Cleveland Clinic Journal of Medicine

Whether subclinical hypothyroidism is clinically important and should be treated remains controversial. Studies have differed in their findings, and although most have found this condition to be associated with a variety of adverse outcomes, large randomized controlled trials are needed to clearly demonstrate its clinical impact in various age groups and the benefit of levothyroxine therapy.

Currently, the best practical approach is to base treatment decisions on the magnitude of elevation of thyroid-stimulating hormone (TSH) and whether the patient has thyroid autoantibodies and associated comorbid conditions.

HIGH TSH, NORMAL FREE T₄ LEVELS

Subclinical hypothyroidism is defined by elevated TSH along with a normal free thyroxine (T₄).¹

The hypothalamic-pituitary-thyroid axis is a balanced homeostatic system, and TSH and thyroid hormone levels have an inverse log-linear relation: if free T₄ and triiodothyronine (T₃) levels go down even a little, TSH levels go up a lot.²

TSH secretion is pulsatile and has a circadian rhythm: serum TSH levels are 50% higher at night and early in the morning than during the rest of the day. Thus, repeated measurements in the same patient can vary by as much as half of the reference range.³

WHAT IS THE UPPER LIMIT OF NORMAL FOR TSH?

The upper limit of normal for TSH, defined as the 97.5th percentile, is approximately 4 or 5 mIU/L depending on the laboratory and the population, but some experts believe it should be lower.³

In favor of a lower upper limit: the distribution of serum TSH levels in the healthy general population does not seem to be a typical bell-shaped Gaussian curve, but rather has a tail at the high end. Some argue that some of the individuals with values in the upper end of the normal range may actually have undiagnosed hypothyroidism and that the upper 97.5th percentile cutoff would be 2.5 mIU/L if these people were excluded.⁴ Also, TSH levels higher than 2.5 mIU/L have been associated with a higher prevalence of antithyroid antibodies and a higher risk of clinical hypothyroidism.⁵

On the other hand, lowering the upper limit of normal to 2.5 mIU/L would result in 4 times as many people receiving a diagnosis of subclinical hypothyroidism, or 22 to 28 million people in the United States.^4,6 Thus, lowering the cutoff may lead to unnecessary therapy and could even harm from overtreatment.

Another argument against lowering the upper limit of normal for TSH is that, with age, serum TSH levels shift higher.⁷ The third National Health and Nutrition Education Survey (NHANES III) found that the 97.5th percentile for serum TSH was 3.56 mIU/L for age group 20 to 29 but 7.49 mIU/L for octogenarians.^7,8

It has been suggested that the upper limit of normal for TSH be adjusted for age, race, sex, and iodine intake.³ Currently available TSH reference ranges are not adjusted for these variables, and there is not enough evidence to suggest age-appropriate ranges,⁹ although higher TSH cutoffs for treatment are advised in elderly patients.¹⁰ Interestingly, higher TSH in older people has been linked to lower mortality rates in some studies.¹¹

Authors of the NHANES III⁸ and Hanford Thyroid Disease study¹² have proposed a cutoff of 4.1 mIU/L for the upper limit of normal for serum TSH in patients with negative antithyroid antibodies and normal findings on thyroid ultrasonography.

SUBCLINICAL HYPOTHYROIDISM IS COMMON

In different studies, the prevalence of subclinical hypothyroidism has been as low as 4% and as high as 20%.^1,8,13 The prevalence is higher in women and increases with age.⁸ It is higher in iodine-sufficient areas, and it increases in iodine-deficient areas with iodine supplementation.¹⁴ Genetics also plays a role, as subclinical hypothyroidism is more common in white people than in African Americans.⁸

A difficulty in estimating the prevalence is the disagreement about the cutoff for TSH, which may differ from that in the general population in certain subgroups such as adolescents, the elderly, and pregnant women.^10,15

A VARIETY OF CAUSES

The most common cause of subclinical hypothyroidism, accounting for 60% to 80% of cases, is Hashimoto (autoimmune) thyroiditis,² in which thyroid peroxidase antibodies are usually present.^2,16

Also important to rule out are false-positive elevations due to substances that interfere with TSH assays (eg, heterophile antibodies, rheumatoid factor, biotin, macro-TSH); reversible causes such as the recovery phase of euthyroid sick syndrome; subacute, painless, or postpartum thyroiditis; central hypo- or hyperthyroidism; and thyroid hormone resistance.

SUBCLINICAL HYPOTHYROIDISM CAN RESOLVE OR PROGRESS 


“Subclinical” suggests that the disease is in its early stage, with changes in TSH already apparent but decreases in thyroid hormone levels yet to come.¹⁷ And indeed, subclinical hypothyroidism can progress to overt hypothyroidism,¹⁸ although it has been reported to resolve spontaneously in half of cases within 2 years,¹⁹ typically in patients with TSH values of 4 to 6 mIU/L.²⁰ The rate of progression to overt hypothyroidism is estimated to be 33% to 55% over 10 to 20 years of follow-up.¹⁸

Figure 1 shows the natural history of subclinical hypothyroidism.¹

GUIDELINES FOR SCREENING DIFFER

Guidelines differ on screening for thyroid disease in the general population, owing to lack of large-scale randomized controlled trials showing treatment benefit in otherwise-healthy people with mildly elevated TSH values.

Various professional societies have adopted different criteria for aggressive case-finding in patients at risk of thyroid disease. Risk factors include family history of thyroid disease, neck irradiation, partial thyroidectomy, dyslipidemia, atrial fibrillation, unexplained weight loss, hyperprolactinemia, autoimmune disorders, and use of medications affecting thyroid function.²³

The US Preventive Services Task Force in 2014 found insufficient evidence on the benefits and harms of screening.²⁴

The American Thyroid Association (ATA) recommends screening adults starting at age 35, with repeat testing every 5 years in patients who have no signs or symptoms of hypothyroidism, and more frequently in those who do.²⁵

The American Association of Clinical Endocrinologists recommends screening in women and older patients. Their guidelines and those of the ATA also suggest screening people at high risk of thyroid disease due to risk factors such as history of autoimmune diseases, neck irradiation, or medications affecting thyroid function.²⁶

The American Academy of Family Physicians recommends screening after age 60.¹⁸

The American College of Physicians recommends screening patients over age 50 who have symptoms.¹⁸

Our approach. Although evidence is lacking to recommend routine screening in adults, aggressive case-finding and treatment in patients at risk of thyroid disease can, we believe, offset the risks associated with subclinical hypothyroidism.²⁴

CLINICAL PRESENTATION

About 70% of patients with subclinical hypothyroidism have no symptoms.¹³

Tiredness was more common in subclinical hypothyroid patients with TSH levels lower than 10 mIU/L compared with euthyroid controls in 1 study, but other studies have been unable to replicate this finding.^27,28

Other frequently reported symptoms include dry skin, cognitive slowing, poor memory, muscle weakness, cold intolerance, constipation, puffy eyes, and hoarseness.¹³

The evidence in favor of levothyroxine therapy to improve symptoms in subclinical hypothyroidism has varied, with some studies showing an improvement in symptom scores compared with placebo, while others have not shown any benefit.^29–31

In one study, the average TSH value for patients whose symptoms did not improve with therapy was 4.6 mIU/L.³¹ An explanation for the lack of effect in this group may be that the TSH values for these patients were in the high-normal range. Also, because most subclinical hypothyroid patients have no symptoms, it is difficult to ascertain symptomatic improvement. Though it is possible to conclude that levothyroxine therapy has a limited role in this group, it is important to also consider the suggestive evidence that untreated subclinical hypothyroidism may lead to increased morbidity and mortality.

ADVERSE EFFECTS OF SUBCLINICAL HYPOTHYROIDISM, EFFECTS OF THERAPY

INDIVIDUALIZED MANAGEMENT AND SHARED DECISION-MAKING

The management of subclinical hypothyroidism should be individualized on the basis of extent of thyroid dysfunction, comorbid conditions, risk factors, and patient preference.¹¹⁸ Shared decision-making is key, weighing the risks and benefits of levothyroxine treatment and the patient’s goals.

The risks of treatment should be kept in mind and explained to the patient. Levothyroxine has a narrow therapeutic range, causing a possibility of overreplacement, and a half-life of 7 days that can cause dosing errors to have longer effect.^118,119

Adherence can be a challenge. The drug needs to be taken on an empty stomach because foods and supplements interfere with its absorption.^118,120 In addition, the cost of medication, frequent biochemical monitoring, and possible need for titration can add to financial burden.

When choosing the dose, one should consider the degree of hypothyroidism or TSH elevation and the patient’s weight, and adjust the dose gently.

If the TSH is high-normal

It is proposed that a TSH range of 3 to 5 mIU/L overlaps with normal thyroid function in a great segment of the population, and at this level it is probably not associated with clinically significant consequences. For these reasons, levothyroxine therapy is not thought to be beneficial for those with TSH in this range.

Pollock et al¹²¹ found that, in patients with symptoms suggesting hypothyroidism and TSH values in the upper end of the normal range, there was no improvement in cognitive function or psychological well-being after 12 weeks of levothyroxine therapy.

However, due to the concern for possible adverse maternal and fetal outcomes and low IQ in children of pregnant patients with subclinical hypothyroidism, levothyroxine therapy is advised in those who are pregnant or planning pregnancy who have TSH levels higher than 2.5 mIU/L, especially if they have thyroid peroxidase antibody. Levothyroxine therapy is not recommended for pregnant patients with negative thyroid peroxidase antibody and TSH within the pregnancy-specific range or less than 4 mIU/L if the reference ranges are unavailable.

Keep in mind that, even at these TSH values, there is risk of progression to overt hypothyroidism, especially in the presence of thyroid peroxidase antibody, so patients in this group should be monitored closely.

If TSH is mildly elevated

The evidence to support levothyroxine therapy in patients with subclinical hypothyroidism with TSH levels less than 10 mIU/L remains inconclusive, and the decision to treat should be based on clinical judgment.² The studies that have looked at the benefit of treating subclinical hypothyroidism in terms of cardiac, neuromuscular, cognitive, and neuropsychiatric outcomes have included patients with a wide range of TSH levels, and some of these studies were not stratified on the basis of degree of TSH elevation.

The risk that subclinical hypothyroidism will progress to overt hypothyroidism in patients with TSH higher than 8 mIU/L is high, and in 70% of these patients, the TSH level rises to more than 10 mIU/L within 4 years. Early treatment should be considered if the TSH is higher than 7 or 8 mIU/L.

If TSH is higher than 10 mIU/L

Figure 2 outlines an algorithmic approach to subclinical hypothyroidism in nonpregnant patients as suggested by Peeters.¹²²

Whether subclinical hypothyroidism is clinically important and should be treated remains controversial. Studies have differed in their findings, and although most have found this condition to be associated with a variety of adverse outcomes, large randomized controlled trials are needed to clearly demonstrate its clinical impact in various age groups and the benefit of levothyroxine therapy.

Currently, the best practical approach is to base treatment decisions on the magnitude of elevation of thyroid-stimulating hormone (TSH) and whether the patient has thyroid autoantibodies and associated comorbid conditions.

HIGH TSH, NORMAL FREE T₄ LEVELS

Subclinical hypothyroidism is defined by elevated TSH along with a normal free thyroxine (T₄).¹

The hypothalamic-pituitary-thyroid axis is a balanced homeostatic system, and TSH and thyroid hormone levels have an inverse log-linear relation: if free T₄ and triiodothyronine (T₃) levels go down even a little, TSH levels go up a lot.²

TSH secretion is pulsatile and has a circadian rhythm: serum TSH levels are 50% higher at night and early in the morning than during the rest of the day. Thus, repeated measurements in the same patient can vary by as much as half of the reference range.³

WHAT IS THE UPPER LIMIT OF NORMAL FOR TSH?

The upper limit of normal for TSH, defined as the 97.5th percentile, is approximately 4 or 5 mIU/L depending on the laboratory and the population, but some experts believe it should be lower.³

In favor of a lower upper limit: the distribution of serum TSH levels in the healthy general population does not seem to be a typical bell-shaped Gaussian curve, but rather has a tail at the high end. Some argue that some of the individuals with values in the upper end of the normal range may actually have undiagnosed hypothyroidism and that the upper 97.5th percentile cutoff would be 2.5 mIU/L if these people were excluded.⁴ Also, TSH levels higher than 2.5 mIU/L have been associated with a higher prevalence of antithyroid antibodies and a higher risk of clinical hypothyroidism.⁵

On the other hand, lowering the upper limit of normal to 2.5 mIU/L would result in 4 times as many people receiving a diagnosis of subclinical hypothyroidism, or 22 to 28 million people in the United States.^4,6 Thus, lowering the cutoff may lead to unnecessary therapy and could even harm from overtreatment.

Another argument against lowering the upper limit of normal for TSH is that, with age, serum TSH levels shift higher.⁷ The third National Health and Nutrition Education Survey (NHANES III) found that the 97.5th percentile for serum TSH was 3.56 mIU/L for age group 20 to 29 but 7.49 mIU/L for octogenarians.^7,8

It has been suggested that the upper limit of normal for TSH be adjusted for age, race, sex, and iodine intake.³ Currently available TSH reference ranges are not adjusted for these variables, and there is not enough evidence to suggest age-appropriate ranges,⁹ although higher TSH cutoffs for treatment are advised in elderly patients.¹⁰ Interestingly, higher TSH in older people has been linked to lower mortality rates in some studies.¹¹

Authors of the NHANES III⁸ and Hanford Thyroid Disease study¹² have proposed a cutoff of 4.1 mIU/L for the upper limit of normal for serum TSH in patients with negative antithyroid antibodies and normal findings on thyroid ultrasonography.

SUBCLINICAL HYPOTHYROIDISM IS COMMON

In different studies, the prevalence of subclinical hypothyroidism has been as low as 4% and as high as 20%.^1,8,13 The prevalence is higher in women and increases with age.⁸ It is higher in iodine-sufficient areas, and it increases in iodine-deficient areas with iodine supplementation.¹⁴ Genetics also plays a role, as subclinical hypothyroidism is more common in white people than in African Americans.⁸

A difficulty in estimating the prevalence is the disagreement about the cutoff for TSH, which may differ from that in the general population in certain subgroups such as adolescents, the elderly, and pregnant women.^10,15

A VARIETY OF CAUSES

The most common cause of subclinical hypothyroidism, accounting for 60% to 80% of cases, is Hashimoto (autoimmune) thyroiditis,² in which thyroid peroxidase antibodies are usually present.^2,16

Also important to rule out are false-positive elevations due to substances that interfere with TSH assays (eg, heterophile antibodies, rheumatoid factor, biotin, macro-TSH); reversible causes such as the recovery phase of euthyroid sick syndrome; subacute, painless, or postpartum thyroiditis; central hypo- or hyperthyroidism; and thyroid hormone resistance.

SUBCLINICAL HYPOTHYROIDISM CAN RESOLVE OR PROGRESS 


“Subclinical” suggests that the disease is in its early stage, with changes in TSH already apparent but decreases in thyroid hormone levels yet to come.¹⁷ And indeed, subclinical hypothyroidism can progress to overt hypothyroidism,¹⁸ although it has been reported to resolve spontaneously in half of cases within 2 years,¹⁹ typically in patients with TSH values of 4 to 6 mIU/L.²⁰ The rate of progression to overt hypothyroidism is estimated to be 33% to 55% over 10 to 20 years of follow-up.¹⁸

Figure 1 shows the natural history of subclinical hypothyroidism.¹

GUIDELINES FOR SCREENING DIFFER

Guidelines differ on screening for thyroid disease in the general population, owing to lack of large-scale randomized controlled trials showing treatment benefit in otherwise-healthy people with mildly elevated TSH values.

