The Journal of Family Practice

Illustrative case

It’s noon, you are finishing up a visit with a 62-year-old man with erectile dysfunction (ED), and you want to evaluate for androgen deficiency. Should you ask him to return for an early-morning visit so you can test his testosterone level?

Increasing public awareness of androgen deficiency has led to more men being tested for testosterone levels. Current Endocrine Society guidelines recommend against routine screening for androgen deficiency in men who do not have symptoms.² However, for men with classic symptoms of androgen deficiency—such as decreased libido, ED, infertility, depression, osteoporosis, loss of secondary sexual characteristics, or reduced muscle bulk or strength—measurement of total testosterone level is recommended.²

Due to the natural diurnal variation in serum testosterone levels, the guidelines recommend collecting the sample in the early morning.² This recommendation is based on small observational studies that included men mostly younger than 45 years of age that found a significant difference in testosterone levels between samples drawn early in the morning and in the afternoon.^3-5

In recent years, several studies have indicated that this variation declines as men age.^4-6 Recently, researchers evaluated the effects of age and time of testing on men’s total testosterone levels.

STUDY SUMMARY: Differences in testosterone levels are significant only in younger men

Welliver et al¹ performed a retrospective chart review of 2569 men seen at a Minneapolis Veterans Affairs hospital for ED who had total testosterone levels measured between 7 am and 2 pm over a 15-year period. Men whose total testosterone levels were outside the normal range (>1000 or <50 ng/dL) or who had total testosterone drawn after 2 pm were excluded. The authors analyzed the results based on age, creating one group for men ages <40 years and 5-year age groups for all other men. Using scatterplot techniques, they separated each age group into 2 subgroups based on draw times—7 am to 9 am, or 9 am to 2 pm—and compared the mean total testosterone level for each age and time.

The participants’ mean age was 63 years. Younger men (<45 years) had the largest variation in serum total testosterone, with a large and significant decrease after 9 am. Only the youngest 2 groups (ages <40 and 40-44 years) showed a large decrease in total testosterone in specimens collected after 9 am compared to those drawn between 7 am and 9 am (mean difference 207 and 149 ng/dL, respectively). This variation was not observed in patients over age 45. Although there was a statistically significant difference between early and later testosterone levels in men ages 70 to 74 years, the absolute difference—34 ng/dL (452 vs 418 ng/dL)—was unlikely to be clinically significant.

WHAT'S NEW: For older men, later testing will not affect results

This study confirms previous research showing that the diurnal effect on testosterone levels becomes blunted with increasing age, at least in this group of men with ED. Allowing older men to have total testosterone levels drawn until 2 pm would allow for greater patient flexibility in draw times with little change in results.

CAVEATS: Study's methodology cannot account for several potential confounders

This retrospective study analyzed only a single random testosterone level measurement from each participant, rather than repeat testosterone levels over the course of a day. However, the study was large (2569 men) and it used mean values, which should at least partially mitigate the effect of having only a single level from each participant.

Only the youngest 2 groups (ages <40 and 40-44 years) showed a large decrease in total testosterone in specimens collected after 9 am compared to those drawn between 7 am and 9 am.

The study measured total testosterone and did not account for potential confounding factors—such as obesity or use of testosterone replacement therapy or androgen deprivation therapy—that could affect sexhormone binding globulin, thus potentially altering total testosterone level. However, the authors estimated that less than 2% of the entire cohort were likely to have unrecognized hormonal manipulation with exogenous gonadotropins.

All of the men in the study were seen for ED, and it could be that men with ED have more flattening of the diurnal variation than men without ED; however, we are unaware of other data that support this.

Up to 30% of men who have an early-morning testosterone level that is low may have a normal result when testing is repeated.^2,5 Therefore, for all men who have low testosterone level test results, draw a repeat total testosterone level before 9 am to confirm the diagnosis. Also, this study did not evaluate the course of testosterone levels throughout the later afternoon and evening, and it remains unclear whether levels can be drawn even later in the day.

CHALLENGES TO IMPLEMENTATION: Your lab's policies might require early-morning draws

There will probably be few barriers to implementing this change, unless local laboratory policies are inflexible regarding the timing of testosterone draws.

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

Illustrative case

It’s noon, you are finishing up a visit with a 62-year-old man with erectile dysfunction (ED), and you want to evaluate for androgen deficiency. Should you ask him to return for an early-morning visit so you can test his testosterone level?

Increasing public awareness of androgen deficiency has led to more men being tested for testosterone levels. Current Endocrine Society guidelines recommend against routine screening for androgen deficiency in men who do not have symptoms.² However, for men with classic symptoms of androgen deficiency—such as decreased libido, ED, infertility, depression, osteoporosis, loss of secondary sexual characteristics, or reduced muscle bulk or strength—measurement of total testosterone level is recommended.²

Due to the natural diurnal variation in serum testosterone levels, the guidelines recommend collecting the sample in the early morning.² This recommendation is based on small observational studies that included men mostly younger than 45 years of age that found a significant difference in testosterone levels between samples drawn early in the morning and in the afternoon.^3-5

In recent years, several studies have indicated that this variation declines as men age.^4-6 Recently, researchers evaluated the effects of age and time of testing on men’s total testosterone levels.

STUDY SUMMARY: Differences in testosterone levels are significant only in younger men

Welliver et al¹ performed a retrospective chart review of 2569 men seen at a Minneapolis Veterans Affairs hospital for ED who had total testosterone levels measured between 7 am and 2 pm over a 15-year period. Men whose total testosterone levels were outside the normal range (>1000 or <50 ng/dL) or who had total testosterone drawn after 2 pm were excluded. The authors analyzed the results based on age, creating one group for men ages <40 years and 5-year age groups for all other men. Using scatterplot techniques, they separated each age group into 2 subgroups based on draw times—7 am to 9 am, or 9 am to 2 pm—and compared the mean total testosterone level for each age and time.

The participants’ mean age was 63 years. Younger men (<45 years) had the largest variation in serum total testosterone, with a large and significant decrease after 9 am. Only the youngest 2 groups (ages <40 and 40-44 years) showed a large decrease in total testosterone in specimens collected after 9 am compared to those drawn between 7 am and 9 am (mean difference 207 and 149 ng/dL, respectively). This variation was not observed in patients over age 45. Although there was a statistically significant difference between early and later testosterone levels in men ages 70 to 74 years, the absolute difference—34 ng/dL (452 vs 418 ng/dL)—was unlikely to be clinically significant.

WHAT'S NEW: For older men, later testing will not affect results

This study confirms previous research showing that the diurnal effect on testosterone levels becomes blunted with increasing age, at least in this group of men with ED. Allowing older men to have total testosterone levels drawn until 2 pm would allow for greater patient flexibility in draw times with little change in results.

CAVEATS: Study's methodology cannot account for several potential confounders

This retrospective study analyzed only a single random testosterone level measurement from each participant, rather than repeat testosterone levels over the course of a day. However, the study was large (2569 men) and it used mean values, which should at least partially mitigate the effect of having only a single level from each participant.

Only the youngest 2 groups (ages <40 and 40-44 years) showed a large decrease in total testosterone in specimens collected after 9 am compared to those drawn between 7 am and 9 am.

The study measured total testosterone and did not account for potential confounding factors—such as obesity or use of testosterone replacement therapy or androgen deprivation therapy—that could affect sexhormone binding globulin, thus potentially altering total testosterone level. However, the authors estimated that less than 2% of the entire cohort were likely to have unrecognized hormonal manipulation with exogenous gonadotropins.

All of the men in the study were seen for ED, and it could be that men with ED have more flattening of the diurnal variation than men without ED; however, we are unaware of other data that support this.

Up to 30% of men who have an early-morning testosterone level that is low may have a normal result when testing is repeated.^2,5 Therefore, for all men who have low testosterone level test results, draw a repeat total testosterone level before 9 am to confirm the diagnosis. Also, this study did not evaluate the course of testosterone levels throughout the later afternoon and evening, and it remains unclear whether levels can be drawn even later in the day.

CHALLENGES TO IMPLEMENTATION: Your lab's policies might require early-morning draws

There will probably be few barriers to implementing this change, unless local laboratory policies are inflexible regarding the timing of testosterone draws.

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

Illustrative case

It’s noon, you are finishing up a visit with a 62-year-old man with erectile dysfunction (ED), and you want to evaluate for androgen deficiency. Should you ask him to return for an early-morning visit so you can test his testosterone level?

Increasing public awareness of androgen deficiency has led to more men being tested for testosterone levels. Current Endocrine Society guidelines recommend against routine screening for androgen deficiency in men who do not have symptoms.² However, for men with classic symptoms of androgen deficiency—such as decreased libido, ED, infertility, depression, osteoporosis, loss of secondary sexual characteristics, or reduced muscle bulk or strength—measurement of total testosterone level is recommended.²

Due to the natural diurnal variation in serum testosterone levels, the guidelines recommend collecting the sample in the early morning.² This recommendation is based on small observational studies that included men mostly younger than 45 years of age that found a significant difference in testosterone levels between samples drawn early in the morning and in the afternoon.^3-5

In recent years, several studies have indicated that this variation declines as men age.^4-6 Recently, researchers evaluated the effects of age and time of testing on men’s total testosterone levels.

