madman
Super Moderator
Abstract
Background. Gynecomastia (GM) is the benign proliferation of glandular tissue of the male breast. It is a common condition, which may occur physiologically and shows three age peaks during a male’s lifespan: infancy, puberty, and senescence. An underlying pathology may be revealed in 45–50% of adult men with GM, such as aggravating medications, systemic diseases, obesity, endocrinopathies, or malignancy.
Objective. To discuss the role of imaging in the evaluation of GM and its contribution to therapeutic decision-making.
Materials/Methods. The current literature was reviewed through PubMed, Scopus, and CENTRAL electronic databases to identify the best available evidence concerning imaging modalities in patients with GM.
Results. Most male breast lesions can be diagnosed on clinical grounds; however, in certain cases, when the physical examination is inconclusive, imaging may be helpful.
Discussion. The main purpose of evaluating a patient with GM is to establish the diagnosis and differentiate true GM from pseudo gynecomastia, exclude breast cancer, and detect the possible cause. GM is seen in mammography as a subareolar opacity and three mammographic patterns of GM are described: nodular, dendritic, and diffuse, corresponding to florid GM of early-onset, fibrous persistent GM, and GM due to exogenous estrogen administration, respectively. In ultrasound, florid GM is depicted as a disk-shaped, hypoechoic area underlying the areola, whereas echogenicity of the lesions increases as fibrosis develops. Data on the use of MRI in the evaluation of the male breast and GM are still limited. Imaging findings can be classified according to the BIRADS (Breast Imaging Reporting and Data System) regarding their malignant potential.
Conclusion. Both mammography and US are sensitive and specific to diagnose GM and distinguish it from breast cancer. When clinical findings are suggestive of malignancy or imaging findings are inconclusive, a histological confirmation should be sought.
1. Introduction
Gynecomastia (GM) is a benign proliferation of glandular tissue of the male breast. It is a common condition as it affects one-third to two-thirds of the male population. It can be unilateral or, most commonly, bilateral, and often asymmetrical (Braunstein, 2007; Narula & Carlson, 2007; Mieritz et al., 2017). It must be differentiated from pseudo gynecomastia (lipomastia), which refers to an excess of fat deposition without glandular proliferation. GM can be either the result of a physiological process (“physiological GM") or a sign of an underlying endocrine or systematic disease (“pathological GM”) (Narula & Carlson, 2014; Swerdloff & Ng, 2019; Braunstein & Anawalt, 2021a).
Physiological GM shows three age peaks during a male’s lifespan (Figure 1) (Braunstein, 1993). The first peak occurs in the neonatal period, affecting 60–90% of neonates, due to the transplacental transfer of maternal estrogens (Nachtigall, 1965; Braunstein, 1993). Neonatal GM is usually regressing spontaneously two to three weeks after delivery, but it may persist or recur three to six months after birth, during the mini-puberty, due to transient activation of the hypothalamic-pituitary-gonadal axis (HPG) (Nachtigall, 1965; McKiernan & Hull, 1981; Jayasinghe et al., 2010). However, it does not persist after the first year of life (Schmidt, 2002). The second peak is observed in puberty with a prevalence of 22–69%, reaching the highest incidence during mid-puberty (Moore et al., 1984; Biro et al., 1990; Braunstein, 1993; Kumanov et al., 2007; Mieritz et al., 2015). It is caused by a transient imbalance in the free androgen-to-free estrogen ratio caused by the earlier rise of serum estradiol (E2) compared with serum androgen concentrations (Moore et al., 1984; Biro et al., 1990). Pubertal GM is characterized by gradual enlargement, usually not greater than 4 cm in diameter, and generally regresses within 1–2 years; it may persist in up to 10% of affected adolescents till adulthood (Nydick et al., 1961; Ma & Geffner 2008). The third peak occurs in middle-aged and elderly men with an incidence of 30–65% (Nuttall, 1979; Niewoehner & Nuttal, 1984; Georgiades et al., 1994). It results in either from increased peripheral aromatase activity, secondary to the increase in total body fat elevated luteinizing hormone (LH) concentrations, and a decrease in serum testosterone (T) concentrations associated with male aging or by an underlying pathology (45–50% of adult men with GM), such as medication, systemic diseases, obesity, or endocrinopathies (Nuttall, 1979; Niewoehner & Nuttal, 1984; Georgiades et al., 1994; Mieritz et al., 2017; Swerdloff & Ng, 2019).
