Benign Breast Conditions: Section 3.a.

CONTENTS:

3.1 The Normal Breast
3.2 The Terminal Duct Lobular Unit (TDLU)
3.3 Non Proliferative Breast Conditions (Fibrocystic Change)
3.3.1 Benign Breast Cysts
3.3.2 Papillary Apocrine Change
3.3.3 Columnar Cell Change
3.3.4 Benign (Epithelial-Related) Calcification
3.3.5 Fat Necrosis
3.3.6 Hamartoma (Lipofibroadenoma, Fibroadenolipoma)
3.3.7 Galactocele (Milk Retention Cyst)
3.3.8 Diabetic Mastopathy (Lymphocytic Mastitis, Lymphocytic   Mastopathy)
3.3.9 Mammary Duct Ectasia
3.3.10 Pseudo-angiomatous Stromal Hyperplasia (PASH)

Forward to 3B on benign hyperplasias. Back to 2E on axilla imaging.

Cysts, and other Benign Breast Conditions

Before beginning this section on benign (non-cancerous) conditions of the breast, it is important to emphasize again, that outside the mammographic screening process, any woman should seek advice from her family physician or breast specialist if she has any of the following symptoms:

• A lump in the breast
• Breast pain
• Thickening of the skin of the breast
• Rash or redness of the breast
• Breast swelling
• Nipple discharge
• Dimpling around the nipple or on the breast skin
• Nipple pain or the nipple turning inward
• Lumps in the arm-pit
• Changes in the appearance of the nipple or breast

 
 

More about Benign Breast Conditions

The majority of female breast abnormalities are benign (non-cancerous). Benign breast conditions, or ‘benign breast change,’ include a spectrum of changes that may present with a cyst or a palpable mass. It is important to establish that the condition is benign as soon as possible, to alleviate any anxiety for the patient.

The incidence of benign breast conditions starts to rise during the second decade and peaks in the fourth and fifth decades. Malignant diseases (breast cancers) have an incidence that continues to increase after the menopause, although at a less rapid pace.

Benign breast conditions arising from the glandular epithelium in the breast go into three histological (microscopic) categories:

1)   non-proliferative;
2)   proliferative without atypia, and
3)   atypical hyperplasia (ADH and ALH) (see Section 4).

The reason for this classification is that some benign conditions may be associated with an increased risk for future cancer. Even if this risk is small, knowing about it can prepare a woman and her physician for increased clinical monitoring, preventive measures or counselling.

In 2012, the World Health Organization (WHO) sought the advice of pathologists, clinicians and oncologists worldwide to produce the 2012 revised WHO Classification of Breast Tumors.   Section 5 will follow this classification system and include any update in terminology, classification and diagnosis.

 
 

This section begins with a description of the normal breast and its components, a description of the terminal duct lobular unit (TDLU) and an account of the non-proliferative breast conditions and proliferative breast conditions, which are without atypia.

Classifications of benign breast conditions

In keeping with the WHO classification system (2012) for benign breast conditions, we use the following categories:-

• Non Proliferative Breast Conditions
• Benign Epithelial Proliferations (without atypia)
• Benign Fibro-epithelial Tumors
• Mesenchymal Tumors of the Breast (Benign)
• Benign Vascular Lesions
• Benign Neural Tumors
• Smooth Muscle Cell Tumors (Benign)
• Benign Conditions of the Male Breast

At the end of this section, there is a list of key references to the published literature, with links to access the articles. There are also some helpful links to patient websites and to sources of further information.

3.1 The Normal Breast

The adult female breast lies between the second and sixth ribs, the sternal edge and the mid-axillary line. Breast tissue is found in the axilla as the ‘axillary tail.’

The breast ‘stroma’ makes up the majority of the breast volume. In the non-lactating state, adipose tissues (fat) and fibrous connective tissue make up  the breast stroma.

The normal female breast is a mixture of connective tissue, blood vessels, nerves and fat, with a covering of skin. It contains breast lobules and ducts that, from puberty to menopause, are under hormonal control.