STUDY SUMMARY: Differences in testosterone levels are significant only in younger men

Welliver et al¹ performed a retrospective chart review of 2569 men seen at a Minneapolis Veterans Affairs hospital for ED who had total testosterone levels measured between 7 am and 2 pm over a 15-year period. Men whose total testosterone levels were outside the normal range (>1000 or <50 ng/dL) or who had total testosterone drawn after 2 pm were excluded. The authors analyzed the results based on age, creating one group for men ages <40 years and 5-year age groups for all other men. Using scatterplot techniques, they separated each age group into 2 subgroups based on draw times—7 am to 9 am, or 9 am to 2 pm—and compared the mean total testosterone level for each age and time.

The participants’ mean age was 63 years. Younger men (<45 years) had the largest variation in serum total testosterone, with a large and significant decrease after 9 am. Only the youngest 2 groups (ages <40 and 40-44 years) showed a large decrease in total testosterone in specimens collected after 9 am compared to those drawn between 7 am and 9 am (mean difference 207 and 149 ng/dL, respectively). This variation was not observed in patients over age 45. Although there was a statistically significant difference between early and later testosterone levels in men ages 70 to 74 years, the absolute difference—34 ng/dL (452 vs 418 ng/dL)—was unlikely to be clinically significant.

WHAT'S NEW: For older men, later testing will not affect results

This study confirms previous research showing that the diurnal effect on testosterone levels becomes blunted with increasing age, at least in this group of men with ED. Allowing older men to have total testosterone levels drawn until 2 pm would allow for greater patient flexibility in draw times with little change in results.

CAVEATS: Study's methodology cannot account for several potential confounders

This retrospective study analyzed only a single random testosterone level measurement from each participant, rather than repeat testosterone levels over the course of a day. However, the study was large (2569 men) and it used mean values, which should at least partially mitigate the effect of having only a single level from each participant.

Only the youngest 2 groups (ages <40 and 40-44 years) showed a large decrease in total testosterone in specimens collected after 9 am compared to those drawn between 7 am and 9 am.

The study measured total testosterone and did not account for potential confounding factors—such as obesity or use of testosterone replacement therapy or androgen deprivation therapy—that could affect sexhormone binding globulin, thus potentially altering total testosterone level. However, the authors estimated that less than 2% of the entire cohort were likely to have unrecognized hormonal manipulation with exogenous gonadotropins.

All of the men in the study were seen for ED, and it could be that men with ED have more flattening of the diurnal variation than men without ED; however, we are unaware of other data that support this.

Up to 30% of men who have an early-morning testosterone level that is low may have a normal result when testing is repeated.^2,5 Therefore, for all men who have low testosterone level test results, draw a repeat total testosterone level before 9 am to confirm the diagnosis. Also, this study did not evaluate the course of testosterone levels throughout the later afternoon and evening, and it remains unclear whether levels can be drawn even later in the day.

CHALLENGES TO IMPLEMENTATION: Your lab's policies might require early-morning draws

There will probably be few barriers to implementing this change, unless local laboratory policies are inflexible regarding the timing of testosterone draws.

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

The United States Preventive Services Task Force (USPSTF) recently released draft recommendations on breast cancer screening, which could be finalized within the next few months.¹ The last time the Task Force (TF) weighed in on this topic was in 2009, just as the Affordable Care Act (ACA) was being debated. At that time, the TF recommendations were so controversial that Congress specified in the ACA that they should not be used to determine insurance coverage (more on this later).

The draft recommendations (TABLE 1)¹ carry a C grade for women ages 40 to 49 years (ie, offer or provide screening mammography for selected patients depending on individual circumstances) and a B grade for biennial screening of women ages 50 to 74. The proposed recommendations are basically the same as the ones made in 2009, with more detailed wording to explain the rationale for the C recommendation, and to address 2 new issues: tomosynthesis (3-D mammography) and adjunctive screening for women with dense breasts. The previous D recommendation against self breast examination was left unchanged.

Benefit of mammography screening varies by decade of life

Breast cancer is the leading cause of non-skin cancers in women and, after lung cancer, the second leading cause of cancer deaths in women. In 2014 there were 233,000 new cases diagnosed and 40,000 breast cancer deaths.^1,2 While the TF found that mammography reduces deaths from breast cancer in women between the ages of 40 and 74, women ages 40 to 49 benefit the least; those ages 60 to 69 benefit the most.^1,3

If 10,000 women are screened routinely for 10 years, 4 breast cancer deaths will be prevented in those ages 40 to 49, 8 in those 50 to 59, and 21 in those 60 to 69.¹ And harms appear to be higher in the younger age group. TABLE 2^1,3 shows some of the harms resulting from one-time mammography screening of 10,000 women in each age group. Notice the benefits listed previously are from repeated screenings over a 10-year period and the harms in TABLE 2^1,3 are from a single mammogram.

The total benefits and harms of biennial screening in 1000 women starting at age 40 (vs age 50) include 8 cancer deaths prevented (vs 7) with a cost of 1529 false positive tests (vs 953); 204 unnecessary breast biopsies (vs 146); and 20 overdiagnoses (vs 18). However, the confidence intervals on these estimates are wide, and in each case, they overlap between the 2 groups.¹

The TF recommended biennial screening for women between the ages of 50 and 74 because observational studies and modeling show no clear benefit with annual screening vs every 2 years, while annual screening results in more false positives and biopsies.

Overdiagnosis may occur in nearly 20% of cases

The potential for overdiagnosis and overtreatment is increasingly recognized as a harm of cancer screening. Overdiagnosis results from detecting a tumor during screening that would not have been detected otherwise and that would not have caused death or disease but is treated anyway. This sometimes occurs with the detection of early tumors that would not have progressed or would have progressed slowly, not causing health problems before the woman dies of other causes.

The TF is one of the only organizations that considers the potential harmful effects of this problem. While it is not possible to know for certain the rate of overdiagnosis that occurs with cancer screening, high-quality studies indicate it is close to 20% for breast cancer.³

Guidance regarding women ages 40 to 49

The new draft recommendations carefully point out that, while the overall benefit of screening women ages 40 to 49 is small, the decision to begin screening before age 50 should be an individual one, and an informed one. They state that women who value the small potential benefit over the potential for harm may choose to be screened, as might women who have a family history of breast cancer. And the recommendations do not apply to women who have a genotype that places them at increased risk for breast cancer.

Tomosynthesis: Evidence of benefit is insufficient

Tomosynthesis as a primary breast cancer screening tool was studied in a separate evidence report commissioned by the TF.⁴ While tomosynthesis, compared with routine mammography, appears to have increased sensitivity and specificity in detecting breast cancer, no studies looked at this technology as a primary screening tool and its effect on breast cancer mortality, overall mortality, and quality of life. Sticking to its nationally-recognized methodological rigor, the TF states that information at this time is insufficient to make a recommendation on the use of tomosynthesis.

Dense breasts: Usefulness of adjunctive screening modalities

Breast density is categorized into 4 groups, from category a (breasts are almost all fatty with little fibro nodular tissue) to category d (breasts are extremely dense).¹ About 43% of women ages 40 to 74 are in categories c and d.¹ Dense breasts adversely affect the accuracy of mammography, decreasing sensitivity and specificity. In one study, sensitivity was 87% in category a and 63% in category d; specificities were 97% and 89%, respectively.⁵

Tomosynthesis, magnetic resonance imaging, and ultrasound, when used in addition to mammography, all appear to detect more cancers, but they also yield more false-positive results.⁶ The long-term outcome of detecting more tumors is not known. For an individual, there are 3 possibilities when a tumor is detected earlier: a better outcome, no difference in outcome, or a worse outcome resulting from overdiagnosis and overtreatment. The TF felt that the available data are insufficient to judge benefits and harms of an increased frequency of screening or the use of adjunctive screening methods in women with dense breasts.

Benefit for women ≥75 years is inconclusive

There are limited data on the impact of mammography on outcomes for women older than 70. The TF feels that, since women ages 60 to 69 benefit the most from mammography, this benefit is likely to carry over into the next decade. Modeling also predicts this.

While mammography helps reduce breast cancer deaths, women ages 40 to 49 benefit the least; women ages 60 to 69 benefit the most.

However, women ages 70 to 74 who have chronic illnesses are unlikely to benefit from mammography. The conditions specifically mentioned are cardiovascular disease, diabetes, lung disease, liver disease, renal failure, acquired immunodeficiency syndrome, and dementia.

For all women ages 75 and older, the TF feels the evidence is insufficient to make a recommendation.

