Hyperplasia and More Benign Breast Conditions: Section 3.b.
CONTENTS:
3.4 Benign Epithelial Proliferations (Without Atypia)
3.4.1 Usual Epithelial Hyperplasia
3.4.2 Usual Ductal Hyperplasia (UDH)
3.4.3 Intraduct Papilloma and Diffuse Papillomatosis
3.4.4 Adenosis
i. Sclerosing Adenosis
ii. Apocrine Adenosis
iii. Microglandular Adenosis
iv. Blunt Duct Adenosis or Columnar Alteration with Prominent Apical Snouts and Secretions (CAPPS)
3.4.5 Radial Scar (Complex Sclerosing Lesion)
3.4.6 Adenomas
i. Tubular Adenoma
ii. Lactating Adenoma
iii. Nipple Adenoma (Florid Papillomatosis, Erosive Adenomatosis)
Forward to 3C on fibroadenomas. Back to 3A on cysts and other benign things
3.4 Benign Epithelial Proliferations (Without Atypia)
Proliferative breast disease without atypia and atypical ductal or lobular hyperplasia is associated with a greater breast cancer risk. The relative risk ranges from 1.3 to 1.9 (Hartmann et al. 2005). A diagnosis of proliferative breast disease should not be regarded as a pre-malignant condition, but it places a woman in a category where increased vigilance is advised regarding breast examination, breast screening and reduction of other risk factors.
3.4.1 Breast Hyperplasia: The Usual Epithelial Hyperplasia
Breast hyperplasia of the epithelium that lines the breast ducts and lobules is seen as part of the physiological change that occurs during a woman’s monthly cycle. The changes of epithelial breast hyperplasia of the ‘usual’ type may show an increased number of epithelial cells, but these do not show cytological (cellular) abnormalities. ‘Usual’ breast hyperplasia is not a ‘pre-malignant’ condition.
Epithelial breast hyperplasia is a common form of proliferative breast disease. For the Pathologist, it can be difficult to distinguish between ductal and lobular hyperplasia and to distinguish between usual ductal or lobular hyperplasia and their atypical counterparts, atypical ductal hyperplasia (ADH) and atypical lobular hyperplasia (ALH).
Lobular epithelial proliferations, both atypical lobular hyperplasia (ALH) and lobular carcinoma in situ (LCIS), are collectively termed ‘lobular neoplasia.’ Unlike ductal lesions, lobular epithelial proliferations are very similar; the difference between atypical lobular hyperplasia (ALH) and lobular carcinoma in situ (LCIS) being a matter of the degree and extent of epithelial proliferation (see Section 4).
The terminology of ‘lobular neoplasia‘ has gained general acceptance because both ALH and LCIS are identified and managed as a risk factor for lobular carcinoma, rather than precursor lesions. Lobular neoplasia is a relatively rare lesion, it rarely manifests itself clinically and is usually identified as an incidental finding in biopsies and excision breast specimens.
Figure 3.16 Mild Ductal Epithelial Hyperplasia.
High power photomicrograph of a section along the breast duct in a
young woman. The epithelial layer is more than two cells thick in areas.
This is benign breast hyperplasia without atypia and may be considered
to be a physiological change of no consequence. (H&E x 40)
3.4.2 Breast Hyperplasia: Usual Ductal Hyperplasia (UDH)
The term usual ductal hyperplasia (UDH) was formerly known as ‘epitheliosis.’ UDH carries a slightly increased risk (about 1.5–2 fold) for breast cancer.
The normal breast duct is lined by two layers of low cuboidal epithelial cells and basal contractile myoepithelial cells. An increase in cell number within the ductal space is epithelial breast hyperplasia.
The further classification of epithelial breast hyperplasia relies upon the cytological features of the proliferating epithelial cells. Usual ductal hyperplasia or simple hyperplasia includes an increased number of cells but without architectural distortion or distension of the contours of the duct.
Mild breast hyperplasia of the usual type, features a three to four cell proliferation of epithelial cells; moderate breast hyperplasia is more than four cells thick, with accompanying bridging of the luminal space. In severe or ‘florid’ breast hyperplasia, the duct lumen is distended and can be completely obliterated or filled with cells.
The most important cytologic features of mild, moderate, or florid epithelial breast hyperplasia are an admixture of cell types (epithelial cells, myoepithelial cells and metaplastic apocrine cells) and variations in the appearances of epithelial cells and their nuclei.
Figure 3.17 Usual Ductal Hyperplasia (UDH)
A high power photomicrograph of a section through a breast duct shows
that the lumen of the duct is almost completely obliterated by proliferating
epithelial cells. These cells are disorganized but without cytological atypia.
The arrows point to the small, dense myoepithelial cells that are mixed
with the ductal cells. The basement membrane of the duct is intact.
This is a benign change. (H&E x60)
3.4.3 Intraductal Papilloma and Diffuse Papillomatosis
An Intraductal papilloma is a benign proliferation of epithelial cells that are found along fibrovascular connective tissue ‘cores.’ Papillomas may be everted (protrusive) or inverted (intrusive).
