The mammary glands develop as solid extensions of the ectoderm into the underlying mesenchyme. These extensions occur along two thickened strips of ectoderm, which start at the axilla and extend to the inguinal region. Later in fetal life, the mammary ridges disappear except in the pectoral area. The breast bud, the pectoral remnant of the mammary ridge, consists of primary ducts and loose stroma. Secondary lactiferous ducts arise from the primary ducts. Each ductal system drains independently into the nipple. At a gestational age of about 40 weeks, the nipples are poorly formed and often depressed. Around the perinatal period, connective tissue grows under the breast bud to form the nipple/ areola complex [1].
During the prepubertal period, the breast tissue hardly undergoes any changes. Breast development is usually the first sign of puberty. The average age for onset of thelarche is 11.2 years, with a range of 9.0 to 13.4 years [2]. The primary hormones influencing breast development is estradiol, which primarily controls ductal development, and progesterone, which promotes lobular development. Corticosteroids and thyroid hormones are implicated in breast development also. The duration of breast maturation can range from 18 months to 9 years. Tanner staging is an accepted and uniform way to describe the pubertal development of the breast (Table 1).
After puberty, changes continue to occur within the female breast. Lobular and stromal units develop between adolescence and pregnancy. This period is characterized by the cyclic activity of hormones related to ovulation. During pregnancy, the breast enlarges to accommodate milk production and lactation; the size involutes after breastfeeding is finished. After age 35, the breast stroma becomes less fibrous and is replaced by fat. The mature breast is softer and less lobular.
Table 1
Tanner stages of breast development [47]
Developmental anomalies of the breast
The absence of nipples (athclia) and the absence of breast tissue (amastia) may occur bilaterally or unilaterally. This rare condition results when the mammary ridges fail to develop or completely disappear. Athelia or amastia may be associated with Poland syndrome, which may include absent chest wall muscles, absence of ribs 2 to 5, webbed fingers, vertebral anomalies, radial nerve palsy, and pectus excavatum. Amastia in girls may be treated with an augmentation mammoplasty using traditional implants or an expander implant [3]. In the latter technique, an expander implant is placed, and the volume of the implant is adjusted with time to match the volume of the contralateral breast tissue. The patient receives a permanent implant after full breast maturity is reached.
An extra breast (polymastia) or extra nipple (polythelia) occurs in approximately 1% of the population. It may be an inheritable condition [4]. Supernumerary nipples are slightly more common in males than in females. Extra breasts or nipples most commonly occur along the milk line, usually just underneath the normally located breasts or nipples. They also have been noted in ectopic sites such as the back or the buttock [5,6]. Accessory or ectopic breast tissue responds to hormonal stimulation and may cause discomfort during menstrual cycles and in the postpartum period. Some authors have reported that these tissues may undergo benign [7] or malignant [8,9] transformation and that resection of ectopic breast tissue should be performed in childhood or early adolescence.
During puberty, breast asymmetry may occur when one breast develops before or more rapidly than the other. The physical examination usually shows homogenous enlargement of one breast with no discrete masses or discharge. Accompanying breast tenderness may be present. If a mass is not present on physical examination or ultrasonography, the patient and parents may be reassured that the asymmetry will become less noticeable with age. If, however, significant asymmetry persists after full breast development, then augmentation or reduction mammoplasty of one side may be considered.
Breast atrophy may occur in the pubertal period. It is usually caused by loss of fat and supportive tissues around the breasts secondary to poor eating habits.
Tuberous breast deformity results from breast hypoplasia, deficient diameter of the mammary base at the horizontal and vertical levels, and the presence of a constricting ring that herniates the nipple areolar complex, causing an overlying protuberant areola [10]. The entity is benign, but it can be of significant cosmetic concern to the patient and her family. In some cases, treatment is reassurance, while reconstructive surgery is indicated for severe tuberous breast deformity.
Macromastia, or enlarged breasts, are often evident during adolescence. Enlarged breasts are associated with complaints of breast pain, back pain, poor posture, shoulder grooving, and problems with self-image. Approximately two-thirds of patients with macromastia are obese. Conservative measures such as weight loss, improved posture, physical therapy, supportive brassieres and nonsteroidal analgesic medications may be recommended first. Reduction mammoplasty, however, significantly improves the symptoms and quality of life for patients [11,12]. Generally, the procedure should be deferred until breast maturation is completed.