Insurance coverage

The ACA mandates that 4 sets of preventive services be included in commercial health insurance plans with no out-of-pocket expenses to the patient: immunizations recommended by the Advisory Committee on Immunization Practices; children’s preventive services recommended by the Health Resources and Services Administration (HRSA); women’s preventive services recommended by HRSA; and recommendations with an A or B rating from the USPSTF.⁷

For children, HRSA opted to use those preventive services listed by the American Academy of Pediatrics in Bright Futures, the society’s national initiative providing recommendations on prevention screenings and well-child visits.⁸ For women, HRSA asked the Institute of Medicine to form a panel to construct a list of recommended preventive services.

At the time the ACA was passed, the TF had just made new recommendations on breast cancer screening, which were very similar to the current draft recommendations. Due to the resulting controversy, Congress mandated that the new recommendations not be used to determine first-dollar insurance coverage, and it cited the TF’s pre-2009 recommendations as the applicable standard.

Those earlier recommendations included annual mammography starting at age 40. The wording of the law, however, was not clear as to future mammography recommendations. One interpretation is that the TF recommendations in place before 2009 are the basis for first-dollar coverage until changed by Congress. Another interpretation is that the ACA special provision trumped only the 2009 recommendations and the 2015 recommendations will become the standard. If the latter turns out to be true, it is not clear if commercial insurance plans will begin to charge co-payments for mammography before age 50 or for mammograms ordered more frequently than every 2 years for women ages 50 to 74.

Annual mammography screening has shown no clear benefit over screening every 2 years, and it results in more false positives and biopsies.

The issue of insurance coverage is important because of the lack of uniformity in recommendations regarding mammography. The American Congress of Obstetricians and Gynecologists,⁹ the American Cancer Society,¹⁰ and the American College of Radiology¹¹ all recommend annual mammography starting at age 40. The American Academy of Family Physicians recommendations¹² mirror those of the USPSTF, and the Canadian Task Force on Preventive Health Care recommends against routine screening for women ages 40 to 49 and recommends mammography every 2 to 3 years for women ages 50 to 74.¹³

USPSTF rationale is informed and accessible for review

Breast cancer screening remains a highly controversial and emotional topic. The USPSTF has made a set of recommendations based on extensive and rigorous evidence reports that consider both benefits and harms. There will be those who vigorously disagree. The evidence reports, recommendations, and rationale behind them are easily accessible on the TF Web site (www.uspreventiveservicestaskforce.org) for those who want to read them.¹

The United States Preventive Services Task Force (USPSTF) recently released draft recommendations on breast cancer screening, which could be finalized within the next few months.¹ The last time the Task Force (TF) weighed in on this topic was in 2009, just as the Affordable Care Act (ACA) was being debated. At that time, the TF recommendations were so controversial that Congress specified in the ACA that they should not be used to determine insurance coverage (more on this later).

The draft recommendations (TABLE 1)¹ carry a C grade for women ages 40 to 49 years (ie, offer or provide screening mammography for selected patients depending on individual circumstances) and a B grade for biennial screening of women ages 50 to 74. The proposed recommendations are basically the same as the ones made in 2009, with more detailed wording to explain the rationale for the C recommendation, and to address 2 new issues: tomosynthesis (3-D mammography) and adjunctive screening for women with dense breasts. The previous D recommendation against self breast examination was left unchanged.

Benefit of mammography screening varies by decade of life

Breast cancer is the leading cause of non-skin cancers in women and, after lung cancer, the second leading cause of cancer deaths in women. In 2014 there were 233,000 new cases diagnosed and 40,000 breast cancer deaths.^1,2 While the TF found that mammography reduces deaths from breast cancer in women between the ages of 40 and 74, women ages 40 to 49 benefit the least; those ages 60 to 69 benefit the most.^1,3

If 10,000 women are screened routinely for 10 years, 4 breast cancer deaths will be prevented in those ages 40 to 49, 8 in those 50 to 59, and 21 in those 60 to 69.¹ And harms appear to be higher in the younger age group. TABLE 2^1,3 shows some of the harms resulting from one-time mammography screening of 10,000 women in each age group. Notice the benefits listed previously are from repeated screenings over a 10-year period and the harms in TABLE 2^1,3 are from a single mammogram.

The total benefits and harms of biennial screening in 1000 women starting at age 40 (vs age 50) include 8 cancer deaths prevented (vs 7) with a cost of 1529 false positive tests (vs 953); 204 unnecessary breast biopsies (vs 146); and 20 overdiagnoses (vs 18). However, the confidence intervals on these estimates are wide, and in each case, they overlap between the 2 groups.¹

The TF recommended biennial screening for women between the ages of 50 and 74 because observational studies and modeling show no clear benefit with annual screening vs every 2 years, while annual screening results in more false positives and biopsies.

Overdiagnosis may occur in nearly 20% of cases

The potential for overdiagnosis and overtreatment is increasingly recognized as a harm of cancer screening. Overdiagnosis results from detecting a tumor during screening that would not have been detected otherwise and that would not have caused death or disease but is treated anyway. This sometimes occurs with the detection of early tumors that would not have progressed or would have progressed slowly, not causing health problems before the woman dies of other causes.

The TF is one of the only organizations that considers the potential harmful effects of this problem. While it is not possible to know for certain the rate of overdiagnosis that occurs with cancer screening, high-quality studies indicate it is close to 20% for breast cancer.³

Guidance regarding women ages 40 to 49

The new draft recommendations carefully point out that, while the overall benefit of screening women ages 40 to 49 is small, the decision to begin screening before age 50 should be an individual one, and an informed one. They state that women who value the small potential benefit over the potential for harm may choose to be screened, as might women who have a family history of breast cancer. And the recommendations do not apply to women who have a genotype that places them at increased risk for breast cancer.

Tomosynthesis: Evidence of benefit is insufficient

Tomosynthesis as a primary breast cancer screening tool was studied in a separate evidence report commissioned by the TF.⁴ While tomosynthesis, compared with routine mammography, appears to have increased sensitivity and specificity in detecting breast cancer, no studies looked at this technology as a primary screening tool and its effect on breast cancer mortality, overall mortality, and quality of life. Sticking to its nationally-recognized methodological rigor, the TF states that information at this time is insufficient to make a recommendation on the use of tomosynthesis.

Dense breasts: Usefulness of adjunctive screening modalities

Breast density is categorized into 4 groups, from category a (breasts are almost all fatty with little fibro nodular tissue) to category d (breasts are extremely dense).¹ About 43% of women ages 40 to 74 are in categories c and d.¹ Dense breasts adversely affect the accuracy of mammography, decreasing sensitivity and specificity. In one study, sensitivity was 87% in category a and 63% in category d; specificities were 97% and 89%, respectively.⁵

Tomosynthesis, magnetic resonance imaging, and ultrasound, when used in addition to mammography, all appear to detect more cancers, but they also yield more false-positive results.⁶ The long-term outcome of detecting more tumors is not known. For an individual, there are 3 possibilities when a tumor is detected earlier: a better outcome, no difference in outcome, or a worse outcome resulting from overdiagnosis and overtreatment. The TF felt that the available data are insufficient to judge benefits and harms of an increased frequency of screening or the use of adjunctive screening methods in women with dense breasts.

Benefit for women ≥75 years is inconclusive

There are limited data on the impact of mammography on outcomes for women older than 70. The TF feels that, since women ages 60 to 69 benefit the most from mammography, this benefit is likely to carry over into the next decade. Modeling also predicts this.

While mammography helps reduce breast cancer deaths, women ages 40 to 49 benefit the least; women ages 60 to 69 benefit the most.

However, women ages 70 to 74 who have chronic illnesses are unlikely to benefit from mammography. The conditions specifically mentioned are cardiovascular disease, diabetes, lung disease, liver disease, renal failure, acquired immunodeficiency syndrome, and dementia.

For all women ages 75 and older, the TF feels the evidence is insufficient to make a recommendation.

Insurance coverage

The ACA mandates that 4 sets of preventive services be included in commercial health insurance plans with no out-of-pocket expenses to the patient: immunizations recommended by the Advisory Committee on Immunization Practices; children’s preventive services recommended by the Health Resources and Services Administration (HRSA); women’s preventive services recommended by HRSA; and recommendations with an A or B rating from the USPSTF.⁷

For children, HRSA opted to use those preventive services listed by the American Academy of Pediatrics in Bright Futures, the society’s national initiative providing recommendations on prevention screenings and well-child visits.⁸ For women, HRSA asked the Institute of Medicine to form a panel to construct a list of recommended preventive services.

At the time the ACA was passed, the TF had just made new recommendations on breast cancer screening, which were very similar to the current draft recommendations. Due to the resulting controversy, Congress mandated that the new recommendations not be used to determine first-dollar insurance coverage, and it cited the TF’s pre-2009 recommendations as the applicable standard.

