us as we heap on the well-deserved accolades on him and his life’s work, and reminisce about our personal encounters and experiences with him over the decades. As we reflect on what he meant to each of us as a friend, a colleague, and a history maker, I think the lesson is that if Carl were here today, he’d say: “OK, that’s all good, thank you for the nice words but what are you doing for black people today? What are you doing to improve their health and life condition today?” I think if we really want to honor his legacy and continue his work, we must be as fearless and focused as he was as we follow his lead and carry on with the work that promotes mental health in the black community. And when we are challenged for wanting to do this work, we must be just as unapologetic and thoughtful as he was, even channeling our own “Carl Bell” moment if needed. As a lifelong martial arts practitioner, I will end with this: “The bamboo which bends in the wind is stronger than the mighty oak which breaks in a storm.” Carl was the bamboo, and he’s with the Ancestors now, encouraging us to do the work and bend not break. Rest, my brother; job well done!

Dr. Stewart is immediate past president of the American Psychiatric Association.

It was a simple message in the body of an email: “A strong voice in and for psychiatry is now silent.”

That is how I shared the news of the passing of Carl Compton Bell, MD, with the leadership of the American Psychiatric Association and what I think Carl would have approved be shared. Although he was a member of APA, he was never interested in the trappings of leadership there or any other organizations of which he was a longtime member, really. He preferred to “do the work” and was known to not suffer fools who were in it to promote themselves. He was always ready, willing, and able to offer guidance or assistance in your work and never failed to have an opinion on what else you needed to do. Some of my favorite memories of Carl are the talks he initiated at the drop of a hat where he “dropped some knowledge” about what he was doing or what you should be doing.

Upon hearing of his death, I described him to someone as fearless, unapologetic, smart, and ready to advocate for black people at the drop of one of the many hats he wore over the years. In fact, his decades of wardrobes is one the other things many of us will remember – the CMHC baseball cap with the “Stop Black on Black” crime T-shirt, the Obama cap paired with an assortment of message T-shirts (depending on what issue he was focused on at the time), and, most recently, the longer hair sticking out from under the wide brim leather cowboy hat with the highway patrol polarized sunglasses.

Whether at the podium presenting or standing in the back of the room, he was a presence, an obvious powerful force in that room. And whether it was the Surgeon General or an audience at the Carter Center, the message was consistent and powerful. An international researcher, clinician, teacher, and author of more than 500 books, chapters, and articles, he spent most of his career directly addressing issues of violence and HIV prevention, misdiagnosis of psychiatric disorders in African Americans, and the psychological effects on children exposed to violence.

Honoring the legacy of Carl Bell is about more than how we can all follow in his footsteps and more about being like him – unapologetically fearless and focused on improving the health, mental health, and overall well-being of black people. He was very clear that his talents, his skills, his focus – whether it was clinical care, training, or research – would be on black people, and he was often amused at the response, mostly from white people, when he stated clearly that this was his focus. He was often challenged by them, and his response as I frequently heard him say was: “I care about black people; I want to help black people.” I think he basically felt that, if it was good for black people, it would also benefit everyone else.

So, there’s a lesson for us as we heap on the well-deserved accolades on him and his life’s work, and reminisce about our personal encounters and experiences with him over the decades. As we reflect on what he meant to each of us as a friend, a colleague, and a history maker, I think the lesson is that if Carl were here today, he’d say: “OK, that’s all good, thank you for the nice words but what are you doing for black people today? What are you doing to improve their health and life condition today?” I think if we really want to honor his legacy and continue his work, we must be as fearless and focused as he was as we follow his lead and carry on with the work that promotes mental health in the black community. And when we are challenged for wanting to do this work, we must be just as unapologetic and thoughtful as he was, even channeling our own “Carl Bell” moment if needed. As a lifelong martial arts practitioner, I will end with this: “The bamboo which bends in the wind is stronger than the mighty oak which breaks in a storm.” Carl was the bamboo, and he’s with the Ancestors now, encouraging us to do the work and bend not break. Rest, my brother; job well done!

Dr. Stewart is immediate past president of the American Psychiatric Association.

It was a simple message in the body of an email: “A strong voice in and for psychiatry is now silent.”

That is how I shared the news of the passing of Carl Compton Bell, MD, with the leadership of the American Psychiatric Association and what I think Carl would have approved be shared. Although he was a member of APA, he was never interested in the trappings of leadership there or any other organizations of which he was a longtime member, really. He preferred to “do the work” and was known to not suffer fools who were in it to promote themselves. He was always ready, willing, and able to offer guidance or assistance in your work and never failed to have an opinion on what else you needed to do. Some of my favorite memories of Carl are the talks he initiated at the drop of a hat where he “dropped some knowledge” about what he was doing or what you should be doing.

Upon hearing of his death, I described him to someone as fearless, unapologetic, smart, and ready to advocate for black people at the drop of one of the many hats he wore over the years. In fact, his decades of wardrobes is one the other things many of us will remember – the CMHC baseball cap with the “Stop Black on Black” crime T-shirt, the Obama cap paired with an assortment of message T-shirts (depending on what issue he was focused on at the time), and, most recently, the longer hair sticking out from under the wide brim leather cowboy hat with the highway patrol polarized sunglasses.

Whether at the podium presenting or standing in the back of the room, he was a presence, an obvious powerful force in that room. And whether it was the Surgeon General or an audience at the Carter Center, the message was consistent and powerful. An international researcher, clinician, teacher, and author of more than 500 books, chapters, and articles, he spent most of his career directly addressing issues of violence and HIV prevention, misdiagnosis of psychiatric disorders in African Americans, and the psychological effects on children exposed to violence.

Honoring the legacy of Carl Bell is about more than how we can all follow in his footsteps and more about being like him – unapologetically fearless and focused on improving the health, mental health, and overall well-being of black people. He was very clear that his talents, his skills, his focus – whether it was clinical care, training, or research – would be on black people, and he was often amused at the response, mostly from white people, when he stated clearly that this was his focus. He was often challenged by them, and his response as I frequently heard him say was: “I care about black people; I want to help black people.” I think he basically felt that, if it was good for black people, it would also benefit everyone else.

So, there’s a lesson for us as we heap on the well-deserved accolades on him and his life’s work, and reminisce about our personal encounters and experiences with him over the decades. As we reflect on what he meant to each of us as a friend, a colleague, and a history maker, I think the lesson is that if Carl were here today, he’d say: “OK, that’s all good, thank you for the nice words but what are you doing for black people today? What are you doing to improve their health and life condition today?” I think if we really want to honor his legacy and continue his work, we must be as fearless and focused as he was as we follow his lead and carry on with the work that promotes mental health in the black community. And when we are challenged for wanting to do this work, we must be just as unapologetic and thoughtful as he was, even channeling our own “Carl Bell” moment if needed. As a lifelong martial arts practitioner, I will end with this: “The bamboo which bends in the wind is stronger than the mighty oak which breaks in a storm.” Carl was the bamboo, and he’s with the Ancestors now, encouraging us to do the work and bend not break. Rest, my brother; job well done!

Dr. Stewart is immediate past president of the American Psychiatric Association.

CASE HT for vasomotor symptoms in perimenopausal woman with cognitive concerns

Jackie is a 49-year-old woman. Her body mass index is 33 kg/m², and she has mild hypertension that is effectively controlled with antihypertensive medications. Otherwise, she is in good health.During her annual gynecologic exam, she reports that for the past 9 months her menstrual cycles have not been as regular as they used to be and that 3 months ago she skipped a cycle. She is having bothersome vasomotor symptoms (VMS) and is concerned about her memory. She says she is forgetful at work and in social situations. During a recent presentation, she could not remember the name of one of her former clients. At a work happy hour, she forgot the name of her coworker’s husband, although she did remember it later after returning home.

Her mother has Alzheimer disease (AD), and Jackie worries about whether she, too, might be developing dementia and whether her memory will fail her in social situations.

She is concerned about using hormone therapy (HT) for her vasomotor symptoms because she has heard that it can lead to breast cancer and/or AD.

How would you advise her?

HT remains the most effective treatment for bothersome VMS, but concerns about its cognitive safety persist. Such concerns, and indeed a black-box warning about the risk of dementia with HT use, initially arose following the 2003 publication of the Women’s Health Initiative Memory Study (WHIMS), a randomized, placebo-controlled trial of HT for the primary prevention of dementia in women aged 65 years and older at baseline.¹ The study found that combination estrogen/progestin therapy was associated with a 2-fold increase in dementia when compared with placebo.

One of the critical questions arising even before WHIMS was whether the cognitive risks associated with HT that were seen in WHIMS apply to younger women. Attempting to answer the question and adding fuel to the fire are the results of a recent case-control study from Finland.² This study compared HT use in Finnish women with and without AD and found that HT use was higher among Finnish women with AD compared with those without AD, regardless of age. The authors concluded, “Our data must be implemented into information for the present and future users of HT, even though the absolute risk increase is small.”

However, given the limitations inherent to observational and registry studies, and the contrasting findings of 3 high-quality, randomized controlled trials (RCTs; more details below), providers actually can reassure younger peri- and postmenopausal women about the cognitive safety of HT.³ They also can explain to patients that cognitive symptoms like the ones described in the case example are normal and provide general guidance to midlife women on how to optimize brain health.

Continue to: Closer look at WHI and RCT research pinpoints cognitively neutral HT...

Closer look at WHI and RCT research pinpoints cognitively neutral HT

In WHIMS, the combination of conjugated equine estrogen (CEE; 0.625 mg/d) plus medroxyprogesterone acetate (MPA; 2.5 mg/d) led to a doubling of the risk of all-cause dementia compared with placebo in a sample of 4,532 women aged 65 years and older at baseline.¹ CEE alone (0.625 mg) did not lead to an increased risk of all-cause dementia.⁴

Whether those formulations led to cognitive impairment in younger postmenopausal women was the focus of WHIMS-Younger (WHIMS-Y), which involved WHI participants aged 50 to 55 years at baseline.⁵ Results revealed neutral cognitive effects (ie, no differences in cognitive performance in women randomly assigned to HT or placebo) in women tested 7.2 years after the end of the WHI trial. WHIMS-Y findings indicated that there were no sustained cognitive risks of CEE or CEE/MPA therapy. Two randomized, placebo-controlled trials involving younger postmenopausal women yielded similar findings.^6,7 HT shown to produce cognitively neutral effects during active treatment included transdermal estradiol plus micronized progesterone,⁶ CEE plus progesterone,⁶ and oral estradiol plus vaginal progesterone gel.⁷ The findings of these randomized trials are critical for guiding decisions regarding the cognitive risks of HT in early postmenopausal women (TABLE 1).

What about women with VMS?

A key gap in knowledge about the cognitive effects of HT is whether HT confers cognitive advantages to women with bothersome VMS. This is a striking absence given that the key indication for HT is the treatment of VMS. While some symptomatic women were included in the trials of HT in younger postmenopausal women described above, no large trial to date has selectively enrolled women with moderate-to-severe VMS to determine if HT is cognitively neutral, beneficial, or detrimental in that group. Some studies involving midlife women have found associations between VMS (as measured with ambulatory skin conductance monitors) and multiple measures of brain health, including memory performance,⁸ small ischemic lesions on structural brain scans,⁹ and altered brain function.¹⁰ In a small trial of a nonhormonal intervention for VMS, improvement in VMS following the intervention was directly related to improvement in memory performance.¹¹ The reliability of these findings continues to be evaluated but raises the hypothesis that VMS treatments might improve memory in midlife women.

Memory complaints common among midlife women

About 60% of women report an undesirable change in memory performance at midlife as compared with earlier in their lives.^12,13 Complaints of forgetfulness are higher in perimenopausal and postmenopausal women compared with premenopausal women, even when those women are similar in age.¹⁴ Two large prospective studies found that memory performance decreases during the perimenopause and then rebounds, suggesting a transient decrease in memory.^15,16 Although cognitive complaints are common among women in their 40s and 50s, AD is rare in that age group. The risk is largely limited to those women with a parent who developed dementia before age 65, as such cases suggest a familial form of AD.

Continue to: What causes cognitive difficulties during midlife?

What causes cognitive difficulties during midlife?

First, some cognitive decline is expected at midlife based on increasing age. Second, above and beyond the role of chronologic aging (ie, getting one year older each year), ovarian aging plays a role. A role of estrogen was verified in clinical trials showing that memory decreased following oophorectomy in premenopausal women in their 40s but returned to presurgical levels following treatment with estrogen therapy (ET).¹⁷ Cohort studies indicate that women who undergo oophorectomy before the typical age of menopause are at increased risk for cognitive impairment or dementia, but those who take ET after oophorectomy until the typical age of menopause do not show that risk.¹⁸

Third, cognitive problems are linked not only to VMS but also to sleep disturbance, depressed mood, and increased anxiety—all of which are common in midlife women.^15,19 Lastly, health factors play a role. Hypertension, obesity, insulin resistance, diabetes, and smoking are associated with adverse brain changes at midlife.²⁰

Giving advice to your patients

First, normalize the cognitive complaints, noting that some cognitive changes are an expected part of aging for all people regardless of whether they are male or female. Advise that while the best studies indicate that these cognitive lapses are especially common in perimenopausal women, they appear to be temporary; women are likely to resume normal cognitive function once the hormonal changes associated with menopause subside.^15,16 Note that the one unknown is the role that VMS play in memory problems and that some studies indicate a link between VMS and cognitive problems. Women may experience some cognitive improvement if VMS are effectively treated.

