Pathological basis of Breast Cancer for Surgeons

Normal Histology

• Clustered acini form the lobule.
• Lobule drain into ductules.
• Many ductules join to form ducts and this in turn drain into collecting ducts.
• Lobules, ductules, ducts and collecting ducts are made up of two layers of epithelium
  • Inner Luminal epithelial cells
  • Outer Myoepithelial cells.
• TDLU – Terminal Ductal Lobular Unit
  • Point at which ducts meet the lobules
  • Most of breast pathologies occur here.

• Invasive Carcinomas are devoid of myoepithelial cells
• Stroma – Interlobular stroma is loose and mildly cellular whereas interductular stroma is collagenous and paucicellular.

Non Invasive Lesions

Intraductal Proliferations

• Hyperplasia, Metaplasia, & Neoplasia arise from TDLU.
• Hyperplasia is typically associated with swirling pattern with haphazard distribution.

Atypical Ductal Proliferations

• No swirling pattern or haphazard distribution.
• Histologically more organized.
• Increased rigidity of cells with pronounced cell membranes – Rookie cutter appearance.
• Micropapillary proliferations may be seen.
• Difficult to distinguish between low grade DCIS and ADH.

Non Invasive Lobular lesions

• Difficult to distinguish between ALH and LCIS
• e cadherin staining in cell membranes is used in distinguishing its integrity. e cadherin staining is negative in LCIS. Distinguishing feature between LCIS and DCIS.
• Relative small sized cells, monotony, dyshesive nature, & occasional intracytoplasmic vacuoles are features of LCIS.

Invasive Lesions

• Most of the invasive lesions arise from TDLU.
• Invasive ductal carcinoma can only be distinguished based on histological appearance and not on site of origin.
• LCIS and DCIS can be the precursors of Invasive ductal carcinoma. LCIS is not the precursor of Invasive lobular carcinoma.
• E-cadherin stains negative in invasive carcinomas as myo-epithelial cells are absent in them.
• 90% of invasive lesions are Invasive ductal carcinoma and rest 10% are Invasive lobular carcinomas.

Invasive Ductal Carcinoma

• Histological tendency towards normal breast epithelium.
• Grading done from I to III based on tubule formation, nuclear pleomorphism and mitotic activity.
• Two types
• No Special type (75%)
• Special Category (25%)
• ER/PR Positive tumours are generally low grade tumours(75%)
• HER2 Positive tumours are generally poorly differentiated and make up 15% of IDC
• Rest 10% are Triple negative.

Invasive Lobular Carcinoma

• Multifocal and poorly delimited.
• Most of them are ER/PR +, HER2 –

Invasive Mammary Carcinoma with mixed ductal & lobular components

• Mimics those of an invasive lobular carcinoma.

Tubular Carcinoma

• Histologically, well formed/low-grade tubular structures with apical snouts & haphazard distribution in a desmoplastic stroma.
• Almost always ER+, PR+, HER2 –
• Serves as a “red flag” if ER/PR – or HER2 +
• Differential Diagnosis – Sclerorising lesions, Microglandular adenosis
• Microglandular adenosis is devoid of myo-epithelial cells, one of the few benign conditions to be devoid of myoepithelial cells. ER-
• Less aggressive clinical course compared to IDC-NST.

Cribriform Carcinoma

• Histologically similar to that of cribriform DCIS
• ER + PR + HER2 –

Mucinous Carcinoma

• Characterized by low to intermediate grade ductal carcinoma embedded within pools of mucinous.
• Diagnosis of mucinous carcinoma to be made only if >90% of the tumour show characteristic mucinous pattern.
• Favourable outcome compared to IDC-NST
• ER + PR + HER2 –
• Occurs in older patients.

Medullary Carcinoma

• Strict adherence to histological criteria essential to make diagnosis.
• High grade with unfavourable prognosis
• Histological criteria
• Syncytial growth pattern
• Lymphoplasmacytic inflammation
• Well delimited borders
• No glandular/tubular differentiation
• Triple Negative (ER-, PR-, HER2-)
• BRCA germline mutations are associated with this type.