Those earlier recommendations included annual mammography starting at age 40. The wording of the law, however, was not clear as to future mammography recommendations. One interpretation is that the TF recommendations in place before 2009 are the basis for first-dollar coverage until changed by Congress. Another interpretation is that the ACA special provision trumped only the 2009 recommendations and the 2015 recommendations will become the standard. If the latter turns out to be true, it is not clear if commercial insurance plans will begin to charge co-payments for mammography before age 50 or for mammograms ordered more frequently than every 2 years for women ages 50 to 74.

Annual mammography screening has shown no clear benefit over screening every 2 years, and it results in more false positives and biopsies.

The issue of insurance coverage is important because of the lack of uniformity in recommendations regarding mammography. The American Congress of Obstetricians and Gynecologists,⁹ the American Cancer Society,¹⁰ and the American College of Radiology¹¹ all recommend annual mammography starting at age 40. The American Academy of Family Physicians recommendations¹² mirror those of the USPSTF, and the Canadian Task Force on Preventive Health Care recommends against routine screening for women ages 40 to 49 and recommends mammography every 2 to 3 years for women ages 50 to 74.¹³

USPSTF rationale is informed and accessible for review

Breast cancer screening remains a highly controversial and emotional topic. The USPSTF has made a set of recommendations based on extensive and rigorous evidence reports that consider both benefits and harms. There will be those who vigorously disagree. The evidence reports, recommendations, and rationale behind them are easily accessible on the TF Web site (www.uspreventiveservicestaskforce.org) for those who want to read them.¹

The United States Preventive Services Task Force (USPSTF) recently released draft recommendations on breast cancer screening, which could be finalized within the next few months.¹ The last time the Task Force (TF) weighed in on this topic was in 2009, just as the Affordable Care Act (ACA) was being debated. At that time, the TF recommendations were so controversial that Congress specified in the ACA that they should not be used to determine insurance coverage (more on this later).

The draft recommendations (TABLE 1)¹ carry a C grade for women ages 40 to 49 years (ie, offer or provide screening mammography for selected patients depending on individual circumstances) and a B grade for biennial screening of women ages 50 to 74. The proposed recommendations are basically the same as the ones made in 2009, with more detailed wording to explain the rationale for the C recommendation, and to address 2 new issues: tomosynthesis (3-D mammography) and adjunctive screening for women with dense breasts. The previous D recommendation against self breast examination was left unchanged.

Benefit of mammography screening varies by decade of life

Breast cancer is the leading cause of non-skin cancers in women and, after lung cancer, the second leading cause of cancer deaths in women. In 2014 there were 233,000 new cases diagnosed and 40,000 breast cancer deaths.^1,2 While the TF found that mammography reduces deaths from breast cancer in women between the ages of 40 and 74, women ages 40 to 49 benefit the least; those ages 60 to 69 benefit the most.^1,3

If 10,000 women are screened routinely for 10 years, 4 breast cancer deaths will be prevented in those ages 40 to 49, 8 in those 50 to 59, and 21 in those 60 to 69.¹ And harms appear to be higher in the younger age group. TABLE 2^1,3 shows some of the harms resulting from one-time mammography screening of 10,000 women in each age group. Notice the benefits listed previously are from repeated screenings over a 10-year period and the harms in TABLE 2^1,3 are from a single mammogram.

The total benefits and harms of biennial screening in 1000 women starting at age 40 (vs age 50) include 8 cancer deaths prevented (vs 7) with a cost of 1529 false positive tests (vs 953); 204 unnecessary breast biopsies (vs 146); and 20 overdiagnoses (vs 18). However, the confidence intervals on these estimates are wide, and in each case, they overlap between the 2 groups.¹

The TF recommended biennial screening for women between the ages of 50 and 74 because observational studies and modeling show no clear benefit with annual screening vs every 2 years, while annual screening results in more false positives and biopsies.

Overdiagnosis may occur in nearly 20% of cases

The potential for overdiagnosis and overtreatment is increasingly recognized as a harm of cancer screening. Overdiagnosis results from detecting a tumor during screening that would not have been detected otherwise and that would not have caused death or disease but is treated anyway. This sometimes occurs with the detection of early tumors that would not have progressed or would have progressed slowly, not causing health problems before the woman dies of other causes.

The TF is one of the only organizations that considers the potential harmful effects of this problem. While it is not possible to know for certain the rate of overdiagnosis that occurs with cancer screening, high-quality studies indicate it is close to 20% for breast cancer.³

Guidance regarding women ages 40 to 49

The new draft recommendations carefully point out that, while the overall benefit of screening women ages 40 to 49 is small, the decision to begin screening before age 50 should be an individual one, and an informed one. They state that women who value the small potential benefit over the potential for harm may choose to be screened, as might women who have a family history of breast cancer. And the recommendations do not apply to women who have a genotype that places them at increased risk for breast cancer.

Tomosynthesis: Evidence of benefit is insufficient

Tomosynthesis as a primary breast cancer screening tool was studied in a separate evidence report commissioned by the TF.⁴ While tomosynthesis, compared with routine mammography, appears to have increased sensitivity and specificity in detecting breast cancer, no studies looked at this technology as a primary screening tool and its effect on breast cancer mortality, overall mortality, and quality of life. Sticking to its nationally-recognized methodological rigor, the TF states that information at this time is insufficient to make a recommendation on the use of tomosynthesis.

Dense breasts: Usefulness of adjunctive screening modalities

Breast density is categorized into 4 groups, from category a (breasts are almost all fatty with little fibro nodular tissue) to category d (breasts are extremely dense).¹ About 43% of women ages 40 to 74 are in categories c and d.¹ Dense breasts adversely affect the accuracy of mammography, decreasing sensitivity and specificity. In one study, sensitivity was 87% in category a and 63% in category d; specificities were 97% and 89%, respectively.⁵

Tomosynthesis, magnetic resonance imaging, and ultrasound, when used in addition to mammography, all appear to detect more cancers, but they also yield more false-positive results.⁶ The long-term outcome of detecting more tumors is not known. For an individual, there are 3 possibilities when a tumor is detected earlier: a better outcome, no difference in outcome, or a worse outcome resulting from overdiagnosis and overtreatment. The TF felt that the available data are insufficient to judge benefits and harms of an increased frequency of screening or the use of adjunctive screening methods in women with dense breasts.

Benefit for women ≥75 years is inconclusive

There are limited data on the impact of mammography on outcomes for women older than 70. The TF feels that, since women ages 60 to 69 benefit the most from mammography, this benefit is likely to carry over into the next decade. Modeling also predicts this.

While mammography helps reduce breast cancer deaths, women ages 40 to 49 benefit the least; women ages 60 to 69 benefit the most.

However, women ages 70 to 74 who have chronic illnesses are unlikely to benefit from mammography. The conditions specifically mentioned are cardiovascular disease, diabetes, lung disease, liver disease, renal failure, acquired immunodeficiency syndrome, and dementia.

For all women ages 75 and older, the TF feels the evidence is insufficient to make a recommendation.

Insurance coverage

The ACA mandates that 4 sets of preventive services be included in commercial health insurance plans with no out-of-pocket expenses to the patient: immunizations recommended by the Advisory Committee on Immunization Practices; children’s preventive services recommended by the Health Resources and Services Administration (HRSA); women’s preventive services recommended by HRSA; and recommendations with an A or B rating from the USPSTF.⁷

For children, HRSA opted to use those preventive services listed by the American Academy of Pediatrics in Bright Futures, the society’s national initiative providing recommendations on prevention screenings and well-child visits.⁸ For women, HRSA asked the Institute of Medicine to form a panel to construct a list of recommended preventive services.

At the time the ACA was passed, the TF had just made new recommendations on breast cancer screening, which were very similar to the current draft recommendations. Due to the resulting controversy, Congress mandated that the new recommendations not be used to determine first-dollar insurance coverage, and it cited the TF’s pre-2009 recommendations as the applicable standard.

Those earlier recommendations included annual mammography starting at age 40. The wording of the law, however, was not clear as to future mammography recommendations. One interpretation is that the TF recommendations in place before 2009 are the basis for first-dollar coverage until changed by Congress. Another interpretation is that the ACA special provision trumped only the 2009 recommendations and the 2015 recommendations will become the standard. If the latter turns out to be true, it is not clear if commercial insurance plans will begin to charge co-payments for mammography before age 50 or for mammograms ordered more frequently than every 2 years for women ages 50 to 74.

Annual mammography screening has shown no clear benefit over screening every 2 years, and it results in more false positives and biopsies.

The issue of insurance coverage is important because of the lack of uniformity in recommendations regarding mammography. The American Congress of Obstetricians and Gynecologists,⁹ the American Cancer Society,¹⁰ and the American College of Radiology¹¹ all recommend annual mammography starting at age 40. The American Academy of Family Physicians recommendations¹² mirror those of the USPSTF, and the Canadian Task Force on Preventive Health Care recommends against routine screening for women ages 40 to 49 and recommends mammography every 2 to 3 years for women ages 50 to 74.¹³

USPSTF rationale is informed and accessible for review

Breast cancer screening remains a highly controversial and emotional topic. The USPSTF has made a set of recommendations based on extensive and rigorous evidence reports that consider both benefits and harms. There will be those who vigorously disagree. The evidence reports, recommendations, and rationale behind them are easily accessible on the TF Web site (www.uspreventiveservicestaskforce.org) for those who want to read them.¹

CASE › A 54-year-old man’s lab results following a routine annual examination reveal a level of IgM M-protein just under 1.5 g/dL. All other lab values, including free light chain (FLC) ratio and bone marrow exam, are normal. No clinical evidence of a related disorder is found. What is the risk that this patient’s condition could progress toward multiple myeloma, and how would you follow up?