Various professional societies have adopted different criteria for aggressive case-finding in patients at risk of thyroid disease. Risk factors include family history of thyroid disease, neck irradiation, partial thyroidectomy, dyslipidemia, atrial fibrillation, unexplained weight loss, hyperprolactinemia, autoimmune disorders, and use of medications affecting thyroid function.²³

The US Preventive Services Task Force in 2014 found insufficient evidence on the benefits and harms of screening.²⁴

The American Thyroid Association (ATA) recommends screening adults starting at age 35, with repeat testing every 5 years in patients who have no signs or symptoms of hypothyroidism, and more frequently in those who do.²⁵

The American Association of Clinical Endocrinologists recommends screening in women and older patients. Their guidelines and those of the ATA also suggest screening people at high risk of thyroid disease due to risk factors such as history of autoimmune diseases, neck irradiation, or medications affecting thyroid function.²⁶

The American Academy of Family Physicians recommends screening after age 60.¹⁸

The American College of Physicians recommends screening patients over age 50 who have symptoms.¹⁸

Our approach. Although evidence is lacking to recommend routine screening in adults, aggressive case-finding and treatment in patients at risk of thyroid disease can, we believe, offset the risks associated with subclinical hypothyroidism.²⁴

CLINICAL PRESENTATION

About 70% of patients with subclinical hypothyroidism have no symptoms.¹³

Tiredness was more common in subclinical hypothyroid patients with TSH levels lower than 10 mIU/L compared with euthyroid controls in 1 study, but other studies have been unable to replicate this finding.^27,28

Other frequently reported symptoms include dry skin, cognitive slowing, poor memory, muscle weakness, cold intolerance, constipation, puffy eyes, and hoarseness.¹³

The evidence in favor of levothyroxine therapy to improve symptoms in subclinical hypothyroidism has varied, with some studies showing an improvement in symptom scores compared with placebo, while others have not shown any benefit.^29–31

In one study, the average TSH value for patients whose symptoms did not improve with therapy was 4.6 mIU/L.³¹ An explanation for the lack of effect in this group may be that the TSH values for these patients were in the high-normal range. Also, because most subclinical hypothyroid patients have no symptoms, it is difficult to ascertain symptomatic improvement. Though it is possible to conclude that levothyroxine therapy has a limited role in this group, it is important to also consider the suggestive evidence that untreated subclinical hypothyroidism may lead to increased morbidity and mortality.

ADVERSE EFFECTS OF SUBCLINICAL HYPOTHYROIDISM, EFFECTS OF THERAPY

INDIVIDUALIZED MANAGEMENT AND SHARED DECISION-MAKING

The management of subclinical hypothyroidism should be individualized on the basis of extent of thyroid dysfunction, comorbid conditions, risk factors, and patient preference.¹¹⁸ Shared decision-making is key, weighing the risks and benefits of levothyroxine treatment and the patient’s goals.

The risks of treatment should be kept in mind and explained to the patient. Levothyroxine has a narrow therapeutic range, causing a possibility of overreplacement, and a half-life of 7 days that can cause dosing errors to have longer effect.^118,119

Adherence can be a challenge. The drug needs to be taken on an empty stomach because foods and supplements interfere with its absorption.^118,120 In addition, the cost of medication, frequent biochemical monitoring, and possible need for titration can add to financial burden.

When choosing the dose, one should consider the degree of hypothyroidism or TSH elevation and the patient’s weight, and adjust the dose gently.

If the TSH is high-normal

It is proposed that a TSH range of 3 to 5 mIU/L overlaps with normal thyroid function in a great segment of the population, and at this level it is probably not associated with clinically significant consequences. For these reasons, levothyroxine therapy is not thought to be beneficial for those with TSH in this range.

Pollock et al¹²¹ found that, in patients with symptoms suggesting hypothyroidism and TSH values in the upper end of the normal range, there was no improvement in cognitive function or psychological well-being after 12 weeks of levothyroxine therapy.

However, due to the concern for possible adverse maternal and fetal outcomes and low IQ in children of pregnant patients with subclinical hypothyroidism, levothyroxine therapy is advised in those who are pregnant or planning pregnancy who have TSH levels higher than 2.5 mIU/L, especially if they have thyroid peroxidase antibody. Levothyroxine therapy is not recommended for pregnant patients with negative thyroid peroxidase antibody and TSH within the pregnancy-specific range or less than 4 mIU/L if the reference ranges are unavailable.

Keep in mind that, even at these TSH values, there is risk of progression to overt hypothyroidism, especially in the presence of thyroid peroxidase antibody, so patients in this group should be monitored closely.

If TSH is mildly elevated

The evidence to support levothyroxine therapy in patients with subclinical hypothyroidism with TSH levels less than 10 mIU/L remains inconclusive, and the decision to treat should be based on clinical judgment.² The studies that have looked at the benefit of treating subclinical hypothyroidism in terms of cardiac, neuromuscular, cognitive, and neuropsychiatric outcomes have included patients with a wide range of TSH levels, and some of these studies were not stratified on the basis of degree of TSH elevation.

The risk that subclinical hypothyroidism will progress to overt hypothyroidism in patients with TSH higher than 8 mIU/L is high, and in 70% of these patients, the TSH level rises to more than 10 mIU/L within 4 years. Early treatment should be considered if the TSH is higher than 7 or 8 mIU/L.

If TSH is higher than 10 mIU/L

Figure 2 outlines an algorithmic approach to subclinical hypothyroidism in nonpregnant patients as suggested by Peeters.¹²²

Whether subclinical hypothyroidism is clinically important and should be treated remains controversial. Studies have differed in their findings, and although most have found this condition to be associated with a variety of adverse outcomes, large randomized controlled trials are needed to clearly demonstrate its clinical impact in various age groups and the benefit of levothyroxine therapy.

Currently, the best practical approach is to base treatment decisions on the magnitude of elevation of thyroid-stimulating hormone (TSH) and whether the patient has thyroid autoantibodies and associated comorbid conditions.

HIGH TSH, NORMAL FREE T₄ LEVELS

Subclinical hypothyroidism is defined by elevated TSH along with a normal free thyroxine (T₄).¹

The hypothalamic-pituitary-thyroid axis is a balanced homeostatic system, and TSH and thyroid hormone levels have an inverse log-linear relation: if free T₄ and triiodothyronine (T₃) levels go down even a little, TSH levels go up a lot.²

TSH secretion is pulsatile and has a circadian rhythm: serum TSH levels are 50% higher at night and early in the morning than during the rest of the day. Thus, repeated measurements in the same patient can vary by as much as half of the reference range.³

WHAT IS THE UPPER LIMIT OF NORMAL FOR TSH?

The upper limit of normal for TSH, defined as the 97.5th percentile, is approximately 4 or 5 mIU/L depending on the laboratory and the population, but some experts believe it should be lower.³

In favor of a lower upper limit: the distribution of serum TSH levels in the healthy general population does not seem to be a typical bell-shaped Gaussian curve, but rather has a tail at the high end. Some argue that some of the individuals with values in the upper end of the normal range may actually have undiagnosed hypothyroidism and that the upper 97.5th percentile cutoff would be 2.5 mIU/L if these people were excluded.⁴ Also, TSH levels higher than 2.5 mIU/L have been associated with a higher prevalence of antithyroid antibodies and a higher risk of clinical hypothyroidism.⁵

On the other hand, lowering the upper limit of normal to 2.5 mIU/L would result in 4 times as many people receiving a diagnosis of subclinical hypothyroidism, or 22 to 28 million people in the United States.^4,6 Thus, lowering the cutoff may lead to unnecessary therapy and could even harm from overtreatment.

Another argument against lowering the upper limit of normal for TSH is that, with age, serum TSH levels shift higher.⁷ The third National Health and Nutrition Education Survey (NHANES III) found that the 97.5th percentile for serum TSH was 3.56 mIU/L for age group 20 to 29 but 7.49 mIU/L for octogenarians.^7,8

It has been suggested that the upper limit of normal for TSH be adjusted for age, race, sex, and iodine intake.³ Currently available TSH reference ranges are not adjusted for these variables, and there is not enough evidence to suggest age-appropriate ranges,⁹ although higher TSH cutoffs for treatment are advised in elderly patients.¹⁰ Interestingly, higher TSH in older people has been linked to lower mortality rates in some studies.¹¹

Authors of the NHANES III⁸ and Hanford Thyroid Disease study¹² have proposed a cutoff of 4.1 mIU/L for the upper limit of normal for serum TSH in patients with negative antithyroid antibodies and normal findings on thyroid ultrasonography.

SUBCLINICAL HYPOTHYROIDISM IS COMMON

In different studies, the prevalence of subclinical hypothyroidism has been as low as 4% and as high as 20%.^1,8,13 The prevalence is higher in women and increases with age.⁸ It is higher in iodine-sufficient areas, and it increases in iodine-deficient areas with iodine supplementation.¹⁴ Genetics also plays a role, as subclinical hypothyroidism is more common in white people than in African Americans.⁸

A difficulty in estimating the prevalence is the disagreement about the cutoff for TSH, which may differ from that in the general population in certain subgroups such as adolescents, the elderly, and pregnant women.^10,15

A VARIETY OF CAUSES

The most common cause of subclinical hypothyroidism, accounting for 60% to 80% of cases, is Hashimoto (autoimmune) thyroiditis,² in which thyroid peroxidase antibodies are usually present.^2,16

Also important to rule out are false-positive elevations due to substances that interfere with TSH assays (eg, heterophile antibodies, rheumatoid factor, biotin, macro-TSH); reversible causes such as the recovery phase of euthyroid sick syndrome; subacute, painless, or postpartum thyroiditis; central hypo- or hyperthyroidism; and thyroid hormone resistance.

SUBCLINICAL HYPOTHYROIDISM CAN RESOLVE OR PROGRESS 


“Subclinical” suggests that the disease is in its early stage, with changes in TSH already apparent but decreases in thyroid hormone levels yet to come.¹⁷ And indeed, subclinical hypothyroidism can progress to overt hypothyroidism,¹⁸ although it has been reported to resolve spontaneously in half of cases within 2 years,¹⁹ typically in patients with TSH values of 4 to 6 mIU/L.²⁰ The rate of progression to overt hypothyroidism is estimated to be 33% to 55% over 10 to 20 years of follow-up.¹⁸

Figure 1 shows the natural history of subclinical hypothyroidism.¹

GUIDELINES FOR SCREENING DIFFER

Guidelines differ on screening for thyroid disease in the general population, owing to lack of large-scale randomized controlled trials showing treatment benefit in otherwise-healthy people with mildly elevated TSH values.

Various professional societies have adopted different criteria for aggressive case-finding in patients at risk of thyroid disease. Risk factors include family history of thyroid disease, neck irradiation, partial thyroidectomy, dyslipidemia, atrial fibrillation, unexplained weight loss, hyperprolactinemia, autoimmune disorders, and use of medications affecting thyroid function.²³

The US Preventive Services Task Force in 2014 found insufficient evidence on the benefits and harms of screening.²⁴

The American Thyroid Association (ATA) recommends screening adults starting at age 35, with repeat testing every 5 years in patients who have no signs or symptoms of hypothyroidism, and more frequently in those who do.²⁵

The American Association of Clinical Endocrinologists recommends screening in women and older patients. Their guidelines and those of the ATA also suggest screening people at high risk of thyroid disease due to risk factors such as history of autoimmune diseases, neck irradiation, or medications affecting thyroid function.²⁶

The American Academy of Family Physicians recommends screening after age 60.¹⁸

The American College of Physicians recommends screening patients over age 50 who have symptoms.¹⁸

Our approach. Although evidence is lacking to recommend routine screening in adults, aggressive case-finding and treatment in patients at risk of thyroid disease can, we believe, offset the risks associated with subclinical hypothyroidism.²⁴

CLINICAL PRESENTATION

About 70% of patients with subclinical hypothyroidism have no symptoms.¹³

Tiredness was more common in subclinical hypothyroid patients with TSH levels lower than 10 mIU/L compared with euthyroid controls in 1 study, but other studies have been unable to replicate this finding.^27,28

Other frequently reported symptoms include dry skin, cognitive slowing, poor memory, muscle weakness, cold intolerance, constipation, puffy eyes, and hoarseness.¹³

The evidence in favor of levothyroxine therapy to improve symptoms in subclinical hypothyroidism has varied, with some studies showing an improvement in symptom scores compared with placebo, while others have not shown any benefit.^29–31

In one study, the average TSH value for patients whose symptoms did not improve with therapy was 4.6 mIU/L.³¹ An explanation for the lack of effect in this group may be that the TSH values for these patients were in the high-normal range. Also, because most subclinical hypothyroid patients have no symptoms, it is difficult to ascertain symptomatic improvement. Though it is possible to conclude that levothyroxine therapy has a limited role in this group, it is important to also consider the suggestive evidence that untreated subclinical hypothyroidism may lead to increased morbidity and mortality.

ADVERSE EFFECTS OF SUBCLINICAL HYPOTHYROIDISM, EFFECTS OF THERAPY

INDIVIDUALIZED MANAGEMENT AND SHARED DECISION-MAKING

The management of subclinical hypothyroidism should be individualized on the basis of extent of thyroid dysfunction, comorbid conditions, risk factors, and patient preference.¹¹⁸ Shared decision-making is key, weighing the risks and benefits of levothyroxine treatment and the patient’s goals.

The risks of treatment should be kept in mind and explained to the patient. Levothyroxine has a narrow therapeutic range, causing a possibility of overreplacement, and a half-life of 7 days that can cause dosing errors to have longer effect.^118,119

Adherence can be a challenge. The drug needs to be taken on an empty stomach because foods and supplements interfere with its absorption.^118,120 In addition, the cost of medication, frequent biochemical monitoring, and possible need for titration can add to financial burden.

When choosing the dose, one should consider the degree of hypothyroidism or TSH elevation and the patient’s weight, and adjust the dose gently.

If the TSH is high-normal

It is proposed that a TSH range of 3 to 5 mIU/L overlaps with normal thyroid function in a great segment of the population, and at this level it is probably not associated with clinically significant consequences. For these reasons, levothyroxine therapy is not thought to be beneficial for those with TSH in this range.

Pollock et al¹²¹ found that, in patients with symptoms suggesting hypothyroidism and TSH values in the upper end of the normal range, there was no improvement in cognitive function or psychological well-being after 12 weeks of levothyroxine therapy.

However, due to the concern for possible adverse maternal and fetal outcomes and low IQ in children of pregnant patients with subclinical hypothyroidism, levothyroxine therapy is advised in those who are pregnant or planning pregnancy who have TSH levels higher than 2.5 mIU/L, especially if they have thyroid peroxidase antibody. Levothyroxine therapy is not recommended for pregnant patients with negative thyroid peroxidase antibody and TSH within the pregnancy-specific range or less than 4 mIU/L if the reference ranges are unavailable.

Keep in mind that, even at these TSH values, there is risk of progression to overt hypothyroidism, especially in the presence of thyroid peroxidase antibody, so patients in this group should be monitored closely.

If TSH is mildly elevated

The evidence to support levothyroxine therapy in patients with subclinical hypothyroidism with TSH levels less than 10 mIU/L remains inconclusive, and the decision to treat should be based on clinical judgment.² The studies that have looked at the benefit of treating subclinical hypothyroidism in terms of cardiac, neuromuscular, cognitive, and neuropsychiatric outcomes have included patients with a wide range of TSH levels, and some of these studies were not stratified on the basis of degree of TSH elevation.

The risk that subclinical hypothyroidism will progress to overt hypothyroidism in patients with TSH higher than 8 mIU/L is high, and in 70% of these patients, the TSH level rises to more than 10 mIU/L within 4 years. Early treatment should be considered if the TSH is higher than 7 or 8 mIU/L.

If TSH is higher than 10 mIU/L

Figure 2 outlines an algorithmic approach to subclinical hypothyroidism in nonpregnant patients as suggested by Peeters.¹²²

Managing patients with malignant pleural effusion can be challenging. Symptoms are often distressing, and its presence signifies advanced disease. Median survival after diagnosis is 4 to 9 months,^1–3 although prognosis varies considerably depending on the type and stage of the malignancy.

How patients are best managed depends on clinical circumstances. Physicians should consider the risks and benefits of each option while keeping in mind realistic goals of care.

This article uses brief case presentations to review management strategies for malignant pleural effusion.

CANCER IS A COMMON CAUSE OF PLEURAL EFFUSION

Physicians and surgeons, especially in tertiary care hospitals, must often manage malignant pleural effusion.⁴ Malignancy is the third leading cause of pleural effusion after heart failure and pneumonia, accounting for 44% to 77% of exudates.⁵ Although pleural effusion can arise secondary to many different malignancies, the most common causes are lung cancer in men and breast cancer in women; these cancers account for about 75% of all cases of malignant pleural effusion.^6,7

A WOMAN ON CHEMOTHERAPY WITH ASYMPTOMATIC PLEURAL EFFUSION

An 18-year-old woman with non-Hodgkin lymphoma has received her first cycle of chemotherapy and is now admitted to the hospital for diarrhea. A routine chest radiograph reveals a left-sided pleural effusion covering one-third of the thoracic cavity. She is asymptomatic and reports no shortness of breath at rest or with exertion. Her oxygen saturation level is above 92% on room air without supplemental oxygen.

