Men and Children



Men and Children


Edi Brogi



BREAST LESIONS IN MALES

Lesions of the breast are rare in men, and they are sampled with fine needle aspiration (FNA) more often than with needle core biopsy (NCB). A pathology group servicing several community hospitals in the Netherlands received only 26 NCB specimens of the male breast between 1993 and the end of 2002, or 2.6 specimens per year (1). Between 2011 and 2013, 539 men underwent mammographic evaluation of a breast mass at a center in Norway (2). FNA was performed in 62% of patients and NCB in 2.2%.


Gynecomastia

Gynecomastia is the most common clinical and pathologic abnormality in the breast of males.


Age

In a recent study (2), the mean age of men with mammographic diagnosis of gynecomastia was 55 years (median age 60 years; range 15-91).


Predisposing Factors

Prepubertal gynecomastia is uncommon, except as a transient phenomenon in newborn male infants exposed to maternal estrogens. Approximately 30% to 40% of pubertal males develop physiologic gynecomastia, which usually regresses spontaneously in a few months. Adult males can develop gynecomastia secondary to systemic metabolic, and/or hormonal imbalances (that is, hyperthyroidism, hepatic cirrhosis, chronic renal failure, chronic pulmonary disease, and hypogonadism), use of hormones (namely, estrogens, androgens, anabolic steroids, finasteride), and other drugs (namely, digitalis, cimetidine, spironolactone, marijuana, tricyclic antidepressants, 3-hydroxy-3-methyl-glutaryl-CoA Acetyl reductase inhibitors for the control of cholesterol level (3,4), imatinib mesylate for the treatment of chronic myeloid leukemia or gastrointestinal stromal tumors (5,6), and antiretroviral therapy in HIV-positive men) (7,8). Gynecomastia secondary to paraneoplastic hormone production has been reported in patients with pulmonary carcinoma and testicular germ cell tumors (9). An association with Klinefelter syndrome is documented (10).


Imaging Studies

Mammographically, gynecomastia has different appearances. In its earliest phase, it appears as a nodular fan-shaped subareolar density. The dendritic phase is characterized by a “flame-shaped” subareolar density with prominent radial extensions; this phase correlates histologically with the onset of stromal fibrosis. Diffuse glandular gynecomastia is characterized by heterogenous breast density, with combination of nodular and dendritic patterns (11). The combined use of mammography and ultrasonography is considered the optimal approach to rule out carcinoma in a patient who presents with clinical findings of gynecomastia (12,13,14). Between 2011 and 2013, 65% of men who underwent mammographic evaluation of a breast mass at a medical center in Norway (2) had gynecomastia with diagnostic mammographic features; 90% of patients also underwent sonographic evaluation. FNA of the lesion was performed in 75% of patients, and only 1% underwent NCB. The diagnosis of gynecomastia was confirmed in all cases.



Microscopic Pathology

The histologic changes of gynecomastia are similar regardless of its etiologic factors. Florid gynecomastia is common in the first year of onset. The ducts are lined by micropapillary and/or flat usual ductal epithelial hyperplasia (Fig. 24.1). Scattered epithelial mitoses may be encountered. Coexisting myoepithelial hyperplasia is common. The periductal stroma shows increased cellularity, prominent vascularity, edema, and a slight chronic inflammatory cell infiltrate. Intermediate gynecomastia shows both florid and fibrous components, and tends to be present for 6 months or less (Fig. 24.2). Fibrous (inactive) gynecomastia is usually seen in long-standing lesions (12 months or longer). The epithelial proliferation is less conspicuous than that in the florid phase; the stroma is more collagenous with less edema, reduced vascularity, and inconspicuous inflammation (Fig. 24.3). Pseudoangiomatous stromal hyperplasia (PASH) can be present in any phase of gynecomastia, but it is more pronounced in the active and intermediate stages (Fig. 24.1).
Gynecomastia-like hyperplasia sometimes occurs in the breast of adolescent females.






FIGURE 24.1 Gynecomastia, Florid. A, B: The ducts show micropapillary usual ductal hyperplasia. The periductal stroma has increased cellularity and prominent vascularity. C: Pseudoangiomatous hyperplasia of the stroma surrounds a duct with myoepithelial hyperplasia.






FIGURE 24.2 Gynecomastia, Intermediate. An intermediate phase lesion with compact epithelial and myoepithelial hyperplasia. An epithelial mitotic figure is present (arrow). Note the periductal edema and hypervascularity.

Additional epithelial changes include lobule formation (Fig. 24.4), focal squamous metaplasia (Fig. 24.5), and apocrine metaplasia. Atypical ductal hyperplasia (ADH) sometimes occurs in gynecomastia (15), and morphologically resembles ADH in the female breast (Fig. 24.6). The ducts with ADH (and also the ducts with ductal carcinoma in situ [DCIS]) usually lack the periductal fibrosis and increased stromal vascularity characteristic of gynecomastia.