Advise patients that the Endocrine Society, the North American Menopause Society (NAMS), and the International Menopause Society all have published guidelines saying that the benefits of HT outweigh the risks for most women aged 50 to 60 years.²¹ For concerns about the cognitive adverse effects of HT, discuss the best quality evidence—that which comes from randomized trials—which shows no harmful effects of HT in midlife women.^5-7 Especially reassuring is that one of these high-quality studies was conducted by the same researchers who found that HT can be risky in older women (ie, the WHI Investigators).⁵

Going one step further: Protecting brain health

As primary care providers to midlife women, ObGyns can go one step further and advise patients on how to proactively nurture their brain health. Great evidence-based resources for information on maintaining brain health include the Alzheimer’s Association (https://www.alz.org) and the Women’s Brain Health Initiative (https://womensbrainhealth.org). Primary prevention of AD begins decades before the typical age of an AD diagnosis, and many risk factors for AD are modifiable.²² Patients can keep their brains healthy through myriad approaches including treating hypertension, reducing body mass index, engaging in regular aerobic exercise (brisk walking is fine), eating a Mediterranean diet, maintaining an active social life, and engaging in novel challenging activities like learning a new language or a new skill like dancing.²⁰

Also important is the overlap between cognitive issues, mood, and alcohol use. In the opening case, Jackie mentions alcohol use and social withdrawal. According to the National Institute on Alcohol Abuse and Alcoholism (NIAAA), low-risk drinking for women is defined as no more than 3 drinks on any single day and no more than 7 drinks per week.²³ Heavy alcohol use not only affects brain function but also mood, and depressed mood can lead women to drink excessively.²⁴

In addition, Jackie’s mother has AD, and that stressor can contribute to depressed feelings, especially if Jackie is involved in caregiving. A quick screen for depression with an instrument like the Patient Health Questionnaire-2 (PHQ-2; TABLE 2)²⁵ can rule out a more serious mood disorder—an approach that is particularly important for patients with a history of major depression, as 58% of those patients experience a major depressive episode during the menopausal transition.²⁶ For this reason, it is important to ask patients like Jackie if they have a history of depression; if they do and were treated medically, consider prescribing the antidepressant that worked in the past. For information on menopause and mood-related issues, providers can access new guidelines from NAMS and the National Network of Depression Centers (NNDC).²⁷ There is also a handy patient information sheet to accompany those guidelines on the NAMS website (https://www.menopause.org/).

Continue to: CASE Resolved...

CASE Resolved

When approaching Jackie, most importantly, I would normalize her experience and tell her that memory problems are common in the menopausal transition, especially for women with bothersome VMS. Research suggests that the memory problems she is experiencing are related to hormonal changes and not to AD, and that her memory will likely improve once she has transitioned through the menopause. I would tell her that AD is rare at midlife unless there is a family history of early onset of AD (before age 65), and I would verify the age at which her mother was diagnosed to confirm that it was late-onset AD.

For now, I would recommend that she be prescribed HT for her bothersome hot flashes using one of the “safe” formulations in the Table on page 24. I also would tell her that there is much she can do to lower her risk of AD and that it is best to start now as she enters her 50s because that is when AD changes typically start in the brain, and she can start to prevent those changes now.

I would tell her that experts in the field of AD agree that these lifestyle interventions are currently the best way to prevent AD and that the more of them she engages in, the more her brain will benefit. I would advise her to continue to manage her hypertension and to consider ways of lowering her BMI to enhance her brain health. Engaging in regular brisk walking or other aerobic exercise, as well as incorporating more of the Mediterranean diet into her daily food intake would also benefit her brain. As a working woman, she is exercising her brain, and she should consider other cognitively challenging activities to keep her brain in good shape.

I would follow up with her in a few months to see if her memory functioning is better. If it is not, and if her VMS continue to be bothersome, I would increase her dose of HT. Only if her VMS are treated but her memory problems are getting worse would I screen her with a Mini-Mental State Exam and refer her to a neurologist for an evaluation.
 

CASE HT for vasomotor symptoms in perimenopausal woman with cognitive concerns

Jackie is a 49-year-old woman. Her body mass index is 33 kg/m², and she has mild hypertension that is effectively controlled with antihypertensive medications. Otherwise, she is in good health.During her annual gynecologic exam, she reports that for the past 9 months her menstrual cycles have not been as regular as they used to be and that 3 months ago she skipped a cycle. She is having bothersome vasomotor symptoms (VMS) and is concerned about her memory. She says she is forgetful at work and in social situations. During a recent presentation, she could not remember the name of one of her former clients. At a work happy hour, she forgot the name of her coworker’s husband, although she did remember it later after returning home.

Her mother has Alzheimer disease (AD), and Jackie worries about whether she, too, might be developing dementia and whether her memory will fail her in social situations.

She is concerned about using hormone therapy (HT) for her vasomotor symptoms because she has heard that it can lead to breast cancer and/or AD.

How would you advise her?

HT remains the most effective treatment for bothersome VMS, but concerns about its cognitive safety persist. Such concerns, and indeed a black-box warning about the risk of dementia with HT use, initially arose following the 2003 publication of the Women’s Health Initiative Memory Study (WHIMS), a randomized, placebo-controlled trial of HT for the primary prevention of dementia in women aged 65 years and older at baseline.¹ The study found that combination estrogen/progestin therapy was associated with a 2-fold increase in dementia when compared with placebo.

One of the critical questions arising even before WHIMS was whether the cognitive risks associated with HT that were seen in WHIMS apply to younger women. Attempting to answer the question and adding fuel to the fire are the results of a recent case-control study from Finland.² This study compared HT use in Finnish women with and without AD and found that HT use was higher among Finnish women with AD compared with those without AD, regardless of age. The authors concluded, “Our data must be implemented into information for the present and future users of HT, even though the absolute risk increase is small.”

However, given the limitations inherent to observational and registry studies, and the contrasting findings of 3 high-quality, randomized controlled trials (RCTs; more details below), providers actually can reassure younger peri- and postmenopausal women about the cognitive safety of HT.³ They also can explain to patients that cognitive symptoms like the ones described in the case example are normal and provide general guidance to midlife women on how to optimize brain health.

Continue to: Closer look at WHI and RCT research pinpoints cognitively neutral HT...

Closer look at WHI and RCT research pinpoints cognitively neutral HT

In WHIMS, the combination of conjugated equine estrogen (CEE; 0.625 mg/d) plus medroxyprogesterone acetate (MPA; 2.5 mg/d) led to a doubling of the risk of all-cause dementia compared with placebo in a sample of 4,532 women aged 65 years and older at baseline.¹ CEE alone (0.625 mg) did not lead to an increased risk of all-cause dementia.⁴

Whether those formulations led to cognitive impairment in younger postmenopausal women was the focus of WHIMS-Younger (WHIMS-Y), which involved WHI participants aged 50 to 55 years at baseline.⁵ Results revealed neutral cognitive effects (ie, no differences in cognitive performance in women randomly assigned to HT or placebo) in women tested 7.2 years after the end of the WHI trial. WHIMS-Y findings indicated that there were no sustained cognitive risks of CEE or CEE/MPA therapy. Two randomized, placebo-controlled trials involving younger postmenopausal women yielded similar findings.^6,7 HT shown to produce cognitively neutral effects during active treatment included transdermal estradiol plus micronized progesterone,⁶ CEE plus progesterone,⁶ and oral estradiol plus vaginal progesterone gel.⁷ The findings of these randomized trials are critical for guiding decisions regarding the cognitive risks of HT in early postmenopausal women (TABLE 1).

What about women with VMS?

A key gap in knowledge about the cognitive effects of HT is whether HT confers cognitive advantages to women with bothersome VMS. This is a striking absence given that the key indication for HT is the treatment of VMS. While some symptomatic women were included in the trials of HT in younger postmenopausal women described above, no large trial to date has selectively enrolled women with moderate-to-severe VMS to determine if HT is cognitively neutral, beneficial, or detrimental in that group. Some studies involving midlife women have found associations between VMS (as measured with ambulatory skin conductance monitors) and multiple measures of brain health, including memory performance,⁸ small ischemic lesions on structural brain scans,⁹ and altered brain function.¹⁰ In a small trial of a nonhormonal intervention for VMS, improvement in VMS following the intervention was directly related to improvement in memory performance.¹¹ The reliability of these findings continues to be evaluated but raises the hypothesis that VMS treatments might improve memory in midlife women.

Memory complaints common among midlife women

About 60% of women report an undesirable change in memory performance at midlife as compared with earlier in their lives.^12,13 Complaints of forgetfulness are higher in perimenopausal and postmenopausal women compared with premenopausal women, even when those women are similar in age.¹⁴ Two large prospective studies found that memory performance decreases during the perimenopause and then rebounds, suggesting a transient decrease in memory.^15,16 Although cognitive complaints are common among women in their 40s and 50s, AD is rare in that age group. The risk is largely limited to those women with a parent who developed dementia before age 65, as such cases suggest a familial form of AD.

Continue to: What causes cognitive difficulties during midlife?

What causes cognitive difficulties during midlife?

First, some cognitive decline is expected at midlife based on increasing age. Second, above and beyond the role of chronologic aging (ie, getting one year older each year), ovarian aging plays a role. A role of estrogen was verified in clinical trials showing that memory decreased following oophorectomy in premenopausal women in their 40s but returned to presurgical levels following treatment with estrogen therapy (ET).¹⁷ Cohort studies indicate that women who undergo oophorectomy before the typical age of menopause are at increased risk for cognitive impairment or dementia, but those who take ET after oophorectomy until the typical age of menopause do not show that risk.¹⁸

Third, cognitive problems are linked not only to VMS but also to sleep disturbance, depressed mood, and increased anxiety—all of which are common in midlife women.^15,19 Lastly, health factors play a role. Hypertension, obesity, insulin resistance, diabetes, and smoking are associated with adverse brain changes at midlife.²⁰

Giving advice to your patients

First, normalize the cognitive complaints, noting that some cognitive changes are an expected part of aging for all people regardless of whether they are male or female. Advise that while the best studies indicate that these cognitive lapses are especially common in perimenopausal women, they appear to be temporary; women are likely to resume normal cognitive function once the hormonal changes associated with menopause subside.^15,16 Note that the one unknown is the role that VMS play in memory problems and that some studies indicate a link between VMS and cognitive problems. Women may experience some cognitive improvement if VMS are effectively treated.

Advise patients that the Endocrine Society, the North American Menopause Society (NAMS), and the International Menopause Society all have published guidelines saying that the benefits of HT outweigh the risks for most women aged 50 to 60 years.²¹ For concerns about the cognitive adverse effects of HT, discuss the best quality evidence—that which comes from randomized trials—which shows no harmful effects of HT in midlife women.^5-7 Especially reassuring is that one of these high-quality studies was conducted by the same researchers who found that HT can be risky in older women (ie, the WHI Investigators).⁵

Going one step further: Protecting brain health

As primary care providers to midlife women, ObGyns can go one step further and advise patients on how to proactively nurture their brain health. Great evidence-based resources for information on maintaining brain health include the Alzheimer’s Association (https://www.alz.org) and the Women’s Brain Health Initiative (https://womensbrainhealth.org). Primary prevention of AD begins decades before the typical age of an AD diagnosis, and many risk factors for AD are modifiable.²² Patients can keep their brains healthy through myriad approaches including treating hypertension, reducing body mass index, engaging in regular aerobic exercise (brisk walking is fine), eating a Mediterranean diet, maintaining an active social life, and engaging in novel challenging activities like learning a new language or a new skill like dancing.²⁰

Also important is the overlap between cognitive issues, mood, and alcohol use. In the opening case, Jackie mentions alcohol use and social withdrawal. According to the National Institute on Alcohol Abuse and Alcoholism (NIAAA), low-risk drinking for women is defined as no more than 3 drinks on any single day and no more than 7 drinks per week.²³ Heavy alcohol use not only affects brain function but also mood, and depressed mood can lead women to drink excessively.²⁴

In addition, Jackie’s mother has AD, and that stressor can contribute to depressed feelings, especially if Jackie is involved in caregiving. A quick screen for depression with an instrument like the Patient Health Questionnaire-2 (PHQ-2; TABLE 2)²⁵ can rule out a more serious mood disorder—an approach that is particularly important for patients with a history of major depression, as 58% of those patients experience a major depressive episode during the menopausal transition.²⁶ For this reason, it is important to ask patients like Jackie if they have a history of depression; if they do and were treated medically, consider prescribing the antidepressant that worked in the past. For information on menopause and mood-related issues, providers can access new guidelines from NAMS and the National Network of Depression Centers (NNDC).²⁷ There is also a handy patient information sheet to accompany those guidelines on the NAMS website (https://www.menopause.org/).

Continue to: CASE Resolved...

CASE Resolved

When approaching Jackie, most importantly, I would normalize her experience and tell her that memory problems are common in the menopausal transition, especially for women with bothersome VMS. Research suggests that the memory problems she is experiencing are related to hormonal changes and not to AD, and that her memory will likely improve once she has transitioned through the menopause. I would tell her that AD is rare at midlife unless there is a family history of early onset of AD (before age 65), and I would verify the age at which her mother was diagnosed to confirm that it was late-onset AD.

For now, I would recommend that she be prescribed HT for her bothersome hot flashes using one of the “safe” formulations in the Table on page 24. I also would tell her that there is much she can do to lower her risk of AD and that it is best to start now as she enters her 50s because that is when AD changes typically start in the brain, and she can start to prevent those changes now.

I would tell her that experts in the field of AD agree that these lifestyle interventions are currently the best way to prevent AD and that the more of them she engages in, the more her brain will benefit. I would advise her to continue to manage her hypertension and to consider ways of lowering her BMI to enhance her brain health. Engaging in regular brisk walking or other aerobic exercise, as well as incorporating more of the Mediterranean diet into her daily food intake would also benefit her brain. As a working woman, she is exercising her brain, and she should consider other cognitively challenging activities to keep her brain in good shape.

I would follow up with her in a few months to see if her memory functioning is better. If it is not, and if her VMS continue to be bothersome, I would increase her dose of HT. Only if her VMS are treated but her memory problems are getting worse would I screen her with a Mini-Mental State Exam and refer her to a neurologist for an evaluation.
 

CASE HT for vasomotor symptoms in perimenopausal woman with cognitive concerns

Jackie is a 49-year-old woman. Her body mass index is 33 kg/m², and she has mild hypertension that is effectively controlled with antihypertensive medications. Otherwise, she is in good health.During her annual gynecologic exam, she reports that for the past 9 months her menstrual cycles have not been as regular as they used to be and that 3 months ago she skipped a cycle. She is having bothersome vasomotor symptoms (VMS) and is concerned about her memory. She says she is forgetful at work and in social situations. During a recent presentation, she could not remember the name of one of her former clients. At a work happy hour, she forgot the name of her coworker’s husband, although she did remember it later after returning home.

Her mother has Alzheimer disease (AD), and Jackie worries about whether she, too, might be developing dementia and whether her memory will fail her in social situations.