The physiological changes that occur with the monthly cycle and during pregnancy and lactation can give rise to a number of worrying but benign focal changes, such as cysts.

Figure 3.1 The Normal Female Breast

A diagram of the female breast (left) showing the
orientation of the ducts, towards the breast nipple.
Most of the breast contains fat and connective tissue.
The mammographic X-ray of the normal breast
(right) is mainly radiolucent (black) because of the fat.
The connective tissue and glandular elements
are grey-white. The white structures are lumps or cysts.

The skin of the breast is thin; it contains hair follicles, exocrine sweat glands and sebaceous glands, just like skin on other parts of the body. The nipple contains sensory nerve endings, sebaceous and apocrine sweat glands.

The areola is circular and pink/brown in color.  So the areola includes Morgagni tubercles which are the openings of the large glands near the periphery (or edge) of the areola.

 
 

More about Normal Breast Anatomy … Sorry

There are muscle elements that envelope the breast, the ‘superficial pectoral fascia,’ that is continuous with the superficial abdominal fascia. The breast tissue lies on the deep pectoral fascia, covering the deep muscles called the ‘pectoralis major’ and ‘serratus anterior.’ The suspensory ‘ligaments of Cooper’ connect the two fascial layers and provide a fibrous support for the breast.

The internal mammary artery provides the main blood supply to the breast but the internal mammary arteries supply the upper outer quadrant.  The lymphatic drainage of the breast is to the internal mammary (IM), axillary and clavicular lymph nodes.

• Level I lymph nodes are lateral to the pectoralis minor muscle
• So, Level II lymph nodes are behind the pectoralis minor muscle
• Level III lymph nodes are above the pectoralis minor muscle.

 
 

3.2 The Terminal Duct Lobular Unit (TDLU)

The micro-anatomical structure, the ‘terminal duct lobular unit’ or TDLU has become central to understanding the origins of breast disease, including breast cancer. The TDLU (also named ‘Type 1 lobule’ ) has the highest rate of epithelial cell proliferation that are more numerous in the breasts of nulliparous women.

 
 

Figure 3.2 The Terminal Duct Lobular Unit (TDLU)

Diagram of the non-lactating breast showing the
arrangement of the ducts and lobules.
B. Low power photomicrograph of the
histology of the normal terminal duct
and lobule (TDLU) with the Alveolus,
Epithelium and basement membrane (*)

Figure 3.3 The Normal Breast Lobule.

Low power photomicrograph of the normal breast
lobule,  seen down the microscope by the
Pathologist. So, we can see  a transected duct
on the right. The lobule and duct has
abasement membrane, below which are
myoepithelial cells. (H&E x 10)

Figure 3.4 Intact Myoepithelial Cell Layer.

High power photomicrograph of the breast
duct.  The pathologist can detect the myoepithelial
cell  histologically due to its expression of
smooth muscle actin.  Immunohistochemistry
(Section 6) localises smooth muscle actin
(ASMA) expression (brown) by the intact
layer of myoepithelial cells. (x 40)

 
 

The epithelial components of the breast, the lobules and ducts, produce and deliver milk during lactation. In the female who is post menarche and pre-menopause, these glandular elements undergo cyclical changes in response to the female hormonal cycle.

Breast lobular and ductal epithelial cells possess estrogen receptors (ER) and progesterone receptors (PR).

The branching ducts connect the lobules of the breast to the nipple.

 
 

For a patient who has had a breast abnormality sampled or removed, the Pathologist will produce a written report with a diagnosis. This diagnosis will allow the physician to manage patient care.

The following are the benign diagnoses that may be found at the end of a Pathology report.

3.3 Non-Proliferative Breast Conditions (Fibrocystic Change)

Non-proliferative epithelial conditions of the breast do not have an association with a risk for developing breast cancer.

These conditions are still often termed ‘fibrocystic changes’ or ‘fibrocystic disease’ and are the most common benign disorders of the breast. These changes affect women between the ages of 20 and 50 years. These lesions may be multi-focal and bilateral and often present as tender nodularities in the breast.