FIGURE 24.3 Gynecomastia, Inactive. This focus features micropapillary epithelial hyperplasia and a mild increase in periductal vascularity. The periductal stroma is collagenized.


Immunohistochemistry

The epithelium of gynecomastia consists of three cell layers (16). The myoepithelial cells express CK5, CK14, and p63 but are negative for estrogen receptor (ER), progesterone receptor (PR), and androgen receptor (AR). The intermediate layer
consists of cuboidal or columnar ductal cells immunoreactive for ER, PR, and AR but negative for CK5 and CK14. The epithelium lining the ductal lumen consists of flattened cells that are reactive for CK5, and CK14, but only weakly positive for ER, PR, and AR. The use of immunohistochemical stains for ER and CK5/6 may be helpful to document foci of ADH in the background of gynecomastia (see also Chapter 8).






FIGURE 24.4 Gynecomastia. Lobule formation in a male breast.


Treatment and Prognosis

Early gynecomastia sometimes may regress when the underlying conditions are treated, or the pathogenetic drugs are discontinued, but in most cases breast enlargement persists. Most patients with gynecomastia receive no specific treatment. The use of radiation (17) and tamoxifen (18) to prevent gynecomastia in men with prostatic carcinoma treated with bicalutamide is a subject of debate. Surgical excision of gynecomastia is indicated clinically only to exclude carcinoma, but sometimes it is performed for cosmetic reasons. Ultrasound-assisted liposuction may be considered in overweight or obese men, when adipose tissue is thought to contribute to the mass (19). Liposuction can result in epithelial displacement that mimics invasive carcinoma (20). A conservative approach is adopted in children with gynecomastia, as the lesions usually resolve without treatment; the use of tamoxifen is discouraged. In a study of men younger than 21 years of age who underwent surgery for gynecomastia (10), the average age at the time of the procedure was 16.2 years, and most patients were overweight or obese. Although carcinoma may rarely arise in conjunction with gynecomastia (15), gynecomastia is not associated with an increased risk of subsequent mammary carcinoma (21).






FIGURE 24.5 Gynecomastia. Florid gynecomastia with squamous metaplasia in hyperplastic duct epithelium. Note mild periductal inflammation.






FIGURE 24.6 Gynecomastia with Atypical Duct Hyperplasia. A: The proliferation is almost entirely epithelial with a minimal myoepithelial component. B: Atypical cribriform duct hyperplasia.


Intraductal Papilloma




Imaging Studies

The mammographic and sonographic appearance of papillomas of the male breast does not differ significantly from that of similar tumors in females (11,22).


Microscopic Features

Papillomas of the male breast are histologically similar to those occurring in females. Multiple papillomas can occur. Because papillary carcinomas of the male breast are relatively more common than papillomas, careful evaluation of the epithelial component is required to rule out atypia or carcinoma (see also discussion in Chapters 4 and 11).


Immunohistochemistry

Myoepithelium lines the fibrovascular cores of papillomas, atypical papillomas, and papillomas involved by DCIS. The absence of myoepithelium in the fibrovascular cores of a papillary lesion supports the diagnosis of papillary carcinoma but does not distinguish between papillary DCIS, encapsulated papillary carcinoma, and invasive papillary carcinoma. CK5/6 immunostain highlights the myoepithelium and also decorates usual ductal hyperplasia (UDH) with a characteristic “checkerboard” pattern, whereas atypical and neoplastic ductal epithelium are usually CK5/6-negative.


Treatment and Prognosis

The need for surgical excision of papillomas without atypia diagnosed at NCB with radiologic and pathologic concordant findings in females is currently subject of investigation (see also Chapter 4). Papillary lesions in the breast of males, including papillomas without epithelial atypia, usually undergo surgical excision. Complete evaluation of the lesion is recommended to rule out the possibility of papillary carcinoma, as the latter is relatively more frequent in males.


Fibroepithelial Lesions


Age

The age of men with fibroadenomas (FAs) in one series (23) ranged from 37 to 71 years; a 20-year-old man had a benign (low grade) phyllodes tumor (PT). A 15-year-old boy with unilateral gynecomastia reportedly had a 7-cm benign fibroepithelial tumor (24).


Predisposing Factors

Fibroepithelial lesions (FELs) usually arise in the context of gynecomastia (23,25,26,27,28), particularly in patients treated with estrogens or antiandrogen therapy, which can result in lobule formation. Other drugs associated with FA and/or fibroadenomatoid alterations include spironolactone, methyldopa, and chlordiazepoxide (23).


