Breast

Other nonneoplastic

Microcalcifications



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PubMed Search: Microcalcifications

Agnes Ikpoto Udoh, M.D., M.B.A.
Jing He, M.D.
Page views in 2024 to date: 2,655
Cite this page: Udoh AI, He J. Microcalcifications. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/breastcalcification.html. Accessed June 16th, 2024.
Definition / general
  • Small deposits of calcium that measure < 0.5 mm in breast tissue and are visible on mammographic imaging (Mol Clin Oncol 2022;16:81)
Essential features
  • Common finding on mammograms and can represent both benign and malignant conditions
  • Microcalcifications are the most common mammographic presentation (~42%) of nonpalpable cancer (AJR Am J Roentgenol 1986;146:661)
  • 2 main types based on biochemical composition
    • Type I: calcium oxalate
    • Type II: calcium phosphate (hydroxyapatite)
Terminology
  • Mammary microcalcifications
  • 2 main types based on biochemical composition
    • Type I: calcium oxalate (CO)
    • Type II: calcium phosphate / hydroxyapatite (HA)
ICD coding
  • Considered a radiologic finding rather than a diagnosis; related ICD codes include
    • ICD-O
      • 8010/2 - carcinoma in situ, NOS
      • 8500/3 - infiltrating duct carcinoma, NOS
    • ICD-10
      • D24 - benign neoplasm of breast
      • C50 - malignant neoplasm of breast
      • N64.89 - other specified disorders of breast
      • N63 - unspecified lump in breast
    • ICD-11
      • 2F30 - benign neoplasm of breast
      • 2C6Z - malignant neoplasms of breast, unspecified
      • GB20.Y - other specified benign breast disease
      • MF30 - breast lump or mass female
Epidemiology
  • Can occur at any age but is more common in older women
  • Women with a history of breast cancer may have a higher likelihood of developing microcalcifications (Breast Cancer Res 2022;24:96)
  • Women with microcalcifications have a higher risk of developing breast cancer (Breast Cancer Res 2022;24:96)
  • Strong association between the presence of calcifications and HER2 overexpression (Mol Oncol 2015;9:967)
Sites
  • Found throughout the breast tissue, most commonly within the mammary ducts and the surrounding fibroglandular tissue (stroma, vessels, skin)
Pathophysiology
  • Thought to arise from mineral deposition, which results from various physiologic processes
    • Secretory
    • Inflammatory
    • Senescence
    • Traumatic injury
    • Necrosis
Etiology
  • Dystrophic calcification in breast tissue is traditionally perceived as a passive phenomenon but type II microcalcifications are often associated with abnormal epithelial cells, suggesting an active process
  • Bone hydroxyapatite (HA) deposition is recognized as an active and physiological process; however, in breast tissue, HA deposition is considered pathological
  • Breast microcalcifications may undergo regulation similar to that of physiologic bone mineralization, despite being considered a pathologic process
  • Formation of mammary microcalcifications likely involves active secretion and may include epithelial to mesenchymal transition (EMT) of breast cells
  • Upregulation of osteogenic proteins, such as osteopontin and BMP2 in breast cancer, suggests a connection between breast cancer and osteogenic characteristics (Mol Clin Oncol 2022;16:81)
Clinical features
  • Asymptomatic and too small to be palpated
  • Identified during a mammogram and classified based on number, size, morphology and distribution using the BI-RADS (breast imaging reporting and data system) scoring system
  • Presence of microcalcifications on mammography has led to the detection of breast tumors as small as 1 - 2 mm (Mol Clin Oncol 2022;16:81)
  • Microcalcifications are present in 50% of carcinomas, compared to 20% in benign breast disease (Mol Clin Oncol 2022;16:81)
  • Only 20% of suspicious microcalcifications are actually part of a malignant process (Br J Cancer 2021;125:759)
Diagnosis
  • Breast microcalcifications are typically first identified during mammography (Mol Clin Oncol 2022;16:81)
  • Radiographical findings and correlation with clinical history is necessary
  • Core biopsy is frequently performed if there are microcalcifications (Korean J Radiol 2015;16:996)
  • Pathological diagnosis needs to correlate with imaging findings
Radiology description
  • Microcalcifications are detected during mammography
  • Based on their number, size, morphology and distribution, a BI-RADS category indicative of the likelihood of malignancy is assigned (see Table 1 and 2)
  • Suspicious microcalcifications are irregular and fine; nonsuspicious are coarse and chunky
  • Pathologists must detect microcalcifications in glass slides that correspond to those observed in radiographs; if microcalcifications are not initially identified, they should consider submitting additional tissue, obtaining additional levels or employing polarized microscopy to identify calcium oxalate (Pathologica 2007;99:5)
  • Note: microcalcifications may be absent from biopsy specimen due to retrieval failure (Radiology 2006;239:61)
  • Note: it is recommended to histologically examine all vacuum assisted breast biopsy specimens, regardless of the presence or absence of microcalcifications (Eur Radiol 2008;18:925)
  • Detection of calcium phosphate microcalcifications is diminished with glyoxal fixative (Eur Radiol 2008;18:925)