But for the patient, there are a variety of confusing names for these common conditions that are of no harm.

The following names are still in use for benign, non-proliferative breast change:

• fibrocystic change,
• fibrocystic disease,
• cystic mastopathy,
• mazoplasia,
• chronic cystic mastitis, and
• mammary dysplasia.

The above rather ‘old-fashioned’ names persist, but the new WHO classification system no longer consider them to be of clinical use.

Women with benign, non-proliferative breast changes have no increase in breast cancer risk.

Figure 3.5 Fibrocystic Change.

Low power photomicrograph shows the dilated breast
lobule (L) with breast fibrosis (F) (pink) and cyst
formation (C). (H&E x 10)

3.3.1 Benign Breast Conditions: Breast Cysts

The most common non-proliferative breast lesions are breast cysts (Schnitt & Collins, 2010). Cysts are fluid-filled, round structures.  Furthermore,  a third of women between 35 and 50 years old have cysts.

Most benign cysts are subclinical and are present as microcysts.  In about 25% of cases, palpable simple cysts are present.

A breast cyst may appear as a solitary breast lump or as multiple lumps. They may present as pain or discomfort and can fluctuate in size and number.

Hormones influence benign breast cysts and so cysts can occur with the menstrual cycle and in peri-menopausal women. So, expect cysts to occur during menstrual cyclic changes and lobular involution in premenopausal and peri-menopausal women.

 
 

Symptomatic and asymptomatic small cysts (micro-cysts) are common in young, pre-menopausal women.

In 2010, the American College of Radiology Imaging Network (ACRIN) 6666 studied the data on the diagnosis of mammographically detected breast abnormalities in a three-year screening study. This study identifies breast cysts in 37.5% of all women who underwent breast cancer screening.  In addition, there is a peak incidence in women between 35 and 50 years of age (Berg et al., 2010).

In this study, cysts were identified more often in pre-menopausal women compared with post-menopausal women; 66 % of HRT users were diagnosed with cysts (Berg et al., 2010). There is no future risk of cancer when a diagnosis of a benign cyst has been made.

Figure 3.6 The Benign Breast Cyst:
Imaging and Histology.

Mammographic X-ray shows a radiolucent (black), round,
fluid-filled cyst. B. The histology of the benign cyst (right)
shows flattened epithelial cells; the wall of the cyst may show
an increase in connective tissue. (H&E x 20)

Figure 3.7 The Benign Breast Cyst:
Fine Needle Aspiration
Cytology (FNAC)

The fluid aspirated from a benign cyst may be yellow or white
and clear or cloudy. b. When the fluid is spun down, the cells
are smeared onto a glass slide, stained and examined
down the microscope, and cohesive sheets of
benign epithelial cells are seen. (PAP x 63)

 
 

3.3.2 Papillary Apocrine Change

The epithelium of the breast duct undergoes apocrine metaplasia quite commonly. Apocrine metaplasia is the replacement of normal epithelial cells by columnar cells that have granular, eosinophilic (pink) cytoplasm and luminal cytoplasmic projections or ‘apical snouts.’ Columnar cells line the dilated breast ducts or are found in papillary proliferations. They are seen more frequently in younger women. Apocrine cells have a characteristic morphology on cytology.

Focal areas of papillary apocrine change within the duct may cause obstruction and are associated with cyst formation. There is no future risk of cancer when a diagnosis of apocrine change has been made.

Figure 3.8 Papillary Apocrine Change.

Photomicrograph taken at high power, shows the eosinophilic
(pink) cells that characterize apocrine change (metaplasia).
(H&E x 60)

3.3.3 Columnar Cell Change

Columnar cell change is another form of epithelial metaplasia and is important for several reasons. Firstly, this represents a spectrum of change that is frequently associated with micro-calcification.

 
 

Columnar cell change is now more commonly seen histologically due to mammographic screening and the detection of micro-calcifications.