Thoracentesis reveals an exudative effusion, and cytologic study shows malignant lymphoid cells, consistent with a malignant pleural effusion. Cultures are negative.

What is the appropriate next step to manage this patient’s effusion?

Observation is reasonable

This patient is experiencing no symptoms and has just begun chemotherapy for her lymphoma. Malignant pleural effusion associated with lymphoma, small-cell lung cancer, and breast cancer is most sensitive to chemotherapy.⁵ For patients who do not have symptoms from the pleural effusion and who are scheduled to receive further chemotherapy, a watch-and-wait approach is reasonable.

It is important to follow the patient for developing symptoms and obtain serial imaging to evaluate for an increase in the effusion size. We recommend repeat imaging at 2- to 4-week intervals, and sooner if symptoms develop.

If progression is evident or if the patient’s oncologist indicates that the cancer is unresponsive to systemic therapy, further intervention may be necessary with one of the options discussed below.

A MAN WITH LUNG CANCER WITH PLEURAL EFFUSION, LUNG COLLAPSE

A 42-year-old man with a history of lung cancer is admitted for worsening shortness of breath. Chest radiography reveals a large left-sided pleural effusion with complete collapse of the left lung and contralateral shift of midline structures (Figure 1). Large-volume thoracentesis improves his symptoms. Pleural fluid cytology is positive for malignant cells. A repeat chest radiograph shows incomplete expansion of the left lung, thick pleura, and pneumothorax, indicating a trapped lung (ie, one unable to expand fully). Two weeks later, his symptoms recur, and chest radiography reveals a recurrent effusion.

How should this effusion be managed?

Indwelling pleural catheter placement

In a retrospective cohort study,⁸ malignant pleural effusion recurred in 97% of patients within 1 month (mean, 4.2 days) of therapeutic aspiration, highlighting the need for definitive treatment.

In the absence of lung expansion, pleuro­desis is rarely successful, and placing an indwelling pleural catheter in symptomatic patients is the preferred strategy. The US Food and Drug Administration approved this use in 1997.⁹

Indwelling pleural catheters are narrow (15.5 French, or about 5 mm in diameter) and soft (made of silicone), with distal fenestrations. The distal end remains positioned in the pleural cavity to enable drainage of pleural fluid. The middle portion passes through subcutaneous tissue, where a polyester cuff prevents dislodgement and infection. The proximal end of the catheter remains outside the patient’s skin and is connected to a 1-way valve that prevents air or fluid flow into the pleural cavity.

Pleural fluid is typically drained every 2 or 3 days for palliation. Patients must be educated about home drainage and proper catheter care.

Although indwelling pleural catheters were first used for patients who were not candidates for pleurodesis, they are now increasingly used as first-line therapy.

Since these devices were introduced, several clinical series including more than 800 patients have found that their use for malignant pleural infusion led to symptomatic improvement in 89% to 100% of cases, with 90% of patients needing no subsequent pleural procedures after catheter insertion.^10–13

Davies et al¹⁴ randomized 106 patients with malignant pleural effusion to either receive an indwelling pleural catheter or undergo pleurodesis. In the first 6 weeks, the 2 groups had about the same incidence of dyspnea, but the catheter group had less dyspnea at 6 months, shorter index hospitalization (0 vs 4 days), fewer hospital days in the first year for treatment-related complications (1 vs 4.5 days), and fewer patients needing follow-up pleural procedures (6% vs 22%). On the other hand, adverse events were more frequent in the indwelling pleural catheter group (40% vs 13%). The most frequent events were pleural infection, cellulitis, and catheter blockage.

Fysh et al¹⁵ also compared indwelling pleural catheter insertion and pleurodesis (based on patient choice) in patients with malignant pleural effusion. As in the previous trial, those who received a catheter required significantly fewer days in the hospital and fewer additional pleural procedures than those who received pleurodesis. Safety profiles and symptom control were comparable.

Indwelling pleural catheters have several other advantages. They have been found to be more cost-effective than talc pleurodesis in patients not expected to live long (survival < 14 weeks).¹⁶ Patients with an indwelling pleural catheter can receive chemotherapy, and concurrent treatment does not increase risk of infection.¹⁷ And a systematic review¹⁸ found a 46% rate of autopleurodesis at a median of 52 days after insertion of an indwelling pleural catheter.

Drainage rate may need to be moderated

Chest pain has been reported with the use of indwelling pleural catheters, related to rapid drainage of the effusion in the setting of failed reexpansion of the trapped lung due to thickened pleura. Drainage schedules may need to be adjusted, with more frequent draining of smaller volumes, to control dyspnea without causing significant pain.

A WOMAN WITH RECURRENT PLEURAL EFFUSION, GOOD PROGNOSIS

A 55-year-old woman with a history of breast cancer presents with shortness of breath. Chest radiography reveals a right-sided effusion, which on thoracentesis is found to be malignant. After fluid removal, repeat chest radiography shows complete lung expansion.

One month later, she returns with symptoms and recurrence of the effusion. Ultrasonography does not reveal any adhesions in the pleural space. Her oncologist informs you that her expected survival is in years.

What is the next step?

Chemical pleurodesis

Chemical pleurodesis involves introducing a sclerosant into the pleural space to provoke an intense inflammatory response, creating adhesions and fibrosis that will obliterate the space. The sclerosing agent (typically talc) can be delivered by tube thoracostomy, video-assisted thoracic surgery (VATS), or medical pleuroscopy. Although the latter 2 methods allow direct visualization of the pleural space and, in theory, a more even distribution of the sclerosing agent, current evidence does not favor 1 option over the other,¹⁹ and practice patterns vary between institutions.

Tube thoracostomy. Typically, the sclerosing agent is administered once a chest radiograph shows lung reexpansion, and tube output of pleural fluid is less than 150 mL/day.¹⁹ However, some studies indicate that if pleural apposition can be confirmed using ultrasonography, then sclerosant administration at that time leads to optimal pleurodesis efficacy and shorter hospitalization.^20,21

VATS is usually done in the operating room with the patient under general anesthesia. A double-lumen endotracheal tube allows for single-lung ventilation; a camera is then inserted into the pleural space of the collapsed lung. Multiple ports of entry are usually employed, and the entire pleural space can be visualized and the sclerosing agent instilled uniformly. The surgeon may alternatively choose to perform mechanical pleurodesis, which entails abrading the visceral and parietal pleura with dry gauze to provoke diffuse petechial hemorrhage and an inflammatory reaction. VATS can also be used to perform biopsy, lobectomy, and pneumonectomy.

Medical pleuroscopy. Medical pleuroscopy is usually done using local anesthesia with the patient awake, moderately sedated, and not intubated. Because no double-lumen endotracheal tube is used, lung collapse may not be complete, making it difficult to completely visualize the entire pleural surfaces.

Although no randomized study of VATS vs medical pleuroscopy exists, a retrospective case-matched study²² comparing VATS (under general anesthesia) to single-port VATS (under local anesthesia) noted equivalent rates of pleurodesis. However, the local anesthesia group had a lower perioperative mortality rate (0% vs 2.3%), a lower postoperative major morbidity rate (5.2% vs 9%), earlier improvement in quality of life, and shorter hospitalization (3 vs 5 days).²² In general, the diagnostic sensitivity of pleuroscopy for pleural malignancy is similar to that of VATS (93% vs 97%).^23,24

A MAN WITH PLEURAL EFFUSION AND A POOR PROGNOSIS

A 60-year-old man with metastatic pancreatic cancer is brought to the clinic for worsening shortness of breath over the past 2 months. During that time, he has lost 6 kg and has become bedridden.

On examination, he has severe cachexia and is significantly short of breath at rest with associated hypoxia. His oncologist expects him to survive less than 3 months.

His laboratory investigations reveal hypoalbuminemia and leukocytosis. A chest radiograph shows a large left-sided pleural effusion that was not present 2 months ago.

What should be done for him?

Thoracentesis, repeat as needed

Malignant pleural effusion causing dyspnea is not uncommon in certain advanced malignancies and may contribute to significant suffering at the end of life. A study of 298 patients with malignant pleural effusion noted that the presence of leukocytosis, hypoalbuminemia, and hypoxemia was associated with a poorer prognosis. Patients having all 3 factors had a median survival of 42 days.²⁵

Thoracentesis, the least invasive option that may improve dyspnea, can be done in the clinic setting and is a reasonable strategy for patients with advanced cancer and an expected survival of less than 3 months.²⁶ Although recurrence is expected, it may take up to a few weeks, and repeat thoracentesis can be performed as needed.

Managing patients with malignant pleural effusion can be challenging. Symptoms are often distressing, and its presence signifies advanced disease. Median survival after diagnosis is 4 to 9 months,^1–3 although prognosis varies considerably depending on the type and stage of the malignancy.

How patients are best managed depends on clinical circumstances. Physicians should consider the risks and benefits of each option while keeping in mind realistic goals of care.

This article uses brief case presentations to review management strategies for malignant pleural effusion.

CANCER IS A COMMON CAUSE OF PLEURAL EFFUSION

Physicians and surgeons, especially in tertiary care hospitals, must often manage malignant pleural effusion.⁴ Malignancy is the third leading cause of pleural effusion after heart failure and pneumonia, accounting for 44% to 77% of exudates.⁵ Although pleural effusion can arise secondary to many different malignancies, the most common causes are lung cancer in men and breast cancer in women; these cancers account for about 75% of all cases of malignant pleural effusion.^6,7

A WOMAN ON CHEMOTHERAPY WITH ASYMPTOMATIC PLEURAL EFFUSION

An 18-year-old woman with non-Hodgkin lymphoma has received her first cycle of chemotherapy and is now admitted to the hospital for diarrhea. A routine chest radiograph reveals a left-sided pleural effusion covering one-third of the thoracic cavity. She is asymptomatic and reports no shortness of breath at rest or with exertion. Her oxygen saturation level is above 92% on room air without supplemental oxygen.

Thoracentesis reveals an exudative effusion, and cytologic study shows malignant lymphoid cells, consistent with a malignant pleural effusion. Cultures are negative.

What is the appropriate next step to manage this patient’s effusion?

Observation is reasonable

This patient is experiencing no symptoms and has just begun chemotherapy for her lymphoma. Malignant pleural effusion associated with lymphoma, small-cell lung cancer, and breast cancer is most sensitive to chemotherapy.⁵ For patients who do not have symptoms from the pleural effusion and who are scheduled to receive further chemotherapy, a watch-and-wait approach is reasonable.

It is important to follow the patient for developing symptoms and obtain serial imaging to evaluate for an increase in the effusion size. We recommend repeat imaging at 2- to 4-week intervals, and sooner if symptoms develop.

If progression is evident or if the patient’s oncologist indicates that the cancer is unresponsive to systemic therapy, further intervention may be necessary with one of the options discussed below.

A MAN WITH LUNG CANCER WITH PLEURAL EFFUSION, LUNG COLLAPSE

A 42-year-old man with a history of lung cancer is admitted for worsening shortness of breath. Chest radiography reveals a large left-sided pleural effusion with complete collapse of the left lung and contralateral shift of midline structures (Figure 1). Large-volume thoracentesis improves his symptoms. Pleural fluid cytology is positive for malignant cells. A repeat chest radiograph shows incomplete expansion of the left lung, thick pleura, and pneumothorax, indicating a trapped lung (ie, one unable to expand fully). Two weeks later, his symptoms recur, and chest radiography reveals a recurrent effusion.

How should this effusion be managed?

Indwelling pleural catheter placement

In a retrospective cohort study,⁸ malignant pleural effusion recurred in 97% of patients within 1 month (mean, 4.2 days) of therapeutic aspiration, highlighting the need for definitive treatment.

In the absence of lung expansion, pleuro­desis is rarely successful, and placing an indwelling pleural catheter in symptomatic patients is the preferred strategy. The US Food and Drug Administration approved this use in 1997.⁹

Indwelling pleural catheters are narrow (15.5 French, or about 5 mm in diameter) and soft (made of silicone), with distal fenestrations. The distal end remains positioned in the pleural cavity to enable drainage of pleural fluid. The middle portion passes through subcutaneous tissue, where a polyester cuff prevents dislodgement and infection. The proximal end of the catheter remains outside the patient’s skin and is connected to a 1-way valve that prevents air or fluid flow into the pleural cavity.

Pleural fluid is typically drained every 2 or 3 days for palliation. Patients must be educated about home drainage and proper catheter care.

Although indwelling pleural catheters were first used for patients who were not candidates for pleurodesis, they are now increasingly used as first-line therapy.

Since these devices were introduced, several clinical series including more than 800 patients have found that their use for malignant pleural infusion led to symptomatic improvement in 89% to 100% of cases, with 90% of patients needing no subsequent pleural procedures after catheter insertion.^10–13

Davies et al¹⁴ randomized 106 patients with malignant pleural effusion to either receive an indwelling pleural catheter or undergo pleurodesis. In the first 6 weeks, the 2 groups had about the same incidence of dyspnea, but the catheter group had less dyspnea at 6 months, shorter index hospitalization (0 vs 4 days), fewer hospital days in the first year for treatment-related complications (1 vs 4.5 days), and fewer patients needing follow-up pleural procedures (6% vs 22%). On the other hand, adverse events were more frequent in the indwelling pleural catheter group (40% vs 13%). The most frequent events were pleural infection, cellulitis, and catheter blockage.

Fysh et al¹⁵ also compared indwelling pleural catheter insertion and pleurodesis (based on patient choice) in patients with malignant pleural effusion. As in the previous trial, those who received a catheter required significantly fewer days in the hospital and fewer additional pleural procedures than those who received pleurodesis. Safety profiles and symptom control were comparable.

Indwelling pleural catheters have several other advantages. They have been found to be more cost-effective than talc pleurodesis in patients not expected to live long (survival < 14 weeks).¹⁶ Patients with an indwelling pleural catheter can receive chemotherapy, and concurrent treatment does not increase risk of infection.¹⁷ And a systematic review¹⁸ found a 46% rate of autopleurodesis at a median of 52 days after insertion of an indwelling pleural catheter.

Drainage rate may need to be moderated

Chest pain has been reported with the use of indwelling pleural catheters, related to rapid drainage of the effusion in the setting of failed reexpansion of the trapped lung due to thickened pleura. Drainage schedules may need to be adjusted, with more frequent draining of smaller volumes, to control dyspnea without causing significant pain.

A WOMAN WITH RECURRENT PLEURAL EFFUSION, GOOD PROGNOSIS

A 55-year-old woman with a history of breast cancer presents with shortness of breath. Chest radiography reveals a right-sided effusion, which on thoracentesis is found to be malignant. After fluid removal, repeat chest radiography shows complete lung expansion.

One month later, she returns with symptoms and recurrence of the effusion. Ultrasonography does not reveal any adhesions in the pleural space. Her oncologist informs you that her expected survival is in years.

What is the next step?

Chemical pleurodesis

Chemical pleurodesis involves introducing a sclerosant into the pleural space to provoke an intense inflammatory response, creating adhesions and fibrosis that will obliterate the space. The sclerosing agent (typically talc) can be delivered by tube thoracostomy, video-assisted thoracic surgery (VATS), or medical pleuroscopy. Although the latter 2 methods allow direct visualization of the pleural space and, in theory, a more even distribution of the sclerosing agent, current evidence does not favor 1 option over the other,¹⁹ and practice patterns vary between institutions.

Tube thoracostomy. Typically, the sclerosing agent is administered once a chest radiograph shows lung reexpansion, and tube output of pleural fluid is less than 150 mL/day.¹⁹ However, some studies indicate that if pleural apposition can be confirmed using ultrasonography, then sclerosant administration at that time leads to optimal pleurodesis efficacy and shorter hospitalization.^20,21

VATS is usually done in the operating room with the patient under general anesthesia. A double-lumen endotracheal tube allows for single-lung ventilation; a camera is then inserted into the pleural space of the collapsed lung. Multiple ports of entry are usually employed, and the entire pleural space can be visualized and the sclerosing agent instilled uniformly. The surgeon may alternatively choose to perform mechanical pleurodesis, which entails abrading the visceral and parietal pleura with dry gauze to provoke diffuse petechial hemorrhage and an inflammatory reaction. VATS can also be used to perform biopsy, lobectomy, and pneumonectomy.

Medical pleuroscopy. Medical pleuroscopy is usually done using local anesthesia with the patient awake, moderately sedated, and not intubated. Because no double-lumen endotracheal tube is used, lung collapse may not be complete, making it difficult to completely visualize the entire pleural surfaces.