Table 1: BI-RADS assessment categories and likelihood of cancer (adapted from Biochim Biophys Acta Rev Cancer 2018;1869:310)
Category Assessment Management Likelihood of cancer
0 Incomplete; needs additional imaging evaluation or prior mammograms for comparison Additional imaging or comparison with prior examination(s) N/A
1 Negative Routine mammography screening 0%
2 Benign Routine mammography screening 0%
3 Probably benign Short interval (6 month) follow up or continued surveillance mammography > 0% but ≤ 2%
4 Suspicious for malignancy
  • 4A: Low suspicion
  • 4B: Moderate suspicion
  • 4C: High suspicion
Tissue diagnosis > 2% but < 95%
  • > 2% to ≤ 10%
  • > 10% to ≤ 50%
  • > 50% to < 95%
5 Highly suggestive of malignancy Tissue diagnosis ≥ 95%
6 Known biopsy proven malignancy Surgical excision when clinically appropriate N/A


Table 2: Mammographic characteristic features of benign versus suspicious breast calcifications (Biochim Biophys Acta Rev Cancer 2018;1869:310, Mol Clin Oncol 2022;16:81, YouTube: Breast Imaging Calcifications - module 2 | Health4TheWorld Academy [Accessed 8 April 2024], Nov Approaches Cancer Study 2021;6:582)
Features Typically Benign Suspicious for Malignancy
Quantity Few Many
Size (diameter) Large and chunky, 1.0 - 4.0 mm < 0.5 mm
Shape Coarse, round, oval, uniform Fine, linear
Borders Well defined, regular Irregular, less defined
Groups 5 calcifications within 1 cm > 5 calcification within 2 cm
Distribution Diffuse / scattered, regional Linear, segmental
Morphology Eggshell-like, popcorn-like, rod-like Amorphous, coarse heterogenous, fine pleomorphic, fine linear branching
Other associations Skin, vascular, dystrophic, milk of calcium, suture, breast infarcts
Radiology images

Contributed by Agnes Ikpoto Udoh, M.D., M.B.A.
Microcalcifications in grouped distribution

Microcalcifications in grouped distribution

Round microcalcifications (BI-RADS 4A)

Round microcalcifications (BI-RADS 4A)

Linear microcalcifications (BI-RADS 4B)

Linear microcalcifications (BI-RADS 4B)

Linear microcalcifications (BI-RADS 4C)

Linear microcalcifications (BI-RADS 4C)



Images hosted on other servers:
Involuting Fibroadenoma with popcorn microcalcifications