The patient with a monoclonal gammopathy has an abnormal proliferation of monoclonal plasma cells that secrete an immunoglobulin, M-protein. This proliferation occurs most often in the bone marrow but can also be found in extra-medullary body tissue. The condition can begin insidiously, remain stable, or progress to frank malignancy causing bone and end-organ destruction. The major challenge is to separate stable, asymptomatic patients who require no treatment from patients with progressive, symptomatic myeloma who require immediate treatment.

Risk for MGUS progression increases markedly with a serum M-protein concentration ≥1.5 g/dL, a non-IgG isotype, or an abnormal serum FLC ratio (<0.26 or >1.65).

An increased, measurable level of serum monoclonal immunoglobulins or FLCs is called monoclonal gammopathy of undetermined significance (MGUS) when there is <3 g/dL monoclonal protein in the serum, <10% monoclonal plasma cells in the bone marrow, and an absence of beta-cell proliferative disorders, lytic bone lesions, anemia, hypercalcemia, or renal insufficiency (TABLE 1).^1,2 Serum and marrow measurements exceeding these values indicate progression of disease to a premalignancy stage. Continued proliferation of plasma cells in the bone marrow results in anemia and bone destruction, while the increase in M-protein leads to end-organ destruction. This final malignant state is multiple myeloma (MM).

Detailed classification of MGUS: A roadmap for monitoring patients

Extensive epidemiologic and clinical studies have refined the classification of MGUS^3-5 and related disorders (TABLES 2-4),³ providing physicians with guidance on how to monitor patients. There are 3 kinds of monoclonal gammopathies, each reflecting a particular type of immunoglobulin involvement—non-IgM, IgM, or light chain. Additionally, within each type of gammopathy, patient-specific characteristics determine 3 categories of clinical significance: premalignancy with low risk of progression (1%-2% per year³); premalignancy with high risk of progression (10% per year³); and malignancy.

Non-IgM MGUS with a high risk of progression is designated smoldering multiple myeloma (SMM) (TABLE 2).³ IgM MGUS with a high risk of progression is defined as smoldering Waldenström macroglobulinemia (SWM), with a predisposition to progress to Waldenström macroglobulinemia (WM) and, rarely, to IgM MM (TABLE 3).³

More recently, it has been reported that approximately 20% of the cases of MM belong to a new entity called light-chain MM that features an absence of heavy chain (IgG, IgA, IgM, IgD, or IgE) secretion in serum.⁶ The premalignant precursor is light-chain MGUS (LC-MGUS). The criteria for LC-MGUS and idiopathic Bence Jones proteinuria are found in TABLE 4.³ Idiopathic Bence Jones proteinuria is equivalent to SMM and SWM due to its higher risk of progression (10%/year)³ to light-chain MM.

Prevalence of MGUS

In general, the prevalence of all types of MGUS increases with age and is affected by race, sex, family history, immunosuppression, and pesticide exposure. The Caucasian American population >50 years exhibits a prevalence of MGUS of approximately 3.2%;⁷ the African American population exhibits a significantly higher prevalence of 5.9% to 8.4%.⁷ Native Asians have a lower rate of MM, and, as expected, a lower MGUS prevalence than is seen in the Western population (Thailand ≈2.3%;⁸ Korea ≈3.3%;⁹ Japan ≈2.1%;¹⁰ China ≈0.8%¹¹). The overall prevalence of the 3 types of MGUS is 4.2% in Caucasians.⁶

Distinguishing stable from progressive disease

The Mayo Clinic’s risk stratification model¹² further specifies risk of disease progression based on 3 indicators: serum M-protein concentration, Ig isotype of M-protein, and serum FLC ratio.

MGUS. A marked increase in risk for disease progression is associated with a serum M-protein concentration ≥1.5 g/dL, a non-IgG isotype, or an abnormal serum FLC ratio (<0.26 or >1.65, reflecting an increase in either the kappa or lambda light chain).¹² An MGUS patient exhibiting all 3 of these features has a 58% absolute risk of developing MM after 20 years of follow-up. A patient with 2 of the 3 abnormalities has a 37% risk of progressing to MM, and one who has just one abnormality has a 21% risk. In contrast, an MGUS patient who has an M-protein level <1.5 g/dL, an IgG isotype, and normal FLC range has only a 5% risk of progression to MM in the same 20 years.¹²

The Spanish Group risk stratification model¹³ is based on 2 risk factors: a high proportion of abnormal plasma cells (aPC) within the bone marrow plasma cell (BMPC) compartment (ie, ≥95% CD56+/CD19-); and an evolving subtype of the disease (defined as an increase in the level of serum M-protein by at least 10% during the first 6 months of follow-up, or a progressive and constant increase of the M-protein until overt MM develops). The 7-year cumulative probability of progression of MGUS to MM: 2% for patients with neither risk factor, 16% with one risk factor, and 72% with both risk factors.¹³

SMM. Classification of this progressive state is defined by a serum level of monoclonal protein (IgG, IgA, IgD, or IgE) ≥3 g/dL or a concentration of clonal bone marrow plasma cells ≥10%; and by an absence of end-organ damage such as hypercalcemia, renal insufficiency, anemia, and bone lesions (CRAB) that can be attributed to a plasma cell proliferative disorder (TABLE 2).³ Both laboratory and clinical criteria must be met.

According to the Mayo Clinic risk stratification model, likelihood of progression reflects combinations of 3 factors: bone marrow plasmacytosis ≥10%, a serum M-protein level ≥3 g/dL, and a serum FLC ratio ≤0.125 or ≥8.¹⁴ Using this stratification scheme, the risk over 10 years of progressing from SMM to MM is 84% for those with all 3 risk factors, 65% with 2 factors, and 52% with one factor.¹⁴ As SMM is defined, there is no upper limit of bone marrow involvement. However, Rajkumar et al¹⁵ found that progression time was significantly shorter (P<.001) among patients with ≥60% bone marrow involvement, compared with those having <60% involvement.

The Spanish Group risk stratification model¹³ uses the same model applied to MGUS: a proportion of abnormal plasma cells in the BMPC compartment ≥95% CD56+/CD19-; and an evolving subtype of disease. The 3-year cumulative probability of progression of SMM to MM is 46% for those with both risk factors, 12% for those with one factor, and <1% for those with no risk factors.¹³

LC-MGUS. The classification of LC-MGUS (TABLE 4)³ is primarily from a Mayo Clinic study⁶ and research on risk stratification is underway at 2 other institutions. False-positive results are possible in patients with renal¹⁶ and inflammatory¹⁷ disorders.

Applying risk stratification to patient management

The current approach to a patient with clearly defined MGUS is a prudent “watch and wait” strategy that specifies monitoring details based on risk category (ALGORITHM).^1,18

MGUS. In the low-risk MGUS group (IgG subtype, M-protein <1.5 g/dL, and normal FLC ratio)³ there is no need for bone marrow examination or skeletal radiography. Repeat the serum protein electrophoresis (SPE) in 6 months, and if there is no significant elevation of M-protein, repeat the SPE every 2 to 3 years.^1,19,20 However, if other findings are suggestive of plasma cell malignancy (anemia, renal insufficiency, hypercalcemia, or bone lesions), bone marrow examination and computed tomographic (CT) scan are advised. Further evaluation of an incidental detection of MGUS is also important since it is occasionally associated with bone diseases,²¹ arterial and venous thrombosis,²² and an increased risk (P<.05) of developing bacterial (pneumonia, osteomyelitis, septicemia, pyelonephritis, cellulitis, endocarditis, and meningitis) and viral (influenza and herpes zoster) infections.²³

Patients in the intermediate- and high-risk MGUS groups with serum monoclonal protein ≥1.5 g/dL, IgA or IgM subtype or an abnormal FLC ratio should undergo tests for CRAB and have bone marrow aspirate and biopsy with cytogenetics, flow cytometry, and fluorescence in situ hybridization (FISH). Patients with IgM MGUS should also undergo a CT scan of the abdomen to rule out the presence of asymptomatic retroperitoneal lymph nodes.^1,19 If the BM examination and CT scan yield negative results, repeat SPE and complete blood count (CBC) after 6 months and annually thereafter for life. IgD or IgE MGUS is rare, and patients exhibit a progression similar to the 20-year risk seen with MGUS generally.