GM is usually asymptomatic and discovered incidentally during a physical examination, especially in adults, as a firm mass of at least 5 mm in diameter located concentrically beneath the nipple-areolar complex. However, in the early phase, it may be presented with breast tenderness and pain, especially in adolescents and cases of rapid progression (Braunstein, 2007; Gikas & Mokbel, 2007; Narula & Carlson, 2007).
Although GM is usually benign, it may cause physical and psychological stress and fear for breast cancer; in rare cases, it may be associated with severe underlying endocrine or systemic disease (Narula & Carlson 2014; Kipling et al., 2014; Rew et al., 2015). Thus, it is of clinical importance to clarify the etiology of GM. Imaging plays a pivotal role in this effort with mammography and ultrasound being the most used and magnetic resonance imaging (MRI) being employed in some special cases. This review aims to discuss the pathophysiology, evaluation, and management of GM, highlighting the prominent role of imaging in diagnostic and therapeutic decision-making.
2. Anatomy - Histology
Histopathologically, GM is characterized by ductal epithelial hyperplasia and increased stromal and periductal connective tissue; however, in contrast to the female breast, TDLU remains vestigial. (Nicolis et al., 1971; Braunstein, 2007; Narula & Carlson, 2007; Kornegooret al., 2012; Lapid et al., 2014). GM is classified in characteristic histologic patterns: florid, and fibrous:
● In the florid pattern, which corresponds to recent-onset GM (duration <6 months), hyperplasia of the ductal epithelium, infiltration of the periductal tissue with inflammatory cells, and surrounding edema are observed. This is the stage of symptomatic GM, which is frequently accompanied by pain and tenderness and might be reversible if the underlying cause is withdrawn.
● On the other hand, the fibrous pattern may be observed after the persistence of 6–12 months, when the glandular elements regress, and stromal fibrosis predominates. This quiescent stage is characterized by dilated ducts with periductal fibrosis, stromal hyalinization, and increased subareolar fat; it is considered irreversible due to chronic changes and fibrosis (Nicolis, 1971; Narula & Carslon, 2007).
3. Pathophysiology
An imbalance of androgens-to-estrogens action on breast tissue is considered the principal mechanism that leads to GM, as male breast tissue has estrogen and androgen receptors. Estrogens stimulate, and androgens inhibit breast tissue proliferation (Sasano, 1996; Marthur & Braunstein 1997; Narula & Carlson, 2014). Thus, GM may result from androgen deficiency, deficient androgen action, estrogen excess, increased estrogen action, or a combination of them. Androgen deficiency and estrogen excess may be either absolute when androgens are below and estrogens above the reference concentrations for young males, respectively, or relative, when both hormones are within the reference range, but the androgen-to-estrogen ratio is abnormal (Narula & Carlson, 2014).
Deficient androgen action in breast tissue might result from either decreased serum concentrations of androgens due to primary or secondary T deficiency or absent or defective androgen receptors. On the other hand, increased peripheral aromatization of androgens to estrogens by the enzyme aromatase may contribute to GM as it leads to estrogen excess. Moreover, estrogen excess may result from increased estrogen production by the testis or the adrenals, resulting from displacement from sex hormone-binding globulin (SHBG), or exogenous administration. In addition to the direct contribution to GM increased estrogen concentrations enhance the production of SHBG, leading to a reduction in free T and, therefore, further decrease of the free androgen-to-free estrogen ratio. Finally, estrogens inhibit LH secretion by the pituitary through the negative feedback mechanism, resulting in secondary T deficiency (Braunstein, 1993; Narula & Carlson, 2014).
*The local hormonal milieu in breast tissue plays a key role in the development of GM. Evidence suggests the contribution of local androgen deficiency or estrogen excess, locally decreased or increased number or activity of androgen or estrogen receptors, and locally increased action of aromatase in mammary tissue in the development of GM (Sasano et al., 1996; Narula & Carlson, 2014).
