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Breast Tumors in Children and Adolescents
Introduction
Breast enlargement in children and adolescents (<20 years of age) can be due to normal or abnormal physiological causes, reactive changes, or neoplastic proliferations. The patient’s age, gender, hormonal status, and other clinical findings need to be considered in concert with the histological findings. The vast majority of breast masses arising in the first 3 decades of life are benign and the approach to managing pediatric and adolescent breast masses should be relatively conservative. It is particularly important in this patient population not to remove the breast bud in the process of performing a biopsy for diagnosis. Inadvertently excising the breast bud will prevent normal breast development and can lead to permanent deformity. Ultrasound is the diagnostic imaging modality of choice in children and adolescents because of its high sensitivity in this age group and lack of ionizing radiation.
Minor breast prominence is normal at birth and can persist into the first year. This transient hypertrophy, which is often bilateral, is due to maternal hormonal influence. After this period, breast tissue involutes until puberty. Breast development in the prepubertal child may be developmental in origin, or can be a sign of an endocrine dysfunction such as from a gonadal or adrenal neoplasm. Developmental and congenital anomalies include supernumerary nipple, asymmetric breast bud, accessory breast tissue, and congenital hypertrophy. At puberty, breast development occurs normally in both genders. In girls, the onset of breast development, or thelarche, usually occurs between the ages of 8 and 10 years and continues through the Tanner stages.
Fibroadenoma and macromastia are the most common causes of breast masses/enlargement in adolescent females, while gynecomastia is the most common cause in adolescent males. Macromastia (i.e., pubertal or juvenile hypertrophy) can cause disproportionate enlargement of one or both breasts in a relatively short period of time (weeks to months). Histological features of macromastia consist of irregularly distributed mammary glands in fibrous stroma. Cysts and varying degrees of ductal hyperplasia can be seen. Terminal duct lobular units (TDLUs) are rare if not absent.
The development of gynecomastia in boys is fundamentally due to a decrease in the level of testosterone relative to that of estrogen. Unilateral or bilateral gynecomastia is common during puberty, occurring in approximately half of adolescent males, in the absence of any underlying endocrinopathy. This physiological process is self-limited and resolves within months to 2 years. Less commonly, gynecomastia can develop due to other causes resulting in hormonal imbalance. These include endocrinopathies, which can also secondarily lead to excessive body fat and peripheral conversion to estrogen, tumors (i.e., estrogen-producing testicular tumors, gonadotropin-secreting tumors, prolactinomas), liver disease, rare conditions (i.e., Klinefelter syndrome, testicular feminization syndrome, neurofibromatosis type I), and pharmacological/recreational drug use (e.g., marijuana, corticosteroids, tricyclic antidepressants). Histologically, the findings in gynecomastia are similar to those found in older male patients.
Other mass-forming breast lesions more commonly seen in adults can occur in the pediatric and adolescent age groups, including fibrocystic changes, pseudoangiomatous stromal hyperplasia (PASH), mastitis/abscess, hematoma, vascular lesions, and fat necrosis. Malignancy in the breast is extremely rare and can occur as a primary or metastatic tumor.
Juvenile Papillomatosis
Although prior examples were sporadically described in the literature, it was not until 1980 that juvenile papillomatosis (JP) was described as a distinct clinicopathological entity. In this sentinel paper, 37 patients were described and the entity was coined Swiss cheese disease owing to its characteristic multicystic appearance. JP may rarely be associated with various types of carcinoma. Patients with JP and female relatives on the patient’s maternal side may have an elevated risk for developing breast carcinoma and should therefore be advised to have regular breast screening.
Clinical Presentation
Patients are typically females ranging from less than their 20 s and 30 s, but patients older than 40 years of age have also been affected. The mean age at presentation of several larger series ranged from 19 to 34 years. Males make up less than 1% of patients reported with JP. JP most often presents as a palpable breast mass. The breast mass is located in the upper outer quadrant in most cases, but other locations including the retroareolar region have been reported. The palpable mass is characteristically firm, solid, mobile, and circumscribed. Pain or nipple discharge is uncommon. Reported tumor sizes have ranged from 1 to 8 cm. The clinical impression is that of a fibroadenoma. Instances of multifocal and bilateral JP have been described, but are uncommon. Irregular menses, age of onset of menses, parity, or oral contraceptive use do not appear to factor into the development of JP. A positive history of familial breast carcinoma has been reported in 5% to 58% of JP patients, with a greater risk of carcinoma affecting maternal relatives (i.e., mother, maternal aunt, maternal grandmother).