Although no randomized study of VATS vs medical pleuroscopy exists, a retrospective case-matched study²² comparing VATS (under general anesthesia) to single-port VATS (under local anesthesia) noted equivalent rates of pleurodesis. However, the local anesthesia group had a lower perioperative mortality rate (0% vs 2.3%), a lower postoperative major morbidity rate (5.2% vs 9%), earlier improvement in quality of life, and shorter hospitalization (3 vs 5 days).²² In general, the diagnostic sensitivity of pleuroscopy for pleural malignancy is similar to that of VATS (93% vs 97%).^23,24

A MAN WITH PLEURAL EFFUSION AND A POOR PROGNOSIS

A 60-year-old man with metastatic pancreatic cancer is brought to the clinic for worsening shortness of breath over the past 2 months. During that time, he has lost 6 kg and has become bedridden.

On examination, he has severe cachexia and is significantly short of breath at rest with associated hypoxia. His oncologist expects him to survive less than 3 months.

His laboratory investigations reveal hypoalbuminemia and leukocytosis. A chest radiograph shows a large left-sided pleural effusion that was not present 2 months ago.

What should be done for him?

Thoracentesis, repeat as needed

Malignant pleural effusion causing dyspnea is not uncommon in certain advanced malignancies and may contribute to significant suffering at the end of life. A study of 298 patients with malignant pleural effusion noted that the presence of leukocytosis, hypoalbuminemia, and hypoxemia was associated with a poorer prognosis. Patients having all 3 factors had a median survival of 42 days.²⁵

Thoracentesis, the least invasive option that may improve dyspnea, can be done in the clinic setting and is a reasonable strategy for patients with advanced cancer and an expected survival of less than 3 months.²⁶ Although recurrence is expected, it may take up to a few weeks, and repeat thoracentesis can be performed as needed.

Managing patients with malignant pleural effusion can be challenging. Symptoms are often distressing, and its presence signifies advanced disease. Median survival after diagnosis is 4 to 9 months,^1–3 although prognosis varies considerably depending on the type and stage of the malignancy.

How patients are best managed depends on clinical circumstances. Physicians should consider the risks and benefits of each option while keeping in mind realistic goals of care.

This article uses brief case presentations to review management strategies for malignant pleural effusion.

CANCER IS A COMMON CAUSE OF PLEURAL EFFUSION

Physicians and surgeons, especially in tertiary care hospitals, must often manage malignant pleural effusion.⁴ Malignancy is the third leading cause of pleural effusion after heart failure and pneumonia, accounting for 44% to 77% of exudates.⁵ Although pleural effusion can arise secondary to many different malignancies, the most common causes are lung cancer in men and breast cancer in women; these cancers account for about 75% of all cases of malignant pleural effusion.^6,7

A WOMAN ON CHEMOTHERAPY WITH ASYMPTOMATIC PLEURAL EFFUSION

An 18-year-old woman with non-Hodgkin lymphoma has received her first cycle of chemotherapy and is now admitted to the hospital for diarrhea. A routine chest radiograph reveals a left-sided pleural effusion covering one-third of the thoracic cavity. She is asymptomatic and reports no shortness of breath at rest or with exertion. Her oxygen saturation level is above 92% on room air without supplemental oxygen.

Thoracentesis reveals an exudative effusion, and cytologic study shows malignant lymphoid cells, consistent with a malignant pleural effusion. Cultures are negative.

What is the appropriate next step to manage this patient’s effusion?

Observation is reasonable

This patient is experiencing no symptoms and has just begun chemotherapy for her lymphoma. Malignant pleural effusion associated with lymphoma, small-cell lung cancer, and breast cancer is most sensitive to chemotherapy.⁵ For patients who do not have symptoms from the pleural effusion and who are scheduled to receive further chemotherapy, a watch-and-wait approach is reasonable.

It is important to follow the patient for developing symptoms and obtain serial imaging to evaluate for an increase in the effusion size. We recommend repeat imaging at 2- to 4-week intervals, and sooner if symptoms develop.

If progression is evident or if the patient’s oncologist indicates that the cancer is unresponsive to systemic therapy, further intervention may be necessary with one of the options discussed below.

A MAN WITH LUNG CANCER WITH PLEURAL EFFUSION, LUNG COLLAPSE

A 42-year-old man with a history of lung cancer is admitted for worsening shortness of breath. Chest radiography reveals a large left-sided pleural effusion with complete collapse of the left lung and contralateral shift of midline structures (Figure 1). Large-volume thoracentesis improves his symptoms. Pleural fluid cytology is positive for malignant cells. A repeat chest radiograph shows incomplete expansion of the left lung, thick pleura, and pneumothorax, indicating a trapped lung (ie, one unable to expand fully). Two weeks later, his symptoms recur, and chest radiography reveals a recurrent effusion.

How should this effusion be managed?

Indwelling pleural catheter placement

In a retrospective cohort study,⁸ malignant pleural effusion recurred in 97% of patients within 1 month (mean, 4.2 days) of therapeutic aspiration, highlighting the need for definitive treatment.

In the absence of lung expansion, pleuro­desis is rarely successful, and placing an indwelling pleural catheter in symptomatic patients is the preferred strategy. The US Food and Drug Administration approved this use in 1997.⁹

Indwelling pleural catheters are narrow (15.5 French, or about 5 mm in diameter) and soft (made of silicone), with distal fenestrations. The distal end remains positioned in the pleural cavity to enable drainage of pleural fluid. The middle portion passes through subcutaneous tissue, where a polyester cuff prevents dislodgement and infection. The proximal end of the catheter remains outside the patient’s skin and is connected to a 1-way valve that prevents air or fluid flow into the pleural cavity.

Pleural fluid is typically drained every 2 or 3 days for palliation. Patients must be educated about home drainage and proper catheter care.

Although indwelling pleural catheters were first used for patients who were not candidates for pleurodesis, they are now increasingly used as first-line therapy.

Since these devices were introduced, several clinical series including more than 800 patients have found that their use for malignant pleural infusion led to symptomatic improvement in 89% to 100% of cases, with 90% of patients needing no subsequent pleural procedures after catheter insertion.^10–13

Davies et al¹⁴ randomized 106 patients with malignant pleural effusion to either receive an indwelling pleural catheter or undergo pleurodesis. In the first 6 weeks, the 2 groups had about the same incidence of dyspnea, but the catheter group had less dyspnea at 6 months, shorter index hospitalization (0 vs 4 days), fewer hospital days in the first year for treatment-related complications (1 vs 4.5 days), and fewer patients needing follow-up pleural procedures (6% vs 22%). On the other hand, adverse events were more frequent in the indwelling pleural catheter group (40% vs 13%). The most frequent events were pleural infection, cellulitis, and catheter blockage.

Fysh et al¹⁵ also compared indwelling pleural catheter insertion and pleurodesis (based on patient choice) in patients with malignant pleural effusion. As in the previous trial, those who received a catheter required significantly fewer days in the hospital and fewer additional pleural procedures than those who received pleurodesis. Safety profiles and symptom control were comparable.

Indwelling pleural catheters have several other advantages. They have been found to be more cost-effective than talc pleurodesis in patients not expected to live long (survival < 14 weeks).¹⁶ Patients with an indwelling pleural catheter can receive chemotherapy, and concurrent treatment does not increase risk of infection.¹⁷ And a systematic review¹⁸ found a 46% rate of autopleurodesis at a median of 52 days after insertion of an indwelling pleural catheter.

Drainage rate may need to be moderated

Chest pain has been reported with the use of indwelling pleural catheters, related to rapid drainage of the effusion in the setting of failed reexpansion of the trapped lung due to thickened pleura. Drainage schedules may need to be adjusted, with more frequent draining of smaller volumes, to control dyspnea without causing significant pain.

A WOMAN WITH RECURRENT PLEURAL EFFUSION, GOOD PROGNOSIS

A 55-year-old woman with a history of breast cancer presents with shortness of breath. Chest radiography reveals a right-sided effusion, which on thoracentesis is found to be malignant. After fluid removal, repeat chest radiography shows complete lung expansion.

One month later, she returns with symptoms and recurrence of the effusion. Ultrasonography does not reveal any adhesions in the pleural space. Her oncologist informs you that her expected survival is in years.

What is the next step?

Chemical pleurodesis

Chemical pleurodesis involves introducing a sclerosant into the pleural space to provoke an intense inflammatory response, creating adhesions and fibrosis that will obliterate the space. The sclerosing agent (typically talc) can be delivered by tube thoracostomy, video-assisted thoracic surgery (VATS), or medical pleuroscopy. Although the latter 2 methods allow direct visualization of the pleural space and, in theory, a more even distribution of the sclerosing agent, current evidence does not favor 1 option over the other,¹⁹ and practice patterns vary between institutions.

Tube thoracostomy. Typically, the sclerosing agent is administered once a chest radiograph shows lung reexpansion, and tube output of pleural fluid is less than 150 mL/day.¹⁹ However, some studies indicate that if pleural apposition can be confirmed using ultrasonography, then sclerosant administration at that time leads to optimal pleurodesis efficacy and shorter hospitalization.^20,21

VATS is usually done in the operating room with the patient under general anesthesia. A double-lumen endotracheal tube allows for single-lung ventilation; a camera is then inserted into the pleural space of the collapsed lung. Multiple ports of entry are usually employed, and the entire pleural space can be visualized and the sclerosing agent instilled uniformly. The surgeon may alternatively choose to perform mechanical pleurodesis, which entails abrading the visceral and parietal pleura with dry gauze to provoke diffuse petechial hemorrhage and an inflammatory reaction. VATS can also be used to perform biopsy, lobectomy, and pneumonectomy.

Medical pleuroscopy. Medical pleuroscopy is usually done using local anesthesia with the patient awake, moderately sedated, and not intubated. Because no double-lumen endotracheal tube is used, lung collapse may not be complete, making it difficult to completely visualize the entire pleural surfaces.

Although no randomized study of VATS vs medical pleuroscopy exists, a retrospective case-matched study²² comparing VATS (under general anesthesia) to single-port VATS (under local anesthesia) noted equivalent rates of pleurodesis. However, the local anesthesia group had a lower perioperative mortality rate (0% vs 2.3%), a lower postoperative major morbidity rate (5.2% vs 9%), earlier improvement in quality of life, and shorter hospitalization (3 vs 5 days).²² In general, the diagnostic sensitivity of pleuroscopy for pleural malignancy is similar to that of VATS (93% vs 97%).^23,24

A MAN WITH PLEURAL EFFUSION AND A POOR PROGNOSIS

A 60-year-old man with metastatic pancreatic cancer is brought to the clinic for worsening shortness of breath over the past 2 months. During that time, he has lost 6 kg and has become bedridden.

On examination, he has severe cachexia and is significantly short of breath at rest with associated hypoxia. His oncologist expects him to survive less than 3 months.

His laboratory investigations reveal hypoalbuminemia and leukocytosis. A chest radiograph shows a large left-sided pleural effusion that was not present 2 months ago.

What should be done for him?

Thoracentesis, repeat as needed

Malignant pleural effusion causing dyspnea is not uncommon in certain advanced malignancies and may contribute to significant suffering at the end of life. A study of 298 patients with malignant pleural effusion noted that the presence of leukocytosis, hypoalbuminemia, and hypoxemia was associated with a poorer prognosis. Patients having all 3 factors had a median survival of 42 days.²⁵

Thoracentesis, the least invasive option that may improve dyspnea, can be done in the clinic setting and is a reasonable strategy for patients with advanced cancer and an expected survival of less than 3 months.²⁶ Although recurrence is expected, it may take up to a few weeks, and repeat thoracentesis can be performed as needed.

At present, 300,000 US women undergo breast augmentation surgery each year,¹ making this the second most common aesthetic procedure in women (after liposuction),^2–4 and making it extremely likely that clinicians will encounter women who have breast implants. In addition, approximately 110,000 women undergo breast reconstructive surgery after mastectomy, of whom more than 88,000 (81%) receive implants (2016 data).⁵

This review discusses the evolution of breast implants, their complications, and key considerations with regard to aesthetic and reconstructive breast surgery, as the principles are similar.

EVOLUTION OF IMPLANTS

Reports of breast augmentation surgery, also known as augmentation mammoplasty, date back to 1895, when a fatty tumor (lipoma) was successfully transplanted from a patient’s back to a breast defect in a mastectomy patient.^2,3,6,7 In the 1930s, implantation of a glass ball into a patient’s breast marked the first implant-based breast augmentation.⁶ By 1954, attempts at breast augmentation using local dermal-fat flaps, adipose tissue, and even omentum were described.

Alloplastic materials gained popularity throughout the 1950s and 1960s and included polyurethane, polytetrafluoroethylene (Teflon), and other synthetics. Adverse reactions associated with alloplastic materials were plentiful: local tissue reactions, distortion of the breast mound, increased firmness, and discomfort all contributed to the eventual discontinuation of their use. The history of alloplastic breast augmentation also included epoxy resin, shellac, beeswax, paraffin, rubber, petroleum jelly, and liquefied silicone. Outcomes were not good, and many patients ultimately needed mastectomy.⁷

The first modern breast prosthesis was developed in 1961, and since then, implant composition and design have evolved significantly.⁸

From silicone to saline, and back again

The first silicone gel implants, introduced in the early 1960s,^8–19 had high complication rates—some centers reported an incidence of capsular contracture of up to 70%.^8,11 This is a foreign body reaction in which pathologic scar tissue encases the implant, causing it to distort, appear misshapen, harden, and even become painful.¹¹ Attempts to minimize this reaction led to later generations of silicone implants with polyurethane shells.¹²

Inflatable implants filled with sterile saline solution were originally developed in France in 1965. Unlike silicone implants, saline implants have undergone minimal changes since their inception, and grew in popularity during the 1970s in view of the high rates of capsular contracture with silicone implants.⁸ However, saline implants have their own problems, and as they became increasingly popular, deflation and the unnatural feel of saline sparked a renewed interest in silicone gel.

By the late 1980s, the thinner-shelled generation of silicone implants displayed its own frustrating complications including implant rupture, capsular contracture, infection, and possible systemic and disseminated granulomatous disease. From 1992 to 2006, the US Food and Drug Administration (FDA) placed a moratorium on silicone implants due to concerns about a possible link with autoimmune and connective tissue diseases and the possible carcinogenic nature of silicone.

While silicone implants were prohibited in the United States, development continued abroad, and eventually the moratorium was lifted after several meta-analyses failed to reveal any link regarding the aforementioned concerns.¹³

Today, silicone gel implants dominate the world market.¹⁴ In the United States, approximately 60% of implants contain silicone gel filler, and trends are similar in Europe.⁷

Table 1 summarizes the evolution of silicone breast implants over the last 50 years.^2,6,11,12Table 2 lists the advantages and disadvantages of silicone and saline breast implants.^2,6,8,15

CURRENT IMPLANT OPTIONS

Currently, 3 companies (Allergan, Mentor, Sientra) manufacture and distribute breast implants and implant-associated products such as tissue expanders and sizers in the US market.⁶

Another company, Motiva, makes an implant that is available in Europe, Asia, and Australia, and the device is currently undergoing a 10-year clinical trial in the United States that began recruiting patients in 16 centers in April 2018.¹⁶ Pending final approval, the Cleveland Clinic Department of Plastic Surgery may be among the centers involved in the clinical trial of the Motiva implant. Innovations in the Motiva implant include a high-performance shell that maintains consistent strength and includes a proprietary barrier layer, improved silicone gel filler, 3-D imprinted surface texturing, and an implant shape that adapts with vertical and horizontal movement. It also contains radio-frequency identification transponders that can transmit data about the implant wirelessly.^17–19

Developed in the 1980s, texturing of the implant surface disrupts capsule formation around the prosthesis. Additionally, texturing stabilizes an anatomically shaped (teardrop) implant within the breast pocket, reducing malrotation.^20,21

The first textured implants were covered with polyurethane foam, but they were ultimately withdrawn from the US market because of concern for in vivo degradation to carcinogenic compounds. The focus subsequently turned to texturing implant shells by mechanically creating pores of different sizes. Smooth implants, by contrast, are manufactured by repeatedly dipping the implant shell into liquid silicone.²

The capsular contraction rate has been shown to be lower with textured silicone than with smooth silicone (number needed to treat = 7–9), and evidence suggests a lower risk of needing a secondary procedure.²¹

Form-stable vs fluid-form

Silicone is a polymer. The physical properties of polymers vary greatly and depend on the length of the individual chains and the degree to which those chains are cross-linked. Liquid silicone contains short chains and sparse cross-linking, resulting in an oily compound well suited for lubrication. Silicone gel contains longer chains and more cross-linking and is therefore more viscous.