Additionally, progesterone, leptin, insulin-like growth factors-1 and -2 (IGF-1 and -2), and prolactin may constitute a different mechanism than secondary hypogonadism that may lead to GM (Sansone et al., 2017). Male breast tissue expresses LH, human chorionic gonadotrophin (hCG), prolactin, progesterone, IGF-1, and IGF-2 receptors; however, the role of the hormones and growth factors above mentioned in the pathogenesis of GM has not been clarified (Carslon et al., 2004; Narula & Carlson, 2014).
4. Causes
5. Evaluation
● 5.1. History
● 5.2. Physical examination
5. 5.3. Laboratory evaluation
Hormonal and biochemical.
6. Imaging
● 6.1. Mammography finding
GM is seen in mammography as a sub-areolar opacity, which may vary in shape according to the underlying histological pattern. Three mammographic patterns of GM are described: nodular, dendritic, and diffuse (Appelbaum et al., 1999).
● Nodular GM is the most common (72%) and corresponds to the florid histological phase and normally obtains a fan-shaped form, which radiates from the nipple and gradually blends into the surrounding fat tissue. Occasionally, this density may be opaque resembling a sphere (Figure 4A).
● Dendritic GM is less frequent (18%) and corresponds to the fibrous histological phase and is depicted as a flame-shaped opacity with projections (dendrites) that irradiate and penetrate the surrounding adipose tissue, which may extend to the upper-outer quadrant of the breast (Figure 4B).
● Diffuse GM is the less common form (~10%) and is typically observed in the enlarged breasts of transgender females under exogenous estrogen administration for gender-affirming hormonal therapy. In this case, the breast resembles a dense female breast in mammography; however, marked by heterogeneity and the absence of Cooper ligaments.
● 6.2. Ultrasound findings
● 6.3. MRI findings
7. Differential diagnosis
● 7.1. Pseudogynecomastia
● 7.2. Male breast cancer
1. 7.2.1. Mammography
2. 7.2.2. Ultrasound
3. 7.2.3. Fine needle aspiration cytology and needle core biopsy
● 7.3. Imaging algorithm
8. Management
● 8.1. Watchful waiting
● 8.2. Medical treatment
● 8.3. Radiotherapy
● 8.4. Surgical therapy
Background. Gynecomastia (GM) is the benign proliferation of glandular tissue of the male breast. It is a common condition, which may occur physiologically and shows three age peaks during a male’s lifespan: infancy, puberty, and senescence. An underlying pathology may be revealed in 45–50% of adult men with GM, such as aggravating medications, systemic diseases, obesity, endocrinopathies, or malignancy.
Objective. To discuss the role of imaging in the evaluation of GM and its contribution to therapeutic decision-making.
Materials/Methods. The current literature was reviewed through PubMed, Scopus, and CENTRAL electronic databases to identify the best available evidence concerning imaging modalities in patients with GM.
Results. Most male breast lesions can be diagnosed on clinical grounds; however, in certain cases, when the physical examination is inconclusive, imaging may be helpful.
Discussion. The main purpose of evaluating a patient with GM is to establish the diagnosis and differentiate true GM from pseudo gynecomastia, exclude breast cancer, and detect the possible cause. GM is seen in mammography as a subareolar opacity and three mammographic patterns of GM are described: nodular, dendritic, and diffuse, corresponding to florid GM of early-onset, fibrous persistent GM, and GM due to exogenous estrogen administration, respectively. In ultrasound, florid GM is depicted as a disk-shaped, hypoechoic area underlying the areola, whereas echogenicity of the lesions increases as fibrosis develops. Data on the use of MRI in the evaluation of the male breast and GM are still limited. Imaging findings can be classified according to the BIRADS (Breast Imaging Reporting and Data System) regarding their malignant potential.
Conclusion. Both mammography and US are sensitive and specific to diagnose GM and distinguish it from breast cancer. When clinical findings are suggestive of malignancy or imaging findings are inconclusive, a histological confirmation should be sought.
1. Introduction
Gynecomastia (GM) is a benign proliferation of glandular tissue of the male breast. It is a common condition as it affects one-third to two-thirds of the male population. It can be unilateral or, most commonly, bilateral, and often asymmetrical (Braunstein, 2007; Narula & Carlson, 2007; Mieritz et al., 2017). It must be differentiated from pseudo gynecomastia (lipomastia), which refers to an excess of fat deposition without glandular proliferation. GM can be either the result of a physiological process (“physiological GM") or a sign of an underlying endocrine or systematic disease (“pathological GM”) (Narula & Carlson, 2014; Swerdloff & Ng, 2019; Braunstein & Anawalt, 2021a).