Juvenile hypertrophy is an extreme form of macromastia that is usually symmetric and occurs at the time of menarche. Both breasts diffusely enlarge. Because the hormonal levels of estradiol and progesterone are normal, it is thought that this condition is caused by an abnormal response of the breast during thelarche [13]. Histologically, the breast shows an increase in connective tissue with moderate ductal proliferation. Although this lesion is benign, adolescents with juvenile breast hypertrophy experience significant discomfort to their neck, shoulders, and back. Hormonal treatment has been tried but, often, surgical intervention such as reduction mammoplasty or subcutaneous mastectomy with placement of an implant is necessary. Recent literature has shown that women who had undergone reduction mammoplasty in adolescence are still able to breastfeed successfully [14].
Breast disorders in prepubertal children
In about 60% of normal newborns, maternal hormones may cause unilateral or bilateral enlargement. Some secretion of an opaque liquid (“witches’ milk”) may accompany these changes. Both of these findings resolve spontaneously and do not require treatment.
Benign premature thelarche is defined as isolated breast development in females between the ages of 6 months and 9 years. Signs of precocious puberty such as presence of pubic hair and accelerated bone growth should be sought carefully during examination, as they may indicate ovarian or adrenal tumors. If thelarche is isolated, treatment is reassurance and re-evaluation every 6 to 12 months. If breast development is progressive or does not regress within 1 to 2 years, an endocrine work-up is recommended. Additionally, if other signs of puberty are present, precocious puberty should be ruled out. Precocious puberty may be central or gonadotropin-releasing hormone (GnRH)- dependent, peripheral (GnRH-independent), or incomplete.
Early onset of puberty is more common in females and often is activated centrally by the premature activation of the hypothalamic- pituitary-gonadal axis. Hypothalamic hamartomas, trauma, and central nervous system (CNS) lesions may cause central precocious puberty; however, it is most commonly idiopathic. The diagnosis is made by giving exogenous GnRH, which results in a dramatic rise in serum follicular stimulating hormone (FSH) and luteinizing hormone (LH). Treatment involves surgical removal of the responsible lesion or the continuous administration of exogenous GnRH to suppress FSH and LH release. Peripheral precocious puberty is caused by sex steroid secretion independent of GnRH release. Causes include McCune- Albright syndrome, administration of exogenous steroids, or circulation of endogenous steroids from an ovarian or an adrenal tumor. Serum FSH and LH levels are usually normal or low.
Breast infections may occur in the newborn period or in the prepubertal patient. In infants, mastitis neonatorum presents as cellulitis with or without an abscess in the second or third week of life. Antibiotics, and, if a significant abscess is present, drainage, are used to treat the infection. In a child or an adolescent, needle aspiration is preferable to incisional drainage to minimize the risk of damage to the breast bud. The infectious agent is usually Streptococcus or Staphylococcus. Recently, it has been recognized that breast abscesses can occur as a sequela of nipple piercing [15]. Infections may occur on the average of 7 months after initial instrumentation in 10% to 20% of people. Healing of the tract takes up to 6 to 12 months after drainage and removal of the foreign body.
Gynecomastia is a benign and usually self-limited condition that occurs in 50% to 60% of boys during early adolescence. This entity is uncommon in prepubertal boys, and often it is associated with endocrine syndromes or tumors. In adolescent boys, it usually occurs about 1 year after the onset of puberty. On examination, gynecomastia presents as discrete, mobile subareolar masses or diffusely enlarged painful breasts. If the mass is large or fixed, or if a d\ischarge is present, further evaluation is necessary. The physical examination in an adolescent with gynecomastia should include a testicular examination. Although simple pubertal gynecomastia is most common, the differential diagnosis for gynecomastia includes Klinefelter’s syndrome, testicular feminization, hormone-secreting tumors, hyperthyroidism, hypothyroidism, cirrhosis, drug use (eg, cimetidine or marijuana), and familial predisposition. Obese young males may present with pseudogynecomastia; weight loss usually is recommended. Patients with mild-to-moderate gynecomastia should be reassured that the condition is self-limited. Breast enlargement of greater than 4 cm rarely resolves spontaneously, however. If the breast enlargement is such that it causes pain, discomfort, or psychological trauma, subcutaneous mastectomies should be performed. The mastectomy is performed through a subareolar incision with or without the use of liposuction.