In “form-stable” implants, the silicone interior has sufficient chain length and cross-linking to retain the designed shape even at rest,² but they require slightly larger incisions.⁷ “Fluid-form” refers to an implant with silicone filler with shorter chain length, less cross-linking, and more fluidity.⁶

Shell

As with silicone fillers, the properties of silicone implant shells also depend on chain length and cross-linking within the polymer. Silicone elastomer shells (Table 1) contain extensively cross-linked chains that impart a flexible yet rubbery character. Silicone elastomers can also be found in facial implants and tissue expanders.²

Implant shape (round vs anatomic)

The shape of an implant is determined by the gel distribution inside of it. To understand gel distribution and implant shape, one must understand the gel-shell ratio. This ratio increases as cohesivity of the filler increases, and it represents increased bonding of the gel filler to the shell and a preserved implant shape at rest.

The gel-shell ratio varies among manufacturers, and a less-viscous filler may be more prone to rippling or loss of upper pole fullness in some patients. For this reason, careful analysis, patient and implant selection, and discussion of complications remain paramount.²

No anatomically shaped implant is manufactured with a smooth shell, but rather with a textured shell that resists malrotation.^6,15 However, in the United States, 95% of patients receive round implants.¹⁶

PATIENT ASSESSMENT

Before breast augmentation surgery, the surgeon assesses a number of factors—physical and psychosocial—and helps the patient choose a type and size of implant. The surgeon and patient also plan where the implants will be placed—ie, above or beneath the chest wall muscle—and where the incisions will be made. Every decision is made in close consultation with the patient, taking into account the patient’s desires and expectations, as well as what the patient’s anatomy allows. An integral component of this shared decision-making process is a discussion of the possible complications, and often photographs to better illustrate what to expect postoperatively. 

Psychosocial factors

One must consider the patient’s psychology, motivations for surgery, and emotional stability. Here, we look for underlying body dysmorphic disorder; excessive or unusual encouragement to undergo the procedure by a spouse, friends, or others; a history of other aesthetic procedures; unrealistic expectations; and other factors influencing the desire to undergo this surgery.

Choosing an implant

Implant selection must take into account the patient’s height, weight,⁷ and overall body morphology: taller patients and those with wider hips or shoulders usually require larger implants. A reliable method for determining the appropriate implant must include the current breast shape, dimensions, volume, skin elasticity, soft-tissue thickness, and overall body habitus. Ultimately, the most important considerations include breast base diameter, implant volume,²⁰ and soft-tissue envelope.

Preoperative sizing can involve placing sample implants within a brassiere so that the patient can preview possible outcomes. This method is particularly effective in minimizing dissatisfaction because it shares ownership of the decision-making process.¹⁵

A computerized implant selection program available in Europe suggests a “best-fit” implant based on a clinician’s measurements.⁷

Traditionally, plastic surgeons place breast implants either beneath the pectoralis major muscle (submuscular placement) or over the pectoralis⁸ but beneath the glandular breast parenchyma (subglandular placement) (Figure 2).⁷

Advantages of submuscular placement are a smoother transition of the upper breast pole from the chest wall and less rippling visible through the skin, due to the additional muscular coverage of the implant. Another advantage is that capsular contraction rates are lower with submuscular placement, likely due to possible contamination of implants by lactiferous ductal microbes when accessing the subglandular plane.^14,20 Disadvantages are pronounced discomfort after surgery and animation deformities with muscle contraction, particularly in young, highly active patients.

A popular modification of submuscular placement involves creating a surgical dissection plane between the subglandular tissue and the pectoralis major fascia. This “dual­­plane” approach allows the parenchyma to retract superiorly and reduce breast ptosis.⁷

Incisions

Table 3 highlights important considerations with regard to incision location.^15,20,21

ANTIBIOTICS

Many surgeons give a single prophylactic dose of antibiotic before surgery, a practice that some studies have shown to be effective in reducing the risk of infection.¹⁵ However, the benefit of routine postoperative use of antibiotics remains unsubstantiated¹⁵: postoperative antibiotic use does not appear to protect against infection, capsular contracture, or overall complications in primary or secondary breast augmentation surgery.²⁰

PERIOPERATIVE PERIOD

At our institution, breast augmentation surgery is an ambulatory procedure—the patient goes home the same day unless circumstances such as pain control warrant admission. This is, however, according to surgeon preference, and differs on a case-by-case basis. General anesthesia is the standard of care.¹⁵

POSTOPERATIVE PERIOD

In the immediate postoperative period, patients are instructed to wear a surgical bra for up to 6 weeks to allow stable scarring. Early mobilization is encouraged.^7,15 Depending on the patient’s situation, recovery, and healing, she may be out of work for about 1 week, sometimes more, sometimes less. 

Additional instructions are surgeon-specific. However, the patient is instructed to avoid bathing, swimming, immersion in water, and wearing underwire brassieres that could impair healing of an inferior incision; instead, patients are often instructed to wear a surgical bra provided on the day of surgery until cleared in the clinic.

Showering is allowed the next day or the second day after surgery, and of course there is no driving while on narcotics. Additionally, patients are counseled extensively regarding hematoma formation and the signs and symptoms of infection.

Patients are typically seen in clinic 1 week after surgery.

The cost of surgery may be $5,000 to $6,000 but can vary significantly from center to center depending on who the patient sees and where, and whether the patient presents for breast reconstruction after cancer or repair of congenital anomalies, or in certain cases of transgender surgery. The patient is typically responsible for the fee, but again this depends on the patient, indications, and particular insurance concerns.

IMPLANT LONGEVITY AND RUPTURE

In the United States, implant rupture rates range from 1.1% to 17.7% at 6 to 10 years after primary augmentation, 2.9% to 14.7% after revision augmentation, 1.5% to 35.4% after primary breast reconstruction, and 0% to 19.6% after revision reconstruction.¹¹

Unfortunately, the existence of multiple implant manufacturers, numerous implant generations, and poorly standardized screening protocols and reporting systems make the true rate of implant rupture difficult to assess without definitive imaging or implant retrieval.¹¹

Damage from surgical instrumentation during implantation is the most common cause of silicone breast implant rupture (50% to 64% of cases).²² Other causes include underfilling and fold flaw from capsular contracture.

Leakage of silicone gel filler may be confined to the periprosthetic capsule (intracapsular rupture) or extend beyond and into the breast parenchyma (extracapsular rupture). One study reported that only 10% of intracapsular ruptures progressed extracapsularly, while 84% of patients with extracapsular involvement remained stable for up to 2 years,²³ indicating that intracapsular rupture may not portend worsening disease.¹¹

Implant rupture occurs silently in most cases, with no clinically detectable signs or symptoms. In other cases, patients may present with alterations in breast shape and size, sudden asymmetry, firmness, pronounced capsular contracture, contour irregularity, or pain.

Aside from physical examination, comprehensive diagnostic testing includes imaging—ultrasonography, mammography, computed tomography, and magnetic resonance imaging (MRI). Of these, MRI is the method of choice, with sensitivity and specificity exceeding 90% for detecting implant rupture.¹¹ Classic findings on MRI include the “linguine” sign from a deflating implant shell, or the teardrop sign from implant sagging. Classic findings on ultrasonography include the “snowstorm” sign of extracapsular rupture and the “stepladder” sign of intracapsular rupture.

Mammography effectively detects free silicone in breast tissue with extracapsular rupture (25% of ruptures according to some studies)²³; however, it cannot detect rupture within the implant capsule. As an aside, submuscular implant placement may interfere less with screening mammography than subglandular implants do.^14,24

Current FDA recommendations to detect implant rupture encourage women with silicone breast implants to undergo screening 3 years after implantation and then every 2 years thereafter; no long-term monitoring is suggested for saline implants.¹⁵ Many plastic surgeons evaluate silicone breast implant patients every 1 to 2 years for contracture and rupture.⁸ Of note, capsular contracture impairs the effectiveness of ultrasonography and may require MRI confirmation.¹¹

If implant rupture is confirmed, the current recommendation is to remove the implant and the capsule. Another implant may be placed depending on the patient’s preference. Rigorous washout remains a key feature of any surgical intervention for ruptured breast implants; however, in the event of extracapsular rupture, resection of silicone granulomas may also be required.¹¹

Reoperation rates for primary breast augmentation surgery approach 20% and are even higher for secondary augmentation over a patient’s lifetime—the highest rate of all aesthetic procedures.^7,14

Capsular contracture is the most common complication of breast augmentation,²⁵ typically presenting within the first postoperative year,^26,27 and the risk increases over time.²⁸ It occurs with both silicone and saline breast implants.

In some studies, the incidence exceeded 4% in the first 2 years after surgery,²⁹ and nearly 50% by 10 years.³⁰ Other studies found rates of 0% to 20% over 13 years.²⁰

The etiology is not well understood and is presumed to be multifactorial, with proposed mechanisms and factors that include bacterial contamination, surface texturing, the implant pocket selected, the incision type, drain placement, antibiotic use, and smoking.²⁵

A meta-analysis from 17,000 implants found that the risk of capsular contracture was significantly higher when an implant was placed in a subglandular pocket than in a submuscular pocket,^22,26 and that although texturing decreased capsular contracture compared with smooth implants, the effect was modest when a textured or smooth implant was placed in a submuscular location.²⁸ With regard to incision location, studies have reported that the incidence of capsular contracture is highest with transaxillary and periareolar incisions, and lowest with inframammary incisions.^20,21

The leading theory is that contamination of the implant (primarily from the mammary ducts) results in biofilm formation. Subclinical hematoma surrounding the implant may also provide key bacterial nutrients.²⁰

Textured implants induce a greater inflammatory response in the capsular tissue, resulting in a thicker capsule; however, contracture rates remain lower with textured than with smooth implants.^14,31 Interestingly, lower rates of capsular contracture have been observed with later-generation, cohesive-gel, form-stable implants than with those of earlier generations.¹²

Although more research is needed, silicone implants appear to confer a higher risk of capsular contracture than saline implants.^14,20

Irrigating the breast pocket intraoperatively with triple antibiotic solution (bacitracin, cefazolin, and gentamicin) before placing the implant may decrease the capsular contracture rate.^15,20

Treatments for capsular contracture include pocket modifications such as capsulotomy (making releasing, relaxing incisions in the scar capsule encasing the implant), capsulectomy (removing portions of or the entire capsule), and replacing the implant in the other pocket (ie, if the original implant was subglandular, the replacement is placed in the submuscular pocket). Patients who have contractures that fail to respond to these treatments may ultimately benefit from implant removal and autologous reconstruction (autoaugmentation) rather than implant replacement.^32,33

ADDITIONAL COMPLICATIONS

Other complications include infection, malposition, rippling, seroma, hematoma, and sensory alterations.

Irrigation during the implantation procedure with a triple antibiotic solution consisting of bacitracin, gentamycin, and cephalexin in normal saline decreases infection and seroma rates.^15,20,34

Some surgeons also choose to irrigate the pocket with a betadine solution, or to cleanse the skin with betadine and place sterile towels and redrape before inserting the implant. Additionally, many prefer using a sterile device much like a pastry funnel called a Keller funnel to insert the implant into the breast pocket.³⁵

Infection is less common with cosmetic augmentations than with implant-based breast reconstruction, likely because of healthier, well-vascularized tissue in patients undergoing cosmetic surgery than in those undergoing mastectomy.¹⁴

Seroma is thought to be a consequence of texturing, and more so with macro- vs microtexturing. Though poorly understood, an association between texturing and double capsules has also been reported.^12,20

After primary breast augmentation, 10-year follow-up rates of capsular contracture, seroma, rippling, and malposition vary across the 3 major silicone implant manufacturers.¹² Hematoma and infection occur in less than 1% of primary augmentation patients.¹⁵

Malposition of the implant over time is less frequent with textured implants because of the higher coefficient of friction compared with smooth implants^.6,8,15

Visible skin rippling may be a consequence of texturing and also of thin body habitus, eg, in patients with a body mass index less than 18.5 kg/m². If the soft-tissue layer of the breast is thin, the natural rippling of smooth saline implant shells are more likely to show when placed in the subglandular pocket. Form-stable implants, by contrast, resist rippling.^12,15

Large implants and extensive lateral dissection can cause alterations in nipple sensation and sensory loss within lower breast pole skin. Axillary incisions may traumatize or damage the intercostobrachial nerve, resulting in upper inner arm sensory aberrations.

Ultimately, the 10-year incidence of secondary surgery ranges from 0% to 36% and the 10-year incidence of capsular contracture ranges from 11% to 19%.¹⁵ Additional cosmetic complaints after augmentation with implants include enlargement of the areola and engorgement of breast veins.¹⁴

BREAST CANCER AND DETECTION

Patients with or without implants do not seem to differ with regard to breast cancer stage upon detection, tumor burden, recurrence, or survival. However, more patients with implants may present with palpable masses, invasive tumors, axillary metastasis, and falsely negative mammograms.

Breast implants may actually facilitate cancer detection on physical examination by providing a more dense or stable surface upon which to palpate the breast tissue. Although they do not necessarily impair mastectomy or breast reconstruction, they may result in an increased rate of revision surgery after breast conservation therapy.^24,36 Mammography remains the standard of care for radiologic diagnosis but can be further supported by MRI and ultrasonography if necessary in patients with implants.

Although concerns persist, multiple studies have demonstrated the safety of fourth- and fifth-generation silicone breast implants with regard to autoimmune disease.⁷

In various clinical studies in mastectomy patients who underwent breast reconstruction with either silicone implants or autologous tissue, no difference was found with regard to the incidence of autoimmune diseases.² Additionally, in meta-analyses of data from more than 87,000 women, no association was found between connective tissue disease and silicone breast implants.^2,11 One study^11,23 noted no increase in autoantibodies in patients with undamaged silicone implants vs patients who experienced rupture.

Studies have also demonstrated that in children born to mothers with breast implants, the risk of rheumatic disease, esophageal disorders, congenital malformations, and death during the perinatal period is comparable with that in controls.³⁷ Another study, examining breastfeeding in women with silicone breast implants, showed no significant difference in silicon levels (used as a proxy for silicone) in breast milk compared with controls without implants; silicon levels were found to be significantly higher in cow’s milk and store-bought formulas.³⁸

BREAST IMPLANT-ASSOCIATED ANAPLASTIC LARGE-CELL LYMPHOMA

Breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) is a subtype of T-cell lymphoma that develops in tissue adjacent to breast implants. It typically presents as breast swelling 2 to 38 years (mean of 8 years) after implant insertion.^39,40 The swelling may be secondary to periprosthetic seroma formation or, more rarely, palpable disease in the axilla. Patients occasionally complain of pain and, rarely, constitutional symptoms.²⁰ BIA-ALCL is not a disease of the surrounding breast tissue, but rather of the fibrous periprosthetic capsule.²¹

Of note, there is no documented case involving smooth implants,^41–43 but it may be related to fifth-generation textured implants.⁶ At present, it is not possible to definitively state which implant is associated with this condition; hence, more data are needed, and this association is currently under study.

The absolute risk of BIA-ALCL was reported in a Dutch study³⁹ as 1 in 35,000 by age 50, 1 in 12,000 by age 70, and 1 in 7,000 by age 75, with a number needed to harm of 6,920. Overall lifetime risk was estimated at 1 in 30,000 for women with textured implants in a 2015 US study.⁴⁰ In comparison, breast cancer risk is about 1 in 8 women. There is no apparent predilection for patients who underwent cosmetic augmentation vs reconstruction, or who received silicone vs saline implants.

The diagnosis is confirmed by ultrasonographically guided fine-needle aspiration of seroma fluid and subsequent immunohistochemical testing for CD30-positive and ALK-negative T lymphocytes. Other than positron-emission tomography for staging after diagnosis confirmation, imaging is ineffective. Expert opinion does not recommend routine screening unless the aforementioned symptoms arise.