She is concerned about using hormone therapy (HT) for her vasomotor symptoms because she has heard that it can lead to breast cancer and/or AD.

How would you advise her?

HT remains the most effective treatment for bothersome VMS, but concerns about its cognitive safety persist. Such concerns, and indeed a black-box warning about the risk of dementia with HT use, initially arose following the 2003 publication of the Women’s Health Initiative Memory Study (WHIMS), a randomized, placebo-controlled trial of HT for the primary prevention of dementia in women aged 65 years and older at baseline.¹ The study found that combination estrogen/progestin therapy was associated with a 2-fold increase in dementia when compared with placebo.

One of the critical questions arising even before WHIMS was whether the cognitive risks associated with HT that were seen in WHIMS apply to younger women. Attempting to answer the question and adding fuel to the fire are the results of a recent case-control study from Finland.² This study compared HT use in Finnish women with and without AD and found that HT use was higher among Finnish women with AD compared with those without AD, regardless of age. The authors concluded, “Our data must be implemented into information for the present and future users of HT, even though the absolute risk increase is small.”

However, given the limitations inherent to observational and registry studies, and the contrasting findings of 3 high-quality, randomized controlled trials (RCTs; more details below), providers actually can reassure younger peri- and postmenopausal women about the cognitive safety of HT.³ They also can explain to patients that cognitive symptoms like the ones described in the case example are normal and provide general guidance to midlife women on how to optimize brain health.

Continue to: Closer look at WHI and RCT research pinpoints cognitively neutral HT...

Closer look at WHI and RCT research pinpoints cognitively neutral HT

In WHIMS, the combination of conjugated equine estrogen (CEE; 0.625 mg/d) plus medroxyprogesterone acetate (MPA; 2.5 mg/d) led to a doubling of the risk of all-cause dementia compared with placebo in a sample of 4,532 women aged 65 years and older at baseline.¹ CEE alone (0.625 mg) did not lead to an increased risk of all-cause dementia.⁴

Whether those formulations led to cognitive impairment in younger postmenopausal women was the focus of WHIMS-Younger (WHIMS-Y), which involved WHI participants aged 50 to 55 years at baseline.⁵ Results revealed neutral cognitive effects (ie, no differences in cognitive performance in women randomly assigned to HT or placebo) in women tested 7.2 years after the end of the WHI trial. WHIMS-Y findings indicated that there were no sustained cognitive risks of CEE or CEE/MPA therapy. Two randomized, placebo-controlled trials involving younger postmenopausal women yielded similar findings.^6,7 HT shown to produce cognitively neutral effects during active treatment included transdermal estradiol plus micronized progesterone,⁶ CEE plus progesterone,⁶ and oral estradiol plus vaginal progesterone gel.⁷ The findings of these randomized trials are critical for guiding decisions regarding the cognitive risks of HT in early postmenopausal women (TABLE 1).

What about women with VMS?

A key gap in knowledge about the cognitive effects of HT is whether HT confers cognitive advantages to women with bothersome VMS. This is a striking absence given that the key indication for HT is the treatment of VMS. While some symptomatic women were included in the trials of HT in younger postmenopausal women described above, no large trial to date has selectively enrolled women with moderate-to-severe VMS to determine if HT is cognitively neutral, beneficial, or detrimental in that group. Some studies involving midlife women have found associations between VMS (as measured with ambulatory skin conductance monitors) and multiple measures of brain health, including memory performance,⁸ small ischemic lesions on structural brain scans,⁹ and altered brain function.¹⁰ In a small trial of a nonhormonal intervention for VMS, improvement in VMS following the intervention was directly related to improvement in memory performance.¹¹ The reliability of these findings continues to be evaluated but raises the hypothesis that VMS treatments might improve memory in midlife women.

Memory complaints common among midlife women

About 60% of women report an undesirable change in memory performance at midlife as compared with earlier in their lives.^12,13 Complaints of forgetfulness are higher in perimenopausal and postmenopausal women compared with premenopausal women, even when those women are similar in age.¹⁴ Two large prospective studies found that memory performance decreases during the perimenopause and then rebounds, suggesting a transient decrease in memory.^15,16 Although cognitive complaints are common among women in their 40s and 50s, AD is rare in that age group. The risk is largely limited to those women with a parent who developed dementia before age 65, as such cases suggest a familial form of AD.

Continue to: What causes cognitive difficulties during midlife?

What causes cognitive difficulties during midlife?

First, some cognitive decline is expected at midlife based on increasing age. Second, above and beyond the role of chronologic aging (ie, getting one year older each year), ovarian aging plays a role. A role of estrogen was verified in clinical trials showing that memory decreased following oophorectomy in premenopausal women in their 40s but returned to presurgical levels following treatment with estrogen therapy (ET).¹⁷ Cohort studies indicate that women who undergo oophorectomy before the typical age of menopause are at increased risk for cognitive impairment or dementia, but those who take ET after oophorectomy until the typical age of menopause do not show that risk.¹⁸

Third, cognitive problems are linked not only to VMS but also to sleep disturbance, depressed mood, and increased anxiety—all of which are common in midlife women.^15,19 Lastly, health factors play a role. Hypertension, obesity, insulin resistance, diabetes, and smoking are associated with adverse brain changes at midlife.²⁰

Giving advice to your patients

First, normalize the cognitive complaints, noting that some cognitive changes are an expected part of aging for all people regardless of whether they are male or female. Advise that while the best studies indicate that these cognitive lapses are especially common in perimenopausal women, they appear to be temporary; women are likely to resume normal cognitive function once the hormonal changes associated with menopause subside.^15,16 Note that the one unknown is the role that VMS play in memory problems and that some studies indicate a link between VMS and cognitive problems. Women may experience some cognitive improvement if VMS are effectively treated.

Advise patients that the Endocrine Society, the North American Menopause Society (NAMS), and the International Menopause Society all have published guidelines saying that the benefits of HT outweigh the risks for most women aged 50 to 60 years.²¹ For concerns about the cognitive adverse effects of HT, discuss the best quality evidence—that which comes from randomized trials—which shows no harmful effects of HT in midlife women.^5-7 Especially reassuring is that one of these high-quality studies was conducted by the same researchers who found that HT can be risky in older women (ie, the WHI Investigators).⁵

Going one step further: Protecting brain health

As primary care providers to midlife women, ObGyns can go one step further and advise patients on how to proactively nurture their brain health. Great evidence-based resources for information on maintaining brain health include the Alzheimer’s Association (https://www.alz.org) and the Women’s Brain Health Initiative (https://womensbrainhealth.org). Primary prevention of AD begins decades before the typical age of an AD diagnosis, and many risk factors for AD are modifiable.²² Patients can keep their brains healthy through myriad approaches including treating hypertension, reducing body mass index, engaging in regular aerobic exercise (brisk walking is fine), eating a Mediterranean diet, maintaining an active social life, and engaging in novel challenging activities like learning a new language or a new skill like dancing.²⁰

Also important is the overlap between cognitive issues, mood, and alcohol use. In the opening case, Jackie mentions alcohol use and social withdrawal. According to the National Institute on Alcohol Abuse and Alcoholism (NIAAA), low-risk drinking for women is defined as no more than 3 drinks on any single day and no more than 7 drinks per week.²³ Heavy alcohol use not only affects brain function but also mood, and depressed mood can lead women to drink excessively.²⁴

In addition, Jackie’s mother has AD, and that stressor can contribute to depressed feelings, especially if Jackie is involved in caregiving. A quick screen for depression with an instrument like the Patient Health Questionnaire-2 (PHQ-2; TABLE 2)²⁵ can rule out a more serious mood disorder—an approach that is particularly important for patients with a history of major depression, as 58% of those patients experience a major depressive episode during the menopausal transition.²⁶ For this reason, it is important to ask patients like Jackie if they have a history of depression; if they do and were treated medically, consider prescribing the antidepressant that worked in the past. For information on menopause and mood-related issues, providers can access new guidelines from NAMS and the National Network of Depression Centers (NNDC).²⁷ There is also a handy patient information sheet to accompany those guidelines on the NAMS website (https://www.menopause.org/).

Continue to: CASE Resolved...

CASE Resolved

When approaching Jackie, most importantly, I would normalize her experience and tell her that memory problems are common in the menopausal transition, especially for women with bothersome VMS. Research suggests that the memory problems she is experiencing are related to hormonal changes and not to AD, and that her memory will likely improve once she has transitioned through the menopause. I would tell her that AD is rare at midlife unless there is a family history of early onset of AD (before age 65), and I would verify the age at which her mother was diagnosed to confirm that it was late-onset AD.

For now, I would recommend that she be prescribed HT for her bothersome hot flashes using one of the “safe” formulations in the Table on page 24. I also would tell her that there is much she can do to lower her risk of AD and that it is best to start now as she enters her 50s because that is when AD changes typically start in the brain, and she can start to prevent those changes now.

I would tell her that experts in the field of AD agree that these lifestyle interventions are currently the best way to prevent AD and that the more of them she engages in, the more her brain will benefit. I would advise her to continue to manage her hypertension and to consider ways of lowering her BMI to enhance her brain health. Engaging in regular brisk walking or other aerobic exercise, as well as incorporating more of the Mediterranean diet into her daily food intake would also benefit her brain. As a working woman, she is exercising her brain, and she should consider other cognitively challenging activities to keep her brain in good shape.

I would follow up with her in a few months to see if her memory functioning is better. If it is not, and if her VMS continue to be bothersome, I would increase her dose of HT. Only if her VMS are treated but her memory problems are getting worse would I screen her with a Mini-Mental State Exam and refer her to a neurologist for an evaluation.
 

Postmenopausal bleeding (PMB) is the presenting sign in most cases of endometrial carcinoma. Prompt evaluation of PMB can exclude, or diagnose, endometrial carcinoma.¹ Although no general consensus exists for PMB evaluation, it involves endometrial assessment with transvaginal ultrasonography (TVUS) and subsequent endometrial biopsy when a thickened endometrium is found. When biopsy results reveal insufficient or scant tissue, further investigation into the etiology of PMB should include office hysteroscopy with possible directed biopsy. In this article I discuss the prevalence of PMB and steps for evaluation, providing clinical takeaways.

Postmenopausal bleeding: Its risk for cancer

Abnormal uterine bleeding (AUB) in a postmenopausal woman is of particular concern to the gynecologist and the patient because of the increased possibility of endometrial carcinoma in this age group. AUB is present in more than 90% of postmenopausal women with endometrial carcinoma, which leads to diagnosis in the early stages of the disease. Approximately 3% to 7% of postmenopausal women with PMB will have endometrial carcinoma.² Most women with PMB, however, experience bleeding secondary to atrophic changes of the vagina or endometrium and not to endometrial carcinoma. (FIGURE 1, VIDEO 1) In addition, women who take gonadal steroids for hormone replacement therapy (HRT) may experience breakthrough bleeding that leads to initial investigation with TVUS.

Video 1

Vidyard Video

The risk of malignancy in polyps in postmenopausal women over the age of 59 who present with PMB is approximately 12%, and hysteroscopic resection should routinely be performed. For asymptomatic patients, the risk of a malignant lesion is low—approximately 3%—and for these women intervention should be assessed individually for the risks of carcinoma and benefits of hysteroscopic removal.³

Clinical takeaway. The high possibility of endometrial carcinoma in postmenopausal women warrants that any patient who is symptomatic with PMB should be presumed to have endometrial cancer until the diagnostic evaluation process proves she does not.

Evaluation of postmenopausal bleeding

Transvaginal ultrasound

As mentioned, no general consensus exists for the evaluation of PMB; however, initial evaluation by TVUS is recommended. The American College of Obstetricians and Gynecologists (ACOG) concluded that when the endometrium measures ≤4 mm with TVUS, the likelihood that bleeding is secondary to endometrial carcinoma is less than 1% (negative predictive value 99%), and endometrial biopsy is not recommended.³ Endometrial sampling in this clinical scenario likely will result in insufficient tissue for evaluation, and it is reasonable to consider initial management for atrophy. A thickened endometrium on TVUS (>4 mm in a postmenopausal woman with PMB) warrants additional evaluation with endometrial sampling (FIGURE 2).

Clinical takeaway. A thickened endometrium on TVUS ≥4 mm in a postmenopausal woman with PMB warrants additional evaluation with endometrial sampling.

Endometrial biopsy

An endometrial biopsy is performed to determine whether endometrial cancer or precancer is present in women with AUB. ACOG recommends that endometrial biopsy be performed for women older than age 45. It is also appropriate in women younger than 45 years if they have risk factors for developing endometrial cancer, including unopposed estrogen exposure (obesity, ovulatory dysfunction), failed medical management of AUB, or persistence of AUB.⁴

Continue to: Endometrial biopsy has some...

Endometrial biopsy has some diagnostic shortcomings, however. In 2016 a systematic review and meta-analysis found that, in women with PMB, the specificity of endometrial biopsy was 98% to 100% (accurate diagnosis with a positive result). The sensitivity (ability to make an accurate diagnosis) of endometrial biopsy to identify endometrial pathology (carcinoma, atypical hyperplasia, and polyps) is lower than typically thought. These investigators found an endometrial biopsy failure rate of 11% (range, 1% to 53%) and rate of insufficient samples of 31% (range, 7% to 76%). In women with insufficient or failed samples, endometrial cancer or precancer was found in 7% (range, 0% to 18%).⁵ Therefore, a negative tissue biopsy result in women with PMB is not considered to be an endpoint, and further evaluation with hysteroscopy to evaluate for focal disease is imperative. The results of endometrial biopsy are only an endpoint to the evaluation of PMB when atypical hyperplasia or endometrial cancer is identified.

Clinical takeaway. A negative tissue biopsy result in women with PMB is not considered to be an endpoint, and further evaluation with hysteroscopy to evaluate for focal disease is imperative.

Hysteroscopy

Hysteroscopy is the gold standard for evaluating the uterine cavity, diagnosing intrauterine pathology, and operative intervention for some causes of AUB. It also is easily performed in the office. This makes the hysteroscope an essential instrument for the gynecologist. Dr. Linda Bradley, a preeminent leader in hysteroscopic surgical education, has coined the phrase, “My hysteroscope is my stethoscope.”⁶ As gynecologists, we should be as adept at using a hysteroscope in the office as the cardiologist is at using a stethoscope.