Breast masses
Neinstein summarized 15 reviews of breast lesions in adolescents and young adults (N = 179) from 1960 to 1999 [13]. Fibroadenomas accounted for 68% of breast masses. Proliferative lesions with fibrocystic changes were second in frequency (19%). Less than 1% of the breast masses were malignant; about a third of these arose from breast tissue, and the remainder consisted of Hodgkin’s lymphomas, lymphosarcoma, angiosarcoma, and other metastatic tumor deposits.
Benign breast masses
In the literature, distinction is made among three types of fibroadenomas: (1) simple fibroadenomas, (2) giant or juvenile fibroadenomas, and (3) phyllodes tumors. Simple fibroadenomas are the most common breast lesion in adolescent females. The patient often finds these lesions by self-examination. Although usually painless and asymptomatic, fibroadenomas may be slightly uncomfortable for a few days before the patient’s menstrual period. Most fibroadenomas occur singly, but up to 25% of patients with fibroadenomas may have more than one lesion. On examination, fibroadenomas are rubbery, well circumscribed, and not fixed to surrounding tissue. Simple fibroadenomas do not distort the patient’s breast configuration. Histologically, simple fibroadenomas consist of proliferating stroma around collections of elongated ducts (Fig. 1).
There have been anecdotal reports of carcinoma arising within a breast fibroadenoma [16]. The average age of occurrence of malignancy is 42 years, however. In 1999, a retrospective study of 1835 patients reported that the risk of invasive cancer was 2.17- fold higher in patients with fibroadenomas [17]. The study did not show an increased risk in patients with no family history of breast cancer or with simple fibroadenomas without associated lesional risk factors (eg, epithelial calcifications, papillary apocrine changes, cysts greater than 3 cm, or sclerosing adenosis). In adolescents and young adults, there had been no documented malignancies occurring within a pre-existing fibroadenoma.
Fig. 1. Histologic findings of a breast fibroadenoma (10 magnification, H&E stain). There are elongated ducts within a fibrous stroma.
The diagnosis of a fibroadenoma usually is made by history and physical examination. Ultrasonography is a reliable and nonpainful confirmatory test. The ultrasonographic findings are of a solid, well-circumscribed, avascular mass. In an adolescent with a fibroadenoma who has no family history of breast cancer, serial monitoring of the lesion every 2 to 3 months may be performed. Alternatively, if the patient and her family wish to have the mass removed, an excisional biopsy is also acceptable. In select patients, the biopsy may be done with intravenous sedation and local anesthesia. General anesthesia may be necessary in patients who are overly anxious, or if the lesions are deep or multiple. If possible, a circumareolar incision should be used to optimize the cosmetic results.
Most longitudinal studies on fibroadenomas show that most lesions may get smaller in size and even completely resolve. Over a 5-year period, Carty followed 25 fibroadenomas and found that 52% became smaller; 16% remained the same size, and 32% enlarged [20]. Similarly, Cant followed 65 lesions and found an actuarial probability of disappearance of 46% of the lesions at 5 years and 69% at 9 years [21]. He found that women younger than 20 had a higher probability of resolution of the fibroadenoma. Size or multiplicity of lesions did not affect the probability of resolution.
Juvenile or giant fibroadenomas are usually large, painless masses greater than 5 cm. The masses may compress adjacent breast tissue and cause considerable distortion. Histologically, giant fibroadenomas are encapsulated with more cellular elements in the stroma surrounding distorted ducts. Excision of the lesion is curative.
Cystosarcoma phyllodes tumors usually present with bulky breast masses that may reach 20 cm in size. These masses are firm and mobile, and the overlying skin may be thin and shiny, with increased vascularity. There is no associated skin dimpling, nipple retraction, or nipple discharge. Patients may present with a rapidly growing, nontender breast mass [18], or with accelerated growth of a previously stable mass.