Treatment involves implant removal and total capsulectomy, with samples sent for pathology study with cytokeratin staining.¹² Of note, in all cases of BIA-ALCL in which the disease was limited to the circumscribed scar tissue of the breast capsule, complete surgical excision has proved curative, whereas incomplete capsulectomy portends a greater risk of recurrence and decreased survival.⁴⁴

In cases of advanced or recurrent ALCL, diagnosed late or inappropriately, the National Comprehensive Cancer Network recommends a multidisciplinary approach involving adjuvant chemotherapy and radiation.⁴⁴ Anecdotally, at our institution, we have recently treated several cases of advanced ALCL presenting with invasive chest wall masses with extirpative surgery and subsequent reconstruction with the assistance of our thoracic surgery colleagues, as well as the aforementioned multidisciplinary approach using adjuvant therapy.

The mechanism of this malignancy is currently under investigation, but the current theory implicates an exaggerated lymphoproliferative response to bacterial contamination of the capsule superimposed upon genetic factors in susceptible patients.^42,43

National societies advise plastic surgeons to discuss the risk of BIA-ALCL with all patients at the time of breast augmentation consultation and to report all confirmed cases to the PROFILE registry (Patient Registry and Outcomes for Breast Implants and Anaplastic Large Cell Lymphoma Etiology and Epidemiology).⁴⁵

ARE PATIENTS HAPPIER AFTERWARD?

Studies have shown that after undergoing breast augmentation surgery, patients note improvement in body image, and satisfaction rates range from 85% to 95% with respect to self-confidence and body image.⁴⁶ An evaluation of patient responses on the validated BREAST-Q Augmentation Questionnaire showed the following satisfaction rates: breasts 83%, psychosocial well-being 88%, and sexual functioning 81%.¹⁵

Although epidemiologic studies have reported higher suicide rates in women with cosmetic breast implants, this likely stems from preoperative psychological factors and underscores the role of psychiatric referral in patients with a mental health history or in those whom the surgeon deems it necessary.⁴⁶

Several high-quality studies have demonstrated that quality of life and psychosocial functioning (including depression) markedly improve after breast augmentation surgery.⁴⁷ Among a cohort of Norwegian patients, breast implant surgery resulted in improved motivation to perform daily activities, as well as improved quality of life from both a psychosocial and aesthetic perspective.⁴⁸ Interestingly, a recent study reported that patients who underwent breast implant surgery alone reported greater satisfaction and psychosocial quality of life than patients who underwent combination breast augmentation and mastopexy (breast-lifting) surgery.⁴⁹

Additional data are needed to refine our understanding of the complex interplay between psychosocial factors before and after surgery in patients seeking and undergoing breast augmentation procedures.

At present, 300,000 US women undergo breast augmentation surgery each year,¹ making this the second most common aesthetic procedure in women (after liposuction),^2–4 and making it extremely likely that clinicians will encounter women who have breast implants. In addition, approximately 110,000 women undergo breast reconstructive surgery after mastectomy, of whom more than 88,000 (81%) receive implants (2016 data).⁵

This review discusses the evolution of breast implants, their complications, and key considerations with regard to aesthetic and reconstructive breast surgery, as the principles are similar.

EVOLUTION OF IMPLANTS

Reports of breast augmentation surgery, also known as augmentation mammoplasty, date back to 1895, when a fatty tumor (lipoma) was successfully transplanted from a patient’s back to a breast defect in a mastectomy patient.^2,3,6,7 In the 1930s, implantation of a glass ball into a patient’s breast marked the first implant-based breast augmentation.⁶ By 1954, attempts at breast augmentation using local dermal-fat flaps, adipose tissue, and even omentum were described.

Alloplastic materials gained popularity throughout the 1950s and 1960s and included polyurethane, polytetrafluoroethylene (Teflon), and other synthetics. Adverse reactions associated with alloplastic materials were plentiful: local tissue reactions, distortion of the breast mound, increased firmness, and discomfort all contributed to the eventual discontinuation of their use. The history of alloplastic breast augmentation also included epoxy resin, shellac, beeswax, paraffin, rubber, petroleum jelly, and liquefied silicone. Outcomes were not good, and many patients ultimately needed mastectomy.⁷

The first modern breast prosthesis was developed in 1961, and since then, implant composition and design have evolved significantly.⁸

From silicone to saline, and back again

The first silicone gel implants, introduced in the early 1960s,^8–19 had high complication rates—some centers reported an incidence of capsular contracture of up to 70%.^8,11 This is a foreign body reaction in which pathologic scar tissue encases the implant, causing it to distort, appear misshapen, harden, and even become painful.¹¹ Attempts to minimize this reaction led to later generations of silicone implants with polyurethane shells.¹²

Inflatable implants filled with sterile saline solution were originally developed in France in 1965. Unlike silicone implants, saline implants have undergone minimal changes since their inception, and grew in popularity during the 1970s in view of the high rates of capsular contracture with silicone implants.⁸ However, saline implants have their own problems, and as they became increasingly popular, deflation and the unnatural feel of saline sparked a renewed interest in silicone gel.

By the late 1980s, the thinner-shelled generation of silicone implants displayed its own frustrating complications including implant rupture, capsular contracture, infection, and possible systemic and disseminated granulomatous disease. From 1992 to 2006, the US Food and Drug Administration (FDA) placed a moratorium on silicone implants due to concerns about a possible link with autoimmune and connective tissue diseases and the possible carcinogenic nature of silicone.

While silicone implants were prohibited in the United States, development continued abroad, and eventually the moratorium was lifted after several meta-analyses failed to reveal any link regarding the aforementioned concerns.¹³

Today, silicone gel implants dominate the world market.¹⁴ In the United States, approximately 60% of implants contain silicone gel filler, and trends are similar in Europe.⁷

Table 1 summarizes the evolution of silicone breast implants over the last 50 years.^2,6,11,12Table 2 lists the advantages and disadvantages of silicone and saline breast implants.^2,6,8,15

CURRENT IMPLANT OPTIONS

Currently, 3 companies (Allergan, Mentor, Sientra) manufacture and distribute breast implants and implant-associated products such as tissue expanders and sizers in the US market.⁶

Another company, Motiva, makes an implant that is available in Europe, Asia, and Australia, and the device is currently undergoing a 10-year clinical trial in the United States that began recruiting patients in 16 centers in April 2018.¹⁶ Pending final approval, the Cleveland Clinic Department of Plastic Surgery may be among the centers involved in the clinical trial of the Motiva implant. Innovations in the Motiva implant include a high-performance shell that maintains consistent strength and includes a proprietary barrier layer, improved silicone gel filler, 3-D imprinted surface texturing, and an implant shape that adapts with vertical and horizontal movement. It also contains radio-frequency identification transponders that can transmit data about the implant wirelessly.^17–19

Developed in the 1980s, texturing of the implant surface disrupts capsule formation around the prosthesis. Additionally, texturing stabilizes an anatomically shaped (teardrop) implant within the breast pocket, reducing malrotation.^20,21

The first textured implants were covered with polyurethane foam, but they were ultimately withdrawn from the US market because of concern for in vivo degradation to carcinogenic compounds. The focus subsequently turned to texturing implant shells by mechanically creating pores of different sizes. Smooth implants, by contrast, are manufactured by repeatedly dipping the implant shell into liquid silicone.²

The capsular contraction rate has been shown to be lower with textured silicone than with smooth silicone (number needed to treat = 7–9), and evidence suggests a lower risk of needing a secondary procedure.²¹

Form-stable vs fluid-form

Silicone is a polymer. The physical properties of polymers vary greatly and depend on the length of the individual chains and the degree to which those chains are cross-linked. Liquid silicone contains short chains and sparse cross-linking, resulting in an oily compound well suited for lubrication. Silicone gel contains longer chains and more cross-linking and is therefore more viscous.

In “form-stable” implants, the silicone interior has sufficient chain length and cross-linking to retain the designed shape even at rest,² but they require slightly larger incisions.⁷ “Fluid-form” refers to an implant with silicone filler with shorter chain length, less cross-linking, and more fluidity.⁶

Shell

As with silicone fillers, the properties of silicone implant shells also depend on chain length and cross-linking within the polymer. Silicone elastomer shells (Table 1) contain extensively cross-linked chains that impart a flexible yet rubbery character. Silicone elastomers can also be found in facial implants and tissue expanders.²

Implant shape (round vs anatomic)

The shape of an implant is determined by the gel distribution inside of it. To understand gel distribution and implant shape, one must understand the gel-shell ratio. This ratio increases as cohesivity of the filler increases, and it represents increased bonding of the gel filler to the shell and a preserved implant shape at rest.

The gel-shell ratio varies among manufacturers, and a less-viscous filler may be more prone to rippling or loss of upper pole fullness in some patients. For this reason, careful analysis, patient and implant selection, and discussion of complications remain paramount.²

No anatomically shaped implant is manufactured with a smooth shell, but rather with a textured shell that resists malrotation.^6,15 However, in the United States, 95% of patients receive round implants.¹⁶

PATIENT ASSESSMENT

Before breast augmentation surgery, the surgeon assesses a number of factors—physical and psychosocial—and helps the patient choose a type and size of implant. The surgeon and patient also plan where the implants will be placed—ie, above or beneath the chest wall muscle—and where the incisions will be made. Every decision is made in close consultation with the patient, taking into account the patient’s desires and expectations, as well as what the patient’s anatomy allows. An integral component of this shared decision-making process is a discussion of the possible complications, and often photographs to better illustrate what to expect postoperatively. 

Psychosocial factors

One must consider the patient’s psychology, motivations for surgery, and emotional stability. Here, we look for underlying body dysmorphic disorder; excessive or unusual encouragement to undergo the procedure by a spouse, friends, or others; a history of other aesthetic procedures; unrealistic expectations; and other factors influencing the desire to undergo this surgery.

Choosing an implant

Implant selection must take into account the patient’s height, weight,⁷ and overall body morphology: taller patients and those with wider hips or shoulders usually require larger implants. A reliable method for determining the appropriate implant must include the current breast shape, dimensions, volume, skin elasticity, soft-tissue thickness, and overall body habitus. Ultimately, the most important considerations include breast base diameter, implant volume,²⁰ and soft-tissue envelope.

Preoperative sizing can involve placing sample implants within a brassiere so that the patient can preview possible outcomes. This method is particularly effective in minimizing dissatisfaction because it shares ownership of the decision-making process.¹⁵

A computerized implant selection program available in Europe suggests a “best-fit” implant based on a clinician’s measurements.⁷

Traditionally, plastic surgeons place breast implants either beneath the pectoralis major muscle (submuscular placement) or over the pectoralis⁸ but beneath the glandular breast parenchyma (subglandular placement) (Figure 2).⁷

Advantages of submuscular placement are a smoother transition of the upper breast pole from the chest wall and less rippling visible through the skin, due to the additional muscular coverage of the implant. Another advantage is that capsular contraction rates are lower with submuscular placement, likely due to possible contamination of implants by lactiferous ductal microbes when accessing the subglandular plane.^14,20 Disadvantages are pronounced discomfort after surgery and animation deformities with muscle contraction, particularly in young, highly active patients.

A popular modification of submuscular placement involves creating a surgical dissection plane between the subglandular tissue and the pectoralis major fascia. This “dual­­plane” approach allows the parenchyma to retract superiorly and reduce breast ptosis.⁷

Incisions

Table 3 highlights important considerations with regard to incision location.^15,20,21

ANTIBIOTICS

Many surgeons give a single prophylactic dose of antibiotic before surgery, a practice that some studies have shown to be effective in reducing the risk of infection.¹⁵ However, the benefit of routine postoperative use of antibiotics remains unsubstantiated¹⁵: postoperative antibiotic use does not appear to protect against infection, capsular contracture, or overall complications in primary or secondary breast augmentation surgery.²⁰

PERIOPERATIVE PERIOD

At our institution, breast augmentation surgery is an ambulatory procedure—the patient goes home the same day unless circumstances such as pain control warrant admission. This is, however, according to surgeon preference, and differs on a case-by-case basis. General anesthesia is the standard of care.¹⁵

POSTOPERATIVE PERIOD

In the immediate postoperative period, patients are instructed to wear a surgical bra for up to 6 weeks to allow stable scarring. Early mobilization is encouraged.^7,15 Depending on the patient’s situation, recovery, and healing, she may be out of work for about 1 week, sometimes more, sometimes less. 

Additional instructions are surgeon-specific. However, the patient is instructed to avoid bathing, swimming, immersion in water, and wearing underwire brassieres that could impair healing of an inferior incision; instead, patients are often instructed to wear a surgical bra provided on the day of surgery until cleared in the clinic.

Showering is allowed the next day or the second day after surgery, and of course there is no driving while on narcotics. Additionally, patients are counseled extensively regarding hematoma formation and the signs and symptoms of infection.

Patients are typically seen in clinic 1 week after surgery.

The cost of surgery may be $5,000 to $6,000 but can vary significantly from center to center depending on who the patient sees and where, and whether the patient presents for breast reconstruction after cancer or repair of congenital anomalies, or in certain cases of transgender surgery. The patient is typically responsible for the fee, but again this depends on the patient, indications, and particular insurance concerns.

IMPLANT LONGEVITY AND RUPTURE

In the United States, implant rupture rates range from 1.1% to 17.7% at 6 to 10 years after primary augmentation, 2.9% to 14.7% after revision augmentation, 1.5% to 35.4% after primary breast reconstruction, and 0% to 19.6% after revision reconstruction.¹¹

Unfortunately, the existence of multiple implant manufacturers, numerous implant generations, and poorly standardized screening protocols and reporting systems make the true rate of implant rupture difficult to assess without definitive imaging or implant retrieval.¹¹

Damage from surgical instrumentation during implantation is the most common cause of silicone breast implant rupture (50% to 64% of cases).²² Other causes include underfilling and fold flaw from capsular contracture.

Leakage of silicone gel filler may be confined to the periprosthetic capsule (intracapsular rupture) or extend beyond and into the breast parenchyma (extracapsular rupture). One study reported that only 10% of intracapsular ruptures progressed extracapsularly, while 84% of patients with extracapsular involvement remained stable for up to 2 years,²³ indicating that intracapsular rupture may not portend worsening disease.¹¹

Implant rupture occurs silently in most cases, with no clinically detectable signs or symptoms. In other cases, patients may present with alterations in breast shape and size, sudden asymmetry, firmness, pronounced capsular contracture, contour irregularity, or pain.

Aside from physical examination, comprehensive diagnostic testing includes imaging—ultrasonography, mammography, computed tomography, and magnetic resonance imaging (MRI). Of these, MRI is the method of choice, with sensitivity and specificity exceeding 90% for detecting implant rupture.¹¹ Classic findings on MRI include the “linguine” sign from a deflating implant shell, or the teardrop sign from implant sagging. Classic findings on ultrasonography include the “snowstorm” sign of extracapsular rupture and the “stepladder” sign of intracapsular rupture.

Mammography effectively detects free silicone in breast tissue with extracapsular rupture (25% of ruptures according to some studies)²³; however, it cannot detect rupture within the implant capsule. As an aside, submuscular implant placement may interfere less with screening mammography than subglandular implants do.^14,24

Current FDA recommendations to detect implant rupture encourage women with silicone breast implants to undergo screening 3 years after implantation and then every 2 years thereafter; no long-term monitoring is suggested for saline implants.¹⁵ Many plastic surgeons evaluate silicone breast implant patients every 1 to 2 years for contracture and rupture.⁸ Of note, capsular contracture impairs the effectiveness of ultrasonography and may require MRI confirmation.¹¹

If implant rupture is confirmed, the current recommendation is to remove the implant and the capsule. Another implant may be placed depending on the patient’s preference. Rigorous washout remains a key feature of any surgical intervention for ruptured breast implants; however, in the event of extracapsular rupture, resection of silicone granulomas may also be required.¹¹

Reoperation rates for primary breast augmentation surgery approach 20% and are even higher for secondary augmentation over a patient’s lifetime—the highest rate of all aesthetic procedures.^7,14

Capsular contracture is the most common complication of breast augmentation,²⁵ typically presenting within the first postoperative year,^26,27 and the risk increases over time.²⁸ It occurs with both silicone and saline breast implants.