It has been known for some time that hysteroscopy improves our diagnostic capabilities over blinded procedures such as endometrial biopsy and dilation and curettage (D&C). As far back as 1989, Dr. Frank Loffer reported the increased sensitivity (ability to make an accurate diagnosis) of hysteroscopy with directed biopsy over blinded D&C (98% vs 65%) in the evaluation of AUB.⁷ Evaluation of the endometrium with D&C is no longer recommended; yet today, few gynecologists perform hysteroscopic-directed biopsy for AUB evaluation instead of blinded tissue sampling despite the clinical superiority and in-office capabilities (FIGURE 3).

Continue to: Hysteroscopy and endometrial carcinoma...

Hysteroscopy and endometrial carcinoma

The most common type of gynecologic cancer in the United States is endometrial adenocarcinoma (type 1 endometrial cancer). There is some concern about the effect of hysteroscopy on endometrial cancer prognosis and the spread of cells to the peritoneum at the time of hysteroscopy. A large meta-analysis found that hysteroscopy performed in the presence of type 1 endometrial cancer statistically significantly increased the likelihood of positive intraperitoneal cytology; however, it did not alter the clinical outcome. It was recommended that hysteroscopy not be avoided for this reason and is helpful in the diagnosis of endometrial cancer, especially in the early stages of disease.⁸

For endometrial cancer type 2 (serous carcinoma, clear cell carcinoma, and carcinosarcoma), Chen and colleagues reported a statistically significant increase in positive peritoneal cytology for cancers evaluated by hysteroscopy versus D&C. The disease-specific survival for the hysteroscopy group was 60 months, compared with 71 months for the D&C group. While this finding was not statistically significant, it was clinically relevant, and the effect of hysteroscopy on prognosis with type 2 endometrial cancer is unclear.⁹

Three clinical scenarios

---

A common occurrence in the evaluation of postmenopausal bleeding (PMB) is an initial TVUS finding of an enlarged endometrium and an endometrial biopsy that is negative or reveals scant or insufficient tissue. Unfortunately, the diagnostic evaluation process often stops here, and a diagnosis for the PMB is never actually identified. Here are several clinical scenarios that highlight the need for hysteroscopy in the initial evaluation of PMB, especially when there is a discordance between transvaginal ultrasonography (TVUS) and endometrial biopsy findings.

Patient 1: Discordant TVUS and biopsy, with benign findings

The patient is a 52-year-old woman who presented to her gynecologist reporting abnormal uterine bleeding (AUB). She has a history of breast cancer, and she completed tamoxifen treatment. Pelvic ultrasonography was performed; an enlarged endometrial stripe of 1.3 cm was found (FIGURE 4A). Endometrial biopsy was performed, showing adequate tissue but with a negative result. The patient is told that she is likely perimenopausal, which is the reason for her bleeding.

At the time of referral, the patient is evaluated with in-office hysteroscopy. Diagnosis of a 5 cm x 7 cm benign endometrial polyp is made. An uneventful hysteroscopic polypectomy is performed (VIDEO 2).

Video 2

Vidyard Video

This scenario illustrates the shortcoming of initial evaluation by not performing a hysteroscopy, especially in a woman with a thickened endometrium with previous tamoxifen therapy. Subsequent visits failed to correlate bleeding etiology with discordant TVUS and endometrial biopsy results with hysteroscopy, and no hysteroscopy was performed in the operating room at the time of D&C.

Patient 2: Discordant TVUS and biopsy, with premalignant findings

The patient is a 62-year-old woman who had incidental findings of a thickened endometrium on computed tomography scan of the pelvis. TVUS confirmed a thickened endometrium measuring 17 mm, and an endometrial biopsy showed scant tissue.

At the time of referral, a diagnostic hysteroscopy was performed in the office. Endometrial atrophy, a large benign appearing polyp, and focal abnormal appearing tissue were seen (FIGURE 5). A decision for polypectomy and directed biopsy was made. Histology findings confirmed benign polyp and atypical hyperplasia (VIDEO 3).

Video 3

Vidyard Video

This scenario illustrates that while the patient was asymptomatic, there was discordance between the TVUS and endometrial biopsy. Hysteroscopy identified a benign endometrial polyp, which is common in asymptomatic postmenopausal patients with a thickened endometrium and endometrial biopsy showing scant tissue. However, addition of the diagnostic hysteroscopy identified focal precancerous tissue, removed under directed biopsy.

Patient 3: Discordant TVUS and biopsy, with malignant findings

The patient is a 68-year-old woman with PMB. TVUS showed a thickened endometrium measuring 14 mm. An endometrial biopsy was negative, showing scant tissue. No additional diagnostic evaluation or management was offered.

Video 4A

Vidyard Video

At the time of referral, the patient was evaluated with in-office diagnostic hysteroscopy, and the patient was found to have endometrial atrophy, benign appearing polyps, and focal abnormal tissue (FIGURE 6). A decision for polypectomy and directed biopsy was made. Histology confirmed benign polyps and grade 1 adenocarcinoma (VIDEOS 4A, 4B, 4C).

Video 4B

Vidyard Video

This scenario illustrates the possibility of having multiple endometrial pathologies present at the time of discordant TVUS and endometrial biopsy. Hysteroscopy plays a critical role in additional evaluation and diagnosis of endometrial carcinoma with directed biopsy, especially in a symptomatic woman with PMB.

Video 4C

Vidyard Video

Conclusion

Evaluation of PMB begins with a screening TVUS. Findings of an endometrium of ≤4 mm indicate a very low likelihood of the presence of endometrial cancer, and treatment for atrophy or changes to hormone replacement therapy regimen is reasonable first-line management; endometrial biopsy is not recommended. For patients with persistent PMB or thickened endometrium ≥4 mm on TVUS, biopsy sampling of the endometrium should be performed. If the endometrial biopsy does not explain the etiology of the PMB with atypical hyperplasia or endometrial cancer, then hysteroscopy should be performed to evaluate for focal endometrial disease and possible directed biopsy.

Postmenopausal bleeding (PMB) is the presenting sign in most cases of endometrial carcinoma. Prompt evaluation of PMB can exclude, or diagnose, endometrial carcinoma.¹ Although no general consensus exists for PMB evaluation, it involves endometrial assessment with transvaginal ultrasonography (TVUS) and subsequent endometrial biopsy when a thickened endometrium is found. When biopsy results reveal insufficient or scant tissue, further investigation into the etiology of PMB should include office hysteroscopy with possible directed biopsy. In this article I discuss the prevalence of PMB and steps for evaluation, providing clinical takeaways.

Postmenopausal bleeding: Its risk for cancer

Abnormal uterine bleeding (AUB) in a postmenopausal woman is of particular concern to the gynecologist and the patient because of the increased possibility of endometrial carcinoma in this age group. AUB is present in more than 90% of postmenopausal women with endometrial carcinoma, which leads to diagnosis in the early stages of the disease. Approximately 3% to 7% of postmenopausal women with PMB will have endometrial carcinoma.² Most women with PMB, however, experience bleeding secondary to atrophic changes of the vagina or endometrium and not to endometrial carcinoma. (FIGURE 1, VIDEO 1) In addition, women who take gonadal steroids for hormone replacement therapy (HRT) may experience breakthrough bleeding that leads to initial investigation with TVUS.

Video 1

Vidyard Video

The risk of malignancy in polyps in postmenopausal women over the age of 59 who present with PMB is approximately 12%, and hysteroscopic resection should routinely be performed. For asymptomatic patients, the risk of a malignant lesion is low—approximately 3%—and for these women intervention should be assessed individually for the risks of carcinoma and benefits of hysteroscopic removal.³

Clinical takeaway. The high possibility of endometrial carcinoma in postmenopausal women warrants that any patient who is symptomatic with PMB should be presumed to have endometrial cancer until the diagnostic evaluation process proves she does not.

Evaluation of postmenopausal bleeding

Transvaginal ultrasound

As mentioned, no general consensus exists for the evaluation of PMB; however, initial evaluation by TVUS is recommended. The American College of Obstetricians and Gynecologists (ACOG) concluded that when the endometrium measures ≤4 mm with TVUS, the likelihood that bleeding is secondary to endometrial carcinoma is less than 1% (negative predictive value 99%), and endometrial biopsy is not recommended.³ Endometrial sampling in this clinical scenario likely will result in insufficient tissue for evaluation, and it is reasonable to consider initial management for atrophy. A thickened endometrium on TVUS (>4 mm in a postmenopausal woman with PMB) warrants additional evaluation with endometrial sampling (FIGURE 2).

Clinical takeaway. A thickened endometrium on TVUS ≥4 mm in a postmenopausal woman with PMB warrants additional evaluation with endometrial sampling.

Endometrial biopsy

An endometrial biopsy is performed to determine whether endometrial cancer or precancer is present in women with AUB. ACOG recommends that endometrial biopsy be performed for women older than age 45. It is also appropriate in women younger than 45 years if they have risk factors for developing endometrial cancer, including unopposed estrogen exposure (obesity, ovulatory dysfunction), failed medical management of AUB, or persistence of AUB.⁴

Continue to: Endometrial biopsy has some...

Endometrial biopsy has some diagnostic shortcomings, however. In 2016 a systematic review and meta-analysis found that, in women with PMB, the specificity of endometrial biopsy was 98% to 100% (accurate diagnosis with a positive result). The sensitivity (ability to make an accurate diagnosis) of endometrial biopsy to identify endometrial pathology (carcinoma, atypical hyperplasia, and polyps) is lower than typically thought. These investigators found an endometrial biopsy failure rate of 11% (range, 1% to 53%) and rate of insufficient samples of 31% (range, 7% to 76%). In women with insufficient or failed samples, endometrial cancer or precancer was found in 7% (range, 0% to 18%).⁵ Therefore, a negative tissue biopsy result in women with PMB is not considered to be an endpoint, and further evaluation with hysteroscopy to evaluate for focal disease is imperative. The results of endometrial biopsy are only an endpoint to the evaluation of PMB when atypical hyperplasia or endometrial cancer is identified.

Clinical takeaway. A negative tissue biopsy result in women with PMB is not considered to be an endpoint, and further evaluation with hysteroscopy to evaluate for focal disease is imperative.

Hysteroscopy

Hysteroscopy is the gold standard for evaluating the uterine cavity, diagnosing intrauterine pathology, and operative intervention for some causes of AUB. It also is easily performed in the office. This makes the hysteroscope an essential instrument for the gynecologist. Dr. Linda Bradley, a preeminent leader in hysteroscopic surgical education, has coined the phrase, “My hysteroscope is my stethoscope.”⁶ As gynecologists, we should be as adept at using a hysteroscope in the office as the cardiologist is at using a stethoscope.

It has been known for some time that hysteroscopy improves our diagnostic capabilities over blinded procedures such as endometrial biopsy and dilation and curettage (D&C). As far back as 1989, Dr. Frank Loffer reported the increased sensitivity (ability to make an accurate diagnosis) of hysteroscopy with directed biopsy over blinded D&C (98% vs 65%) in the evaluation of AUB.⁷ Evaluation of the endometrium with D&C is no longer recommended; yet today, few gynecologists perform hysteroscopic-directed biopsy for AUB evaluation instead of blinded tissue sampling despite the clinical superiority and in-office capabilities (FIGURE 3).

Continue to: Hysteroscopy and endometrial carcinoma...

Hysteroscopy and endometrial carcinoma

The most common type of gynecologic cancer in the United States is endometrial adenocarcinoma (type 1 endometrial cancer). There is some concern about the effect of hysteroscopy on endometrial cancer prognosis and the spread of cells to the peritoneum at the time of hysteroscopy. A large meta-analysis found that hysteroscopy performed in the presence of type 1 endometrial cancer statistically significantly increased the likelihood of positive intraperitoneal cytology; however, it did not alter the clinical outcome. It was recommended that hysteroscopy not be avoided for this reason and is helpful in the diagnosis of endometrial cancer, especially in the early stages of disease.⁸

For endometrial cancer type 2 (serous carcinoma, clear cell carcinoma, and carcinosarcoma), Chen and colleagues reported a statistically significant increase in positive peritoneal cytology for cancers evaluated by hysteroscopy versus D&C. The disease-specific survival for the hysteroscopy group was 60 months, compared with 71 months for the D&C group. While this finding was not statistically significant, it was clinically relevant, and the effect of hysteroscopy on prognosis with type 2 endometrial cancer is unclear.⁹

Three clinical scenarios

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A common occurrence in the evaluation of postmenopausal bleeding (PMB) is an initial TVUS finding of an enlarged endometrium and an endometrial biopsy that is negative or reveals scant or insufficient tissue. Unfortunately, the diagnostic evaluation process often stops here, and a diagnosis for the PMB is never actually identified. Here are several clinical scenarios that highlight the need for hysteroscopy in the initial evaluation of PMB, especially when there is a discordance between transvaginal ultrasonography (TVUS) and endometrial biopsy findings.

Patient 1: Discordant TVUS and biopsy, with benign findings

The patient is a 52-year-old woman who presented to her gynecologist reporting abnormal uterine bleeding (AUB). She has a history of breast cancer, and she completed tamoxifen treatment. Pelvic ultrasonography was performed; an enlarged endometrial stripe of 1.3 cm was found (FIGURE 4A). Endometrial biopsy was performed, showing adequate tissue but with a negative result. The patient is told that she is likely perimenopausal, which is the reason for her bleeding.

At the time of referral, the patient is evaluated with in-office hysteroscopy. Diagnosis of a 5 cm x 7 cm benign endometrial polyp is made. An uneventful hysteroscopic polypectomy is performed (VIDEO 2).

Video 2

Vidyard Video

This scenario illustrates the shortcoming of initial evaluation by not performing a hysteroscopy, especially in a woman with a thickened endometrium with previous tamoxifen therapy. Subsequent visits failed to correlate bleeding etiology with discordant TVUS and endometrial biopsy results with hysteroscopy, and no hysteroscopy was performed in the operating room at the time of D&C.

Patient 2: Discordant TVUS and biopsy, with premalignant findings

The patient is a 62-year-old woman who had incidental findings of a thickened endometrium on computed tomography scan of the pelvis. TVUS confirmed a thickened endometrium measuring 17 mm, and an endometrial biopsy showed scant tissue.