Clinical Imaging
The imaging characteristics are suggestive but not diagnostic for JP. Mammographic changes are similar to those seen in fibroadenomas or cysts ( Fig. 33.1A ), but in some cases, the lesion is undetectable by this modality, suggesting its limited diagnostic utility. Mammographic calcifications are not usually appreciated. An ill-defined heterogeneous mass with small round echo-free areas (cystic) near tumor borders can be seen by ultrasound. Posterior shadowing is not characteristic. Numerous small internal cysts best observed on a T2-weighted sequence on magnetic resonance imaging (MRI) are suggestive of the diagnosis. Owing to the young age of these patients, ultrasound is commonly employed for diagnosis and postoperative surveillance.
Gross Pathology
Excised specimens reveal a nodular or lobulated mass. The cut surface shows multiple cysts of varying sizes as well as areas that are gritty or show small papillary excrescences ( Fig. 33.1B ). Pale yellow specks scattered between cysts can be seen. The tumor border is discrete but not sharply delineated. Low-power view of a slide with JP has a characteristic cystic appearance likened to Swiss cheese ( Fig. 33.1C ).
Microscopic Pathology
A closely arranged constellation of benign proliferative components makes up each case of JP. The specific proliferative changes and the degree to which they constitute an individual case are widely variable ( Fig. 33.2 ). Cysts of various sizes that are lined by flat or cuboidal epithelium or apocrine metaplasia are a constant feature and are essential in making the diagnosis ( Fig. 33.3 ). Cysts and dilated ducts containing lipid-laden histiocytes are typically seen (essentially duct ectasia). These ducts may rupture and be associated with a chronic inflammatory response in the adjacent stroma ( Fig. 33.4 ). These areas correspond to yellow specks seen by gross examination. Ductal hyperplasia of varying proliferative degrees is another predominant histological feature, but other proliferative changes including papillomas and adenosis are commonly seen ( Fig. 33.5 ). In some cases, central necrosis in florid (often solid papillary) ductal hyperplasia can be present but is not to be considered a clinically significant “atypical” finding ( Fig. 33.6 ). Moreover, occasional epithelial mitoses are not uncommon in such florid epithelial proliferations. Whether within a duct or a cyst, a distinctive finding is the histological transition of ductal hyperplasia to apocrine metaplasia/hyperplasia ( Fig. 33.7 ). This feature is uncommon outside the context of JP, which makes it a helpful diagnostic aid. The hyperplastic components of JP show the typical mosaic staining pattern with cytokeratin (CK) 5/6 and show heterogenous staining with estrogen receptors (ER), similar to usual ductal hyperplasia (UDH) outside the setting of JP.
Sclerosis can involve most or some of the lesion ( Fig. 33.8 ). This leads to distortion of ducts and cysts, whereas at other times it manifests primarily as nodular sclerosing adenosis ( Fig. 33.9 ). If sclerosis is pervasive enough, the fundamental lesion of JP can be obscured by the radial sclerosing lesion it is forming ( Fig. 33.10 ). Microscopic calcifications can be seen in foci of sclerosing adenosis or ductal hyperplasia. Fibroadenomatoid change can be present in some cases. Examples containing a close arrangement of only a few components such as cysts and papillomas should not be considered diagnostic for JP.
A core needle biopsy (CNB) may reveal what appears to be a complex radial sclerosing lesion or papillary lesion ( Fig. 33.11A ). Ductal hyperplasia merging with apocrine metaplasia can be a helpful clue to the diagnosis. ( Fig. 33.11B ). Other cases may only show features of duct ectasia. Correlation with imaging is important and a definitive diagnosis of JP should be made after review of the excisional biopsy specimen.
Rarely, ADH and carcinoma arise in JP. ADH of the cribriform and micropapillary patterns is most common ( Fig. 33.12A and B ). Coexisting carcinoma is rare at the time of diagnosis but has been found in up to 15% of studied patients. Ductal carcinoma in situ (DCIS), lobular carcinoma in situ (LCIS) ( Fig. 33.12C ), invasive ductal carcinoma (IDC), invasive lobular carcinoma, and secretory carcinoma in association with JP have been described.
Molecular Pathology
The genetic features of JP have been evaluated in two studies to date, in which the proliferative epithelial components of JP underwent sequencing analyses. In a study of 10 JP cases, Guillet reported PIK3CA hotspot mutations in eight out of 10 cases and AKT1 mutations in two out of 10 cases. Mutations in ATM, MET, FGFR3, PTEN, NF1, and GNAS genes were detected in other cases. In a separate study, whole exome sequencing analysis of JP revealed clonal PIK3CA hotspot mutations in two of three cases studied. In one case in which ER+ invasive carcinoma of no special type (NST) and DCIS coexisted with JP, the separate JP, DCIS, and invasive carcinoma components were found to be clonally related and shared a clonal PIK3CA E542K hotspot mutation. This is an uncommon finding and further studies are necessary to determine the molecular relationship between coexisting JP and carcinoma. The results of these studies further expand the spectrum of benign breast lesions harboring PI3K-AKT1 pathway mutations, including papillary neoplasms and ductal hyperplasia. Interestingly, rare cases of JP have been reported in patients with Cowden syndrome and Proteus syndrome, two syndromes affecting the PIK3CA pathway. Thus far, BRCA1 or BRCA2 mutations have not been reported to play a role in these patients.