In some studies, the incidence exceeded 4% in the first 2 years after surgery,²⁹ and nearly 50% by 10 years.³⁰ Other studies found rates of 0% to 20% over 13 years.²⁰

The etiology is not well understood and is presumed to be multifactorial, with proposed mechanisms and factors that include bacterial contamination, surface texturing, the implant pocket selected, the incision type, drain placement, antibiotic use, and smoking.²⁵

A meta-analysis from 17,000 implants found that the risk of capsular contracture was significantly higher when an implant was placed in a subglandular pocket than in a submuscular pocket,^22,26 and that although texturing decreased capsular contracture compared with smooth implants, the effect was modest when a textured or smooth implant was placed in a submuscular location.²⁸ With regard to incision location, studies have reported that the incidence of capsular contracture is highest with transaxillary and periareolar incisions, and lowest with inframammary incisions.^20,21

The leading theory is that contamination of the implant (primarily from the mammary ducts) results in biofilm formation. Subclinical hematoma surrounding the implant may also provide key bacterial nutrients.²⁰

Textured implants induce a greater inflammatory response in the capsular tissue, resulting in a thicker capsule; however, contracture rates remain lower with textured than with smooth implants.^14,31 Interestingly, lower rates of capsular contracture have been observed with later-generation, cohesive-gel, form-stable implants than with those of earlier generations.¹²

Although more research is needed, silicone implants appear to confer a higher risk of capsular contracture than saline implants.^14,20

Irrigating the breast pocket intraoperatively with triple antibiotic solution (bacitracin, cefazolin, and gentamicin) before placing the implant may decrease the capsular contracture rate.^15,20

Treatments for capsular contracture include pocket modifications such as capsulotomy (making releasing, relaxing incisions in the scar capsule encasing the implant), capsulectomy (removing portions of or the entire capsule), and replacing the implant in the other pocket (ie, if the original implant was subglandular, the replacement is placed in the submuscular pocket). Patients who have contractures that fail to respond to these treatments may ultimately benefit from implant removal and autologous reconstruction (autoaugmentation) rather than implant replacement.^32,33

ADDITIONAL COMPLICATIONS

Other complications include infection, malposition, rippling, seroma, hematoma, and sensory alterations.

Irrigation during the implantation procedure with a triple antibiotic solution consisting of bacitracin, gentamycin, and cephalexin in normal saline decreases infection and seroma rates.^15,20,34

Some surgeons also choose to irrigate the pocket with a betadine solution, or to cleanse the skin with betadine and place sterile towels and redrape before inserting the implant. Additionally, many prefer using a sterile device much like a pastry funnel called a Keller funnel to insert the implant into the breast pocket.³⁵

Infection is less common with cosmetic augmentations than with implant-based breast reconstruction, likely because of healthier, well-vascularized tissue in patients undergoing cosmetic surgery than in those undergoing mastectomy.¹⁴

Seroma is thought to be a consequence of texturing, and more so with macro- vs microtexturing. Though poorly understood, an association between texturing and double capsules has also been reported.^12,20

After primary breast augmentation, 10-year follow-up rates of capsular contracture, seroma, rippling, and malposition vary across the 3 major silicone implant manufacturers.¹² Hematoma and infection occur in less than 1% of primary augmentation patients.¹⁵

Malposition of the implant over time is less frequent with textured implants because of the higher coefficient of friction compared with smooth implants^.6,8,15

Visible skin rippling may be a consequence of texturing and also of thin body habitus, eg, in patients with a body mass index less than 18.5 kg/m². If the soft-tissue layer of the breast is thin, the natural rippling of smooth saline implant shells are more likely to show when placed in the subglandular pocket. Form-stable implants, by contrast, resist rippling.^12,15

Large implants and extensive lateral dissection can cause alterations in nipple sensation and sensory loss within lower breast pole skin. Axillary incisions may traumatize or damage the intercostobrachial nerve, resulting in upper inner arm sensory aberrations.

Ultimately, the 10-year incidence of secondary surgery ranges from 0% to 36% and the 10-year incidence of capsular contracture ranges from 11% to 19%.¹⁵ Additional cosmetic complaints after augmentation with implants include enlargement of the areola and engorgement of breast veins.¹⁴

BREAST CANCER AND DETECTION

Patients with or without implants do not seem to differ with regard to breast cancer stage upon detection, tumor burden, recurrence, or survival. However, more patients with implants may present with palpable masses, invasive tumors, axillary metastasis, and falsely negative mammograms.

Breast implants may actually facilitate cancer detection on physical examination by providing a more dense or stable surface upon which to palpate the breast tissue. Although they do not necessarily impair mastectomy or breast reconstruction, they may result in an increased rate of revision surgery after breast conservation therapy.^24,36 Mammography remains the standard of care for radiologic diagnosis but can be further supported by MRI and ultrasonography if necessary in patients with implants.

Although concerns persist, multiple studies have demonstrated the safety of fourth- and fifth-generation silicone breast implants with regard to autoimmune disease.⁷

In various clinical studies in mastectomy patients who underwent breast reconstruction with either silicone implants or autologous tissue, no difference was found with regard to the incidence of autoimmune diseases.² Additionally, in meta-analyses of data from more than 87,000 women, no association was found between connective tissue disease and silicone breast implants.^2,11 One study^11,23 noted no increase in autoantibodies in patients with undamaged silicone implants vs patients who experienced rupture.

Studies have also demonstrated that in children born to mothers with breast implants, the risk of rheumatic disease, esophageal disorders, congenital malformations, and death during the perinatal period is comparable with that in controls.³⁷ Another study, examining breastfeeding in women with silicone breast implants, showed no significant difference in silicon levels (used as a proxy for silicone) in breast milk compared with controls without implants; silicon levels were found to be significantly higher in cow’s milk and store-bought formulas.³⁸

BREAST IMPLANT-ASSOCIATED ANAPLASTIC LARGE-CELL LYMPHOMA

Breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) is a subtype of T-cell lymphoma that develops in tissue adjacent to breast implants. It typically presents as breast swelling 2 to 38 years (mean of 8 years) after implant insertion.^39,40 The swelling may be secondary to periprosthetic seroma formation or, more rarely, palpable disease in the axilla. Patients occasionally complain of pain and, rarely, constitutional symptoms.²⁰ BIA-ALCL is not a disease of the surrounding breast tissue, but rather of the fibrous periprosthetic capsule.²¹

Of note, there is no documented case involving smooth implants,^41–43 but it may be related to fifth-generation textured implants.⁶ At present, it is not possible to definitively state which implant is associated with this condition; hence, more data are needed, and this association is currently under study.

The absolute risk of BIA-ALCL was reported in a Dutch study³⁹ as 1 in 35,000 by age 50, 1 in 12,000 by age 70, and 1 in 7,000 by age 75, with a number needed to harm of 6,920. Overall lifetime risk was estimated at 1 in 30,000 for women with textured implants in a 2015 US study.⁴⁰ In comparison, breast cancer risk is about 1 in 8 women. There is no apparent predilection for patients who underwent cosmetic augmentation vs reconstruction, or who received silicone vs saline implants.

The diagnosis is confirmed by ultrasonographically guided fine-needle aspiration of seroma fluid and subsequent immunohistochemical testing for CD30-positive and ALK-negative T lymphocytes. Other than positron-emission tomography for staging after diagnosis confirmation, imaging is ineffective. Expert opinion does not recommend routine screening unless the aforementioned symptoms arise.

Treatment involves implant removal and total capsulectomy, with samples sent for pathology study with cytokeratin staining.¹² Of note, in all cases of BIA-ALCL in which the disease was limited to the circumscribed scar tissue of the breast capsule, complete surgical excision has proved curative, whereas incomplete capsulectomy portends a greater risk of recurrence and decreased survival.⁴⁴

In cases of advanced or recurrent ALCL, diagnosed late or inappropriately, the National Comprehensive Cancer Network recommends a multidisciplinary approach involving adjuvant chemotherapy and radiation.⁴⁴ Anecdotally, at our institution, we have recently treated several cases of advanced ALCL presenting with invasive chest wall masses with extirpative surgery and subsequent reconstruction with the assistance of our thoracic surgery colleagues, as well as the aforementioned multidisciplinary approach using adjuvant therapy.

The mechanism of this malignancy is currently under investigation, but the current theory implicates an exaggerated lymphoproliferative response to bacterial contamination of the capsule superimposed upon genetic factors in susceptible patients.^42,43

National societies advise plastic surgeons to discuss the risk of BIA-ALCL with all patients at the time of breast augmentation consultation and to report all confirmed cases to the PROFILE registry (Patient Registry and Outcomes for Breast Implants and Anaplastic Large Cell Lymphoma Etiology and Epidemiology).⁴⁵

ARE PATIENTS HAPPIER AFTERWARD?

Studies have shown that after undergoing breast augmentation surgery, patients note improvement in body image, and satisfaction rates range from 85% to 95% with respect to self-confidence and body image.⁴⁶ An evaluation of patient responses on the validated BREAST-Q Augmentation Questionnaire showed the following satisfaction rates: breasts 83%, psychosocial well-being 88%, and sexual functioning 81%.¹⁵

Although epidemiologic studies have reported higher suicide rates in women with cosmetic breast implants, this likely stems from preoperative psychological factors and underscores the role of psychiatric referral in patients with a mental health history or in those whom the surgeon deems it necessary.⁴⁶

Several high-quality studies have demonstrated that quality of life and psychosocial functioning (including depression) markedly improve after breast augmentation surgery.⁴⁷ Among a cohort of Norwegian patients, breast implant surgery resulted in improved motivation to perform daily activities, as well as improved quality of life from both a psychosocial and aesthetic perspective.⁴⁸ Interestingly, a recent study reported that patients who underwent breast implant surgery alone reported greater satisfaction and psychosocial quality of life than patients who underwent combination breast augmentation and mastopexy (breast-lifting) surgery.⁴⁹

Additional data are needed to refine our understanding of the complex interplay between psychosocial factors before and after surgery in patients seeking and undergoing breast augmentation procedures.

At present, 300,000 US women undergo breast augmentation surgery each year,¹ making this the second most common aesthetic procedure in women (after liposuction),^2–4 and making it extremely likely that clinicians will encounter women who have breast implants. In addition, approximately 110,000 women undergo breast reconstructive surgery after mastectomy, of whom more than 88,000 (81%) receive implants (2016 data).⁵

This review discusses the evolution of breast implants, their complications, and key considerations with regard to aesthetic and reconstructive breast surgery, as the principles are similar.

EVOLUTION OF IMPLANTS

Reports of breast augmentation surgery, also known as augmentation mammoplasty, date back to 1895, when a fatty tumor (lipoma) was successfully transplanted from a patient’s back to a breast defect in a mastectomy patient.^2,3,6,7 In the 1930s, implantation of a glass ball into a patient’s breast marked the first implant-based breast augmentation.⁶ By 1954, attempts at breast augmentation using local dermal-fat flaps, adipose tissue, and even omentum were described.

Alloplastic materials gained popularity throughout the 1950s and 1960s and included polyurethane, polytetrafluoroethylene (Teflon), and other synthetics. Adverse reactions associated with alloplastic materials were plentiful: local tissue reactions, distortion of the breast mound, increased firmness, and discomfort all contributed to the eventual discontinuation of their use. The history of alloplastic breast augmentation also included epoxy resin, shellac, beeswax, paraffin, rubber, petroleum jelly, and liquefied silicone. Outcomes were not good, and many patients ultimately needed mastectomy.⁷

The first modern breast prosthesis was developed in 1961, and since then, implant composition and design have evolved significantly.⁸

From silicone to saline, and back again

The first silicone gel implants, introduced in the early 1960s,^8–19 had high complication rates—some centers reported an incidence of capsular contracture of up to 70%.^8,11 This is a foreign body reaction in which pathologic scar tissue encases the implant, causing it to distort, appear misshapen, harden, and even become painful.¹¹ Attempts to minimize this reaction led to later generations of silicone implants with polyurethane shells.¹²

Inflatable implants filled with sterile saline solution were originally developed in France in 1965. Unlike silicone implants, saline implants have undergone minimal changes since their inception, and grew in popularity during the 1970s in view of the high rates of capsular contracture with silicone implants.⁸ However, saline implants have their own problems, and as they became increasingly popular, deflation and the unnatural feel of saline sparked a renewed interest in silicone gel.

By the late 1980s, the thinner-shelled generation of silicone implants displayed its own frustrating complications including implant rupture, capsular contracture, infection, and possible systemic and disseminated granulomatous disease. From 1992 to 2006, the US Food and Drug Administration (FDA) placed a moratorium on silicone implants due to concerns about a possible link with autoimmune and connective tissue diseases and the possible carcinogenic nature of silicone.

While silicone implants were prohibited in the United States, development continued abroad, and eventually the moratorium was lifted after several meta-analyses failed to reveal any link regarding the aforementioned concerns.¹³

Today, silicone gel implants dominate the world market.¹⁴ In the United States, approximately 60% of implants contain silicone gel filler, and trends are similar in Europe.⁷

Table 1 summarizes the evolution of silicone breast implants over the last 50 years.^2,6,11,12Table 2 lists the advantages and disadvantages of silicone and saline breast implants.^2,6,8,15

CURRENT IMPLANT OPTIONS

Currently, 3 companies (Allergan, Mentor, Sientra) manufacture and distribute breast implants and implant-associated products such as tissue expanders and sizers in the US market.⁶

Another company, Motiva, makes an implant that is available in Europe, Asia, and Australia, and the device is currently undergoing a 10-year clinical trial in the United States that began recruiting patients in 16 centers in April 2018.¹⁶ Pending final approval, the Cleveland Clinic Department of Plastic Surgery may be among the centers involved in the clinical trial of the Motiva implant. Innovations in the Motiva implant include a high-performance shell that maintains consistent strength and includes a proprietary barrier layer, improved silicone gel filler, 3-D imprinted surface texturing, and an implant shape that adapts with vertical and horizontal movement. It also contains radio-frequency identification transponders that can transmit data about the implant wirelessly.^17–19

Developed in the 1980s, texturing of the implant surface disrupts capsule formation around the prosthesis. Additionally, texturing stabilizes an anatomically shaped (teardrop) implant within the breast pocket, reducing malrotation.^20,21

The first textured implants were covered with polyurethane foam, but they were ultimately withdrawn from the US market because of concern for in vivo degradation to carcinogenic compounds. The focus subsequently turned to texturing implant shells by mechanically creating pores of different sizes. Smooth implants, by contrast, are manufactured by repeatedly dipping the implant shell into liquid silicone.²

The capsular contraction rate has been shown to be lower with textured silicone than with smooth silicone (number needed to treat = 7–9), and evidence suggests a lower risk of needing a secondary procedure.²¹

Form-stable vs fluid-form

Silicone is a polymer. The physical properties of polymers vary greatly and depend on the length of the individual chains and the degree to which those chains are cross-linked. Liquid silicone contains short chains and sparse cross-linking, resulting in an oily compound well suited for lubrication. Silicone gel contains longer chains and more cross-linking and is therefore more viscous.

In “form-stable” implants, the silicone interior has sufficient chain length and cross-linking to retain the designed shape even at rest,² but they require slightly larger incisions.⁷ “Fluid-form” refers to an implant with silicone filler with shorter chain length, less cross-linking, and more fluidity.⁶

Shell

As with silicone fillers, the properties of silicone implant shells also depend on chain length and cross-linking within the polymer. Silicone elastomer shells (Table 1) contain extensively cross-linked chains that impart a flexible yet rubbery character. Silicone elastomers can also be found in facial implants and tissue expanders.²

Implant shape (round vs anatomic)

The shape of an implant is determined by the gel distribution inside of it. To understand gel distribution and implant shape, one must understand the gel-shell ratio. This ratio increases as cohesivity of the filler increases, and it represents increased bonding of the gel filler to the shell and a preserved implant shape at rest.

The gel-shell ratio varies among manufacturers, and a less-viscous filler may be more prone to rippling or loss of upper pole fullness in some patients. For this reason, careful analysis, patient and implant selection, and discussion of complications remain paramount.²

No anatomically shaped implant is manufactured with a smooth shell, but rather with a textured shell that resists malrotation.^6,15 However, in the United States, 95% of patients receive round implants.¹⁶

PATIENT ASSESSMENT

Before breast augmentation surgery, the surgeon assesses a number of factors—physical and psychosocial—and helps the patient choose a type and size of implant. The surgeon and patient also plan where the implants will be placed—ie, above or beneath the chest wall muscle—and where the incisions will be made. Every decision is made in close consultation with the patient, taking into account the patient’s desires and expectations, as well as what the patient’s anatomy allows. An integral component of this shared decision-making process is a discussion of the possible complications, and often photographs to better illustrate what to expect postoperatively. 

Psychosocial factors

One must consider the patient’s psychology, motivations for surgery, and emotional stability. Here, we look for underlying body dysmorphic disorder; excessive or unusual encouragement to undergo the procedure by a spouse, friends, or others; a history of other aesthetic procedures; unrealistic expectations; and other factors influencing the desire to undergo this surgery.