SMM. Given the increased risk of progression from SMM to MM compared with MGUS (all risk groups), the 2010 International Myeloma Working Group (IMWG) has suggested monitoring SMM patients more frequently—ie, SPE every 2 to 3 months in the first year following diagnosis.¹ Repeat SPE in the second year every 4 to 6 months, and, if results are clinically stable, every 6 to 12 months thereafter. In addition to a baseline bone marrow examination (including cytogenetics, flow cytometry, and FISH studies), consider ordering magnetic resonance imaging of the spine and pelvis to detect occult lesions, as their presence predicts a more rapid progression to MM.²⁴ During the course of the follow-up, evaluate any unexplained anemia or renal function impairment for its origin. A report of MGUS progression over more than a decade to SMM and then to MM illustrates prudent monitoring of a patient.²⁵

LC-MGUS. Once LC-MGUS is detected, first rule out AL-amyloidosis, light-chain deposition disease, or cast nephropathy. If no malignant state is present, repeat the FLC serum assay every 6 months with renal function tests. Idiopathic Bence Jones proteinuria and LC-MGUS have some overlap and both entities put patients at risk for developing MM or amyloidosis. It is not uncommon for MGUS to be accompanied by Bence Jones proteinuria.

Likelihood of SMM progression varies with the combination of 3 factors: bone marrow plasmacytosis ≥10%, a serum M-protein level ≥3 g/dL, and a serum FLC ratio ≤0.125 or ≥8.

In addition to a thorough history and physical examination, recommended followup for both of these entities includes CBC, creatinine, serum FLC, and 24-hour urine protein electrophoresis.⁶ With idiopathic Bence Jones proteinuria, a monoclonal protein evident on urine protein electrophoresis at >500 mg/24 hr must be followed up with tests for other signs of malignancy (CRAB) and BM examination to exclude the possibility of MM.⁶

Treatment of MGUS to prevent progression

Multiple myeloma is still an incurable disease. Since MGUS is a precursor of MM, attempts have been made to either slow its progression or eradicate it. Several independent intervention studies²⁶ for the precursor diseases MGUS and SMM have been conducted or are ongoing. Thus far, no conclusive preventive treatment has been found and the 2010 IMWG guidelines do not recommend preventive therapy for MGUS and SMM patients by means of any drug, unless it is a part of a clinical trial.¹

CASE › The patient profiled at the start of this article has one abnormal risk factor (IgM isotype) and has a low risk of progression to MM. Management should follow the steps outlined in the ALGORITHM^1,18 for low-risk IgM MGUS: repeat SPE, CBC, and CT scan in 6 months and annually thereafter. If any abnormality is observed, rule out the possibilities of IgM SWM, IgM WM, or rapid progression to MM, and consider referral to an oncologist.

CORRESPONDENCE
John M. Boltri, MD, Department of Family and Community Medicine, Northeast Ohio Medical University, College of Medicine, 4209 St. Rt. 44, PO Box 95, Rootstown, Ohio 44272; jboltri@neomed.edu.

ACKNOWLEDGEMENTS
The authors thank Kenneth F. Tucker, MD (Webber Cancer Center, St John Macomb-Oakland Hospital, Warren, Mich) and Elizabeth Sykes, MD (Professor, Oakland University, William Beaumont School of Medicine, Rochester, Mich) for their review of this article.

CASE › A 54-year-old man’s lab results following a routine annual examination reveal a level of IgM M-protein just under 1.5 g/dL. All other lab values, including free light chain (FLC) ratio and bone marrow exam, are normal. No clinical evidence of a related disorder is found. What is the risk that this patient’s condition could progress toward multiple myeloma, and how would you follow up?

The patient with a monoclonal gammopathy has an abnormal proliferation of monoclonal plasma cells that secrete an immunoglobulin, M-protein. This proliferation occurs most often in the bone marrow but can also be found in extra-medullary body tissue. The condition can begin insidiously, remain stable, or progress to frank malignancy causing bone and end-organ destruction. The major challenge is to separate stable, asymptomatic patients who require no treatment from patients with progressive, symptomatic myeloma who require immediate treatment.

Risk for MGUS progression increases markedly with a serum M-protein concentration ≥1.5 g/dL, a non-IgG isotype, or an abnormal serum FLC ratio (<0.26 or >1.65).

An increased, measurable level of serum monoclonal immunoglobulins or FLCs is called monoclonal gammopathy of undetermined significance (MGUS) when there is <3 g/dL monoclonal protein in the serum, <10% monoclonal plasma cells in the bone marrow, and an absence of beta-cell proliferative disorders, lytic bone lesions, anemia, hypercalcemia, or renal insufficiency (TABLE 1).^1,2 Serum and marrow measurements exceeding these values indicate progression of disease to a premalignancy stage. Continued proliferation of plasma cells in the bone marrow results in anemia and bone destruction, while the increase in M-protein leads to end-organ destruction. This final malignant state is multiple myeloma (MM).

Detailed classification of MGUS: A roadmap for monitoring patients

Extensive epidemiologic and clinical studies have refined the classification of MGUS^3-5 and related disorders (TABLES 2-4),³ providing physicians with guidance on how to monitor patients. There are 3 kinds of monoclonal gammopathies, each reflecting a particular type of immunoglobulin involvement—non-IgM, IgM, or light chain. Additionally, within each type of gammopathy, patient-specific characteristics determine 3 categories of clinical significance: premalignancy with low risk of progression (1%-2% per year³); premalignancy with high risk of progression (10% per year³); and malignancy.

Non-IgM MGUS with a high risk of progression is designated smoldering multiple myeloma (SMM) (TABLE 2).³ IgM MGUS with a high risk of progression is defined as smoldering Waldenström macroglobulinemia (SWM), with a predisposition to progress to Waldenström macroglobulinemia (WM) and, rarely, to IgM MM (TABLE 3).³

More recently, it has been reported that approximately 20% of the cases of MM belong to a new entity called light-chain MM that features an absence of heavy chain (IgG, IgA, IgM, IgD, or IgE) secretion in serum.⁶ The premalignant precursor is light-chain MGUS (LC-MGUS). The criteria for LC-MGUS and idiopathic Bence Jones proteinuria are found in TABLE 4.³ Idiopathic Bence Jones proteinuria is equivalent to SMM and SWM due to its higher risk of progression (10%/year)³ to light-chain MM.

Prevalence of MGUS

In general, the prevalence of all types of MGUS increases with age and is affected by race, sex, family history, immunosuppression, and pesticide exposure. The Caucasian American population >50 years exhibits a prevalence of MGUS of approximately 3.2%;⁷ the African American population exhibits a significantly higher prevalence of 5.9% to 8.4%.⁷ Native Asians have a lower rate of MM, and, as expected, a lower MGUS prevalence than is seen in the Western population (Thailand ≈2.3%;⁸ Korea ≈3.3%;⁹ Japan ≈2.1%;¹⁰ China ≈0.8%¹¹). The overall prevalence of the 3 types of MGUS is 4.2% in Caucasians.⁶

Distinguishing stable from progressive disease

The Mayo Clinic’s risk stratification model¹² further specifies risk of disease progression based on 3 indicators: serum M-protein concentration, Ig isotype of M-protein, and serum FLC ratio.

MGUS. A marked increase in risk for disease progression is associated with a serum M-protein concentration ≥1.5 g/dL, a non-IgG isotype, or an abnormal serum FLC ratio (<0.26 or >1.65, reflecting an increase in either the kappa or lambda light chain).¹² An MGUS patient exhibiting all 3 of these features has a 58% absolute risk of developing MM after 20 years of follow-up. A patient with 2 of the 3 abnormalities has a 37% risk of progressing to MM, and one who has just one abnormality has a 21% risk. In contrast, an MGUS patient who has an M-protein level <1.5 g/dL, an IgG isotype, and normal FLC range has only a 5% risk of progression to MM in the same 20 years.¹²

The Spanish Group risk stratification model¹³ is based on 2 risk factors: a high proportion of abnormal plasma cells (aPC) within the bone marrow plasma cell (BMPC) compartment (ie, ≥95% CD56+/CD19-); and an evolving subtype of the disease (defined as an increase in the level of serum M-protein by at least 10% during the first 6 months of follow-up, or a progressive and constant increase of the M-protein until overt MM develops). The 7-year cumulative probability of progression of MGUS to MM: 2% for patients with neither risk factor, 16% with one risk factor, and 72% with both risk factors.¹³

SMM. Classification of this progressive state is defined by a serum level of monoclonal protein (IgG, IgA, IgD, or IgE) ≥3 g/dL or a concentration of clonal bone marrow plasma cells ≥10%; and by an absence of end-organ damage such as hypercalcemia, renal insufficiency, anemia, and bone lesions (CRAB) that can be attributed to a plasma cell proliferative disorder (TABLE 2).³ Both laboratory and clinical criteria must be met.