A working classification of columnar cell lesions has been proposed by Schnitt and Vincent-Salomon to include columnar cell change, columnar cell hyperplasia and atypical columnar cell lesions, also known as flat epithelial atypia (FEA) (Schnitt & Vincent-Salomon, 2003).

Figure 3.9 Columnar Cell Change

Photomicrograph shows overlapping, elongated columnar
epithelial cells. There are foci of ‘ring’ calcification, C.
(H&E x 20)

3.3.4 Benign (Epithelial-Related) Calcification

Calcification or micro-calcification can be seen on imaging and under the microscope; it can be found in benign conditions but is also associated with areas of atypia and cancer.

The interpretation of the breast findings, when associated with calcifications, are particularly important. This is why these abnormalities are often biopsied.

If ‘calcifications’ or ‘micro-calcifications’ are reported without any abnormality, then they are of no clinical consequence.

 
 

The benign breast conditions that may be associated with micro-calcification (BI-RADS 1 or 2) include:-

• calcification of blood vessels walls;
• ‘popcorn’ calcifications of involuted fibroadenoma;
• large, rod-like calcification of duct ectasia;
• round and punctate calcifications of adenosis and fibrocystic change;
• oval calcifications with a lucent center of fat necrosis and fibroadenoma;
• ‘rim’ calcifications from cyst walls;
• ‘dystrophic’ calcifications in fat necrosis;
• micro-calcifications and ‘psammoma bodies’ of columnar or mucinous lesions.

Figure 3.10 Benign Micro-calcification.

a. Micro-calcifications (dark blue) seen associated
with columnar cell change within the duct epithelium.
b. Round micro-calcifications associated with a
fibroadenoma.

3.3.5 Benign Breast Conditions: Fat Necrosis

Fat necrosis is quite a common cause of a breast lump or mass. It results from trauma to the breast. Fat necrosis is totally benign and has no clinical implications for the patient.

 
 

Because the mammographic appearances are those of an ill-defined, spiculated mass, which cannot be further characterized by other imaging techniques and because fat necrosis may be associated with some cancers, a histological diagnosis is required.

The histology of fat necrosis is very characteristic, with foamy macrophages (or histiocytes) and macrophage giant cells, fat cells, fibrosis and chronic inflammation. A ‘pure’ lesion of fat necrosis is not associated with subsequent breast cancer.

 
 

Figure 3.11 Fat Necrosis.

A. Photomicrograph of the fine needle aspiration cytology
(FNAC) which can be diagnostic. Cytology shows foamy
macrophages containing lipid droplets, with multi-nucleated
giant cells (PAP). Inset shows the cytology of a multinucleated
foamy cell (Giemsa). B. Photomicrograph of the histology
shows necrosis, foamy macrophages, inflammatory
cells and multinucleated giant cells.  (Courtesy
of: Breast Pathology on the Web. 2014. Thomas, J).

3.3.6 Hamartoma (Lipofibroadenoma, Fibroadenolipoma)

A hamartoma is defined as a collection of normal tissue elements, arranged in a disorganized way. The benign breast hamartoma presents as a well-circumscribed, dense, breast lump that contains glands, fat and connective tissue in varying proportions. The breast hamartoma presents as an encapsulated mass which may be mobile but which is usually painless.

It can be difficult to make a diagnosis of hamartoma by FNA or CNB alone.  So complete excision and microscopic examination are the treatment of choice because there is a small chance of a co-existent cancer.  If the Pathology is reported as benign, there is no indication that subsequent cancer may develop (Guray & Sahin, 2006).

Figure 3.12 Breast Hamartoma.

A. Mammographic X-ray image of a benign hamartoma of the
breast shows the sharply-defined edge. B. Photomicrograph
shows the histology of the edge of the hamartoma and the normal,
but compressed breast tissue. (H&E x 10)

3.3.7 Galactocele (Milk Retention Cyst)

Obstruction to a milk duct is the main cause for these benign cysts.   Fine needle aspiration (FNA) is diagnostic. On mammography, the diagnostic cystic appearance may include a fat fluid-level.

