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Calcification in breast lesions: pathologists’ perspective
  1. G M Tse1,
  2. P-H Tan2,
  3. A L M Pang3,
  4. A P Y Tang4,
  5. H S Cheung5
  1. 1
    Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong
  2. 2
    Department of Pathology, Singapore General Hospital, Singapore
  3. 3
    Department of Diagnostic Radiology and Organ Imaging, Prince of Wales Hospital, The Chinese University of Hong Kong
  4. 4
    Department of Radiology, North District Hospital, Hong Kong
  5. 5
    Department of Radiology, International Islamic University, Kuantan, Malaysia
  1. Dr Gary M Tse, Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, Ngan Shing Street, Shatin, NT, Hong Kong SAR; garytse{at}cuhk.edu.hk

Abstract

Evaluation of calcification in breast lesions is a major assessment criterion for breast mammography. The morphology and distribution of the calcification are related to the histology of the lesions. Radiologically, calcifications can be divided into: benign; intermediate concern; and higher probability of malignancy according to the morphology. Different pathological entities may give rise to different calcifications. Fibrocystic changes may give rise to milk of calcium or teacup type calcification, or small calcifications occurring in a cluster. Fibroadenoma may be associated with large popcorn like calcifications, and sclerosing adenosis may have fine, punctate or granular calcifications. Fat necrosis may give rise to egg shell calcification. Precursor malignant lesions give rise to benign to indeterminate type calcifications, and may occasionally be associated with malignant type calcifications. For malignant lesions, ductal carcinoma in situ and invasive duct carcinoma may be associated with large irregular, rod or V shaped, pleomorphic or branching type calcifications that follow the distribution of the duct. Furthermore, analysis of the characteristics of the calcifications may help to predict the tumour size and grade, and presence of invasion.

https://doi.org/10.1136/jcp.2006.046201

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    Early detection of breast cancer is important in reducing morbidity and mortality, particularly in the asymptomatic population. Mammography is currently the only widely used screening modality; it is able to detect approximately 90% of cancers in asymptomatic women up to 2 years before the cancers become symptomatic.1 One of the mammographic features frequently assessed is calcification within the breast lesions or tissue.

    For symptomatic cancer, which may present as a mass lesion, detection of calcification is not crucial to the diagnosis, as the malignancy can be confirmed by other diagnostic modalities. It is in the non-palpable group that detection and characterisation of the calcifications is important. Mammographically detected non-palpable breast lesions are often detected as calcifications alone, calcifications with architectural distortion or calcifications associated with a mass.2 Calcification is particularly important for ductal carcinoma in situ (DCIS), which is the “pre-invasive” stage of breast cancer; as such this lesion does not possess significant metastatic potential, and can be treated more conservatively, with excellent outcome.3 The incidence of calcification in DCIS has been reported to range from 42 to 72%.4 5 The presence of calcifications is more common in DCIS in younger women5 and in higher grade lesions.4

    The other important role in the evaluation of calcifications in breast mammography is in the follow-up of breast cancer patients having breast conservation therapy (BCT). It has been reported that calcifications are detected in 29–80% of recurrences, either as calcification alone or in association with other mammographic signs.5–8

    RADIOLOGICAL CLASSIFICATION

    The classification of breast calcification is based on the assessment of morphology and distribution, as recommended by the American College of Radiologists, in the Breast Imaging Reporting and Data System (BI-RADS).9 10

    The BI-RADS calcifications are divided into: typically benign; intermediate concern calcifications; and higher probability of malignancy (see box 1).

    Box 1 Classification of calcification pattern, according to the Breast Imaging Reporting and Data System (BI-RADS)

    Typically benign

    1. Lucent centred deposits of skin calcifications.

    2. Parallel tracks, or linear tubular calcifications of vascular calcifications.

    3. Coarse (popcorn) calcifications occurring in involuting fibroadenomas.

    4. Large rod like calcifications that are continuous rods but may occasionally be branching, usually more than 1 mm in diameter, and may have lucent centres, as seen in duct ectasia.

    5. Round calcifications are usually considered benign when small (<1 mm), and they are present within the lobular acini.

    6. Lucent centre calcifications are benign calcifications that range from <1 mm to >1 cm. They are smooth surfaced, round or oval, and have lucent centres. These are seen in fat necrosis or calcified debris in ducts, or in some fibroadenomas.

    7. Eggshell or rim calcifications are thin calcifications that appear as calcium deposits on the surface of a sphere; the calcification is usually <1 mm on side view. They are seen in the cyst wall.