At the time of referral, a diagnostic hysteroscopy was performed in the office. Endometrial atrophy, a large benign appearing polyp, and focal abnormal appearing tissue were seen (FIGURE 5). A decision for polypectomy and directed biopsy was made. Histology findings confirmed benign polyp and atypical hyperplasia (VIDEO 3).

Video 3

Vidyard Video

This scenario illustrates that while the patient was asymptomatic, there was discordance between the TVUS and endometrial biopsy. Hysteroscopy identified a benign endometrial polyp, which is common in asymptomatic postmenopausal patients with a thickened endometrium and endometrial biopsy showing scant tissue. However, addition of the diagnostic hysteroscopy identified focal precancerous tissue, removed under directed biopsy.

Patient 3: Discordant TVUS and biopsy, with malignant findings

The patient is a 68-year-old woman with PMB. TVUS showed a thickened endometrium measuring 14 mm. An endometrial biopsy was negative, showing scant tissue. No additional diagnostic evaluation or management was offered.

Video 4A

Vidyard Video

At the time of referral, the patient was evaluated with in-office diagnostic hysteroscopy, and the patient was found to have endometrial atrophy, benign appearing polyps, and focal abnormal tissue (FIGURE 6). A decision for polypectomy and directed biopsy was made. Histology confirmed benign polyps and grade 1 adenocarcinoma (VIDEOS 4A, 4B, 4C).

Video 4B

Vidyard Video

This scenario illustrates the possibility of having multiple endometrial pathologies present at the time of discordant TVUS and endometrial biopsy. Hysteroscopy plays a critical role in additional evaluation and diagnosis of endometrial carcinoma with directed biopsy, especially in a symptomatic woman with PMB.

Video 4C

Vidyard Video

Conclusion

Evaluation of PMB begins with a screening TVUS. Findings of an endometrium of ≤4 mm indicate a very low likelihood of the presence of endometrial cancer, and treatment for atrophy or changes to hormone replacement therapy regimen is reasonable first-line management; endometrial biopsy is not recommended. For patients with persistent PMB or thickened endometrium ≥4 mm on TVUS, biopsy sampling of the endometrium should be performed. If the endometrial biopsy does not explain the etiology of the PMB with atypical hyperplasia or endometrial cancer, then hysteroscopy should be performed to evaluate for focal endometrial disease and possible directed biopsy.

Postmenopausal bleeding (PMB) is the presenting sign in most cases of endometrial carcinoma. Prompt evaluation of PMB can exclude, or diagnose, endometrial carcinoma.¹ Although no general consensus exists for PMB evaluation, it involves endometrial assessment with transvaginal ultrasonography (TVUS) and subsequent endometrial biopsy when a thickened endometrium is found. When biopsy results reveal insufficient or scant tissue, further investigation into the etiology of PMB should include office hysteroscopy with possible directed biopsy. In this article I discuss the prevalence of PMB and steps for evaluation, providing clinical takeaways.

Postmenopausal bleeding: Its risk for cancer

Abnormal uterine bleeding (AUB) in a postmenopausal woman is of particular concern to the gynecologist and the patient because of the increased possibility of endometrial carcinoma in this age group. AUB is present in more than 90% of postmenopausal women with endometrial carcinoma, which leads to diagnosis in the early stages of the disease. Approximately 3% to 7% of postmenopausal women with PMB will have endometrial carcinoma.² Most women with PMB, however, experience bleeding secondary to atrophic changes of the vagina or endometrium and not to endometrial carcinoma. (FIGURE 1, VIDEO 1) In addition, women who take gonadal steroids for hormone replacement therapy (HRT) may experience breakthrough bleeding that leads to initial investigation with TVUS.

Video 1

Vidyard Video

The risk of malignancy in polyps in postmenopausal women over the age of 59 who present with PMB is approximately 12%, and hysteroscopic resection should routinely be performed. For asymptomatic patients, the risk of a malignant lesion is low—approximately 3%—and for these women intervention should be assessed individually for the risks of carcinoma and benefits of hysteroscopic removal.³

Clinical takeaway. The high possibility of endometrial carcinoma in postmenopausal women warrants that any patient who is symptomatic with PMB should be presumed to have endometrial cancer until the diagnostic evaluation process proves she does not.

Evaluation of postmenopausal bleeding

Transvaginal ultrasound

As mentioned, no general consensus exists for the evaluation of PMB; however, initial evaluation by TVUS is recommended. The American College of Obstetricians and Gynecologists (ACOG) concluded that when the endometrium measures ≤4 mm with TVUS, the likelihood that bleeding is secondary to endometrial carcinoma is less than 1% (negative predictive value 99%), and endometrial biopsy is not recommended.³ Endometrial sampling in this clinical scenario likely will result in insufficient tissue for evaluation, and it is reasonable to consider initial management for atrophy. A thickened endometrium on TVUS (>4 mm in a postmenopausal woman with PMB) warrants additional evaluation with endometrial sampling (FIGURE 2).

Clinical takeaway. A thickened endometrium on TVUS ≥4 mm in a postmenopausal woman with PMB warrants additional evaluation with endometrial sampling.

Endometrial biopsy

An endometrial biopsy is performed to determine whether endometrial cancer or precancer is present in women with AUB. ACOG recommends that endometrial biopsy be performed for women older than age 45. It is also appropriate in women younger than 45 years if they have risk factors for developing endometrial cancer, including unopposed estrogen exposure (obesity, ovulatory dysfunction), failed medical management of AUB, or persistence of AUB.⁴

Continue to: Endometrial biopsy has some...

Endometrial biopsy has some diagnostic shortcomings, however. In 2016 a systematic review and meta-analysis found that, in women with PMB, the specificity of endometrial biopsy was 98% to 100% (accurate diagnosis with a positive result). The sensitivity (ability to make an accurate diagnosis) of endometrial biopsy to identify endometrial pathology (carcinoma, atypical hyperplasia, and polyps) is lower than typically thought. These investigators found an endometrial biopsy failure rate of 11% (range, 1% to 53%) and rate of insufficient samples of 31% (range, 7% to 76%). In women with insufficient or failed samples, endometrial cancer or precancer was found in 7% (range, 0% to 18%).⁵ Therefore, a negative tissue biopsy result in women with PMB is not considered to be an endpoint, and further evaluation with hysteroscopy to evaluate for focal disease is imperative. The results of endometrial biopsy are only an endpoint to the evaluation of PMB when atypical hyperplasia or endometrial cancer is identified.

Clinical takeaway. A negative tissue biopsy result in women with PMB is not considered to be an endpoint, and further evaluation with hysteroscopy to evaluate for focal disease is imperative.

Hysteroscopy

Hysteroscopy is the gold standard for evaluating the uterine cavity, diagnosing intrauterine pathology, and operative intervention for some causes of AUB. It also is easily performed in the office. This makes the hysteroscope an essential instrument for the gynecologist. Dr. Linda Bradley, a preeminent leader in hysteroscopic surgical education, has coined the phrase, “My hysteroscope is my stethoscope.”⁶ As gynecologists, we should be as adept at using a hysteroscope in the office as the cardiologist is at using a stethoscope.

It has been known for some time that hysteroscopy improves our diagnostic capabilities over blinded procedures such as endometrial biopsy and dilation and curettage (D&C). As far back as 1989, Dr. Frank Loffer reported the increased sensitivity (ability to make an accurate diagnosis) of hysteroscopy with directed biopsy over blinded D&C (98% vs 65%) in the evaluation of AUB.⁷ Evaluation of the endometrium with D&C is no longer recommended; yet today, few gynecologists perform hysteroscopic-directed biopsy for AUB evaluation instead of blinded tissue sampling despite the clinical superiority and in-office capabilities (FIGURE 3).

Continue to: Hysteroscopy and endometrial carcinoma...

Hysteroscopy and endometrial carcinoma

The most common type of gynecologic cancer in the United States is endometrial adenocarcinoma (type 1 endometrial cancer). There is some concern about the effect of hysteroscopy on endometrial cancer prognosis and the spread of cells to the peritoneum at the time of hysteroscopy. A large meta-analysis found that hysteroscopy performed in the presence of type 1 endometrial cancer statistically significantly increased the likelihood of positive intraperitoneal cytology; however, it did not alter the clinical outcome. It was recommended that hysteroscopy not be avoided for this reason and is helpful in the diagnosis of endometrial cancer, especially in the early stages of disease.⁸

For endometrial cancer type 2 (serous carcinoma, clear cell carcinoma, and carcinosarcoma), Chen and colleagues reported a statistically significant increase in positive peritoneal cytology for cancers evaluated by hysteroscopy versus D&C. The disease-specific survival for the hysteroscopy group was 60 months, compared with 71 months for the D&C group. While this finding was not statistically significant, it was clinically relevant, and the effect of hysteroscopy on prognosis with type 2 endometrial cancer is unclear.⁹

Three clinical scenarios

---

A common occurrence in the evaluation of postmenopausal bleeding (PMB) is an initial TVUS finding of an enlarged endometrium and an endometrial biopsy that is negative or reveals scant or insufficient tissue. Unfortunately, the diagnostic evaluation process often stops here, and a diagnosis for the PMB is never actually identified. Here are several clinical scenarios that highlight the need for hysteroscopy in the initial evaluation of PMB, especially when there is a discordance between transvaginal ultrasonography (TVUS) and endometrial biopsy findings.

Patient 1: Discordant TVUS and biopsy, with benign findings

The patient is a 52-year-old woman who presented to her gynecologist reporting abnormal uterine bleeding (AUB). She has a history of breast cancer, and she completed tamoxifen treatment. Pelvic ultrasonography was performed; an enlarged endometrial stripe of 1.3 cm was found (FIGURE 4A). Endometrial biopsy was performed, showing adequate tissue but with a negative result. The patient is told that she is likely perimenopausal, which is the reason for her bleeding.

At the time of referral, the patient is evaluated with in-office hysteroscopy. Diagnosis of a 5 cm x 7 cm benign endometrial polyp is made. An uneventful hysteroscopic polypectomy is performed (VIDEO 2).

Video 2

Vidyard Video

This scenario illustrates the shortcoming of initial evaluation by not performing a hysteroscopy, especially in a woman with a thickened endometrium with previous tamoxifen therapy. Subsequent visits failed to correlate bleeding etiology with discordant TVUS and endometrial biopsy results with hysteroscopy, and no hysteroscopy was performed in the operating room at the time of D&C.

Patient 2: Discordant TVUS and biopsy, with premalignant findings

The patient is a 62-year-old woman who had incidental findings of a thickened endometrium on computed tomography scan of the pelvis. TVUS confirmed a thickened endometrium measuring 17 mm, and an endometrial biopsy showed scant tissue.

At the time of referral, a diagnostic hysteroscopy was performed in the office. Endometrial atrophy, a large benign appearing polyp, and focal abnormal appearing tissue were seen (FIGURE 5). A decision for polypectomy and directed biopsy was made. Histology findings confirmed benign polyp and atypical hyperplasia (VIDEO 3).

Video 3

Vidyard Video

This scenario illustrates that while the patient was asymptomatic, there was discordance between the TVUS and endometrial biopsy. Hysteroscopy identified a benign endometrial polyp, which is common in asymptomatic postmenopausal patients with a thickened endometrium and endometrial biopsy showing scant tissue. However, addition of the diagnostic hysteroscopy identified focal precancerous tissue, removed under directed biopsy.

Patient 3: Discordant TVUS and biopsy, with malignant findings

The patient is a 68-year-old woman with PMB. TVUS showed a thickened endometrium measuring 14 mm. An endometrial biopsy was negative, showing scant tissue. No additional diagnostic evaluation or management was offered.

Video 4A

Vidyard Video

At the time of referral, the patient was evaluated with in-office diagnostic hysteroscopy, and the patient was found to have endometrial atrophy, benign appearing polyps, and focal abnormal tissue (FIGURE 6). A decision for polypectomy and directed biopsy was made. Histology confirmed benign polyps and grade 1 adenocarcinoma (VIDEOS 4A, 4B, 4C).

Video 4B

Vidyard Video

This scenario illustrates the possibility of having multiple endometrial pathologies present at the time of discordant TVUS and endometrial biopsy. Hysteroscopy plays a critical role in additional evaluation and diagnosis of endometrial carcinoma with directed biopsy, especially in a symptomatic woman with PMB.

Video 4C

Vidyard Video

Conclusion

Evaluation of PMB begins with a screening TVUS. Findings of an endometrium of ≤4 mm indicate a very low likelihood of the presence of endometrial cancer, and treatment for atrophy or changes to hormone replacement therapy regimen is reasonable first-line management; endometrial biopsy is not recommended. For patients with persistent PMB or thickened endometrium ≥4 mm on TVUS, biopsy sampling of the endometrium should be performed. If the endometrial biopsy does not explain the etiology of the PMB with atypical hyperplasia or endometrial cancer, then hysteroscopy should be performed to evaluate for focal endometrial disease and possible directed biopsy.

The state with the best hospital now has the best health care to go along with it, and the last frontier is also last in the nation in health care.

In the 2019 edition of its annual ranking of state health care systems, personal finance website WalletHub named Minnesota the best less than a week after U.S. News & World Report called the Mayo Clinic the top hospital in the country.

The WalletHub ranking, which included Washington, D.C., also put Alaska’s health care system at No. 51. Just one step above in the 50th spot was North Carolina, with Mississippi (49), South Carolina (48), and Arkansas (47) occupying the rest of the bottom five. Louisiana, which jumped from 51st in 2018 to 44th this year, was the only state to move out of the bottom five, WalletHub reported.

Joining Minnesota in the top five were Massachusetts (2), Rhode Island (3), D.C. (4), and Vermont (5), which was the home of last year’s best health care. North Dakota, which moved up 12 spots this year all the way to 9th, had the second-largest climb of any state: Montana catapulted 15 spots this year to finish 17th overall, WalletHub said.

For 2019, the company compared the states and D.C. using 43 measures of cost, accessibility, and outcome. The cost dimension’s six metrics included cost of a medical visit and share of adults with no doctor visits because of cost. The accessibility dimension consisted of 23 metrics, including hospital beds per capita, geriatricians per population aged 65 years and older, and Medicaid acceptance rate among physicians. The outcomes dimension included 14 metrics, among them share of patients readmitted to hospitals and share of nonimmunized children.