Invasive Papillary Carcinoma

• Characteristic growth pattern of tumour clusters in clear spaces
• ER/PR + with Variable HER2
• Lymph node involvement at presentation

Metaplastic Carcinoma

• Represents more of a category of tumour types than a single histological entity.
• Any breast malignancy that shows an epithelial phenotype that has undergone transformation into either a nonglandular lineage or a mesenchymal lineage is included.
• Squamous cell carcinoma, adenosquamous carcinoma, metaplastic squamous cell carcinoma, malignant spindle cell lesions with epithelial markers are included.
• Triple Negative

Adenoid Cystic Carcinoma

• Identical to Salivary counterpart
• Solid, cribriform & tubular epithelial components.
• Unlike Salivary counterpart, lymphovascular invasion is rare.
• Triple negative but with excellent prognosis.

Phylloides Tumour

• Composed of epithelial & stromal components.
• Characteristics can range from low grade benign to high grade malignancy.
• Low Grade resembles fibroadenoma & may be difficult to differentiate on biopsy.
• WHO Criteria for Phylloides Tumor

Papillary Lesions

• Can range from benign lesions like Intraductal papilloma to atypical lesions and Carcionomas.

Intraductal Papilloma

• Ductal spaces involved by proliferating epithelial cells overlying fibrovascular cores.
• May involve central or peripheral ducts.
• Atypical papillomas warrant management similar to ADH.
• Absence of myoepithelial cells doesn’t confirm invasive lesion.
• Atypical Papilloma Vs Papilloma with DCIS – Size threshold of 3 mm is used to distinguish between them.

Papillary Ductal Carcinoma in Situ

• Architectural variant of DCIS.
• Different lesion than intraductal papilloma with DCIS.
• There is no underlying papilloma
• Papillary component is a secondary structure of the DCIS.

Papillary Carcinoma

• Encapsulated Papillary Carcinoma & Solid Papillary Carcinoma
• Encapsulated Papillary Carcinoma
• Well-delimited and surrounded by a capsule.
• Treated as in-situ carcinomas as the risk of metastasis is low.
• Solid Papillary Carcinoma
• Multinodular
• No secondary papillary structures as seen in other papillary lesions.
• Grows as multiple nests with circumscribed/contoured margins.

Prognostic/Predictive Factors

• Prognostic factors predict the course that a disease will take in the absence of therapy. These include age, comorbidities, tumor size, histologic grade, nodal status and molecular tests
• Predictive factors forecast the likelihood that a patient will benefit from a given therapy. They are generally assessed by immunohistochemical analysis (ER/PR/HER2) or molecular methods (Her2, PDL1).
• ER/PR immunostains are based on nuclear reactivity and are scored from 0% to 100%. It is categorized as negative when it shows low level reactivity( ~10% to 40% of benign breast epithelial elements). It can also show varying degrees of intensity ( Weak/Intermediate/Strong). Weak reactivity shouldn’t be the criteria if majority of cells show it.
• HER2 ananlysis is based on membranous reactivity. Circumferential & complete membranous reactivity in >10% of tumor cells is regarded as Positive. Those with incomplete or no staining in <10% of tumor cells is Negative. Faint staining in > 10% of cases is considered Negative. Weak or moderate staining in >10% cases is regarded as Equivocal.

Molecular Classification

• Classification based on Estrogen receptor, Keratin expression and HER2 status.
• Breast Cancers expressing keratin comprise largest groups
• Four main category are : Luminal A, Luminal B, HER2 and basal-like
• Luminal A & Luminal B types express luminal keratins (Cytokeratins 8 & 18)
• Luminal B express Proliferation related Proteins and also some Luminal B express HER2. (Triple Positive)
• HER2 group overexpress Her2 Proteins and are generally high grade.
• Basal-like express Cytokeratins 5,14 & 17 and are generally high grade. They belong to Triple Negative category. Not all Triple negative tumors are basal-like.