    8. Milk of calcium calcifications are well defined, semilunar, crescent or curvilinear shape (teacup shaped), consistent with sedimented calcifications in cysts.

    9. Suture calcifications are mostly linear, with knots frequently visible, and represent calcium on suture material. They are relatively common in the post-irradiated breast.

    10. Dystrophic calcifications tend to be irregular, >0.5 mm and have lucent centres. They are usually formed in the irradiated or traumatised breast.

    11. Punctate calcification:– round or oval, <0.5 mm with well defined margins.

    Intermediate concern, suspicious calcifications

    1. Amorphous or indistinct calcifications are often round or “flake” shape, but are small or hazy in appearance. A more specific morphological classification cannot be determined.

    2. Coarse heterogeneous calcifications: these are irregular conspicuous calcifications that are larger than 0.5 mm, and tend to coalesce.

    Higher probability of malignancy

    1. Fine pleomorphic calcifications.

    2. Fine linear, or fine linear branching calcifications are thin irregular calcifications that appear linear, but are discontinuous and <0.5 mm in width, suggesting filling of ductal lumen of a cancer involved duct.

    In addition, there is a distribution modifier that is to be used, namely diffuse or scattered, regional, grouped or clustered, linear or segmental, with increasing risk of malignancy (see box 2).

    Calcifications in general, when they are diffuse and not segmental in distribution, are less worrisome as this indicates a diffuse process, typically in fibrocystic changes, which involve the whole breast. Grouped or clustered calcifications may be indicative of either benign or malignant lesions, as the higher density of calcification is suggestive of a more active or proliferative process resulting in increased secretion density. Segmental calcification is worrisome as it suggests a local lesion that spread within the ductal system, with high grade DCIS being the prototype lesion.

    Box 2 Breast Imaging Reporting and Data System (BI-RADS) classification: the distribution modifiers

    1. Diffuse or scattered: calcifications that are distributed randomly throughout the breast.

    2. Regional: calcifications within a large volume of breast tissue (>2 cm3), not necessarily conforming to a ductal distribution.

    3. Grouped or clustered: when there are at least five calcifications occurring in a small volume (<1 cm3).

    4. Linear: calcifications arrayed in a line that may have branching points.

    5. Segmental: worrisome, as the distribution suggests deposits within a duct and its branches, suggestive of multifocal cancer within a breast segment.

    Using this system, and combining the morphology and distribution pattern of the calcifications, an overall assessment categorisation is made, as follows9:

    • Category 0: Need additional imaging evaluation. Assessment is incomplete, needing additional imaging evaluation; almost always used in the screening setting only.

    • Category 1: Negative. No abnormalities detected.

    • Category 2: Benign findings. Some features worthy of description, but are confidently diagnosed as benign.

    • Category 3: Probably benign, short follow up interval suggested. The lesions have a high probability of being benign, but stability over time is preferably to be established.

    • Category 4: Suspicious abnormality, biopsy should be considered. Although the lesions do not have the characteristic morphologies of breast cancer, they possess a definite probability of being malignant.

    • Category 5: Highly suggestive of malignancy. Appropriate action should be taken.

    • Category 6: Known biopsy proven malignancy. Reserved for lesions with biopsy proof of malignancy.

    For the non-radiology breast healthcare professionals, a simplified descriptive classification may be useful. In general, calcifications that are large (>1 mm), smooth, round, dense, scattered over a large area, bilateral or associated with some benign processes are classified as benign. Malignant calcifications are of two types: clustered or linear. Clustered calcifications (at least 4–5 calcifications in 1 cm3 area) are pleomorphic and/or punctuate (tiny dots <1 mm, resembling salt). Linear calcifications include branching calcifications that form casts of the ducts.11 Stability over time should also be considered in the evaluation of calcifications. Static calcifications are considered benign, and new or increased calcifications, when compared with previous mammography, may be viewed with suspicion. Calcifications that are neither clearly benign nor clearly malignant are considered indeterminate and must be treated as malignant until proven otherwise.2 11–15