Minnesota was the only state to finish in the top 10 of all three dimensions. D.C. was ranked first in cost and Maine was the leader in access – as each was last year – and Massachusetts was ranked first in outcomes, the WalletHub data show.

The lowest-ranked states for each category in 2019 were the same as in 2018: Alaska (cost), Texas (access), and Mississippi (outcomes), according to the WalletHub analysis, which was based on data from 21 sources, including the Bureau of Labor Statistics, the Centers for Medicare & Medicaid Services, and the Kaiser Family Foundation.

rfranki@mdedge.com

The state with the best hospital now has the best health care to go along with it, and the last frontier is also last in the nation in health care.

In the 2019 edition of its annual ranking of state health care systems, personal finance website WalletHub named Minnesota the best less than a week after U.S. News & World Report called the Mayo Clinic the top hospital in the country.

The WalletHub ranking, which included Washington, D.C., also put Alaska’s health care system at No. 51. Just one step above in the 50th spot was North Carolina, with Mississippi (49), South Carolina (48), and Arkansas (47) occupying the rest of the bottom five. Louisiana, which jumped from 51st in 2018 to 44th this year, was the only state to move out of the bottom five, WalletHub reported.

Joining Minnesota in the top five were Massachusetts (2), Rhode Island (3), D.C. (4), and Vermont (5), which was the home of last year’s best health care. North Dakota, which moved up 12 spots this year all the way to 9th, had the second-largest climb of any state: Montana catapulted 15 spots this year to finish 17th overall, WalletHub said.

For 2019, the company compared the states and D.C. using 43 measures of cost, accessibility, and outcome. The cost dimension’s six metrics included cost of a medical visit and share of adults with no doctor visits because of cost. The accessibility dimension consisted of 23 metrics, including hospital beds per capita, geriatricians per population aged 65 years and older, and Medicaid acceptance rate among physicians. The outcomes dimension included 14 metrics, among them share of patients readmitted to hospitals and share of nonimmunized children.


Minnesota was the only state to finish in the top 10 of all three dimensions. D.C. was ranked first in cost and Maine was the leader in access – as each was last year – and Massachusetts was ranked first in outcomes, the WalletHub data show.

The lowest-ranked states for each category in 2019 were the same as in 2018: Alaska (cost), Texas (access), and Mississippi (outcomes), according to the WalletHub analysis, which was based on data from 21 sources, including the Bureau of Labor Statistics, the Centers for Medicare & Medicaid Services, and the Kaiser Family Foundation.

rfranki@mdedge.com

The state with the best hospital now has the best health care to go along with it, and the last frontier is also last in the nation in health care.

In the 2019 edition of its annual ranking of state health care systems, personal finance website WalletHub named Minnesota the best less than a week after U.S. News & World Report called the Mayo Clinic the top hospital in the country.

The WalletHub ranking, which included Washington, D.C., also put Alaska’s health care system at No. 51. Just one step above in the 50th spot was North Carolina, with Mississippi (49), South Carolina (48), and Arkansas (47) occupying the rest of the bottom five. Louisiana, which jumped from 51st in 2018 to 44th this year, was the only state to move out of the bottom five, WalletHub reported.

Joining Minnesota in the top five were Massachusetts (2), Rhode Island (3), D.C. (4), and Vermont (5), which was the home of last year’s best health care. North Dakota, which moved up 12 spots this year all the way to 9th, had the second-largest climb of any state: Montana catapulted 15 spots this year to finish 17th overall, WalletHub said.

For 2019, the company compared the states and D.C. using 43 measures of cost, accessibility, and outcome. The cost dimension’s six metrics included cost of a medical visit and share of adults with no doctor visits because of cost. The accessibility dimension consisted of 23 metrics, including hospital beds per capita, geriatricians per population aged 65 years and older, and Medicaid acceptance rate among physicians. The outcomes dimension included 14 metrics, among them share of patients readmitted to hospitals and share of nonimmunized children.


Minnesota was the only state to finish in the top 10 of all three dimensions. D.C. was ranked first in cost and Maine was the leader in access – as each was last year – and Massachusetts was ranked first in outcomes, the WalletHub data show.

The lowest-ranked states for each category in 2019 were the same as in 2018: Alaska (cost), Texas (access), and Mississippi (outcomes), according to the WalletHub analysis, which was based on data from 21 sources, including the Bureau of Labor Statistics, the Centers for Medicare & Medicaid Services, and the Kaiser Family Foundation.

rfranki@mdedge.com

More than two-thirds of physicians have personally experienced some level of burnout, according to a new survey by real-time market insights technology firm InCrowd.

The overall prevalence of personal burnout experience was 68% among respondents, and another 28% said that they had not felt burned out but knew other physicians who had, InCrowd reported Aug. 6.

Specialty appeared to play a part given that 79% of primary care physicians reported experiencing burnout versus 57% of specialists. In response to an open-ended question about ability to manage burnout, the most common answer (23%) was that specialty played a large role, with “no role/all specialties affected equally” next at 13%. Equal proportions of respondents, however, said that specialists (24%) and primary care physicians (24%) were the group most affected, InCrowd said.

There was also a disconnect regarding age. When answering another open-ended question about the effects of age, 23% of those surveyed said that older physicians are more affected, compared with 9% who put the greater burden on younger physicians. The self-reporting of burnout, however, showed that younger physicians were much more likely to experience its effects than their older counterparts: 70% of those aged 30-39 years and 74% of those 40-49 versus 22% of those aged 70-80, InCrowd reported.

InCrowd noted that its results fall within the range of other recent surveys involving burnout in physicians that have shown levels that were lower, at 44% (MedScape, 2019) or 43.9% (American Academy of Family Physicians, 2019), and those that were higher, at 77.8% (The Physicians Foundation/Merritt Hawkins, 2018).

“The alarming persistence of physician burnout over the years and across multiple studies unfortunately demonstrates that we have not yet turned the tide on this problematic issue,” Diane Hayes, PhD, president of InCrowd, said in a statement accompanying the survey results. “Since we last looked at this in 2016, there really haven’t been any notable improvements. The healthcare industry would benefit from refining and expanding current initiatives to assure adequate staffing levels needed to deliver the quality care patients deserve.”

The survey was conducted June 6-7, 2019, and involved responses from 612 physicians (51% primary care providers, 49% specialists).

rfranki@mdedge.com

More than two-thirds of physicians have personally experienced some level of burnout, according to a new survey by real-time market insights technology firm InCrowd.

The overall prevalence of personal burnout experience was 68% among respondents, and another 28% said that they had not felt burned out but knew other physicians who had, InCrowd reported Aug. 6.

Specialty appeared to play a part given that 79% of primary care physicians reported experiencing burnout versus 57% of specialists. In response to an open-ended question about ability to manage burnout, the most common answer (23%) was that specialty played a large role, with “no role/all specialties affected equally” next at 13%. Equal proportions of respondents, however, said that specialists (24%) and primary care physicians (24%) were the group most affected, InCrowd said.

There was also a disconnect regarding age. When answering another open-ended question about the effects of age, 23% of those surveyed said that older physicians are more affected, compared with 9% who put the greater burden on younger physicians. The self-reporting of burnout, however, showed that younger physicians were much more likely to experience its effects than their older counterparts: 70% of those aged 30-39 years and 74% of those 40-49 versus 22% of those aged 70-80, InCrowd reported.

InCrowd noted that its results fall within the range of other recent surveys involving burnout in physicians that have shown levels that were lower, at 44% (MedScape, 2019) or 43.9% (American Academy of Family Physicians, 2019), and those that were higher, at 77.8% (The Physicians Foundation/Merritt Hawkins, 2018).

“The alarming persistence of physician burnout over the years and across multiple studies unfortunately demonstrates that we have not yet turned the tide on this problematic issue,” Diane Hayes, PhD, president of InCrowd, said in a statement accompanying the survey results. “Since we last looked at this in 2016, there really haven’t been any notable improvements. The healthcare industry would benefit from refining and expanding current initiatives to assure adequate staffing levels needed to deliver the quality care patients deserve.”

The survey was conducted June 6-7, 2019, and involved responses from 612 physicians (51% primary care providers, 49% specialists).

rfranki@mdedge.com

More than two-thirds of physicians have personally experienced some level of burnout, according to a new survey by real-time market insights technology firm InCrowd.

The overall prevalence of personal burnout experience was 68% among respondents, and another 28% said that they had not felt burned out but knew other physicians who had, InCrowd reported Aug. 6.

Specialty appeared to play a part given that 79% of primary care physicians reported experiencing burnout versus 57% of specialists. In response to an open-ended question about ability to manage burnout, the most common answer (23%) was that specialty played a large role, with “no role/all specialties affected equally” next at 13%. Equal proportions of respondents, however, said that specialists (24%) and primary care physicians (24%) were the group most affected, InCrowd said.

There was also a disconnect regarding age. When answering another open-ended question about the effects of age, 23% of those surveyed said that older physicians are more affected, compared with 9% who put the greater burden on younger physicians. The self-reporting of burnout, however, showed that younger physicians were much more likely to experience its effects than their older counterparts: 70% of those aged 30-39 years and 74% of those 40-49 versus 22% of those aged 70-80, InCrowd reported.

InCrowd noted that its results fall within the range of other recent surveys involving burnout in physicians that have shown levels that were lower, at 44% (MedScape, 2019) or 43.9% (American Academy of Family Physicians, 2019), and those that were higher, at 77.8% (The Physicians Foundation/Merritt Hawkins, 2018).

“The alarming persistence of physician burnout over the years and across multiple studies unfortunately demonstrates that we have not yet turned the tide on this problematic issue,” Diane Hayes, PhD, president of InCrowd, said in a statement accompanying the survey results. “Since we last looked at this in 2016, there really haven’t been any notable improvements. The healthcare industry would benefit from refining and expanding current initiatives to assure adequate staffing levels needed to deliver the quality care patients deserve.”

The survey was conducted June 6-7, 2019, and involved responses from 612 physicians (51% primary care providers, 49% specialists).

rfranki@mdedge.com

Even when a standard HIV RNA test is negative, some patients may still have viral DNA in their cerebrospinal fluid (CSF)—and that could be a predictor of later memory and concentration problems, say researchers who conducted a National Institute of Health (NIH)-funded study of patients on long-term antiretroviral therapy (ART).

The 69 participants, enrolled in the AIDS Clinical Trials Group HIV Reservoirs Cohort Study, had infections controlled with ART for a median of 9 years. Calling it a “striking observation,” the researchers found nearly half of the patients had viral DNA in CSF cells, although the standard viral load tests of the cell-free CSF fluid were positive in only 4% of the patients.

Of the 30 patients with persistent HIV, 9 (30%) experienced neurocognitive difficulties in a 7-domain neuropsychological test battery. Among 35 participants with no detectable HIV DNA in CSF, 4 (11%) were clinically impaired.

The low rates of detectable HIV RNA in the cell-free CSF fraction and within CSF cell pellets suggest low levels of HIV transcription within cells and infrequent release into the extracellular space during systemically suppressive ART, the researchers say.

The brain is one of the first targets of the virus, and CNS manifestations are common. Neurocognitive impairment in HIV-positive patients is probably related to multiple factors, including HIV infection, age, neuroinflammation, and comorbid conditions, including substance abuse, the researchers say. There also may be a “legacy effect,” in which processes associated with long-term exposure to HIV before ART leads to irreversible neurologic injury and more extensive infection of CSF cells. Lack of an association with inflammatory biomarkers in this study suggested that current inflammation does not lead to present neurocognitive dysfunction, the researchers say, but does not rule out prior inflammation as the underlying cause of neuronal injury.

Still, given that brain tissue in living individuals is “inaccessible” (as the researchers put it), CSF offers a window into neuropathogenesis of HIV. Studies have found a range between 15% and 55% of participants develop an HIV-associated neurocognitive disorder (HAND). The new findings may support a role of persistent HIV-infected cells, but the researchers emphasize that the association does not confirm that HIV DNA causes HAND. However, they add, persistent HIV in “sanctuary sites” despite ART presents a barrier to curing the infection. Their study, they say, indicates that examination of CSF cells is important in assessing residual HIV in compartments during ART.

Even when a standard HIV RNA test is negative, some patients may still have viral DNA in their cerebrospinal fluid (CSF)—and that could be a predictor of later memory and concentration problems, say researchers who conducted a National Institute of Health (NIH)-funded study of patients on long-term antiretroviral therapy (ART).

The 69 participants, enrolled in the AIDS Clinical Trials Group HIV Reservoirs Cohort Study, had infections controlled with ART for a median of 9 years. Calling it a “striking observation,” the researchers found nearly half of the patients had viral DNA in CSF cells, although the standard viral load tests of the cell-free CSF fluid were positive in only 4% of the patients.

Of the 30 patients with persistent HIV, 9 (30%) experienced neurocognitive difficulties in a 7-domain neuropsychological test battery. Among 35 participants with no detectable HIV DNA in CSF, 4 (11%) were clinically impaired.

The low rates of detectable HIV RNA in the cell-free CSF fraction and within CSF cell pellets suggest low levels of HIV transcription within cells and infrequent release into the extracellular space during systemically suppressive ART, the researchers say.

The brain is one of the first targets of the virus, and CNS manifestations are common. Neurocognitive impairment in HIV-positive patients is probably related to multiple factors, including HIV infection, age, neuroinflammation, and comorbid conditions, including substance abuse, the researchers say. There also may be a “legacy effect,” in which processes associated with long-term exposure to HIV before ART leads to irreversible neurologic injury and more extensive infection of CSF cells. Lack of an association with inflammatory biomarkers in this study suggested that current inflammation does not lead to present neurocognitive dysfunction, the researchers say, but does not rule out prior inflammation as the underlying cause of neuronal injury.

Still, given that brain tissue in living individuals is “inaccessible” (as the researchers put it), CSF offers a window into neuropathogenesis of HIV. Studies have found a range between 15% and 55% of participants develop an HIV-associated neurocognitive disorder (HAND). The new findings may support a role of persistent HIV-infected cells, but the researchers emphasize that the association does not confirm that HIV DNA causes HAND. However, they add, persistent HIV in “sanctuary sites” despite ART presents a barrier to curing the infection. Their study, they say, indicates that examination of CSF cells is important in assessing residual HIV in compartments during ART.