Once a diagnosis of galactocele has been made, no excision or further treatment is required. There is no increased risk for breast cancer.

3.3.8 Diabetic Mastopathy (Lymphocytic Mastitis, Lymphocytic Mastopathy)

This condition is seen in pre-menopausal women who have Type I diabetes mellitus. It is an important condition to recognize as the mammographic appearance can be suspicious.

Diabetic mastopathy shows dense scar tissue with lymphocyte (inflammatory cell) infiltrates seen around breast lobules, ducts and vessels. These features strongly suggest an auto-immune condition.

If diabetic mastopathy is diagnosed on core needle biopsy (CNB), no further treatment is required and there is no increased risk for cancer.

Figure 3.13 Diabetic Mastopathy.

A. Mammographic X-ray of an irregular mass in a diabetic
woman,  shows the irregular margins of the mass.
B. Photomicrograph of the biopsy histology shows an area
of  obliteration of  small ducts and peri-ductal
blood vessels by lymphocytes. (H&E x20)

3.3.9 Benign Breast Conditions: Mammary Duct Ectasia

Mammary duct ectasia is seen in middle-aged to elderly women who have had children (parous women). The presentation is often with nipple discharge, pain, a sub-areolar mass or nipple inversion; all of which are worrying symptoms and signs.

Mammary duct ectasia is also associated with micro-calcifications and can have a worrying mammographic appearance.

The histological features include dilated sub-areolar breast ducts containing secretions. Foamy macrophages are present in the duct lumen and wall.

Following a diagnosis of mammary duct ectasia, the breast cancer physicians will often use conservative treatment. However, there is no increase in the risk for breast cancer following a  mammary duct ectasia diagnosis.

 
 

Figure 3.14 Mammary Duct Ectasia.

Photomicrograph of a section through a sub-areolar
breast duct, shows foamy lipid-filled macrophages
in the duct wall.  (H&E x40)

3.3.10 Pseudo-angiomatous Stromal Hyperplasia (PASH)

Pseudo-angiomatous stromal hyperplasia (PASH) is a newly-described, benign myofibroblastic proliferation of the breast. The lesion does not contain glandular elements. It is usually an incidental finding on histology of the breast, but it can present clinically as a mass. (Mercado et al., 2004).

The condition is hormonally-dependent and occurs in pre-menopausal women, or in women taking HRT. The imaging findings are non-specific, so specialists recommend biopsy for diagnosis. Treatment is usually with wide local excision.  There is no increase in the risk of future breast cancer with this type of tumor.

 
 

Figure 3.15 Pseudo-Angiomatous Stromal
Hyperplasia (PASH).

High power photomicrograph of the histology of a biopsy
from a patient with pseudo-angiomatous stromal
hyperplasia (PASH).  There is dense connective tissue
(pink) with slit-like spaces around blood vessels.   Endothelial cells line these space (H&E x40)

References:

Schnitt, S.J., Collins, L.C. Pathology of benign breast disorders. In: Breast diseases, 4th ed, Harris, JR, et al (Eds), Lippincott, Philadelphia 2010.

Berg, W.A., Sechtin, A.G., Marques, H., Zhang, Z. (2010). Cystic breast masses and the ACRIN 6666 experience. Radiol Clin North Am. 48(5), 931-87. (Retrieved October 5^th 2014): https://www.ncbi.nlm.nih.gov/pubmed/20868895

More references for this section are on this page.

Patient Information:

American Cancer Society Non-Cancerous Breast Conditions. (Retrieved January 25^th2015): http://www.cancer.org/healthy/findcancerearly/womenshealth/non-cancerousbreastconditions/non-cancerous-breast-conditions-toc

National Cancer Institute.. Mammograms. (Retrieved January 25^th2015):
http://www.cancer.gov/cancertopics/factsheet/detection/mammograms

More patient information for this section is on this page.

Forward to 3B on benign hyperplasias. Back to 2E on axilla imaging.