Phyllodes tumors represent 0.4% of all adolescent breast masses [18]. Rajan reviewed 45 female adolescents with phyllodes tumors; 75% were benign and 25% were malignant. Ultrasonography cannot distinguish between a fibroadenoma and a phyllodes tumor [19]. Microscopically, benign phyllodes tumors have a hyperplastic and cellular stromal component compared with fibroadenomas. Phyllodes tumors are not fully encapsulated, often extending into surrounding normal breast tissue. Malignant phyllodes tumors are defined by the presence cellular atypia, anaplasia, and high mitotic activity in the cells within the stroma.
Phyllodes tumors should be excised completely with a surrounding rim of normal tissue. Incomplete excision results in recurrence. Adjunct chemotherapy or radiation has no role in the treatment of nonmetastatic disease. Unlike in adults, where a mastectomy is recommended, breast conservation is recommended in adolescents.
Physiologic breast changes
Breast pain (mastalgia)
Cystic mastalgia is defined as breast pain or discomfort, which occurs about 1 week before a menstrual period and subsides after menses. The pain is usually diffuse and bilateral and may involve the upper arms and axillae. This is more common in women in their 20s and 30s. In contrast, noncyclic mastalgia is more common in women in their 40s and often involves a specific region of the breast.
Adolescents with breast pain usually are treated with reassurance, local heat, and analgesics. Good breast support is achieved with an appropriately fitted brassiere that should be worn during the day and at night. Medications such as diuretics, vitamin B, vitamin B6, or vitamin E, have not been shown to be beneficial in several clinical trials [22]. Although abstinence from caffeine often is recommended, its benefit is unsubstantiated. In Europe, evening primrose oil has been used for mastalgia with a reported response rate of 44% [23]. The recommended dose is 1000 mg orally taken three times a day for at least 3 months. This medication is available without prescription in pharmacies and herbal supplement stores. There are no reported adverse effects. In adult females, danazol, tamoxifen, and bromocriptine have been effective [24], although there are no reports for adolescent patients.
Proliferative breast changes (“fibrocystic disease”)
Nodular changes in the breast are present in as many as 85% of women. Adolescent breasts are typically fibrous with small lumps (
For adult patients, fibrocystic changes are classified into three histologic categories: nonproliferative changes, proliferative changes without atypia, and proliferative changes with atypia. Adults with proliferative changes or atypia have a higher risk of future malignancies. Proliferative changes such as moderate-to- florid hyperplasia, sclerosing adenomas, or papilloma with a fibrovascular core, have been associated with a 1.5- twofold increased risk of malignancy. Patients with atypical or lobular hyperplasia have a 4.4-fold increase in cancer risk, which increases to ninefold with a positive family history of breast cancer[26]. Screening guidelines for adults with a history of atypia on breast biopsy include monthly breast self-examinations (BSE), physician examinations every 6 to 12 months, and a yearly mammogram. These recommendations should be followed in adolescents. As will be describe subsequently, however, breast ultrasonography may be more useful than mammograms in evaluating adolescent breast tissue.
Nipple discharge
When an adolescent presents with nipple discharge, the characteristics of the fluid provide clues to the underlying pathology. A milky discharge or galactorrhea often is caused by an increase in prolactin. In adolescents, the causes are varied and include prolactinomas, hypothyroidism, pregnancy, and postpartum st\ates. Exogenous medications such as oral contraceptives, phenothiazones, estrogens, androgens, and spironolactone may cause galactorrhea.
Thin, brown discharge that occurs episodically may come from Montgomery’s tubercles [13]. These are small papules arising from sebaceous glands associated with lactiferous ducts. There may be an accompanying mass underneath the areola. The discharge usually disappears after 4 to 6 weeks.
Purulent discharge is associated with an infection of the breast. An accompanying abscess may be present. Treatment includes antibiotics that are effective against Streptococcus or Staphylococcus species. Warm compresses and analgesics may alleviate associated discomfort.
Intraductal papillomas are the most common cause of bloody nipple discharge in women. They are rare in adolescents, occurring in 1.2% of biopsied lesions in this age group [13]. Intraductal papillomas are outgrowths of the epithelial lining within a lactiferous duct. Trauma can break off the stalk of the papilloma, creating a bloody discharge. Papillomas may be associated with a soft mass in the ipsilateral breast. Treatment involves excision.