Even when a standard HIV RNA test is negative, some patients may still have viral DNA in their cerebrospinal fluid (CSF)—and that could be a predictor of later memory and concentration problems, say researchers who conducted a National Institute of Health (NIH)-funded study of patients on long-term antiretroviral therapy (ART).

The 69 participants, enrolled in the AIDS Clinical Trials Group HIV Reservoirs Cohort Study, had infections controlled with ART for a median of 9 years. Calling it a “striking observation,” the researchers found nearly half of the patients had viral DNA in CSF cells, although the standard viral load tests of the cell-free CSF fluid were positive in only 4% of the patients.

Of the 30 patients with persistent HIV, 9 (30%) experienced neurocognitive difficulties in a 7-domain neuropsychological test battery. Among 35 participants with no detectable HIV DNA in CSF, 4 (11%) were clinically impaired.

The low rates of detectable HIV RNA in the cell-free CSF fraction and within CSF cell pellets suggest low levels of HIV transcription within cells and infrequent release into the extracellular space during systemically suppressive ART, the researchers say.

The brain is one of the first targets of the virus, and CNS manifestations are common. Neurocognitive impairment in HIV-positive patients is probably related to multiple factors, including HIV infection, age, neuroinflammation, and comorbid conditions, including substance abuse, the researchers say. There also may be a “legacy effect,” in which processes associated with long-term exposure to HIV before ART leads to irreversible neurologic injury and more extensive infection of CSF cells. Lack of an association with inflammatory biomarkers in this study suggested that current inflammation does not lead to present neurocognitive dysfunction, the researchers say, but does not rule out prior inflammation as the underlying cause of neuronal injury.

Still, given that brain tissue in living individuals is “inaccessible” (as the researchers put it), CSF offers a window into neuropathogenesis of HIV. Studies have found a range between 15% and 55% of participants develop an HIV-associated neurocognitive disorder (HAND). The new findings may support a role of persistent HIV-infected cells, but the researchers emphasize that the association does not confirm that HIV DNA causes HAND. However, they add, persistent HIV in “sanctuary sites” despite ART presents a barrier to curing the infection. Their study, they say, indicates that examination of CSF cells is important in assessing residual HIV in compartments during ART.

About half of papers in a sample of psychiatry and psychology journals have evidence of “spin” in the abstract, according to an analysis published in BMJ Evidence-Based Medicine.

Samuel Jellison, a third-year medical student at Oklahoma State University, Tulsa, and coauthors wrote that the results of randomized, controlled trials should be reported objectively because of their importance for psychiatry clinical practice. However, given that researchers were allowed more latitude in the abstract of a paper to highlight certain results or conclusions, the abstract might not accurately represent the findings of the study.

To evaluate this, the authors investigated the use of spin in abstracts, which they defined as “‘use of specific reporting strategies, from whatever motive, to highlight that the experimental treatment is beneficial, despite a statistically nonsignificant difference for the primary outcome, or to distract the reader from statistically nonsignificant results.”

They analyzed 116 randomized, controlled trials of interventions where there was a nonsignificant primary endpoint and found that 56% of those contained spin in the abstract. Spin was evident in 2% of publication titles, 21% of abstract results sections, and 49.1% of abstract conclusions sections. In 15% of trials, spin was found both in the results and the conclusions.

Spin was more common in trials of pharmacologic treatments, compared with nonpharmacologic treatments. However, the study did not find a higher level of spin in industry-funded studies, and in fact, spin was more common in publicly funded research.

The most common form of spin was focusing on a statistically significant primary or secondary endpoint while omitting one or more nonsignificant primary endpoints. Other spin strategies included claiming noninferiority or equivalence for a statistically nonsignificant endpoint; using phrases such as “trend towards significance”; or focusing on statistically significant subgroup analyses, such as per protocol instead of intention to treat.

The authors observed that most physicians only read article abstracts, and up to one-quarter of editorial decisions are based on the abstract alone.

“Adding spin to the abstract of an article may mislead physicians who are attempting to draw conclusions about a treatment for patients,” they wrote, while calling for efforts to discourage spin in abstracts.

In an interview, Paul S. Nestadt, MD, said the findings were not surprising.

“The proportion [56%] of psychiatry and psychology abstracts which Jellison et al. found to contain spin is similar to that found in broader studies of all biomedical literature in previous reviews,” said Dr. Nestadt, assistant professor in the department of psychiatry and behavioral sciences at Johns Hopkins University, Baltimore. “It is disheartening that attempts to mislead have become ‘standard of care’ in medical literature, but it is a predictable outcome of increasing competition for shrinking grant funding, awarded partly on the basis of publication history in leading journals that maintain clear publication biases toward positive results.

“As the authors point out, we all share a responsibility to call out spin when we see it, whether in our role as reviewer, editor, coauthor, or as the writers themselves.”

Neither Mr. Jellison nor his coauthors reported funding or conflicts of interest.

SOURCE: Jellison S et al. BMJ Evid Based Med. 2019 Aug 5. doi: 10.1136/bmjebm-2019-111176.

About half of papers in a sample of psychiatry and psychology journals have evidence of “spin” in the abstract, according to an analysis published in BMJ Evidence-Based Medicine.

Samuel Jellison, a third-year medical student at Oklahoma State University, Tulsa, and coauthors wrote that the results of randomized, controlled trials should be reported objectively because of their importance for psychiatry clinical practice. However, given that researchers were allowed more latitude in the abstract of a paper to highlight certain results or conclusions, the abstract might not accurately represent the findings of the study.

To evaluate this, the authors investigated the use of spin in abstracts, which they defined as “‘use of specific reporting strategies, from whatever motive, to highlight that the experimental treatment is beneficial, despite a statistically nonsignificant difference for the primary outcome, or to distract the reader from statistically nonsignificant results.”

They analyzed 116 randomized, controlled trials of interventions where there was a nonsignificant primary endpoint and found that 56% of those contained spin in the abstract. Spin was evident in 2% of publication titles, 21% of abstract results sections, and 49.1% of abstract conclusions sections. In 15% of trials, spin was found both in the results and the conclusions.

Spin was more common in trials of pharmacologic treatments, compared with nonpharmacologic treatments. However, the study did not find a higher level of spin in industry-funded studies, and in fact, spin was more common in publicly funded research.

The most common form of spin was focusing on a statistically significant primary or secondary endpoint while omitting one or more nonsignificant primary endpoints. Other spin strategies included claiming noninferiority or equivalence for a statistically nonsignificant endpoint; using phrases such as “trend towards significance”; or focusing on statistically significant subgroup analyses, such as per protocol instead of intention to treat.

The authors observed that most physicians only read article abstracts, and up to one-quarter of editorial decisions are based on the abstract alone.

“Adding spin to the abstract of an article may mislead physicians who are attempting to draw conclusions about a treatment for patients,” they wrote, while calling for efforts to discourage spin in abstracts.

In an interview, Paul S. Nestadt, MD, said the findings were not surprising.

“The proportion [56%] of psychiatry and psychology abstracts which Jellison et al. found to contain spin is similar to that found in broader studies of all biomedical literature in previous reviews,” said Dr. Nestadt, assistant professor in the department of psychiatry and behavioral sciences at Johns Hopkins University, Baltimore. “It is disheartening that attempts to mislead have become ‘standard of care’ in medical literature, but it is a predictable outcome of increasing competition for shrinking grant funding, awarded partly on the basis of publication history in leading journals that maintain clear publication biases toward positive results.

“As the authors point out, we all share a responsibility to call out spin when we see it, whether in our role as reviewer, editor, coauthor, or as the writers themselves.”

Neither Mr. Jellison nor his coauthors reported funding or conflicts of interest.

SOURCE: Jellison S et al. BMJ Evid Based Med. 2019 Aug 5. doi: 10.1136/bmjebm-2019-111176.

About half of papers in a sample of psychiatry and psychology journals have evidence of “spin” in the abstract, according to an analysis published in BMJ Evidence-Based Medicine.

Samuel Jellison, a third-year medical student at Oklahoma State University, Tulsa, and coauthors wrote that the results of randomized, controlled trials should be reported objectively because of their importance for psychiatry clinical practice. However, given that researchers were allowed more latitude in the abstract of a paper to highlight certain results or conclusions, the abstract might not accurately represent the findings of the study.

To evaluate this, the authors investigated the use of spin in abstracts, which they defined as “‘use of specific reporting strategies, from whatever motive, to highlight that the experimental treatment is beneficial, despite a statistically nonsignificant difference for the primary outcome, or to distract the reader from statistically nonsignificant results.”

They analyzed 116 randomized, controlled trials of interventions where there was a nonsignificant primary endpoint and found that 56% of those contained spin in the abstract. Spin was evident in 2% of publication titles, 21% of abstract results sections, and 49.1% of abstract conclusions sections. In 15% of trials, spin was found both in the results and the conclusions.

Spin was more common in trials of pharmacologic treatments, compared with nonpharmacologic treatments. However, the study did not find a higher level of spin in industry-funded studies, and in fact, spin was more common in publicly funded research.

The most common form of spin was focusing on a statistically significant primary or secondary endpoint while omitting one or more nonsignificant primary endpoints. Other spin strategies included claiming noninferiority or equivalence for a statistically nonsignificant endpoint; using phrases such as “trend towards significance”; or focusing on statistically significant subgroup analyses, such as per protocol instead of intention to treat.

The authors observed that most physicians only read article abstracts, and up to one-quarter of editorial decisions are based on the abstract alone.

“Adding spin to the abstract of an article may mislead physicians who are attempting to draw conclusions about a treatment for patients,” they wrote, while calling for efforts to discourage spin in abstracts.

In an interview, Paul S. Nestadt, MD, said the findings were not surprising.

“The proportion [56%] of psychiatry and psychology abstracts which Jellison et al. found to contain spin is similar to that found in broader studies of all biomedical literature in previous reviews,” said Dr. Nestadt, assistant professor in the department of psychiatry and behavioral sciences at Johns Hopkins University, Baltimore. “It is disheartening that attempts to mislead have become ‘standard of care’ in medical literature, but it is a predictable outcome of increasing competition for shrinking grant funding, awarded partly on the basis of publication history in leading journals that maintain clear publication biases toward positive results.

“As the authors point out, we all share a responsibility to call out spin when we see it, whether in our role as reviewer, editor, coauthor, or as the writers themselves.”

Neither Mr. Jellison nor his coauthors reported funding or conflicts of interest.

SOURCE: Jellison S et al. BMJ Evid Based Med. 2019 Aug 5. doi: 10.1136/bmjebm-2019-111176.

The need for universal screening for Lynch syndrome in elderly patients with newly diagnosed colorectal cancer (CRC) has been questioned, according to results from a retrospective cohort study.

In addition, discontinuing reflex CRC screening for Lynch syndrome in patients over age 80 years could be feasible because of very low efficiency.

“The universal strategy advocates screening all patients with newly diagnosed CRC for Lynch syndrome and has been shown to be the most sensitive method,” wrote Dan Li, MD, of Kaiser Permanente Northern California, Santa Clara, and colleagues. The findings were published in Annals of Internal Medicine.

The researchers studied 3,891 patients with newly diagnosed CRC who were screened for Lynch syndrome from 2011 to 2016. Data were collected from a population-based screening program at Kaiser Permanente Northern California.

“The system provides comprehensive medical care for more than 4 million members across 21 medical centers covering urban, suburban, and semirural areas,” Dr. Li and his colleagues wrote.

To compare universal and age-restricted screening, the team obtained surgical samples of all newly diagnosed CRC tumors and tested them for reflex mismatch repair protein expression using immunohistochemistry.

Subsequently, the age-restricted screening groups were divided into several age categories, ranging from age 50 to 85 years.

The diagnostic yield, defined as the “percentage of patients with pathogenic reflex mismatch repair gene variants among all patients with CRC screened with immunohistochemistry,” was measured and compared with the universal screening technique.

“We calculated the number of patients with CRC who needed to be screened in each age group to identify one case of Lynch syndrome by dividing the number of patients screened in each age group by the number of Lynch syndrome cases diagnosed in that group,” they explained.

After analysis, the researchers detected a total of 63 cases of Lynch syndrome (diagnostic yield, 1.62%) with universal screening, among which 5 (7.9%) were over age 70 years and 1 (1.6%) was over age 80 years.

When patients with CRC who were universally screened were used as the denominator, 58 cases (diagnostic yield, 1.49%) were detected in those with CRC diagnosed at or prior to age 70 years.

In addition, in patients diagnosed at or before age 75 and 80 years, 60 and 62 cases of Lynch syndrome (diagnostic yield, 1.54% and 1.59%) were detected, respectively.

“The incremental diagnostic yield decreased substantially after age 70 to 75 years,” they wrote.

With these findings, Dr. Li and his colleagues suggested that cessation of screening for Lynch syndrome post age 80 years may be acceptable, especially in resource-limited environments.

“Using age as the primary criterion is a simple method of selecting patients for Lynch syndrome screening in clinical practice,” they added.

In accordance with previous studies, a major reduction in Lynch syndrome incidence has been noted among elderly populations.

There remains a need for additional studies exploring the effects of diagnosing Lynch syndrome in elderly patients on family members.

The researchers acknowledged a key limitation of the study was that patients who did not finish germline analysis but were eligible for it were excluded from certain measurements. To reduce potential bias, the team conducted a sensitivity analysis, and the findings were negligible with respect to main results.

“Given the geographic variation in the reported prevalence of Lynch syndrome, the diagnostic efficiency of Lynch syndrome screening among elderly populations should be further investigated in other populations,” they concluded.

The study was funded by Kaiser Permanente Northern California. The authors reported financial affiliations with Bayer, Clinical Genomics, Covidien, Exact Sciences, Motus GI, Quorum, Universal DX, and the National Cancer Institute.

SOURCE: Li D et al. Ann Intern Med. 2019 Jun 11. doi: 10.7326/M18-3316.

The need for universal screening for Lynch syndrome in elderly patients with newly diagnosed colorectal cancer (CRC) has been questioned, according to results from a retrospective cohort study.

In addition, discontinuing reflex CRC screening for Lynch syndrome in patients over age 80 years could be feasible because of very low efficiency.