Physiological GM shows three age peaks during a male’s lifespan (Figure 1) (Braunstein, 1993). The first peak occurs in the neonatal period, affecting 60–90% of neonates, due to the transplacental transfer of maternal estrogens (Nachtigall, 1965; Braunstein, 1993). Neonatal GM is usually regressing spontaneously two to three weeks after delivery, but it may persist or recur three to six months after birth, during the mini-puberty, due to transient activation of the hypothalamic-pituitary-gonadal axis (HPG) (Nachtigall, 1965; McKiernan & Hull, 1981; Jayasinghe et al., 2010). However, it does not persist after the first year of life (Schmidt, 2002). The second peak is observed in puberty with a prevalence of 22–69%, reaching the highest incidence during mid-puberty (Moore et al., 1984; Biro et al., 1990; Braunstein, 1993; Kumanov et al., 2007; Mieritz et al., 2015). It is caused by a transient imbalance in the free androgen-to-free estrogen ratio caused by the earlier rise of serum estradiol (E2) compared with serum androgen concentrations (Moore et al., 1984; Biro et al., 1990). Pubertal GM is characterized by gradual enlargement, usually not greater than 4 cm in diameter, and generally regresses within 1–2 years; it may persist in up to 10% of affected adolescents till adulthood (Nydick et al., 1961; Ma & Geffner 2008). The third peak occurs in middle-aged and elderly men with an incidence of 30–65% (Nuttall, 1979; Niewoehner & Nuttal, 1984; Georgiades et al., 1994). It results in either from increased peripheral aromatase activity, secondary to the increase in total body fat elevated luteinizing hormone (LH) concentrations, and a decrease in serum testosterone (T) concentrations associated with male aging or by an underlying pathology (45–50% of adult men with GM), such as medication, systemic diseases, obesity, or endocrinopathies (Nuttall, 1979; Niewoehner & Nuttal, 1984; Georgiades et al., 1994; Mieritz et al., 2017; Swerdloff & Ng, 2019).
GM is usually asymptomatic and discovered incidentally during a physical examination, especially in adults, as a firm mass of at least 5 mm in diameter located concentrically beneath the nipple-areolar complex. However, in the early phase, it may be presented with breast tenderness and pain, especially in adolescents and cases of rapid progression (Braunstein, 2007; Gikas & Mokbel, 2007; Narula & Carlson, 2007).
Although GM is usually benign, it may cause physical and psychological stress and fear for breast cancer; in rare cases, it may be associated with severe underlying endocrine or systemic disease (Narula & Carlson 2014; Kipling et al., 2014; Rew et al., 2015). Thus, it is of clinical importance to clarify the etiology of GM. Imaging plays a pivotal role in this effort with mammography and ultrasound being the most used and magnetic resonance imaging (MRI) being employed in some special cases. This review aims to discuss the pathophysiology, evaluation, and management of GM, highlighting the prominent role of imaging in diagnostic and therapeutic decision-making.
2. Anatomy - Histology
Histopathologically, GM is characterized by ductal epithelial hyperplasia and increased stromal and periductal connective tissue; however, in contrast to the female breast, TDLU remains vestigial. (Nicolis et al., 1971; Braunstein, 2007; Narula & Carlson, 2007; Kornegooret al., 2012; Lapid et al., 2014). GM is classified in characteristic histologic patterns: florid, and fibrous:
● In the florid pattern, which corresponds to recent-onset GM (duration <6 months), hyperplasia of the ductal epithelium, infiltration of the periductal tissue with inflammatory cells, and surrounding edema are observed. This is the stage of symptomatic GM, which is frequently accompanied by pain and tenderness and might be reversible if the underlying cause is withdrawn.
● On the other hand, the fibrous pattern may be observed after the persistence of 6–12 months, when the glandular elements regress, and stromal fibrosis predominates. This quiescent stage is characterized by dilated ducts with periductal fibrosis, stromal hyalinization, and increased subareolar fat; it is considered irreversible due to chronic changes and fibrosis (Nicolis, 1971; Narula & Carslon, 2007).