Treatment and Prognosis
Wide local excision is curative. Although recurrence can occur if incompletely excised, further excision for lesions that have been grossly excised is not recommended. Re-excision should be considered in incompletely excised JP cases with atypical hyperplasia, carcinoma, or instances of recurrent disease. The risk of developing breast carcinoma in patients previously diagnosed with unilateral JP appears to be low. In one study of 41 patients with JP, 10% developed carcinoma with a median follow-up period of 14 years. In another report, only two (1.6%) of 113 patients with JP subsequently developed carcinoma over a mean follow-up of approximately 9 years. Therefore, clinical and imaging follow-up is recommended for patients with JP.
Differential Diagnosis
Because individual components of JP represent the spectrum of fibrocystic disease, the distinction from fibrocystic changes must be made. Other lesions that are often seen within JP, such as duct ectasia, papillary proliferations, and sclerosing lesions, are also in the differential diagnosis of JP, particularly if only a small part of the lesion is seen in a core biopsy. Histological findings of a localized arrangement of proliferative components, the presence of multiple cysts, some filled with foamy macrophages, and the histological transition of ductal hyperplasia to apocrine metaplasia/hyperplasia are more affirming of JP than other features. Cystic hypersecretory proliferations are uncommon mass-forming proliferations characterized by large cysts. Cysts in cystic hypersecretory proliferations are filled with dense eosinophilic colloid-like secretion, whereas cysts and ducts in JP are filled with either histiocytes or secretion that lacks the colloid-like quality. Correlation with clinical features, in particular, the young age of the patient and a clinically evident discrete mass, provide further supporting evidence for JP.
Key Clinical and Pathological Features
Juvenile papillomatosis
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Definition: a benign proliferative lesion, also known as Swiss cheese disease .
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Incidence/location: rare; commonly occurs in the upper outer quadrant of the breast.
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Clinical features: patients are typically females ranging in age from teens to 30 s, and present with a self-discovered breast mass. The clinical impression is that of a fibroadenoma.
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Imaging features: imaging features may be suggestive but not diagnostic of JP. Features overlap with those of fibroadenoma and cysts. Ultrasound is the modality of choice for diagnosis and postoperative surveillance.
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Prognosis/treatment: patients are treated with surgical excision. The long-term prognosis is uncertain owing to lack of published studies with sufficiently long follow-up. Some studies suggest that JP may be a marker for increased risk of breast carcinoma in the patient’s female relatives.
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Gross: nodular or lobulated discrete mass, ranging in size from 1 to 7 cm in greatest dimension. Cut section shows multiple cystic spaces with intervening fibrous tissue. Gritty, yellow specks or small papillary excrescences may be seen.
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Microscopic: a closely arranged constellation of benign proliferative elements, including cysts (some with luminal histiocytes), ductal hyperplasia, papillomas, sclerosing adenosis, and apocrine metaplasia.
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Molecular: PI3K-AKT1 pathway mutations.
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Differential diagnosis: fibrocystic changes, duct ectasia, sclerosing lesions, cystic hypersecretory proliferations.
Papillary Ductal Hyperplasia (Papilloma, Papillomatosis)
Papillary ductal hyperplasia (PDH), whether in the form of a solitary papilloma or diffusely involving multiple ducts (i.e., papillomatosis), is uncommonly found as the dominant histological finding in children and adolescents. Although not considered to be a distinct clinicopathological entity, patients whose histological findings were initially believed to be consistent with JP but fell short of the diagnosis became part of a larger group with similar findings in two studies. Before these studies, young patients with PDH were occasionally included in studies composed mostly of older patients. Sporadic case reports or small series of children or adolescents with similar findings, most commonly solitary papillomas, have also been reported. It should be kept in mind that papillary carcinoma is extremely rare in children and adolescents.
Clinical Presentation
The vast majority of cases of PDH affect females with rare instances occurring in males, the latter under the clinical impression of gynecomastia in some instances. The majority of patients present with a palpable solitary breast mass with or without nipple discharge or tenderness. Some patients noticed an abnormal thickening or enlargement of the breast. The most common location is in the retroareolar region. Both breasts are equally affected. The physical examination findings can vary from vague thickening to discrete nodularity.
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