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Breast Diseases
Development, Anatomy, and Physiology
At the end of week 4 of human embryonic development, paired thickenings appear in the ectoderm on the ventral aspect of the torso. Extending from the axilla to the inguinal region, they form the mammary ridges or “milk lines.” Subsequently they regress and leave a pair of primary mammary buds at the level of the fourth and fifth intercostal spaces. The primary buds thicken into lens-shaped mammary placodes. Epithelial cells invade the underlying mesenchyme during weeks 7 and 8 to form the primitive mammary disk. In week 9, a surge of mesenchymal proliferation occurs, coincident with a thinning of the overlying epithelium. A dense mesenchymal stroma then coalesces around the bud.
Between weeks 10 and 12, epithelial buds form, begin to branch, and extend into the epithelial–mesenchyme boundary. By the first half of the second trimester (weeks 13–20), there are 15–20 solid epithelial cords that converge at the nipples. Ramification processes continue to week 32, when the cords undergo apoptosis to establish tubules and alveoli. At birth, male and female mammary glands are equally formed, each consisting of about 20 lactiferous ducts that open into a dimple. Late in the final trimester, proliferation of the mesoderm beneath the dimple transforms it into a true nipple with an areola. Placental estrogens during the final weeks of gestation cause breast buds to enlarge to create a true breast nodule at birth, about 1 cm in size, in both genders.
Gonadotropin-releasing hormone (GnRH) from the hypothalamus influences the infant breast apart from its familiar role in the initiation of puberty and regulation of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary. Suppressed from mid-gestation, it becomes active after birth and causes gonadotropin levels to rise in early infancy, the “mini-puberty of early infancy,” that matures ovarian follicles in girls and causes penile and testicular growth and descent in boys. The events also stimulate persistent breast enlargement well into the first few months of life and as late as 18 months after birth. Also elevated are prolactin levels, which may stimulate the production of small amounts of milk (“witch’s milk”). Endocrine events become quiescent with the active inhibition of GnRH at about 6 months in boys and 3–4 years in girls. The infant breast involutes into a prepubertal state, with minimal breast tissue and a nipple nearly flush with the skin in both boys and girls.
Puberty is triggered by the hypothalamus with an increase in the activity of the GnRH pulse generator, but the mechanism of how the event is initiated remains unclear. GnRH drives gonadotropin secretion that is responsible for maturation of ovarian follicles, maintenance of the corpus luteum, and estradiol and progesterone synthesis in the female, and for maintaining spermatogenesis and testicular testosterone secretion in the male. The first sign of puberty in girls, thelarche, is the appearance of a breast bud. The appearance of pubic and axillary hair, pubarche, is a process that is dependent on the adrenal production of androgens and generally appears within a year after thelarche. Menarche, the final event of puberty, occurs a little more than 2 years after thelarche.
Marshall and Tanner formally described the development of the mature female breast in five stages, a process that takes about 4.5 years :
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Stage 1: Preadolescent; elevation of papilla only
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Stage 2: Breast bud stage; elevation of breast and areola as a small mound, enlargement of areola diameter
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Stage 3: Further enlargement of breast and areola, with no separation of their contours
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Stage 4: Projection of the areola and papilla to form a secondary mound above the level of the breast
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Stage 5: Mature stage: Projection of papilla only, resulting from recession of the areola to the general contour of the breast
Pathophysiology
Benign female breast disease in children can be seen as an aberration of normal development and involution (ANDI). ANDI organizes benign breast disorders and diseases into a framework of normal events of breast development: fibroadenoma, a disorder of normal lobular development; juvenile hypertrophy, stroma development; cysts and ductal ectasia, involution. The breast in early infancy goes through similar events during the mini-puberty, so some of the same categories of disorders can also be found during infancy and early childhood. ANDI is a useful framework that organizes benign breast disorders with commonsense therapeutic strategies.
Breast cancer is extremely rare in pediatric age patients, seen almost exclusively in late adolescence when encountered. Dysregulation of genetic controls of breast embryogenesis, such as homeobox genes, may play a role in the development of adult breast cancer.
Disorders of Development and Growth
neonatal hypertrophy
As discussed previously, the newborn breast bud enlarges during the mini-puberty of early infancy ( Fig. 74.1 ). This phase seldom lasts longer than a few months. Infant breast enlargement involutes spontaneously within a few weeks without specific treatment.
Polythelia
Extra nipples and occasionally areolae may develop anywhere along the milk line from axilla to pubis in up to 5% of children, most commonly on the chest below the actual breast ( Fig. 74.2 ). An auxiliary breast is rarely encountered as a discrete mass, with or without a nipple, most commonly in the axilla. Unsightly structures should be removed by surgery or liposuction.
Hypoplasia and Aplasia
Breast asymmetry is common ( Fig. 74.3 ). Profound differences in size may lead to cosmetic surgery, including augmentation of the smaller breast with implant, and reduction and mastopexy of the larger breast, once both breasts are fully developed at age 17–18. Use of tissue expanders may be necessary if differences are extreme, or combining augmentation of the smaller breast with reduction of the larger one.