    PATHOLOGICAL CORRELATION

    Benign breast diseases16

    • Fibrocystic changes include a spectrum of histological alterations, most of which will not result in calcifications. Calcifications tend to occur in the fluid within the small cysts; when duct ectasia is present, larger calcifications may also be seen. The calcifications are the “milk of calcium” or “teacup” types with typically curvilinear to crescent shapes, attributed by the high concentration of calcium salt content of the secretion as well as stagnation. The teacup appearance is caused by the calcium deposits floating within the lumen. In adenosis, the calcifications are usually small and microscopic in size. These calcifications may not be individually detected by mammography, but their accumulation in a small area may lead to a summation effect resulting in a cluster.17 In the case of duct ectasia, again, calcification is superimposed on the secretory material inside the dilated ducts, but this time the calcification is in the form of larger rods or broken needles, deriving from the cast of the ducts; they are more diffuse, usually bilateral, tend to radiate from the nipple, and are much denser than malignant calcifications (as seen in DCIS).2 15 18 19 In addition to these characteristic morphologies, the distribution may also offer a clue as to the nature of the calcification. Closer examination of the mammogram may reveal the presence of similar calcifications diffusely, and also in the contralateral breast. When the calcification is localised to a segment, the possibility of DCIS has to be considered (figs 1,2,3,4).

    • Fibroadenoma is common in younger women but calcification of fibroadenoma in this age group is uncommon. It is in the postmenopausal population that the fibroadenomas regress and become hyalinised; there may be superimposed calcification. The morphology of the calcification is characteristically coarse or popcorn in appearance, and as such, is considered to be totally benign (figs 5,6).

    • Sclerosing adenosis usually presents with calcification together with architectural distortion. Clinically and radiologically, it is a mimic of breast cancer. Mammographically the calcifications are always fine, with variable sizes (punctuate or granular), and may occur in a cluster.16 Sometimes the calcifications may be large enough to form “diplococcus” or “rosette” patterns.

    • Fat necrosis results from trauma to the breast, with death and liquefaction of the fat cells, forming a central core of fat, with associated inflammation. The lesion may be encapsulated or unencapsulated. When encapsulated, the wall may become calcified into lucent, circular, egg-shell like calcifications, but if unencapsulated, the calcification patterns are variable, and may be either benign looking if they form smooth, round bodies, or malignant looking if they are pleomorphic14 20 (fig 7).

    • Other benign conditions associated with calcification include vascular calcification, suture calcification and post-radiation calcifications. Vascular calcifications are common, and do not pose diagnostic problems because in most cases, the calcifications are characteristically serpentine or tramline in appearance. Occasionally early vascular calcifications may cause problems, as the calcification may be one sided rather than tramline, particularly when it is associated with dense breast tissue shadow.16 The calcification of sutures can occasionally be seen, particularly in the irradiated breast. The features are characteristic, with linear calcifications, sometimes even with knots. In breasts receiving radiation for the treatment of malignancy, calcification can occur anywhere within the irradiated area because of injury, necrosis and sloughed cells.7 It has been reported that calcifications may be found in 3% of patients undergoing lumpectomy and radiotherapy for breast cancer,21 and can occur up to 5 years.7 The morphology of post-irradiation calcifications is variable, ranging from small, round, smooth, scattered calcifications to plaques. Some of the calcifications may resemble malignant calcification, and caution needs to be exercised to differentiate a recurrent lesion from surgery reactions. Typically localisation within the lumpectomy site, occurring within 6–26 months would suggest a possibly benign nature.7 8 11 21

    Figure 1
    Figure 1 Craniocaudal view mammography showing bilateral punctate and granular calcification.
    Figure 2
    Figure 2 Corresponding histology (to fig 1) showing fibrocystic changes of the breast with secretory type calcification present within the lumen.
    Figure 3
    Figure 3 Craniocaudal view mammography showing pleomorphic type calcification.
    Figure 4
    Figure 4 Corresponding histology (to fig 3) showing fibrocystic changes with large and irregular foci of calcifications present within the stroma.
    Figure 5
    Figure 5 Mammography showing a nodular soft tissue mass with large popcorn type calcification.
    Figure 6
    Figure 6 Corresponding histology (to fig 5) showing a fibroadenoma with hyalinisation and large piece of calcification.
    Figure 7
    Figure 7 Left mediolateral oblique view mammography showing lucent, circular calcification of fat necrosis.

    CANCER PRECURSOR LESIONS

    There is recent evidence that columnar cell changes, particularly those with atypia (sometimes known as flat epithelial atypia, FEA),22 23 atypical duct hyperplasia (ADH), and lobular neoplasia, which includes atypical lobular hyperplasia (ALH) or lobular carcinoma in situ (LCIS) can all be considered precursor lesions for low grade breast carcinoma.24 One characteristic of this group of lesions is they are mostly non-palpable, hence are more frequently detected mammographically in the screening setting.