Involuting fibroadenoma with popcorn microcalcifications

Breast calcification BI-RADS 2

Breast calcification BI-RADS 2

Linear microcalcifications in DCIS

Linear microcalcifications in DCIS

Prognostic factors
  • Microcalcifications are associated with both favorable prognostic factors (i.e., small size and hormone receptor positivity) and unfavorable factors (i.e., high grade), depending on the associated diagnosis (Cancer 2017;123:219)
  • Casting (duct centric) calcification subtype is an independent unfavorable prognostic factor in breast cancer patients, affecting ~10 - 12% of cases; it is associated with specific genetic and molecular characteristics and is linked to decreased overall survival rates (Semin Cancer Biol 2021;72:165)
Case reports
  • 27 year old woman with pleomorphic calcifications and segmental distribution on mammography, highly suggestive of breast cancer; however, the pathological findings were fibrocystic disease (Radiol Case Rep 2023;18:3828)
  • 42 year old breastfeeding woman with multiple groups of microcalcifications in bilateral breasts (Breast J 2004;10:247)
  • 54 year old woman with a history of gastric cancer and pleomorphic microcalcifications in the breast (J Breast Cancer 2012;15:356)
  • 73 year old woman diagnosed with primary breast amyloidosis and persistent microcalcifications (Int J Surg Pathol 2013;21:177)
Treatment
Gross description
  • Typically, specimens come as core biopsies
Microscopic (histologic) description
  • There are 2 primary types of microcalcifications based on biochemical composition: calcium oxalate and calcium phosphate
  • Calcium oxalate (type I)
    • Less common
    • These crystals do not bind with the hematoxylin stain and appear as clear refractile structures; they are best visualized under polarized light, with the condenser flipped down for optimal observation (Am J Surg Pathol 1990;14:961, Mod Pathol 1992;5:146)
    • Predominantly found within benign cysts or terminal ductules, often demonstrating histological features of apocrine cells
    • Can be associated with lobular carcinoma in situ and are rarely seen in association with invasive carcinoma (Am J Surg Pathol 1991;15:586)
  • Calcium phosphate (type II)
    • More common
    • Manifest as purple / blue psammoma-like aggregates, either solitary or clustered, when stained with H&E
    • May be observed in both benign and malignant lesions; they are commonly associated with premalignant and malignant lesions (Mol Clin Oncol 2022;16:81)
  • If a mammogram reveals the presence of microcalcifications, diligent efforts should be undertaken to locate them; furthermore, the presence of microcalcifications must be documented in the histology report, along with any associated lesions
  • Location of the microcalcifications may suggest the following possible differentials
    • Lobular calcifications
      • Cystic breast disease
      • Milk of calcium
      • Sclerosing adenosis
      • Atypical lobular hyperplasia (ALH)
      • Lobular carcinoma in situ (LCIS)
      • Invasive lobular carcinoma (ILC)
    • Ductal calcifications
      • Columnar cell change
      • Flat epithelial atypia (FEA)
      • Atypical ductal hyperplasia (ADH)
      • Ductal carcinoma in situ (DCIS)
      • Invasive ductal carcinoma (IDC)
  • The following steps are recommended to locate the microcalcifications
    • Step 1: examine the H&E stained slides meticulously for microcalcifications
    • Step 2: if not apparent on H&E, utilize polarized light microscopy, especially for detecting calcium oxalate crystals
    • Step 3: consider cutting deeper levels of the H&E slides to further evaluate for microcalcifications
    • Step 4: utilize Xray imaging of the tissue block for enhanced detection
    • Step 5: consult with the radiologist to confirm that the lesion has been biopsied
Microscopic (histologic) images

Contributed by Jing He, M.D.
DCIS with microcalcifications DCIS with microcalcifications

DCIS

Collagenous spherulosis with microcalcifications

Collagenous spherulosis

Fibroadenomatous change

Fibroadenomatous change

Fibroadenoma with microcalcifications

Columnar cell lesion

Apocrine metaplasia with microcalcifications

Apocrine metaplasia


Radial scar with microcalcifications

Radial scar

Papillary lesion with microcalcifications

Papillary lesion

Fibrocystic changes with microcalcifications

Fibrocystic changes

Invasive mammary carcinoma with tubular features

Invasive mammary carcinoma with tubular features

IDC after neoadjuvant chemotherapy with microcalcifications

IDC after neoadjuvant chemotherapy

Sclerosing adenosis with microcalcifications

Sclerosing adenosis


LCIS with microcalcifications

LCIS

Fat necrosis with microcalcifications

Fat necrosis

Flat epithelial atypia with microcalcifications

Flat epithelial atypia

Usual ductal hyperplasia with microcalcifications

Usual ductal hyperplasia

Fibrocystic changes with calcium oxalate calcifications

Fibrocystic changes with calcium oxalate calcifications

Calcium oxalate calcifications with polarized light

Calcium oxalate calcifications with polarized light

Videos

Breast imaging: calcifications (basic radiology)

Breast imaging calcifications (module 1)

Breast imaging calcifications (module 2)

