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Fibrocystic Change and Usual Epithelial Hyperplasia of Ductal Type Fibrocystic Change
Fibrocystic change (FCC) refers to a complex of lesions including gross and/or microscopic cysts, apocrine metaplasia, fibrosis, and blunt duct adenosis (BDA), and minor degrees of sclerosing adenosis and usual epithelial hyperplasia. It is important to realize that cystic change is an alteration of lobules. Three-dimensional studies of sections with FCC have established that the cysts gradually develop first by dilatation and then by coalescence of ductules with unfolding of the terminal duct lobular units (TDLUs). There is evidence that endogenous and exogenous factors may play a role; however, there is controversy as to the mechanisms that govern this process.
Other names that have been applied include mammary dysplasia, chronic cystic mastitis, and diffuse cystic mastopathy. These terms and especially the term fibrocystic disease were abandoned in favor of fibrocystic change , as defined above at the consensus meeting in New York in 1985.
Clinical Presentation
FCC occurs with great frequency in the general population. At the clinical level it affects women between the ages of 25 and 50 years; it is rare in women younger than 20. The condition usually affects both breasts with formation of palpable nodularity in the tissue with preference of the outer upper quadrant. Occasionally the process is more localized and may produce a clinically detectable lump. When symptomatic, patients have breast tenderness, swelling, or pain, and may also complain of menstrual abnormalities. With menopause and involution the symptoms may subside, although microscopically the lesions persist in postmenopausal women.
Key Clinical Features
Fibrocystic Change
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Incidence/location: Common change in women between the ages of 25 and 50 years, rare in women younger than 20.
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Clinical features: Often a palpable nodularity of one or both breasts or a localized lump. May cause tenderness, swelling, or pain.
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Imaging features: With mammography, usually a nodular or solitary round/oval and well-circumscribed mass of low to intermediate density, with no distinction to solid masses (carcinoma, fibroadenoma). Less often, microcalcifications such as clustered pleomorphic adenomas (PAs) of the psammoma type or weddellite type, or more characteristic of a teacup appearance. With ultrasound, mostly characteristic of cysts that lack internal echoes and show an increased echogenicity of the posterior tissue.
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Prognosis/treatment: No increase in the risk of developing breast cancer.
Hormonal abnormalities that have been implied in the pathogenesis of these changes include a relative excess of estrogen over progesterone, hyperprolactinemia, and increased thyroid hormone activity. This is in line with reports according to which the use of oral contraceptives decreases the risk of FCC owing to their potential to adjust hormonal imbalances. For symptomatic patients, hormonal treatments with progestins and tamoxifen and synthetic steroids such as Danazol have been recommended.
Clinical Imaging
Mammography
FCC is characterized by cysts, densities, and/or less often microcalcifications. Mammographically generalized FCC appears as nodular densities of breast tissue; solitary cysts can appear as round or ovoid or as well-circumscribed masses, usually with low to intermediate density ( Fig. 18.1A ).
They may, however, be invisible in dense breasts. There is usually no tissue reaction surrounding the cysts. Cysts cannot be distinguished from solid masses on mammography. The most typical benign-type calcification arising within FCC is the teacup calcification ( Fig. 18.2A to B ). This occurs because the calcified secretions within the cysts (“milk of calcium”) settle to the bottom of the cyst so that when the patient is standing, they are seen on the lateral view like a teacup from the side. Conversely, the secretion of cysts may calcify to produce tiny homogeneous or slightly pleomorphic calcifications.
Ultrasound
Ultrasound is the most important method in assessing a cyst. Ultrasound of simple cysts lacks internal echoes and shows an increased echogenicity of the posterior tissue ( Fig. 18.1B ). Echoes within the cysts can be due to blood clots, increased protein content as a result of inflammation, or papillary type and/or solid epithelial cell proliferations.
Magnetic Resonance Imaging
On magnetic resonance imaging (MRI), FCC of the breast has a wide spectrum of morphological and kinetic features. Two types of FCC are found: a more diffuse type of nonmass lesion (39%) showing a benign enhancement kinetic pattern with medium wash-in in the early phase (90%); and a focal mass-type lesion (35%) with an enhancement kinetic pattern usually showing a rapid upslope mimicking breast cancer (73%). MRI features of focal FCC usually present as a focal mass–type lesion that is usually not a malignancy and leads to unnecessary operation. Owing to the accuracy of ultrasound in assessing cystic change, MRI is not used routinely.
Gross Pathology
The cut surface of tissue with FCC is characterized by randomly distributed cysts of varying size filled with straw-colored to dark brown fluid ( Fig. 18.3 ). Owing to their appearance, the larger cysts are known as blue-dome cysts. The cysts sit in a fibrofatty to fibrous tissue stroma.
Microscopic Pathology
The basic morphological hallmarks of FCC are discussed in the following sections.
Cysts
Cysts are the most characteristic feature of FCC found in patients presenting with a breast lump. Cysts often occur in clusters ( Fig. 18.4A ) and can measure up to several centimeters. Wellings and Alpers performed a subgross analysis of 186 breasts with FCC. They found initial cystic changes with apocrine metaplasia in TDLUs and concluded that the cysts in FCC derive from lobules rather than from ducts as a result of unfolding of lobular ductules and terminal ducts. Thus, smaller cysts coalesce to form larger cysts. In subgross sections the dilated ductules or even whole lobules can be seen clustered together, usually with remnants of normal lobules ( Fig. 18.4 ). Cysts of 1 to 2 mm in diameter have cuboidal or typical apocrine glandular epithelium ( Fig. 18.5 ) and an outer layer of myoepithelium whereas larger cysts are often lined with an attenuated and flattened epithelium.