Microscopic Pathology

The morphology of FELs in men resembles that of equivalent lesions in females. Some lesions clinically regarded as FAs may just represent nodular foci of gynecomastia. PASH is common in the stroma of gynecomastia, and can be mass-forming (29).


Treatment and Prognosis

The treatment of PTs in men is similar to that of equivalent tumors in females. Most PTs in men are clinically benign.


Proliferative Fibrocystic Changes


Age and Predisposing Factors

Proliferative fibrocystic changes (FCCs) in the male breast are extremely rare. Most men with proliferative FCCs were under 50 years of age at the time of diagnosis (30,31,32,33). At least two men were described as karyotypically and phenotypically normal (30,31). Hormonal imbalance is usually the predisposing factor.


Microscopic Pathology

Proliferative FCCs in men include apocrine cysts, papillary apocrine metaplasia, UDH, and duct stasis with mastitis. The microscopic features in some lesions can resemble those of juvenile papillomatosis (JP) (32).



Carcinoma of the Male Breast


Incidence and Ethnicity

The standardized incidence rate of breast carcinoma in men is 0.4 per 100,000 person-years (34), and it is highest in men aged 85 years or older (35). A rise in the incidence of breast carcinoma in males has been observed recently across all racial and ethnic groups (36,37). In a California-based population study (37), 70% of men with breast carcinoma were non-Hispanic white. Race and ethnicity did not affect patient survival.


Age

The median age at diagnosis of invasive carcinoma is 68 years (37), but carcinoma can occur at any age, including rare cases in boys. Younger men have significantly more HER2-positive carcinomas (37). The median age of men with DCIS was 58 years in one study (38) and 65 years in another (39).


Predisposing Factors

Hormonal imbalance (namely, testicular dysfunction, hyperprolactinemia, prolonged estrogen or anabolic steroid treatment, hepatic insufficiency, etc.) is one of the most common predisposing factors. The association with prostatic carcinoma is partly due to hormonal treatment but may also reflect a genetic predisposition (40,41). Most men with familial breast carcinoma are BRCA2 germline mutation carriers; BRCA1 germline mutations are less common (42,43). The mean age at diagnosis in men with BRCA2-associated breast carcinoma is 59 years, and about 25% have prostate carcinoma and/or contralateral breast carcinoma. HER2 positivity in male breast carcinoma is significantly
associated with BRCA2 germline mutation carrier status (43). Klinefelter syndrome is also a predisposing genetic condition. Men with prior diagnosis of breast carcinoma have a 30-fold increased risk of developing a contralateral breast carcinoma; the risk is 110-fold higher if breast carcinoma was diagnosed before the age of 50 years (44). Radiation exposure and exposure to high environmental temperatures have also been implicated as possible risk factors. Gynecomastia is neither a predisposing factor nor a morphologic precursor of breast carcinoma.



Imaging Studies

Mammography and ultrasonography of invasive carcinoma typically reveal a mass with irregular margins (11). Concurrent gynecomastia may occasionally obscure a carcinoma, but ultrasonography usually distinguishes the two lesions. Encapsulated papillary carcinoma appears as a discrete mass with a regular contour, and may contain calcifications. Ultrasound examination documents a cystic lesion with an internal papillary component. The presence of an irregular border may be evidence of invasion. Microcalcifications are detected in 10% to 30% of male breast carcinomas, including DCIS, encapsulated papillary carcinoma, and invasive carcinoma. At present, there are no guidelines recommending mammographic screening for men, even in individuals with known genetic predisposition. The MRI findings of breast carcinomas in males resemble those of similar tumors in females.






FIGURE 24.7 Male Breast, Invasive Ductal Carcinoma. A, B: The patient was an 85-year-old man with a palpable tumor. The needle core biopsy specimen reveals (A) invasive ductal carcinoma, moderately differentiated. Gland formation is evident (B). The invasive carcinoma was positive for estrogen receptor (ER) in 95% of the cells (not shown). C: The needle core biopsy specimen from a palpable mass in the breast of a 51-year-old male reveals poorly differentiated invasive ductal carcinoma with an area of necrosis. The carcinoma is associated with stromal desmoplasia. This carcinoma was also strongly and diffusely positive for ER (not shown).


Microscopic Pathology


Invasive Carcinoma

Approximately 90% of carcinomas in men are invasive ductal carcinomas, and most are moderately or poorly differentiated (37,43,45,46,47,48,49,50) (Fig. 24.7). Apocrine differentiation can be present. A small percentage of invasive carcinomas have tubular, cribriform, mucinous, micropapillary, secretory, and adenoid cystic morphology (37,43,45,46,47,48,49). In a series of men with familial breast carcinoma, invasive micropapillary morphology showed a trend for association with BRCA2 germline mutation status (42).

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Nov 17, 2018 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Men and Children
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