Serosanguineous discharge may be associated with cystic proliferative changes, trauma, or less likely, a malignancy. Patients should be evaluated with a careful breast examination and close follow-up. There are no studies supporting use of cytologic evaluation of nipple discharge in the adolescent population.
Malignant disease of the breast
Malignant breast disease is distinctly uncommon in adolescents. In this age group, only one-third of malignancies involving the breast arise from primary breast tissue; the rest arise from nonbreast tissue (eg, rhabdomyosarcoma) or metastatic disease [27- 30].
In children and adolescents, the most common finding of breast cancer is a hard and irregularly shaped mass, which may be fixed to the surrounding tissues [31]. Nodal involvement, skin changes, and nipple retraction are uncommon in this age group. A third of these patients have a positive family history of breast cancer. Although premenopausal women seem to have a more aggressive disease histologically [32], there are no data on whether this finding is seen in adolescents.
An American female has an 11% lifetime risk of developing breast cancer. The first-degree relative (mother, sister, or daughter) of a breast cancer patient has a 22% to 33% risk of developing breast cancer in her lifetime [33,34]. This risk increases to ninefold when the relative had bilateral premenopausal breast cancer.
About 5% of all breast cancer is classified as hereditary breast cancer. Hereditary breast cancer syndromes have the following characteristics: onset of breast cancer before age 50, autosomal dominant inheritance, and the presence of other multiple primary cancers. Members of these families should undergo screening for breast cancer susceptibility genes.
About eight breast cancer susceptibility genes have been mapped. BRCA-1 and BRCA-2 mutations account for about 80% of hereditary breast cancer. Mutations of the BRCA-1 gene located on chromosome 17 have linkage with breast, ovarian and prostate cancers. BRCA-1 is highly penetrant, conferring an 83% breast cancer risk and a 63% ovarian cancer risk by age 70. BRCA-2 mutations, located on chromosome 13, have linkage with male and female breast cancer. A BRCA-1 mutation may occur in about 1% of women of Ashkenazi heritage [35]. A cumulative breast cancer risk of 60% to 80% exists for women with BRCA-1 or BRCA-2 mutations over their lifetime [36,37].
There are other groups known to have an increased susceptibility to breast cancer. Families with Li-Fraumeni Syndrome have p53 mutations causing an increased risk for sarcomas, breast cancer, lung cancer, laryngeal cancer, leukemia, and adrenal cortical carcinoma [38]. The pattern of transmission is autosomal dominant. Three-quarters of women with Li-Fraumeni syndrome develop breast cancer between the ages of 22 and 45 years. Rarely, breast tumors may develop in adolescence.
Recommendations for screening for families with hereditary breast cancer include twice-a-year physical examination. Screening mammograms are performed once or twice yearly, beginning at an age 10 years younger than the youngest affected relative and no later than 35 years. Adolescents who carry BRCA1 or BRCA2 gene mutations should begin breast self-examination at ages 18 to 21 years [39].
Exposure to ionizing radiation is a definite risk for breast cancer. The patient’s age during exposure is correlated directly with the risk, with younger patients having the greatest predisposition. A 20% rate of bilateral tumors also has been reported [40]. There is a long latency period for development of neoplasms. Women who were exposed to ionizing radiation before age 30 (ie, mantle irradiation for Hodgkin’s, thymic irradiation for enlargement, radiation from nuclear fall-out or radiation for mastitis or tuberculosis) are advised to have monthly BSEs and twice yearly physician examinations. Yearly mammography is recommended after 25 years of age. Ultrasonography is recommended before this age, because breast denseness in younger women makes mammographic evaluation of limited value.
Diagnostic modalities
History
Evaluation of breast complaints in adolescents should start with a detailed history. Questions should be asked about the duration of the mass, associated discomfort or discharge, changes temporally related to menstrual periods, age of menarche, and pregnancy history. A risk assessment for breast malignancy is determined by a family history of breast cancer, history of previous malignancies, and history of previous irradiation.