Sample pathology report
  • Breast, right, 3 o'clock, 5 cm from nipple, microcalcifications, stereotactic core biopsy:
    • Sclerosing adenosis with associated microcalcifications
Differential diagnosis
  • Dystrophic calcification:
    • These can develop in areas of old scarring and may warrant biopsy during follow up after conservation surgery for malignant disease
    • Typically, they appear coarse and may exhibit an eggshell-like appearance
    • They can pose a diagnostic challenge if they are arranged in clusters
  • Vascular calcification:
    • Typically conspicuous but can resemble casting calcifications
    • They are arranged in parallel streaks and distributed along a vessel
Board review style question #1

Which of the following characteristics is most suggestive of benign microcalcifications on mammography?

  1. Fine pleomorphic calcifications
  2. Linear or branching distribution
  3. Round or oval shape with smooth borders
  4. Segmental distribution
Board review style answer #1
C. Round or oval shape with smooth borders. Benign microcalcifications commonly exhibit a round or oval shape with smooth margins, which typically suggest benign conditions like fibrocystic changes or benign breast calcifications. Answer B is incorrect because linear or branching distribution is more commonly associated with malignant lesions, particularly ductal carcinoma in situ (DCIS). Answer A is incorrect because fine pleomorphic calcifications are irregular in shape and size and have a higher likelihood of being associated with malignant lesions than the classifications that are round with smooth borders. Answer D is incorrect because segmental distribution is usually suggestive of malignancy; however, there are few reports of its association with fibrocystic change (Radiol Case Rep 2023;18:3828).

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Reference: Microcalcifications
Board review style question #2
What is the recommended next step if microcalcifications are not initially identified in histological examination?

  1. Consult with a radiologist for further imaging
  2. Submit additional tissue for analysis
  3. Disregard the findings as insignificant
  4. Perform electron microscopy for better resolution
Board review style answer #2
B. Submit additional tissue for analysis. Of the provided options, the best option would be to submit additional tissue for analysis. It would be most appropriate to first obtain additional levels before doing so, after which you should employ polarized microscopy to identify calcium oxalate crystals if still not seen on H&E. Answer A is incorrect because while consulting with a radiologist for further imaging might be a further step taken in the diagnostic process, it is not the recommended next step if microcalcifications are not initially identified in histological examination. Answer C is incorrect because disregarding the findings as insignificant without further investigation would be inappropriate and potentially harmful. Microcalcifications can be indicative of various benign and malignant conditions, so their presence or absence could have implications for diagnosis and treatment planning. Dismissing them without proper evaluation could lead to missed diagnoses or incorrect management decisions. Answer D is incorrect because electron microscopy is a highly specialized technique used for examining ultrastructural details of tissues at a very high resolution. While electron microscopy can provide detailed information, it is not routinely used for identifying microcalcifications in breast tissue.

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Reference: Microcalcifications
Board review style question #3

A premenopausal woman is seen for bilateral breast tenderness. She is not pregnant or on hormone therapy. Mammography of the breast revealed grouped punctate and indistinct calcifications measuring 6 mm, BIRADS 4A. No lesions are seen in the other breast. A follow up biopsy is shown above. IHC showed heterogenous ER staining and positive CK5/6. What is the most likely diagnosis?

  1. DCIS with microcalcifications
  2. Fat necrosis with microcalcificatons
  3. Invasive ductal carcinoma with microcalcificatons
  4. Usual ductal hyperplasia with microcalcifications
Board review style answer #3
D. Usual ductal hyperplasia with microcalcifications. The histology shows benign appearing hyperplastic ductal cells admixed with myoepithelial cells with associated microcalcifications. Answer A is incorrect because of the presence of myoepithelial cells and heterogenous ER staining. In DCIS, ER is diffuse strong positive. Answer C is incorrect because the cells appear benign with myoepithelial cells admixed with the ductal cells. Myoepithelial cells are absent in invasive breast cancer. Also, radiology had a low suspicion for malignancy. Answer D is incorrect because fat necrosis usually follows trauma and consists of cystic spaces surrounded by lipid laden (foamy) macrophages. Though histiocytes can be seen in this picture the more appropriate diagnosis is usual ductal hyperplasia.

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Reference: Microcalcifications
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