Choosing an implant

Implant selection must take into account the patient’s height, weight,⁷ and overall body morphology: taller patients and those with wider hips or shoulders usually require larger implants. A reliable method for determining the appropriate implant must include the current breast shape, dimensions, volume, skin elasticity, soft-tissue thickness, and overall body habitus. Ultimately, the most important considerations include breast base diameter, implant volume,²⁰ and soft-tissue envelope.

Preoperative sizing can involve placing sample implants within a brassiere so that the patient can preview possible outcomes. This method is particularly effective in minimizing dissatisfaction because it shares ownership of the decision-making process.¹⁵

A computerized implant selection program available in Europe suggests a “best-fit” implant based on a clinician’s measurements.⁷

Traditionally, plastic surgeons place breast implants either beneath the pectoralis major muscle (submuscular placement) or over the pectoralis⁸ but beneath the glandular breast parenchyma (subglandular placement) (Figure 2).⁷

Advantages of submuscular placement are a smoother transition of the upper breast pole from the chest wall and less rippling visible through the skin, due to the additional muscular coverage of the implant. Another advantage is that capsular contraction rates are lower with submuscular placement, likely due to possible contamination of implants by lactiferous ductal microbes when accessing the subglandular plane.^14,20 Disadvantages are pronounced discomfort after surgery and animation deformities with muscle contraction, particularly in young, highly active patients.

A popular modification of submuscular placement involves creating a surgical dissection plane between the subglandular tissue and the pectoralis major fascia. This “dual­­plane” approach allows the parenchyma to retract superiorly and reduce breast ptosis.⁷

Incisions

Table 3 highlights important considerations with regard to incision location.^15,20,21

ANTIBIOTICS

Many surgeons give a single prophylactic dose of antibiotic before surgery, a practice that some studies have shown to be effective in reducing the risk of infection.¹⁵ However, the benefit of routine postoperative use of antibiotics remains unsubstantiated¹⁵: postoperative antibiotic use does not appear to protect against infection, capsular contracture, or overall complications in primary or secondary breast augmentation surgery.²⁰

PERIOPERATIVE PERIOD

At our institution, breast augmentation surgery is an ambulatory procedure—the patient goes home the same day unless circumstances such as pain control warrant admission. This is, however, according to surgeon preference, and differs on a case-by-case basis. General anesthesia is the standard of care.¹⁵

POSTOPERATIVE PERIOD

In the immediate postoperative period, patients are instructed to wear a surgical bra for up to 6 weeks to allow stable scarring. Early mobilization is encouraged.^7,15 Depending on the patient’s situation, recovery, and healing, she may be out of work for about 1 week, sometimes more, sometimes less. 

Additional instructions are surgeon-specific. However, the patient is instructed to avoid bathing, swimming, immersion in water, and wearing underwire brassieres that could impair healing of an inferior incision; instead, patients are often instructed to wear a surgical bra provided on the day of surgery until cleared in the clinic.

Showering is allowed the next day or the second day after surgery, and of course there is no driving while on narcotics. Additionally, patients are counseled extensively regarding hematoma formation and the signs and symptoms of infection.

Patients are typically seen in clinic 1 week after surgery.

The cost of surgery may be $5,000 to $6,000 but can vary significantly from center to center depending on who the patient sees and where, and whether the patient presents for breast reconstruction after cancer or repair of congenital anomalies, or in certain cases of transgender surgery. The patient is typically responsible for the fee, but again this depends on the patient, indications, and particular insurance concerns.

IMPLANT LONGEVITY AND RUPTURE

In the United States, implant rupture rates range from 1.1% to 17.7% at 6 to 10 years after primary augmentation, 2.9% to 14.7% after revision augmentation, 1.5% to 35.4% after primary breast reconstruction, and 0% to 19.6% after revision reconstruction.¹¹

Unfortunately, the existence of multiple implant manufacturers, numerous implant generations, and poorly standardized screening protocols and reporting systems make the true rate of implant rupture difficult to assess without definitive imaging or implant retrieval.¹¹

Damage from surgical instrumentation during implantation is the most common cause of silicone breast implant rupture (50% to 64% of cases).²² Other causes include underfilling and fold flaw from capsular contracture.

Leakage of silicone gel filler may be confined to the periprosthetic capsule (intracapsular rupture) or extend beyond and into the breast parenchyma (extracapsular rupture). One study reported that only 10% of intracapsular ruptures progressed extracapsularly, while 84% of patients with extracapsular involvement remained stable for up to 2 years,²³ indicating that intracapsular rupture may not portend worsening disease.¹¹

Implant rupture occurs silently in most cases, with no clinically detectable signs or symptoms. In other cases, patients may present with alterations in breast shape and size, sudden asymmetry, firmness, pronounced capsular contracture, contour irregularity, or pain.

Aside from physical examination, comprehensive diagnostic testing includes imaging—ultrasonography, mammography, computed tomography, and magnetic resonance imaging (MRI). Of these, MRI is the method of choice, with sensitivity and specificity exceeding 90% for detecting implant rupture.¹¹ Classic findings on MRI include the “linguine” sign from a deflating implant shell, or the teardrop sign from implant sagging. Classic findings on ultrasonography include the “snowstorm” sign of extracapsular rupture and the “stepladder” sign of intracapsular rupture.

Mammography effectively detects free silicone in breast tissue with extracapsular rupture (25% of ruptures according to some studies)²³; however, it cannot detect rupture within the implant capsule. As an aside, submuscular implant placement may interfere less with screening mammography than subglandular implants do.^14,24

Current FDA recommendations to detect implant rupture encourage women with silicone breast implants to undergo screening 3 years after implantation and then every 2 years thereafter; no long-term monitoring is suggested for saline implants.¹⁵ Many plastic surgeons evaluate silicone breast implant patients every 1 to 2 years for contracture and rupture.⁸ Of note, capsular contracture impairs the effectiveness of ultrasonography and may require MRI confirmation.¹¹

If implant rupture is confirmed, the current recommendation is to remove the implant and the capsule. Another implant may be placed depending on the patient’s preference. Rigorous washout remains a key feature of any surgical intervention for ruptured breast implants; however, in the event of extracapsular rupture, resection of silicone granulomas may also be required.¹¹

Reoperation rates for primary breast augmentation surgery approach 20% and are even higher for secondary augmentation over a patient’s lifetime—the highest rate of all aesthetic procedures.^7,14

Capsular contracture is the most common complication of breast augmentation,²⁵ typically presenting within the first postoperative year,^26,27 and the risk increases over time.²⁸ It occurs with both silicone and saline breast implants.

In some studies, the incidence exceeded 4% in the first 2 years after surgery,²⁹ and nearly 50% by 10 years.³⁰ Other studies found rates of 0% to 20% over 13 years.²⁰

The etiology is not well understood and is presumed to be multifactorial, with proposed mechanisms and factors that include bacterial contamination, surface texturing, the implant pocket selected, the incision type, drain placement, antibiotic use, and smoking.²⁵

A meta-analysis from 17,000 implants found that the risk of capsular contracture was significantly higher when an implant was placed in a subglandular pocket than in a submuscular pocket,^22,26 and that although texturing decreased capsular contracture compared with smooth implants, the effect was modest when a textured or smooth implant was placed in a submuscular location.²⁸ With regard to incision location, studies have reported that the incidence of capsular contracture is highest with transaxillary and periareolar incisions, and lowest with inframammary incisions.^20,21

The leading theory is that contamination of the implant (primarily from the mammary ducts) results in biofilm formation. Subclinical hematoma surrounding the implant may also provide key bacterial nutrients.²⁰

Textured implants induce a greater inflammatory response in the capsular tissue, resulting in a thicker capsule; however, contracture rates remain lower with textured than with smooth implants.^14,31 Interestingly, lower rates of capsular contracture have been observed with later-generation, cohesive-gel, form-stable implants than with those of earlier generations.¹²

Although more research is needed, silicone implants appear to confer a higher risk of capsular contracture than saline implants.^14,20

Irrigating the breast pocket intraoperatively with triple antibiotic solution (bacitracin, cefazolin, and gentamicin) before placing the implant may decrease the capsular contracture rate.^15,20

Treatments for capsular contracture include pocket modifications such as capsulotomy (making releasing, relaxing incisions in the scar capsule encasing the implant), capsulectomy (removing portions of or the entire capsule), and replacing the implant in the other pocket (ie, if the original implant was subglandular, the replacement is placed in the submuscular pocket). Patients who have contractures that fail to respond to these treatments may ultimately benefit from implant removal and autologous reconstruction (autoaugmentation) rather than implant replacement.^32,33

ADDITIONAL COMPLICATIONS

Other complications include infection, malposition, rippling, seroma, hematoma, and sensory alterations.

Irrigation during the implantation procedure with a triple antibiotic solution consisting of bacitracin, gentamycin, and cephalexin in normal saline decreases infection and seroma rates.^15,20,34

Some surgeons also choose to irrigate the pocket with a betadine solution, or to cleanse the skin with betadine and place sterile towels and redrape before inserting the implant. Additionally, many prefer using a sterile device much like a pastry funnel called a Keller funnel to insert the implant into the breast pocket.³⁵

Infection is less common with cosmetic augmentations than with implant-based breast reconstruction, likely because of healthier, well-vascularized tissue in patients undergoing cosmetic surgery than in those undergoing mastectomy.¹⁴

Seroma is thought to be a consequence of texturing, and more so with macro- vs microtexturing. Though poorly understood, an association between texturing and double capsules has also been reported.^12,20

After primary breast augmentation, 10-year follow-up rates of capsular contracture, seroma, rippling, and malposition vary across the 3 major silicone implant manufacturers.¹² Hematoma and infection occur in less than 1% of primary augmentation patients.¹⁵

Malposition of the implant over time is less frequent with textured implants because of the higher coefficient of friction compared with smooth implants^.6,8,15

Visible skin rippling may be a consequence of texturing and also of thin body habitus, eg, in patients with a body mass index less than 18.5 kg/m². If the soft-tissue layer of the breast is thin, the natural rippling of smooth saline implant shells are more likely to show when placed in the subglandular pocket. Form-stable implants, by contrast, resist rippling.^12,15

Large implants and extensive lateral dissection can cause alterations in nipple sensation and sensory loss within lower breast pole skin. Axillary incisions may traumatize or damage the intercostobrachial nerve, resulting in upper inner arm sensory aberrations.

Ultimately, the 10-year incidence of secondary surgery ranges from 0% to 36% and the 10-year incidence of capsular contracture ranges from 11% to 19%.¹⁵ Additional cosmetic complaints after augmentation with implants include enlargement of the areola and engorgement of breast veins.¹⁴

BREAST CANCER AND DETECTION

Patients with or without implants do not seem to differ with regard to breast cancer stage upon detection, tumor burden, recurrence, or survival. However, more patients with implants may present with palpable masses, invasive tumors, axillary metastasis, and falsely negative mammograms.

Breast implants may actually facilitate cancer detection on physical examination by providing a more dense or stable surface upon which to palpate the breast tissue. Although they do not necessarily impair mastectomy or breast reconstruction, they may result in an increased rate of revision surgery after breast conservation therapy.^24,36 Mammography remains the standard of care for radiologic diagnosis but can be further supported by MRI and ultrasonography if necessary in patients with implants.

Although concerns persist, multiple studies have demonstrated the safety of fourth- and fifth-generation silicone breast implants with regard to autoimmune disease.⁷

In various clinical studies in mastectomy patients who underwent breast reconstruction with either silicone implants or autologous tissue, no difference was found with regard to the incidence of autoimmune diseases.² Additionally, in meta-analyses of data from more than 87,000 women, no association was found between connective tissue disease and silicone breast implants.^2,11 One study^11,23 noted no increase in autoantibodies in patients with undamaged silicone implants vs patients who experienced rupture.

Studies have also demonstrated that in children born to mothers with breast implants, the risk of rheumatic disease, esophageal disorders, congenital malformations, and death during the perinatal period is comparable with that in controls.³⁷ Another study, examining breastfeeding in women with silicone breast implants, showed no significant difference in silicon levels (used as a proxy for silicone) in breast milk compared with controls without implants; silicon levels were found to be significantly higher in cow’s milk and store-bought formulas.³⁸

BREAST IMPLANT-ASSOCIATED ANAPLASTIC LARGE-CELL LYMPHOMA

Breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) is a subtype of T-cell lymphoma that develops in tissue adjacent to breast implants. It typically presents as breast swelling 2 to 38 years (mean of 8 years) after implant insertion.^39,40 The swelling may be secondary to periprosthetic seroma formation or, more rarely, palpable disease in the axilla. Patients occasionally complain of pain and, rarely, constitutional symptoms.²⁰ BIA-ALCL is not a disease of the surrounding breast tissue, but rather of the fibrous periprosthetic capsule.²¹

Of note, there is no documented case involving smooth implants,^41–43 but it may be related to fifth-generation textured implants.⁶ At present, it is not possible to definitively state which implant is associated with this condition; hence, more data are needed, and this association is currently under study.

The absolute risk of BIA-ALCL was reported in a Dutch study³⁹ as 1 in 35,000 by age 50, 1 in 12,000 by age 70, and 1 in 7,000 by age 75, with a number needed to harm of 6,920. Overall lifetime risk was estimated at 1 in 30,000 for women with textured implants in a 2015 US study.⁴⁰ In comparison, breast cancer risk is about 1 in 8 women. There is no apparent predilection for patients who underwent cosmetic augmentation vs reconstruction, or who received silicone vs saline implants.

The diagnosis is confirmed by ultrasonographically guided fine-needle aspiration of seroma fluid and subsequent immunohistochemical testing for CD30-positive and ALK-negative T lymphocytes. Other than positron-emission tomography for staging after diagnosis confirmation, imaging is ineffective. Expert opinion does not recommend routine screening unless the aforementioned symptoms arise.

Treatment involves implant removal and total capsulectomy, with samples sent for pathology study with cytokeratin staining.¹² Of note, in all cases of BIA-ALCL in which the disease was limited to the circumscribed scar tissue of the breast capsule, complete surgical excision has proved curative, whereas incomplete capsulectomy portends a greater risk of recurrence and decreased survival.⁴⁴

In cases of advanced or recurrent ALCL, diagnosed late or inappropriately, the National Comprehensive Cancer Network recommends a multidisciplinary approach involving adjuvant chemotherapy and radiation.⁴⁴ Anecdotally, at our institution, we have recently treated several cases of advanced ALCL presenting with invasive chest wall masses with extirpative surgery and subsequent reconstruction with the assistance of our thoracic surgery colleagues, as well as the aforementioned multidisciplinary approach using adjuvant therapy.

The mechanism of this malignancy is currently under investigation, but the current theory implicates an exaggerated lymphoproliferative response to bacterial contamination of the capsule superimposed upon genetic factors in susceptible patients.^42,43

National societies advise plastic surgeons to discuss the risk of BIA-ALCL with all patients at the time of breast augmentation consultation and to report all confirmed cases to the PROFILE registry (Patient Registry and Outcomes for Breast Implants and Anaplastic Large Cell Lymphoma Etiology and Epidemiology).⁴⁵

ARE PATIENTS HAPPIER AFTERWARD?

Studies have shown that after undergoing breast augmentation surgery, patients note improvement in body image, and satisfaction rates range from 85% to 95% with respect to self-confidence and body image.⁴⁶ An evaluation of patient responses on the validated BREAST-Q Augmentation Questionnaire showed the following satisfaction rates: breasts 83%, psychosocial well-being 88%, and sexual functioning 81%.¹⁵

Although epidemiologic studies have reported higher suicide rates in women with cosmetic breast implants, this likely stems from preoperative psychological factors and underscores the role of psychiatric referral in patients with a mental health history or in those whom the surgeon deems it necessary.⁴⁶

Several high-quality studies have demonstrated that quality of life and psychosocial functioning (including depression) markedly improve after breast augmentation surgery.⁴⁷ Among a cohort of Norwegian patients, breast implant surgery resulted in improved motivation to perform daily activities, as well as improved quality of life from both a psychosocial and aesthetic perspective.⁴⁸ Interestingly, a recent study reported that patients who underwent breast implant surgery alone reported greater satisfaction and psychosocial quality of life than patients who underwent combination breast augmentation and mastopexy (breast-lifting) surgery.⁴⁹

Additional data are needed to refine our understanding of the complex interplay between psychosocial factors before and after surgery in patients seeking and undergoing breast augmentation procedures.