Key Pathological Features
Fibrocystic Change
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Gross pathology: Cut surface of fibrosed tissue with randomly distributed cysts of varying size filled with straw-colored to dark brown fluid. Micro- and macrocysts (>4 mm).
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Microscopic pathology: Basic morphological hallmarks include (1) cysts of varying size, often in “lobular” clusters, often lined with apocrine epithelium with larger cysts lined with attenuated epithelium, and potentially resulting in rupture due to inflammatory response; (2) apocrine change, in which cells have abundant granular eosinophilic cytoplasm (excess of mitochondria), often with apocrine snouts and enlarged nuclei with prominent nucleoli, and the potential for the presence of micropapillary or cribriform hyperplasia; (3) fibrosis and hyalinosis with considerable variations of intensity; (4) calcifications, the most characteristic showing the teacup appearance; and (5) blunt duct adenosis with enlarged lobule(s) due to hypertrophy and hyperplasia of epithelium and stroma, potentially variable inner lining, and most importantly, columnar cell change (CCC) or columnar cell hyperplasia (CCH) (others with epithelium of no specific type or with apocrine change).
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Immunohistochemistry: Cysts, usually with CK8/18+ and only occasionally with CK5/14+ luminal cells, and myoepithelial cells positive for myoepithelial markers such as sm-actin. Apocrine change is always negative for CK5/14 and estrogen receptors (ER) and positive for GCDFP15 and androgen receptors (AR). CCC/CCH CK8/18+, CK5/14–, ER+, and BCL2+.
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Other special studies: Molecular studies show a high frequency of loss of heterozygosity (LOH) in apocrine metaplasia and an increase in genetic changes from apocrine change to invasive apocrine carcinoma. It was concluded that a proportion of papillary apocrine metaplasia may be clonal neoplasms which might be regarded as putative nonobligate precursors to apocrine carcinoma.
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Differential diagnosis: Cystic change versus (1) cystic hypersecretory hyperplasia, (2) mucocele-like cyst, (3) periductal mastitis, and (4) galactocele. BDA/CCC/CCH versus flat epithelial atypia.
An outer layer of myoepithelial cells can usually be demonstrated in hematoxylin-eosin (H&E)–stained sections, but occasionally smooth muscle actin (SMA), calponin, or p63 immunostains are needed. Sometimes only a single cell layer is found or the epithelium may be completely missing. The cystic fluid contains a group of proteins including gross cystic disease fluid proteins (GCDFPs), immunoglobulins, and electrolytes. Sometimes tension cysts evolve in the process of FCC. They are defined as apocrine cysts containing fluid under pressure, often with rupture and inflammation. Tension cysts usually have a highly attenuated, barely visible apocrine epithelial lining and a fibrous capsule. Often the lining is detached. The lumen may contain foam cells. If ruptured, an inflammatory response results with polymorphonuclear leucocytes, foamy histiocytes, lymphocytes, and plasma cells. The extrusion of particulate matter such as crystalline may elicit a strong histiocytic reaction including foreign-body giant cells. Clinically, ruptured cysts present as a painful and tender lump.
Apocrine Metaplasia
This metaplastic change originates in the TDLU, is common in the female breast after the age of 30 years, and persists postmenopausal. In general, apocrine metaplasia is seen in an enlarged lobular cluster of cystic ductules similar to BDA. Furthermore, it is frequently encountered in the epithelium of tension cysts. The apocrine cells ( Fig. 18.5 ) are large cuboidal cells that contain abundant eosinophilic granular, periodic acid-Schiff–positive, diastase-resistant cytoplasmic granules caused by the presence of excess mitochondria ( Fig. 18.5B ). They often contain yellow-brown pigment and vacuoles in the apical portion of the cells.
Apocrine snouts can usually be observed. The cells may be moderately pleomorphic, and may show micropapillary, small papillary tufts (papillary apocrine change) and even more complex growth patterns. Although the nuclei are usually large, they are regular and normochromic and contain a single uniform nucleolus ( Fig. 18.5A ). The association of these cells with normal cells in adjacent epithelial structures helps the pathologist avoid categorizing these cells as malignant. GCDFPs, especially GCDFP-15, a 15kD glycoprotein, can be demonstrated immunohistochemically in apocrine change. In contrast to normal breast epithelium, apocrine cells usually lack ER and progesterone receptors (PgR) but express AR.
Fibrosis and Hyalinization
Fibrosis and hyalinization of the involved tissue are features often associated with FCC. They show considerable variations of intensity, however.
Calcifications
Calcifications are occasionally seen, which are of two types: those composed of calcium phosphate (psammoma-type calcifications) and those composed of calcium oxalate (weddellite-type calcifications). The former are densely hematoxyphilic, round to ovoid, noncrystalline, nonbirefringent deposits that are easily recognized on H&E sections. The individual deposit may be of small size (<80–100 mm) so that they are only identified mammographically when present in clusters or as calcified contents in the cyst fluid (milk of calcium; see earlier and Fig. 18.2B ). The latter are rarely encountered in breast pathology and consist of amber material easily missed on H&E sections. However, they are readily seen as large, angulated, birefringent crystals with polarized lenses ( Fig. 18.6 ), are nearly always associated with benign disease, and are typically found in apocrine lesions.
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