“The universal strategy advocates screening all patients with newly diagnosed CRC for Lynch syndrome and has been shown to be the most sensitive method,” wrote Dan Li, MD, of Kaiser Permanente Northern California, Santa Clara, and colleagues. The findings were published in Annals of Internal Medicine.

The researchers studied 3,891 patients with newly diagnosed CRC who were screened for Lynch syndrome from 2011 to 2016. Data were collected from a population-based screening program at Kaiser Permanente Northern California.

“The system provides comprehensive medical care for more than 4 million members across 21 medical centers covering urban, suburban, and semirural areas,” Dr. Li and his colleagues wrote.

To compare universal and age-restricted screening, the team obtained surgical samples of all newly diagnosed CRC tumors and tested them for reflex mismatch repair protein expression using immunohistochemistry.

Subsequently, the age-restricted screening groups were divided into several age categories, ranging from age 50 to 85 years.

The diagnostic yield, defined as the “percentage of patients with pathogenic reflex mismatch repair gene variants among all patients with CRC screened with immunohistochemistry,” was measured and compared with the universal screening technique.

“We calculated the number of patients with CRC who needed to be screened in each age group to identify one case of Lynch syndrome by dividing the number of patients screened in each age group by the number of Lynch syndrome cases diagnosed in that group,” they explained.

After analysis, the researchers detected a total of 63 cases of Lynch syndrome (diagnostic yield, 1.62%) with universal screening, among which 5 (7.9%) were over age 70 years and 1 (1.6%) was over age 80 years.

When patients with CRC who were universally screened were used as the denominator, 58 cases (diagnostic yield, 1.49%) were detected in those with CRC diagnosed at or prior to age 70 years.

In addition, in patients diagnosed at or before age 75 and 80 years, 60 and 62 cases of Lynch syndrome (diagnostic yield, 1.54% and 1.59%) were detected, respectively.

“The incremental diagnostic yield decreased substantially after age 70 to 75 years,” they wrote.

With these findings, Dr. Li and his colleagues suggested that cessation of screening for Lynch syndrome post age 80 years may be acceptable, especially in resource-limited environments.

“Using age as the primary criterion is a simple method of selecting patients for Lynch syndrome screening in clinical practice,” they added.

In accordance with previous studies, a major reduction in Lynch syndrome incidence has been noted among elderly populations.

There remains a need for additional studies exploring the effects of diagnosing Lynch syndrome in elderly patients on family members.

The researchers acknowledged a key limitation of the study was that patients who did not finish germline analysis but were eligible for it were excluded from certain measurements. To reduce potential bias, the team conducted a sensitivity analysis, and the findings were negligible with respect to main results.

“Given the geographic variation in the reported prevalence of Lynch syndrome, the diagnostic efficiency of Lynch syndrome screening among elderly populations should be further investigated in other populations,” they concluded.

The study was funded by Kaiser Permanente Northern California. The authors reported financial affiliations with Bayer, Clinical Genomics, Covidien, Exact Sciences, Motus GI, Quorum, Universal DX, and the National Cancer Institute.

SOURCE: Li D et al. Ann Intern Med. 2019 Jun 11. doi: 10.7326/M18-3316.

The need for universal screening for Lynch syndrome in elderly patients with newly diagnosed colorectal cancer (CRC) has been questioned, according to results from a retrospective cohort study.

In addition, discontinuing reflex CRC screening for Lynch syndrome in patients over age 80 years could be feasible because of very low efficiency.

“The universal strategy advocates screening all patients with newly diagnosed CRC for Lynch syndrome and has been shown to be the most sensitive method,” wrote Dan Li, MD, of Kaiser Permanente Northern California, Santa Clara, and colleagues. The findings were published in Annals of Internal Medicine.

The researchers studied 3,891 patients with newly diagnosed CRC who were screened for Lynch syndrome from 2011 to 2016. Data were collected from a population-based screening program at Kaiser Permanente Northern California.

“The system provides comprehensive medical care for more than 4 million members across 21 medical centers covering urban, suburban, and semirural areas,” Dr. Li and his colleagues wrote.

To compare universal and age-restricted screening, the team obtained surgical samples of all newly diagnosed CRC tumors and tested them for reflex mismatch repair protein expression using immunohistochemistry.

Subsequently, the age-restricted screening groups were divided into several age categories, ranging from age 50 to 85 years.

The diagnostic yield, defined as the “percentage of patients with pathogenic reflex mismatch repair gene variants among all patients with CRC screened with immunohistochemistry,” was measured and compared with the universal screening technique.

“We calculated the number of patients with CRC who needed to be screened in each age group to identify one case of Lynch syndrome by dividing the number of patients screened in each age group by the number of Lynch syndrome cases diagnosed in that group,” they explained.

After analysis, the researchers detected a total of 63 cases of Lynch syndrome (diagnostic yield, 1.62%) with universal screening, among which 5 (7.9%) were over age 70 years and 1 (1.6%) was over age 80 years.

When patients with CRC who were universally screened were used as the denominator, 58 cases (diagnostic yield, 1.49%) were detected in those with CRC diagnosed at or prior to age 70 years.

In addition, in patients diagnosed at or before age 75 and 80 years, 60 and 62 cases of Lynch syndrome (diagnostic yield, 1.54% and 1.59%) were detected, respectively.

“The incremental diagnostic yield decreased substantially after age 70 to 75 years,” they wrote.

With these findings, Dr. Li and his colleagues suggested that cessation of screening for Lynch syndrome post age 80 years may be acceptable, especially in resource-limited environments.

“Using age as the primary criterion is a simple method of selecting patients for Lynch syndrome screening in clinical practice,” they added.

In accordance with previous studies, a major reduction in Lynch syndrome incidence has been noted among elderly populations.

There remains a need for additional studies exploring the effects of diagnosing Lynch syndrome in elderly patients on family members.

The researchers acknowledged a key limitation of the study was that patients who did not finish germline analysis but were eligible for it were excluded from certain measurements. To reduce potential bias, the team conducted a sensitivity analysis, and the findings were negligible with respect to main results.

“Given the geographic variation in the reported prevalence of Lynch syndrome, the diagnostic efficiency of Lynch syndrome screening among elderly populations should be further investigated in other populations,” they concluded.

The study was funded by Kaiser Permanente Northern California. The authors reported financial affiliations with Bayer, Clinical Genomics, Covidien, Exact Sciences, Motus GI, Quorum, Universal DX, and the National Cancer Institute.

SOURCE: Li D et al. Ann Intern Med. 2019 Jun 11. doi: 10.7326/M18-3316.

When it comes to cardiovascular disease (CVD) risk after a breast cancer diagnosis, it’s not so much a matter of the amount of body fat carried but rather where it is located, results of a retrospective cohort study of nearly 3,000 survivors suggest.

“It is well known that higher body mass index (BMI) is associated with CVD mortality in the general population. However, BMI is not always an accurate proxy for individual-level adiposity and does not describe adipose tissue distribution,” note lead investigator Elizabeth M. Cespedes Feliciano, ScD, of Kaiser Permanente Northern California, Oakland, Calif., and coinvestigators.

The investigators studied 2,943 survivors of nonmetastatic breast cancer having a mean age of 56 years who were initially CVD free, using clinically acquired CT scans obtained near diagnosis to measure adiposity in three compartments: visceral, subcutaneous, and intramuscular.

The cohort experienced 328 CVD events (nonfatal stroke, myocardial infarction, heart failure, or CVD death) during a median follow-up of 6 years, the investigators reported in Journal of Clinical Oncology. The 10-year cumulative incidence was 15%.

In analyses that were adjusted for potential confounders and took into account competing risks, survivors’ CVD risk increased significantly with each standard deviation (SD) increase in visceral adiposity (hazard ratio, 1.15; 95% confidence interval, 1.03-1.29) and each SD increase in intramuscular adiposity (HR, 1.21; 95% CI, 1.06-1.37). The association for subcutaneous adiposity was not significant.

Findings were similar across all BMI categories. Of particular note, among survivors having a normal BMI, risk of CVD events increased by 70% with each SD greater visceral adiposity (HR, 1.70; 95% CI, 1.10-2.62).

Risk also rose with BMI exceeding the normal range, but the association became significant only in survivors with a BMI placing them in obesity class II (35 kg/m² or greater) (HR, 1.70; 95% CI, 1.20-2.42).

“Although it has been assumed that excess adiposity increases the risk of CVD after breast cancer, this first-of-its-kind study demonstrates that adipose tissue distribution best identifies patients with breast cancer with higher CVD risk after diagnosis, including those with normal BMI,” Dr. Cespedes Feliciano and coinvestigators note.

“Software is now available that automatically measures body composition from clinically acquired CT scans, facilitating clinical integration,” they note. “Measures of adipose tissue distribution from CT or anthropometry (e.g., waist circumference) may help identify individuals with high CVD risk and tailor prevention efforts to patients’ body composition.”

Dr. Cespedes Feliciano disclosed no relevant conflicts of interest. The study did not receive any specific funding.

SOURCE: Cespedes Feliciano EM et al. J Clin Oncol. 2019 Aug 1. doi: 10.1200/JCO.19.00286.

When it comes to cardiovascular disease (CVD) risk after a breast cancer diagnosis, it’s not so much a matter of the amount of body fat carried but rather where it is located, results of a retrospective cohort study of nearly 3,000 survivors suggest.

“It is well known that higher body mass index (BMI) is associated with CVD mortality in the general population. However, BMI is not always an accurate proxy for individual-level adiposity and does not describe adipose tissue distribution,” note lead investigator Elizabeth M. Cespedes Feliciano, ScD, of Kaiser Permanente Northern California, Oakland, Calif., and coinvestigators.

The investigators studied 2,943 survivors of nonmetastatic breast cancer having a mean age of 56 years who were initially CVD free, using clinically acquired CT scans obtained near diagnosis to measure adiposity in three compartments: visceral, subcutaneous, and intramuscular.

The cohort experienced 328 CVD events (nonfatal stroke, myocardial infarction, heart failure, or CVD death) during a median follow-up of 6 years, the investigators reported in Journal of Clinical Oncology. The 10-year cumulative incidence was 15%.

In analyses that were adjusted for potential confounders and took into account competing risks, survivors’ CVD risk increased significantly with each standard deviation (SD) increase in visceral adiposity (hazard ratio, 1.15; 95% confidence interval, 1.03-1.29) and each SD increase in intramuscular adiposity (HR, 1.21; 95% CI, 1.06-1.37). The association for subcutaneous adiposity was not significant.

Findings were similar across all BMI categories. Of particular note, among survivors having a normal BMI, risk of CVD events increased by 70% with each SD greater visceral adiposity (HR, 1.70; 95% CI, 1.10-2.62).

Risk also rose with BMI exceeding the normal range, but the association became significant only in survivors with a BMI placing them in obesity class II (35 kg/m² or greater) (HR, 1.70; 95% CI, 1.20-2.42).

“Although it has been assumed that excess adiposity increases the risk of CVD after breast cancer, this first-of-its-kind study demonstrates that adipose tissue distribution best identifies patients with breast cancer with higher CVD risk after diagnosis, including those with normal BMI,” Dr. Cespedes Feliciano and coinvestigators note.

“Software is now available that automatically measures body composition from clinically acquired CT scans, facilitating clinical integration,” they note. “Measures of adipose tissue distribution from CT or anthropometry (e.g., waist circumference) may help identify individuals with high CVD risk and tailor prevention efforts to patients’ body composition.”

Dr. Cespedes Feliciano disclosed no relevant conflicts of interest. The study did not receive any specific funding.

SOURCE: Cespedes Feliciano EM et al. J Clin Oncol. 2019 Aug 1. doi: 10.1200/JCO.19.00286.

When it comes to cardiovascular disease (CVD) risk after a breast cancer diagnosis, it’s not so much a matter of the amount of body fat carried but rather where it is located, results of a retrospective cohort study of nearly 3,000 survivors suggest.

“It is well known that higher body mass index (BMI) is associated with CVD mortality in the general population. However, BMI is not always an accurate proxy for individual-level adiposity and does not describe adipose tissue distribution,” note lead investigator Elizabeth M. Cespedes Feliciano, ScD, of Kaiser Permanente Northern California, Oakland, Calif., and coinvestigators.

The investigators studied 2,943 survivors of nonmetastatic breast cancer having a mean age of 56 years who were initially CVD free, using clinically acquired CT scans obtained near diagnosis to measure adiposity in three compartments: visceral, subcutaneous, and intramuscular.

The cohort experienced 328 CVD events (nonfatal stroke, myocardial infarction, heart failure, or CVD death) during a median follow-up of 6 years, the investigators reported in Journal of Clinical Oncology. The 10-year cumulative incidence was 15%.

In analyses that were adjusted for potential confounders and took into account competing risks, survivors’ CVD risk increased significantly with each standard deviation (SD) increase in visceral adiposity (hazard ratio, 1.15; 95% confidence interval, 1.03-1.29) and each SD increase in intramuscular adiposity (HR, 1.21; 95% CI, 1.06-1.37). The association for subcutaneous adiposity was not significant.

Findings were similar across all BMI categories. Of particular note, among survivors having a normal BMI, risk of CVD events increased by 70% with each SD greater visceral adiposity (HR, 1.70; 95% CI, 1.10-2.62).

Risk also rose with BMI exceeding the normal range, but the association became significant only in survivors with a BMI placing them in obesity class II (35 kg/m² or greater) (HR, 1.70; 95% CI, 1.20-2.42).

“Although it has been assumed that excess adiposity increases the risk of CVD after breast cancer, this first-of-its-kind study demonstrates that adipose tissue distribution best identifies patients with breast cancer with higher CVD risk after diagnosis, including those with normal BMI,” Dr. Cespedes Feliciano and coinvestigators note.

“Software is now available that automatically measures body composition from clinically acquired CT scans, facilitating clinical integration,” they note. “Measures of adipose tissue distribution from CT or anthropometry (e.g., waist circumference) may help identify individuals with high CVD risk and tailor prevention efforts to patients’ body composition.”

Dr. Cespedes Feliciano disclosed no relevant conflicts of interest. The study did not receive any specific funding.

SOURCE: Cespedes Feliciano EM et al. J Clin Oncol. 2019 Aug 1. doi: 10.1200/JCO.19.00286.