Papillomas may cause obstruction to breast ducts and can be associated with breast cysts. Papillomas may be diagnosed on biopsy. If a papilloma is excised and diagnosed on ‘lumpectomy,’ no further excision may be required.
Complete excision of a benign papilloma may be recommended, to exclude any associated, more worrying features.
The condition, ‘diffuse papillomatosis’ (multiple papillomas) is defined as a minimum of five papillomas per breast segment. It may present as a palpable breast lump, as nodules on ultrasound, or may be the cause of nipple discharge. These papillomas may be seen on ductography. Following excision, no further treatment is needed, and there is no increased risk for cancer.
Figure 3.18 Intraductal Papilloma.
A. X-ray findings from a ductogram from a woman presenting
with nipple discharge and breast pain shows a dilated, partially
obstructed breast duct. B. Photomicrograph of the histology of a
transverse section of the obstructed duct shows an
intraductal papilloma. (H&E x 20)
3.4.4 Adenosis
Adenosis is a benign proliferative condition that includes an increased number of glandular components or an increase in their size, and usually involves the breast lobules. Of the different types of adenosis, sclerosing adenosis, apocrine adenosis and microglandular adenosis are the most common.
i. Sclerosing Adenosis
Sclerosing adenosis is a benign lesion centered around the breast lobule. It consists of disordered glandular, myoepithelial, and connective tissue elements. Sclerosing adenosis can mimic infiltrating carcinoma in imaging and microscopically; it can be a challenge to diagnose when the Pathologist examines a core needle biopsy (CNB).
Sclerosing adenosis is associated with a variety of proliferative lesions, including epithelial hyperplasias, intraduct papilloma, complex sclerosing lesion (radial scar), calcification, and apocrine change; it can co-exist with both invasive and in situ cancers.
Studies of the risk of subsequent breast cancer in women with sclerosing adenosis have been conflicting. This year, studies by Visscher and colleagues from the Mayo Benign Breast Disease Cohort have found that sclerosing adenosis as a single abnormality conveys an approximate doubling of breast cancer risk. The diagnosis of sclerosing adenosis assist risk prediction for women after a breast biopsy (Visscher et al., 2014).
Figure 3.19 Sclerosing Adenosis. A.
Mammographic X-ray shows clustered micro-calcification within
the breast. B. Photomicrograph of the mammographically
abnormal area of the breast shows sclerosing adenosis.
The glands are irregularly arranged in dense connective tissue
with many of the glands containing calcifications.
(H&E x 40)
Figure 3.20 Sclerosing Adenosis.
A. Photomicrograph of another pattern of sclerosing
adenosis, where the distorted glands appear to infiltrate fat.
These are benign glands. B. Photomicrograph of
sclerosing adenosis where the glands are present in
hyalinized, dense fibrous tissue. Although the appearances
can be worrying, these are benign glands. (H&E x 20)
ii. Apocrine Adenosis
Apocrine adenosis is a variant of microglandular adenosis, and the term is used to describe a variety of apocrine cell changes when found in more than 50% of the area of adenosis.
iii. Microglandular Adenosis
Microglandular adenosis of the breast consists of a proliferation of small, round glands irregularly scattered within dense fibrous tissue and/or adipose tissue.
On microscopy, most of the glands have open lumina that contain eosinophilic (pink) material. The histology of microglandular adenosis shows lack of the outer myoepithelial layer seen in other forms of adenosis. The lack of a myoepithelial cell layer makes it difficult to differentiate microglandular adenosis from a tubular carcinoma on microscopy. It is the finding of a basal lamina (with laminin or Type IV collagen markers) that encircles glandular structures that can be used to make the correct diagnosis.
Microglandular adenosis is benign, but it has a tendency to recur if not completely excised.
Figure 3.21 Microglandular Adenosis.
Low power photomicrograph of the histology of microglandular
adenosis, shows the characteristic round glands in
adipose tissue (fat) and connective tissue.
(H&E x 20)
iv. Blunt Duct Adenosis or ‘Columnar Alteration with Prominent Apical Snouts and Secretions’ (CAPPS)
Blunt duct adenosis, is also called columnar cell change (CCC), columnar alteration with prominent apical snouts and secretions (CAPPS), columnar metaplasia and enlarged lobular units with columnar alteration.
This is a benign, metaplastic epithelial change. This form of adenosis is important because columnar change is associated with micro-calcifications and also because columnar cell change can undergo hyperplasia, columnar cell hyperplasia (CCH). Columnar cell lesions with atypia are called flat epithelial atypia (FEA) and are discussed in Section 4.
3.4.5 Radial Scar (Complex Sclerosing Lesion)
Radial scar of the breast is a benign condition, but it can be difficult to diagnose mammographically and microscopically. The radial scar is also known as a complex sclerosing lesion and consists of central scar-like tissue surrounded by irregular breast glands.