3. Pathophysiology
An imbalance of androgens-to-estrogens action on breast tissue is considered the principal mechanism that leads to GM, as male breast tissue has estrogen and androgen receptors. Estrogens stimulate, and androgens inhibit breast tissue proliferation (Sasano, 1996; Marthur & Braunstein 1997; Narula & Carlson, 2014). Thus, GM may result from androgen deficiency, deficient androgen action, estrogen excess, increased estrogen action, or a combination of them. Androgen deficiency and estrogen excess may be either absolute when androgens are below and estrogens above the reference concentrations for young males, respectively, or relative, when both hormones are within the reference range, but the androgen-to-estrogen ratio is abnormal (Narula & Carlson, 2014).
Deficient androgen action in breast tissue might result from either decreased serum concentrations of androgens due to primary or secondary T deficiency or absent or defective androgen receptors. On the other hand, increased peripheral aromatization of androgens to estrogens by the enzyme aromatase may contribute to GM as it leads to estrogen excess. Moreover, estrogen excess may result from increased estrogen production by the testis or the adrenals, resulting from displacement from sex hormone-binding globulin (SHBG), or exogenous administration. In addition to the direct contribution to GM increased estrogen concentrations enhance the production of SHBG, leading to a reduction in free T and, therefore, further decrease of the free androgen-to-free estrogen ratio. Finally, estrogens inhibit LH secretion by the pituitary through the negative feedback mechanism, resulting in secondary T deficiency (Braunstein, 1993; Narula & Carlson, 2014).
*The local hormonal milieu in breast tissue plays a key role in the development of GM. Evidence suggests the contribution of local androgen deficiency or estrogen excess, locally decreased or increased number or activity of androgen or estrogen receptors, and locally increased action of aromatase in mammary tissue in the development of GM (Sasano et al., 1996; Narula & Carlson, 2014).
Additionally, progesterone, leptin, insulin-like growth factors-1 and -2 (IGF-1 and -2), and prolactin may constitute a different mechanism than secondary hypogonadism that may lead to GM (Sansone et al., 2017). Male breast tissue expresses LH, human chorionic gonadotrophin (hCG), prolactin, progesterone, IGF-1, and IGF-2 receptors; however, the role of the hormones and growth factors above mentioned in the pathogenesis of GM has not been clarified (Carslon et al., 2004; Narula & Carlson, 2014).
4. Causes
5. Evaluation
● 5.1. History
● 5.2. Physical examination
5. 5.3. Laboratory evaluation
Hormonal and biochemical.
6. Imaging
● 6.1. Mammography finding
GM is seen in mammography as a sub-areolar opacity, which may vary in shape according to the underlying histological pattern. Three mammographic patterns of GM are described: nodular, dendritic, and diffuse (Appelbaum et al., 1999).
● Nodular GM is the most common (72%) and corresponds to the florid histological phase and normally obtains a fan-shaped form, which radiates from the nipple and gradually blends into the surrounding fat tissue. Occasionally, this density may be opaque resembling a sphere (Figure 4A).
● Dendritic GM is less frequent (18%) and corresponds to the fibrous histological phase and is depicted as a flame-shaped opacity with projections (dendrites) that irradiate and penetrate the surrounding adipose tissue, which may extend to the upper-outer quadrant of the breast (Figure 4B).
● Diffuse GM is the less common form (~10%) and is typically observed in the enlarged breasts of transgender females under exogenous estrogen administration for gender-affirming hormonal therapy. In this case, the breast resembles a dense female breast in mammography; however, marked by heterogeneity and the absence of Cooper ligaments.
● 6.2. Ultrasound findings
● 6.3. MRI findings
7. Differential diagnosis
● 7.1. Pseudogynecomastia
● 7.2. Male breast cancer
1. 7.2.1. Mammography
2. 7.2.2. Ultrasound
3. 7.2.3. Fine needle aspiration cytology and needle core biopsy
● 7.3. Imaging algorithm
8. Management
● 8.1. Watchful waiting
● 8.2. Medical treatment
● 8.3. Radiotherapy
● 8.4. Surgical therapy