    In FEA, in which cytological atypia superimposes on architectural features of columnar cell changes or columnar cell hyperplasia, calcification is frequently present; in fact these lesions are detected because of the associated calcification. The characteristic pattern of the calcification is that of luminal secretion, which is an active calcification mechanism (see below) and the calcification shows a granular morphology.25 In another study,26 calcification was observed in 9 of 16 (56%) cases of “atypical cystic lobules”, the cytological and architectural patterns of which were similar to what is currently known as FEA. Again, the calcification was described as of secretory type.

    A similar phenomenon has been reported for ADH, which by itself is quite uncommon, but the detection rate is on the increase with improved mammography screening. The calcification associated with ADH usually exhibits high density, showing clustered punctate calcification, and may be considered indeterminate radiologically.27

    Lobular neoplasia is now considered essentially a precursor lesion, with the biological distinction between ALH and LCIS becoming blurred.28 Calcification can also be found in lobular neoplasia. In a review of 1819 stereotactic vacuum assisted biopsy specimens,29 27 cases of pure lobular neoplasia were identified; among these, 22 cases presented with calcification, including 19 with calcification only and 3 with calcification associated with a mass lesion. In this mammographically detected series, the incidence of calcification in lobular neoplasia was 81% (22 of 27 cases). Pathologically two forms of calcifications were identified:

    • A classic, non-necrotic form of calcification, which is similar to that observed in benign proliferative processes.30

    • A pleomorphic, necrotic form of calcification associated LCIS, with calcification being associated with the necrotic debris that resembles comedo necrosis of high grade ductal carcinoma (see below).

    In the same large series,29 the morphology of the calcifications of many of these cases were worrisome, with the majority of the cases being considered BI-RADS category 4 (86%, 22 cases), and 3 and 1 cases (11% and 4%) respectively considered BI-RADS categories 3 and 5. Interestingly the presence of a “high grade” LCIS with comedo type calcification pattern has also been reported independently by another group.31

    MALIGNANT BREAST DISEASES

    Two mechanisms are responsible for malignant calcifications of the breast: secretion and necrosis. Secretion related calcification is an active mechanism, with the tumour cells producing secretory vesicles that discharge into the extracellular matrix, and calcification forming around them. This is the mechanism for low grade DCIS. In necrosis related calcification, which is a passive mechanism, calcification occurs in the necrotic debris; this is seen in high grade DCIS.17

    Ductal carcinoma in situ

    Microcalcification is the commonest mammographic feature of DCIS, occurring in 80–90% of DCIS with mammographic abnormality.32 The characteristics of the calcifications can be grouped according to distribution, number, morphology and changes over time.33 The distribution of the cluster shape of calcification of DCIS tends to be irregular; this is due to the fact that DCIS tends to grow in a ductal distribution both towards and away from the nipple. In fact, most of the calcifications of DCIS are irregular in shape and up to 10% are V shaped. Inside the cluster, distribution of the calcifications tends to be ductal in orientation, particularly in the absence of rods or branching. It should also be noted that diffuse calcification within the breast and bilateral calcifications are not suggestive of DCIS. The number of calcifications within the cluster has also been reported to be important. Most calcifications associated with DCIS have been reported to consist of more than 10 calcium flakes in the vast majority of cases.33 However, in situations with newly developed calcification, particularly with a ductal distribution, the threshold for suspecting DCIS should be lower. Morphologically, the most common feature of DCIS calcifications is granular or amorphous calcifications that are irregular in shape and size within the cluster. This type of calcification morphology can represent those that are found in the “cribs” of the cribriform DCIS. However, these features are not specific. In contrast, rod shaped, pleomorphic, linear or branching calcifications are less common, but are derived from calcification of the extensive necrosis that is usually associated with high grade DCIS. Occasionally even this type of calcification has to be differentiated from that of duct ectasia; the differences have been mentioned above. Interestingly, even for high grade DCIS, the characteristic rod shaped or branching calcifications may not necessarily be present when the DCIS is small. Hence it is not appropriate to assume that clusters of punctuate or granular calcification in a ductal distribution could only represent low grade DCIS; it could also represent a small/early high grade DCIS.34 In addition to the difference in calcification morphology, it has also been reported that the percentage of calcification in high grade DCIS was higher than in low grade DCIS (>90% compared to 50–60%)32 35 (figs 8,9).

    Figure 8
    Figure 8 Craniocaudal view mammography showing pleomorphic calcifications that are large, and follow ductal distribution.
    Figure 9
    Figure 9 Corresponding histology (to fig 8) showing ductal carcinoma in situ with calcification within ductal lumen.