The entire abnormality usually needs to be examined microscopically. An incisional biopsy or a CNB can only give the impression of these areas of scar tissue and distorted glands.
If the final diagnosis is of radial scar or complex sclerosing lesion and there is no associated abnormality, no further action is needed and there is no increased risk of cancer.
Figure 3.22 Radial Scar or Complex Sclerosing Lesion.
A. Mammographic X-ray of a stellate abnormality in the breast.
B. Photomicrograph of the excised mass shows a central scarred
area from which radiate irregular but benign glands. This is
the classical appearance of radial scar. (H&E x 10)
3.4.6 Adenomas
An adenoma is a benign new growth of glandular epithelial cells and so the breast may be a site for adenomas arising from the ductal or lobular epithelial cells.
Adenomas of the breast are common and have no association with concurrent or future cancer. The term ‘adenoma’ and ‘fibro-epithelial lesion’ are often used inter-changeably.
i. Tubular Adenoma
Tubular adenoma is a pure adenoma or glandular tumor of the breast. Tubular adenoma presents in women of reproductive age as a solitary, well-circumscribed mass. Radiographically, tubular adenoma may resemble the appearance of non-calcified fibroadenoma.
The microscopy of a tubular adenoma shows tightly-packed tubular or glandular structures; these tubules are regular in size, regular in shape and seen in a sparsely cellular stroma.
Tubular adenomas often contain micro-calcifications inside dilated tubules; the numerous tiny and irregular micro-calcifications are seen on mammography and ultrasonography.
Tubular adenoma may be distinguished from fibroadenoma and nipple adenoma by the absence of stroma. Tubular adenoma is not associated with an increased subsequent risk of breast cancer.
ii. Lactating Adenoma
Lactating adenoma is the most common breast lump found during pregnancy and the puerperium. Lactating adenoma presents as a solitary or multiple, palpable, mobile breast mass that tends to be small (< 3 cm).
On gross examination, the lactating adenoma is well-circumscribed and lobulated. The histology shows hyperplastic lobules in which proliferating glands are lined by actively secreting cells.
Although the lactating adenoma may spontaneously involute, surgical removal may be necessary. Lactating adenoma does not recur locally, and there is no proven malignant potential.
Figure 3.23 Breast Adenomas. A. Tubular Adenoma.
Photomicrograph of the histological appearance of
tubular adenoma. These benign glands may be irregularly
arranged but show no cytological atypia. Secretions and
intra-gland calcifications are a feature. B. Lactating
Adenoma. Abundant, irregular, densely-packed
glands contain pink proteinaceous secretions.
(H&E x10 & x20)
iii. Nipple Adenoma (Florid Papillomatosis of the Nipple, Erosive Adenomatosis)
Nipple adenoma is also known as florid papillomatosis of the nipple ducts or erosive adenomatosis and is a benign tumor arising from the ductal epithelium.
Nipple adenoma is important as it can mimic Paget’s disease clinically. On microscopy, it may be difficult to distinguish from adenocarcinoma.
Nipple adenoma presents clinically as a palpable mass of the papilla of the nipple, often with erosion of the nipple and nipple discharge.
Histologically, nipple adenoma shows proliferating ductal structures that reach into the breast stroma. A double layer of epithelium lines the adenomatous ducts; this microscopic feature supports their benign nature. The presence of keratin-filled cysts and tiny apical cell ‘snouts’ are other histological features.
A biopsy is necessary for diagnosis. Nipple adenoma is treated by complete excision of the tumor. Nipple adenoma is a benign lesion, but rarely, malignant change within or adjacent to nipple adenoma has been reported.
Figure 3.24 Nipple Adenoma.
Low power scanning photomicrograph of the
breast nipple shows the appearance of a nipple
adenoma, arising from and replacing the
sub-areolar ducts. (H&E x4)
References
Hartmann LC, Sellers TA, Frost MH, Lingle WL, Degnim AM, Ghosh K, et al. Benign breast disease and the risk of breast cancer. N Engl J Med 2005;353:229–37. (Retrieved November 5th 2014): https://www.ncbi.nlm.nih.gov/pubmed/16034008
Visscher, D.W., Nassar, A., Gegnim, A.C. et al. (2014). Sclerosing adenosis and risk of breast cancer. Breast Cancer Res Treat 144(1), 205-12. (Retrieved November 5th 2014): https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3924024/
Patient Information
American Cancer Society. Breast Hyperplasia. (Retrieved January 20th2015):
http://www.cancer.org/healthy/findcancerearly/womenshealth/non-cancerousbreastconditions/non-cancerous-breast-conditions-hyperplasia
Breast Cancer Org.. Benign breast conditions: Not all lumps are cancer. (Retrieved January 18th2015):
http://www.cancer.org/treatment/understandingyourdiagnosis/examsandtestdescriptions/forwomenfacingabreastbiopsy/breast-biopsy-benign-breast-conditions
Forward to 3C on fibroadenomas Back to 3A on cysts and other benign things.
