After CNB, the radiologist must correlate imaging findings w/ the histopathologic results to ensure appropriate management.

• Concordance: when histopathologic diagnosis accounts for the imaging features

• Discordance: when imaging findings are not explained by the histopathologic diagnosis.

Detecting discordance minimizes the change of a misdiagnosis related to undersampling a missed target, small target that was missed at pathologic analysis or interpretation error.

Pathologists may request specimen radiography to identify the calcs or prior bx site denoted by a clip. This helps pathologist focus on high-yield areas w/n the excised tissue.

Histologic subtypes of breast CA are microscopically evaluated on the basis of the cell of origin, growth pattern, morphology, and tumor grade. 

• The combo of these features informs the prognosis and guides management.

(1) Cell of origin: ductal vs lobular

• 80% invasive ductal carcinoma not otherwise specified

  • Heterogeneous group of tumors that appear as nonspecific sheets, nests, or cords of cells invading through the basement membrane. 

• 10-15% invasive lobular carcinoma  

  • characterized by linear growth and a lack of cohesiveness

• Most often, the cell type can be determined w H=E staining. For equivocal cases, IHC analysis is used to look specifically for...

  • E-cadherin

    • Absent in lobular carcinomas 2/2 inactivation of CDH1 (e-cadherin protein-coding gene)

  • p120 Catenin

    • Cytoplasmic expression in lobular carcinomas

    • Membranous expression in others

  • Beta-catenin

    • Absent in lobular carcinomas

(2) Pattern of growth

• What is happening to the basement membrane (BM) which separates neoplastic cells from breast stroma?

  • In situ dz - intact BM 

  • Invasive dz - neoplasm extends through the BM into the stroma w/ potential for mets

• Pathologists rely on specific IHC markers to confirm invasion and better characterize the specific subtype of malignancy.

  • Invasive - lacks myoepithelial cell layer

    • Lack of myoepithelial cells markers such as smm actin, p63, calponin, and smm myosin heavy chain

(3) Tumor grade (biologic aggressiveness)

• Assessed on the basis of the lvel of differentiation (amount of gland formation), pleomorphism (nuclear features), and proliferation (mitotic activity)

• Grade options: low, intermediate, high grade

  • High - <10% gland formation, prominent nuclear pleomorphism, > 16 mitoses per 10 HP fields.

  • Low - >75% gland formation, uniform cells w/ small nuclei, and <7 mitoses per 10 HP fields.

(4) Characterize invasive malignancies into molecular subtypes based on specific genes and proteins that influence cellular behavior.

• Estrogen receptor (ER)

  • Functions as signal transduction molecule that stimulates normal breast development with a tumorigenic effect in binding to the ER leading to proliferative changes that contribute to carcinogenesis. 

  • 70-80% of breast CA are ER+

• Progesterone receptor (PR)

  • Functions as critical regulator of transcription and an activator of signal transduction pathways in the downstream ER signaling cascade ultimately resulting in cell growth.

• HER2

  • Epidermal growth factor receptor proto-oncogene (ERBB2) encodes a cell surface transmembrane receptor protein (HER2/erbB2) neu), regulating cell growth and proliferation.

  • ERBB2 amplification leads to increased mitogenic transduction, rapid tumor growth, cellular aggressiveness, and a poor prognosis.

  • 15-30% of breast CA are ERBB2 amplified and assoc w a shortened survival, increased recurrence rate, and poor response to chemotherapy.

  • ERBB2-targeted therapies have improved overall prognoses, with trastuzumab therapy resulting in an approx 50% decrease in dz recurrence and an approx 30% in death rate.

• Ki-67

  • Nuclear prolieration marker that is used to distinguish luminal subtypes of breast malignancy.

  • The higher the Ki-67 proliferation rate, the poorer the outcome. 

• Using these 4 tumor markers, at least 5 main molecular subtypes of invasive breast CA have been reported

  • Luminal A

    • Well-differentiated, ER and/or PR+, HER2-

    • Low Ki-67 proliferation rate and lower grade

    • Assoc w/ a relatively good prognosis

  • Luminal B

    • ER and/or PR+, HER2-

    • High proliferation rate with rapid growth

    • Tend to have poorer prognosis and often larger at diagnosis w/ higher tumor grade and more locally advanced dz. 

  • Luminal B-HER2

    • ER and/or PR+ w/ high Ki-67 proliferation rate but HER2+

  • HER2

    • ER and PR-, HER2+ w/ high Ki-67 proliferation rate

    • More biologically aggressive than luminal CA and assoc w a worse prognosis.

  • Triple-negative basal like

    • ER, PR, HER2= w/ high Ki-67 proliferation rate.

In the absence of the usual markers, other markers such as GATA-3 and SOX-10 are used to confirm breast origin.

• Triple neg tumors that demonstrate basal phenotype markers such as high-molecular weight cytokeratin (HMWCK) including cytokeratin 5, 6, 14, 17 are subcategorized as basal like and protend a worse prognosis. compared w/ triple-negative tumors that are negative for HMWCK.

• Overall triple neg tumors are more aggressive than luminal subtypes, are assoc w/ BRCA1 mutation and occur more frequently in younger women. 

• This molecular subtyping directly guides treatment, with luminal cancers being receptive to hormonal therapy and HER2+ cancers being responsive to HER2-targeted therapy.

Imaging characteristics of the molecular subtypes have been assoc w specific imaging features

• Triple neg are often detected clinically or as interval CA. At imaging, they appear as masses w an irregular shape and ill-defined margins on mammograms and as a hypoechoic or heterogeneous mass w/ ill-defined margins on US images. Can have benign features such as round or oval shape and circumscribed margin. microcalcifications are uncommon.

• HER2+ CA are frequently assoc w/ calcs (pleomorphic, amorphous, punctate) and masses that are spiculated, microlobulated or angular margins.

• While calcs are seen in the majority of HER2 positive Ca they are not specific and can be seen in luminal CA as well. On US images, HER2+ lesions commonly appear hypoechoic.

• Luminal type CA often appear as masses w calcs on mammograms and as irregular masses w angular or microlobulated margins on US images.