    In the non-palpable DCIS, the extent of the calcification may be an indicator of the actual lesion size. In the estimation of the size of DCIS, particularly for the non-palpable lesions, mammography is useful. In the mammographic estimation of lesional size, it has been reported that estimation based on calcification distribution is more accurate than basing on architectural distortion alone.36 In general, mammography tends to underestimate the extent of the DCIS, but as the calcification associated with high grade comedo type DCIS is more extensive, assessing the extent of calcification may reflect more accurately the size of the tumour.35 37 38

    Invasive carcinoma

    Calcifications are commonly observed in invasive breast carcinomas, being present in about 50% of invasive carcinoma in a study involving almost 700 cancers.39 There have been very few studies investigating whether the morphology of calcifications could be helpful to differentiate the histology type of breast cancers. One study40 showed no correlation between the presence of calcifications and histological type. For studies describing the morphology of calcifications in particular breast cancers, no specific calcification morphology has been described.41 However, in the study of Holland and Hendriks,42 though different morphology of calcifications could be identified in DCIS, it was found that fine granular calcifications are more likely to be found in well differentiated DCIS, whereas linear or coarse granular calcifications are more likely to be found in poorly differentiated DCIS. Viewed from another angle, among all malignancies associated with calcification, pure DCIS accounted for about 64% of such calcifications, whereas DCIS with foci of invasion accounted for 32%, with pure invasive carcinoma accounting for 4%.43 Interestingly, a relation has been found between the percentage of calcified invasive breast cancer and age. In patients younger than 40 years of age, the percentage of invasive tumours having calcifications was 88%; the percentage dropped to 22% for patients aged 70 or older.39 In addition, another study showed that the presence of calcification is positively associated with a higher histological grade of the invasive tumour, with up to 40% of grade 3 tumours showing some form of calcification, compared to about 20% of the grade 1 and 2 tumours.39 This correlation is particularly evident with the comedo type calcification with linear, rod shaped to branching calcifications. One of the major sites of calcification of invasive carcinomas is the associated DCIS. In general, high grade invasive tumours tend to be associated with high grade DCIS, and low grade invasive tumours tend to be associated with low grade DCIS.44 45 The higher percentage of calcification in high grade invasive carcinoma can be partly explained by the higher percentage of calcification in the associated higher grade DCIS.32 35 To view this observation from another perspective, is it possible to predict, based on the calcifications, the chance of invasion associated with the calcifications? Some authors reported that increased chance of invasion was associated with higher cluster area of the calcifications,46 whereas others reported an association with higher number of calcium flakes but not cluster size; the higher number of calcium flakes was believed to reflect the higher volume of DCIS.43 47 The morphology of the calcification may also imply different chances of invasion, with mixed coarse (comedo) and granular type calcification being associated with a higher chance of invasion than pure granular type (32% vs 11%).43

    SUMMARY

    Mammographic detection of calcification remains the mainstay of detection of non-palpable breast malignancy. In general, calcifications that are large (>1 mm), smooth, round, dense, scattered over a large area, bilateral or associated with some benign process are classified as benign. Malignant calcifications show clustered or linear morphology. Clustered calcifications (at least 4–5 calcifications in 1 cm3 area) are pleomorphic and/or punctuate (tiny dots <1 mm, resembling salt). Linear calcifications, including branching calcifications, are derived from casts of the ducts, particularly those with necrotic content. Stability over time should also be considered: static calcifications are considered benign, and new or increased calcifications must be viewed with suspicion. Precursor malignant lesions may show variable patterns of calcification. DCIS is the most common malignancy to present with calcification. Morphologically, the most common calcification patterns are granular or amorphous calcifications that are irregular in shape and size within the cluster; this may correspond to those that are found in the “cribs” of the cribriform DCIS. In contrast, rod shaped, pleomorphic, linear or branching type calcifications are less common, but are derived from calcification of the extensive necrosis that is usually associated with high grade DCIS. These patterns are also seen in invasive carcinomas. In addition, analysis of the morphology, distribution, size and number of calcifications may help to predict the tumour size, grade and the presence of invasive focus within DCIS.

    Take-home messages

    • Mammographic detection of calcification remains the mainstay of detection of non-palpable breast malignancy.

    • Benign breast calcifications are large (>1 mm), smooth, round, dense, and scattered over a large area, or may be bilateral.

    • Malignant calcifications show clustered (at least 4–5 calcifications in 1 cm3 area) or linear (include branching) morphology.

    • Precursor malignant lesions may show variable patterns of calcification.

    • Calcifications in ductal carcinoma in situ may be granular, amorphous (low grade) or rod shaped; pleomorphic, linear or branching (high grade) patterns are associated with necrosis.

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    Footnotes

    • Competing interests: None declared.