Examination
When performing a breast examination in an adolescent, it is important to keep in mind that she may have physical and emotional discomfort associated with the office visit. It is valuable to discuss with the patient what the examination will entail before performing it. The patient should be provided a gown to minimize exposure. A chaperone, preferably a parent, should be present. It is recommended that a male physician should have a female office staff member in attendance during the examination.
Inspection is performed with the patient sitting with her hands along her sides or with both hands on her hips. Skin dimpling, nipple retraction, and breast asymmetry are noted.
Palpation is performed with the patient in the supine position. The patient should place the ipsilateral arm behind her head and the other arm along her side. Although many techniques are described in the literature (ie, concentric circles, spokes of a wheel, and others), the important point is to palpate every part of the breast including the subareolar area and the axillary tail. The nipple then is pressed gently to see if a discharge is present. Make certain to warn the patient before performing this last maneuver. If a mass is present, characterize its size, contour, regularity, and adherence to surrounding tissue. The examination is repeated on the other breast.
Nodal basins in the axillary, supraclavicular, and infraclavicular areas are examined bilaterally to check for enlarged lymph nodes.
An important part of the breast examination is teaching the patient how to perform breast self-examination. It is helpful to provide the patient with an explanatory brochure on breast self- examination.
Radiologic evaluation
The dense adolescent breast is not evaluated well by mammography. In this age group, ultrasonography is used to characterize the nature of the lesions [41-44]. Color Doppler may enhance the diagnosis further. Because cysts are avascular; fibroadenomas are solid and hypovascular, and abscesses have increased blood flow.
Other modalities such as contrast-enhanced MRI, positron emission scanning, and CT may be helpful, especially in patients with malignancies that are not from primary breast tissue [45,46].
Fine needle aspiration (FNA) is used in a limited fashion in children and adolescents [45]. If a mass is cystic, complete aspiration of the mass may be diagnostic and therapeutic. Although the experience in the adult population shows that FNA has a high sensitivity and specificity for diagnosing solid lesions, the use of fine needle aspiration is limited in the pediatric population. The physical and emotional discomfort associated with FNA in younger patients may preclude its performance. Most patients and their parents come to the surgeon’s office with the expectation that the mass requires removal. In the appropriate patient, a physical examination, FNA, and follow-up may be an appropriate course of action for a benign mass, such as a fibroadenoma.
Core needle breast biopsies performed under sonographic and stereotactic guidance have been used with increasing frequency in the adult population. This modality has not been studied in adolescents.
Surgical considerations in the young patient
In very young and preadolescent children, a biopsy should be considered with extreme caution, because the developing breast bud may be harmed irreparably, even with a needle aspirate. When an excisional biopsy is performed in a postpubertal patient, a circumareolar incision is preferred for better cosmetic results. If the mass is distant from the areola, however, an incision directly overlying the mass may be performed.
Simple mastectomy for gynecomastia is performed using a circumarealoar incision. Obese patients may benefit from concomitant liposuction.
Summary
Although breast cancer is rare in childhood and adolescence, breast concerns among patients in this age group are common. Benign proliferative changes and benign masses such as fibroadenomas are the most common entities encountered in the adolescent patient. Evaluation of breast complaints includes a careful history and physical examination. Ultrasonography is the best adjunctive radiologic modality to assess the adolescent breast. Surgical interven\tion usually is contraindicated in prepubertal patients. In the postpubertal patient, discrete breast masses, which are not suspicious on clinical examination, may be observed. Additionally, FNA and surgical removal are also safe diagnostic and therapeutic alternatives in this patient population.
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Marjorie J. Area MD(a,b,*), Donna A. Caniano MD(c,d)
a Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wl 53226, USA
b Children ‘s Hospital of Wisconsin, 9000 West Wisconsin Avenue, Milwaukee, Wl 53226, USA
c The Ohio State University College of Medicine and Public Health, 410 West 10th Avenue, Columbus, OH 43210, USA
d Children’s Hospital, Division of Pediatric Surgery, ED 379, 700 Children’s Drive, Columbus, OH 43205, USA
* Corresponding author. Children’s Hospital of Wisconsin, 9000 West Wisconsin Avenue, Milwaukee, WI 53226.
E-mail address: [email protected] (M.J. Area).
Copyright Hanley & Belfus, Inc. Oct 2004
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