According to the Mayo Clinic risk stratification model, likelihood of progression reflects combinations of 3 factors: bone marrow plasmacytosis ≥10%, a serum M-protein level ≥3 g/dL, and a serum FLC ratio ≤0.125 or ≥8.¹⁴ Using this stratification scheme, the risk over 10 years of progressing from SMM to MM is 84% for those with all 3 risk factors, 65% with 2 factors, and 52% with one factor.¹⁴ As SMM is defined, there is no upper limit of bone marrow involvement. However, Rajkumar et al¹⁵ found that progression time was significantly shorter (P<.001) among patients with ≥60% bone marrow involvement, compared with those having <60% involvement.

The Spanish Group risk stratification model¹³ uses the same model applied to MGUS: a proportion of abnormal plasma cells in the BMPC compartment ≥95% CD56+/CD19-; and an evolving subtype of disease. The 3-year cumulative probability of progression of SMM to MM is 46% for those with both risk factors, 12% for those with one factor, and <1% for those with no risk factors.¹³

LC-MGUS. The classification of LC-MGUS (TABLE 4)³ is primarily from a Mayo Clinic study⁶ and research on risk stratification is underway at 2 other institutions. False-positive results are possible in patients with renal¹⁶ and inflammatory¹⁷ disorders.

Applying risk stratification to patient management

The current approach to a patient with clearly defined MGUS is a prudent “watch and wait” strategy that specifies monitoring details based on risk category (ALGORITHM).^1,18

MGUS. In the low-risk MGUS group (IgG subtype, M-protein <1.5 g/dL, and normal FLC ratio)³ there is no need for bone marrow examination or skeletal radiography. Repeat the serum protein electrophoresis (SPE) in 6 months, and if there is no significant elevation of M-protein, repeat the SPE every 2 to 3 years.^1,19,20 However, if other findings are suggestive of plasma cell malignancy (anemia, renal insufficiency, hypercalcemia, or bone lesions), bone marrow examination and computed tomographic (CT) scan are advised. Further evaluation of an incidental detection of MGUS is also important since it is occasionally associated with bone diseases,²¹ arterial and venous thrombosis,²² and an increased risk (P<.05) of developing bacterial (pneumonia, osteomyelitis, septicemia, pyelonephritis, cellulitis, endocarditis, and meningitis) and viral (influenza and herpes zoster) infections.²³

Patients in the intermediate- and high-risk MGUS groups with serum monoclonal protein ≥1.5 g/dL, IgA or IgM subtype or an abnormal FLC ratio should undergo tests for CRAB and have bone marrow aspirate and biopsy with cytogenetics, flow cytometry, and fluorescence in situ hybridization (FISH). Patients with IgM MGUS should also undergo a CT scan of the abdomen to rule out the presence of asymptomatic retroperitoneal lymph nodes.^1,19 If the BM examination and CT scan yield negative results, repeat SPE and complete blood count (CBC) after 6 months and annually thereafter for life. IgD or IgE MGUS is rare, and patients exhibit a progression similar to the 20-year risk seen with MGUS generally.

SMM. Given the increased risk of progression from SMM to MM compared with MGUS (all risk groups), the 2010 International Myeloma Working Group (IMWG) has suggested monitoring SMM patients more frequently—ie, SPE every 2 to 3 months in the first year following diagnosis.¹ Repeat SPE in the second year every 4 to 6 months, and, if results are clinically stable, every 6 to 12 months thereafter. In addition to a baseline bone marrow examination (including cytogenetics, flow cytometry, and FISH studies), consider ordering magnetic resonance imaging of the spine and pelvis to detect occult lesions, as their presence predicts a more rapid progression to MM.²⁴ During the course of the follow-up, evaluate any unexplained anemia or renal function impairment for its origin. A report of MGUS progression over more than a decade to SMM and then to MM illustrates prudent monitoring of a patient.²⁵

LC-MGUS. Once LC-MGUS is detected, first rule out AL-amyloidosis, light-chain deposition disease, or cast nephropathy. If no malignant state is present, repeat the FLC serum assay every 6 months with renal function tests. Idiopathic Bence Jones proteinuria and LC-MGUS have some overlap and both entities put patients at risk for developing MM or amyloidosis. It is not uncommon for MGUS to be accompanied by Bence Jones proteinuria.

Likelihood of SMM progression varies with the combination of 3 factors: bone marrow plasmacytosis ≥10%, a serum M-protein level ≥3 g/dL, and a serum FLC ratio ≤0.125 or ≥8.

In addition to a thorough history and physical examination, recommended followup for both of these entities includes CBC, creatinine, serum FLC, and 24-hour urine protein electrophoresis.⁶ With idiopathic Bence Jones proteinuria, a monoclonal protein evident on urine protein electrophoresis at >500 mg/24 hr must be followed up with tests for other signs of malignancy (CRAB) and BM examination to exclude the possibility of MM.⁶

Treatment of MGUS to prevent progression

Multiple myeloma is still an incurable disease. Since MGUS is a precursor of MM, attempts have been made to either slow its progression or eradicate it. Several independent intervention studies²⁶ for the precursor diseases MGUS and SMM have been conducted or are ongoing. Thus far, no conclusive preventive treatment has been found and the 2010 IMWG guidelines do not recommend preventive therapy for MGUS and SMM patients by means of any drug, unless it is a part of a clinical trial.¹

CASE › The patient profiled at the start of this article has one abnormal risk factor (IgM isotype) and has a low risk of progression to MM. Management should follow the steps outlined in the ALGORITHM^1,18 for low-risk IgM MGUS: repeat SPE, CBC, and CT scan in 6 months and annually thereafter. If any abnormality is observed, rule out the possibilities of IgM SWM, IgM WM, or rapid progression to MM, and consider referral to an oncologist.

CORRESPONDENCE
John M. Boltri, MD, Department of Family and Community Medicine, Northeast Ohio Medical University, College of Medicine, 4209 St. Rt. 44, PO Box 95, Rootstown, Ohio 44272; jboltri@neomed.edu.

ACKNOWLEDGEMENTS
The authors thank Kenneth F. Tucker, MD (Webber Cancer Center, St John Macomb-Oakland Hospital, Warren, Mich) and Elizabeth Sykes, MD (Professor, Oakland University, William Beaumont School of Medicine, Rochester, Mich) for their review of this article.

CASE › A 54-year-old man’s lab results following a routine annual examination reveal a level of IgM M-protein just under 1.5 g/dL. All other lab values, including free light chain (FLC) ratio and bone marrow exam, are normal. No clinical evidence of a related disorder is found. What is the risk that this patient’s condition could progress toward multiple myeloma, and how would you follow up?

The patient with a monoclonal gammopathy has an abnormal proliferation of monoclonal plasma cells that secrete an immunoglobulin, M-protein. This proliferation occurs most often in the bone marrow but can also be found in extra-medullary body tissue. The condition can begin insidiously, remain stable, or progress to frank malignancy causing bone and end-organ destruction. The major challenge is to separate stable, asymptomatic patients who require no treatment from patients with progressive, symptomatic myeloma who require immediate treatment.

Risk for MGUS progression increases markedly with a serum M-protein concentration ≥1.5 g/dL, a non-IgG isotype, or an abnormal serum FLC ratio (<0.26 or >1.65).

An increased, measurable level of serum monoclonal immunoglobulins or FLCs is called monoclonal gammopathy of undetermined significance (MGUS) when there is <3 g/dL monoclonal protein in the serum, <10% monoclonal plasma cells in the bone marrow, and an absence of beta-cell proliferative disorders, lytic bone lesions, anemia, hypercalcemia, or renal insufficiency (TABLE 1).^1,2 Serum and marrow measurements exceeding these values indicate progression of disease to a premalignancy stage. Continued proliferation of plasma cells in the bone marrow results in anemia and bone destruction, while the increase in M-protein leads to end-organ destruction. This final malignant state is multiple myeloma (MM).

Detailed classification of MGUS: A roadmap for monitoring patients

Extensive epidemiologic and clinical studies have refined the classification of MGUS^3-5 and related disorders (TABLES 2-4),³ providing physicians with guidance on how to monitor patients. There are 3 kinds of monoclonal gammopathies, each reflecting a particular type of immunoglobulin involvement—non-IgM, IgM, or light chain. Additionally, within each type of gammopathy, patient-specific characteristics determine 3 categories of clinical significance: premalignancy with low risk of progression (1%-2% per year³); premalignancy with high risk of progression (10% per year³); and malignancy.

Non-IgM MGUS with a high risk of progression is designated smoldering multiple myeloma (SMM) (TABLE 2).³ IgM MGUS with a high risk of progression is defined as smoldering Waldenström macroglobulinemia (SWM), with a predisposition to progress to Waldenström macroglobulinemia (WM) and, rarely, to IgM MM (TABLE 3).³

More recently, it has been reported that approximately 20% of the cases of MM belong to a new entity called light-chain MM that features an absence of heavy chain (IgG, IgA, IgM, IgD, or IgE) secretion in serum.⁶ The premalignant precursor is light-chain MGUS (LC-MGUS). The criteria for LC-MGUS and idiopathic Bence Jones proteinuria are found in TABLE 4.³ Idiopathic Bence Jones proteinuria is equivalent to SMM and SWM due to its higher risk of progression (10%/year)³ to light-chain MM.