Breast development is affected by Poland’s syndrome, a range of malformations characterized by varying degrees of hypoplasia and aplasia of the breast and nipple, pectoralis major and sternocleidomastoid muscles, thorax, and hand. Reconstruction strategies depend on the extent of breast hypoplasia and the degree of pectoral and thoracic maldevelopment. The most profound defects will require reconstruction with a prosthesis and chest wall augmentation using a variety of flap techniques.
Incisions for a central venous catheter, chest tube, and drainage of a breast abscess may interfere with later breast growth and development. Extreme care must be taken when placing these incisions, particularly in premature infants in whom the breast bud may be barely visible. Thoracotomy and chest wall reconstruction for pectus deformities may interfere with breast development in older children.
Bilateral hypoplasia suggests delayed puberty, defined clinically by the absence or incomplete development of secondary sexual characteristics by age 13 in girls and age 14 years in boys. Hypogonadism is the absence of physical signs of puberty by age 18 in both genders. Delayed puberty requires evaluation by a pediatric endocrinologist for ovarian failure, including gonadal dysgenesis, congenital adrenal hyperplasia, varieties of intersex disorders, and hypogonadotrophism.
Atrophy of the breast may result from weight loss from any cause. Hypothalamic suppression and hypoestrogenism may complicate eating disorders, further retarding breast growth. In an otherwise well-nourished adolescent, breast atrophy should prompt a search for endocrine disorders that result in low estrogen or increased androgens.
Premature Thelarche
The differential diagnosis of breast enlargement in female patients changes with age and is summarized in Table 74.1 . Premature thelarche is breast development before 6 years of age. It is isolated if it occurs without pubic/axillary hair growth, vaginal mucosal estrogenization, and a linear growth spurt. It is unilateral in 50% of cases. It has a peak incidence between 6 months and 2 years and resolves in more than half of patients.
Table 74.1
Causes of Breast Enlargement in Female Patients
| Bilateral | Unilateral |
|---|---|
| Infancy | |
| Normal breast bud | Normal breast bud |
| Neonatal hypertrophy | Neonatal hypertrophy |
| Childhood | |
| Premature thelarche | Asynchronous thelarche |
| Precocious puberty a | Simple cyst |
| Adolescent | |
| Virginal hypertrophy | Giant fibroadenoma |
| Phyllodes tumor | |
| Leukemia | |
| Lymphoma | |
| Metastatic cancer b | |
| Primary breast cancer | |
a Idiopathic, CNS aberrations, gonadotropin-independent, functional ovarian cysts, McCune–Albright syndrome, granulosa cell ovarian tumor, exogenous estrogen, profound primary hypothyroidism.
b Rhabdomyosarcoma, neuroblastoma, retinoblastoma, and osteosarcoma.
Premature thelarche may be associated with precocious puberty. Precocious puberty has a peak incidence between 5 and 8 years, later than true premature thelarche. Adrenarche (onset of androgen production, responsible for the appearance of pubic and axillary hair, acne, body odor, and linear growth acceleration) and gonadarche (onset of gonadal function, signaled by ovulation and menarche in female adolescents) signal that precocious puberty is occurring. Gentle retraction of the labia allows inspection of the vaginal mucosa. The prepubertal vaginal mucosa is reddish and delicate compared with the estrogenized mucosa, which is pink and thicker. About 20% of girls with premature thelarche go on to develop precocious puberty during follow-up. Both premature thelarche and precocious puberty require pediatric endocrinology evaluation. The management of precocious puberty has been revolutionized with the development of GnRH analogs for the long-term suppression of gonadotropins.
The definition of the age of normal pubertal timing continues to be a matter of intense debate. The decline in the age of menarche has stabilized at 12.5 years, with the lower range of the onset of puberty (thelarche) set at 6 years for African American girls and 7 for white girls. Using thelarche is problematic because the increasing prevalence of obesity complicates the assessment of the onset of breast development.
Drug, toxic, and environmental causes of premature thelarche should be considered. A number of compounds have been implicated in the disorder, including xenoestrogens (compounds that bind to the estrogen receptor); phytoestrogens (compounds in plants); environmental toxins (pesticides, cosmetics, and packaging material); and estrogens in poultry, cosmetics, and hair products. Early exposure to such products may have implications for the later development of breast cancer.
Hypertrophy
Virginal breast hypertrophy arises from exaggerated responses to pubertal hormonal fluxes. Both stroma and ducts are hypertrophic. The sheer weight of the breast may cause ischemia and necrosis. Tamoxifen may ameliorate the abnormal growth, but in most cases reduction mammoplasty is required. Subsequent resections may be necessary even with postoperative tamoxifen therapy.
Unilateral hypertrophy may produce enough asymmetry so that the patient is self-conscious of her appearance. Unequal breast size is common, so decisions regarding surgery require judgment. Differences in size may return if surgery is performed too early and the breasts continue to grow after operation. Once Tanner stage 5 breast maturity is reached, equalization of the size of the breasts is reasonable using augmentation and reduction techniques.
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