Prevalence of MGUS

In general, the prevalence of all types of MGUS increases with age and is affected by race, sex, family history, immunosuppression, and pesticide exposure. The Caucasian American population >50 years exhibits a prevalence of MGUS of approximately 3.2%;⁷ the African American population exhibits a significantly higher prevalence of 5.9% to 8.4%.⁷ Native Asians have a lower rate of MM, and, as expected, a lower MGUS prevalence than is seen in the Western population (Thailand ≈2.3%;⁸ Korea ≈3.3%;⁹ Japan ≈2.1%;¹⁰ China ≈0.8%¹¹). The overall prevalence of the 3 types of MGUS is 4.2% in Caucasians.⁶

Distinguishing stable from progressive disease

The Mayo Clinic’s risk stratification model¹² further specifies risk of disease progression based on 3 indicators: serum M-protein concentration, Ig isotype of M-protein, and serum FLC ratio.

MGUS. A marked increase in risk for disease progression is associated with a serum M-protein concentration ≥1.5 g/dL, a non-IgG isotype, or an abnormal serum FLC ratio (<0.26 or >1.65, reflecting an increase in either the kappa or lambda light chain).¹² An MGUS patient exhibiting all 3 of these features has a 58% absolute risk of developing MM after 20 years of follow-up. A patient with 2 of the 3 abnormalities has a 37% risk of progressing to MM, and one who has just one abnormality has a 21% risk. In contrast, an MGUS patient who has an M-protein level <1.5 g/dL, an IgG isotype, and normal FLC range has only a 5% risk of progression to MM in the same 20 years.¹²

The Spanish Group risk stratification model¹³ is based on 2 risk factors: a high proportion of abnormal plasma cells (aPC) within the bone marrow plasma cell (BMPC) compartment (ie, ≥95% CD56+/CD19-); and an evolving subtype of the disease (defined as an increase in the level of serum M-protein by at least 10% during the first 6 months of follow-up, or a progressive and constant increase of the M-protein until overt MM develops). The 7-year cumulative probability of progression of MGUS to MM: 2% for patients with neither risk factor, 16% with one risk factor, and 72% with both risk factors.¹³

SMM. Classification of this progressive state is defined by a serum level of monoclonal protein (IgG, IgA, IgD, or IgE) ≥3 g/dL or a concentration of clonal bone marrow plasma cells ≥10%; and by an absence of end-organ damage such as hypercalcemia, renal insufficiency, anemia, and bone lesions (CRAB) that can be attributed to a plasma cell proliferative disorder (TABLE 2).³ Both laboratory and clinical criteria must be met.

According to the Mayo Clinic risk stratification model, likelihood of progression reflects combinations of 3 factors: bone marrow plasmacytosis ≥10%, a serum M-protein level ≥3 g/dL, and a serum FLC ratio ≤0.125 or ≥8.¹⁴ Using this stratification scheme, the risk over 10 years of progressing from SMM to MM is 84% for those with all 3 risk factors, 65% with 2 factors, and 52% with one factor.¹⁴ As SMM is defined, there is no upper limit of bone marrow involvement. However, Rajkumar et al¹⁵ found that progression time was significantly shorter (P<.001) among patients with ≥60% bone marrow involvement, compared with those having <60% involvement.

The Spanish Group risk stratification model¹³ uses the same model applied to MGUS: a proportion of abnormal plasma cells in the BMPC compartment ≥95% CD56+/CD19-; and an evolving subtype of disease. The 3-year cumulative probability of progression of SMM to MM is 46% for those with both risk factors, 12% for those with one factor, and <1% for those with no risk factors.¹³

LC-MGUS. The classification of LC-MGUS (TABLE 4)³ is primarily from a Mayo Clinic study⁶ and research on risk stratification is underway at 2 other institutions. False-positive results are possible in patients with renal¹⁶ and inflammatory¹⁷ disorders.

Applying risk stratification to patient management

The current approach to a patient with clearly defined MGUS is a prudent “watch and wait” strategy that specifies monitoring details based on risk category (ALGORITHM).^1,18

MGUS. In the low-risk MGUS group (IgG subtype, M-protein <1.5 g/dL, and normal FLC ratio)³ there is no need for bone marrow examination or skeletal radiography. Repeat the serum protein electrophoresis (SPE) in 6 months, and if there is no significant elevation of M-protein, repeat the SPE every 2 to 3 years.^1,19,20 However, if other findings are suggestive of plasma cell malignancy (anemia, renal insufficiency, hypercalcemia, or bone lesions), bone marrow examination and computed tomographic (CT) scan are advised. Further evaluation of an incidental detection of MGUS is also important since it is occasionally associated with bone diseases,²¹ arterial and venous thrombosis,²² and an increased risk (P<.05) of developing bacterial (pneumonia, osteomyelitis, septicemia, pyelonephritis, cellulitis, endocarditis, and meningitis) and viral (influenza and herpes zoster) infections.²³

Patients in the intermediate- and high-risk MGUS groups with serum monoclonal protein ≥1.5 g/dL, IgA or IgM subtype or an abnormal FLC ratio should undergo tests for CRAB and have bone marrow aspirate and biopsy with cytogenetics, flow cytometry, and fluorescence in situ hybridization (FISH). Patients with IgM MGUS should also undergo a CT scan of the abdomen to rule out the presence of asymptomatic retroperitoneal lymph nodes.^1,19 If the BM examination and CT scan yield negative results, repeat SPE and complete blood count (CBC) after 6 months and annually thereafter for life. IgD or IgE MGUS is rare, and patients exhibit a progression similar to the 20-year risk seen with MGUS generally.

SMM. Given the increased risk of progression from SMM to MM compared with MGUS (all risk groups), the 2010 International Myeloma Working Group (IMWG) has suggested monitoring SMM patients more frequently—ie, SPE every 2 to 3 months in the first year following diagnosis.¹ Repeat SPE in the second year every 4 to 6 months, and, if results are clinically stable, every 6 to 12 months thereafter. In addition to a baseline bone marrow examination (including cytogenetics, flow cytometry, and FISH studies), consider ordering magnetic resonance imaging of the spine and pelvis to detect occult lesions, as their presence predicts a more rapid progression to MM.²⁴ During the course of the follow-up, evaluate any unexplained anemia or renal function impairment for its origin. A report of MGUS progression over more than a decade to SMM and then to MM illustrates prudent monitoring of a patient.²⁵

LC-MGUS. Once LC-MGUS is detected, first rule out AL-amyloidosis, light-chain deposition disease, or cast nephropathy. If no malignant state is present, repeat the FLC serum assay every 6 months with renal function tests. Idiopathic Bence Jones proteinuria and LC-MGUS have some overlap and both entities put patients at risk for developing MM or amyloidosis. It is not uncommon for MGUS to be accompanied by Bence Jones proteinuria.

Likelihood of SMM progression varies with the combination of 3 factors: bone marrow plasmacytosis ≥10%, a serum M-protein level ≥3 g/dL, and a serum FLC ratio ≤0.125 or ≥8.

In addition to a thorough history and physical examination, recommended followup for both of these entities includes CBC, creatinine, serum FLC, and 24-hour urine protein electrophoresis.⁶ With idiopathic Bence Jones proteinuria, a monoclonal protein evident on urine protein electrophoresis at >500 mg/24 hr must be followed up with tests for other signs of malignancy (CRAB) and BM examination to exclude the possibility of MM.⁶

Treatment of MGUS to prevent progression

Multiple myeloma is still an incurable disease. Since MGUS is a precursor of MM, attempts have been made to either slow its progression or eradicate it. Several independent intervention studies²⁶ for the precursor diseases MGUS and SMM have been conducted or are ongoing. Thus far, no conclusive preventive treatment has been found and the 2010 IMWG guidelines do not recommend preventive therapy for MGUS and SMM patients by means of any drug, unless it is a part of a clinical trial.¹

CASE › The patient profiled at the start of this article has one abnormal risk factor (IgM isotype) and has a low risk of progression to MM. Management should follow the steps outlined in the ALGORITHM^1,18 for low-risk IgM MGUS: repeat SPE, CBC, and CT scan in 6 months and annually thereafter. If any abnormality is observed, rule out the possibilities of IgM SWM, IgM WM, or rapid progression to MM, and consider referral to an oncologist.

CORRESPONDENCE
John M. Boltri, MD, Department of Family and Community Medicine, Northeast Ohio Medical University, College of Medicine, 4209 St. Rt. 44, PO Box 95, Rootstown, Ohio 44272; jboltri@neomed.edu.

ACKNOWLEDGEMENTS
The authors thank Kenneth F. Tucker, MD (Webber Cancer Center, St John Macomb-Oakland Hospital, Warren, Mich) and Elizabeth Sykes, MD (Professor, Oakland University, William Beaumont School of Medicine, Rochester, Mich) for their review of this article.