Case 1: 55-Year-Old Female with Hard, Fixed Right Breast Swelling

Diagnosis

• Hard, fixed swelling (fixation due to invasion into surrounding structures and desmoplastic reaction)
• Postmenopausal age (55 years) - peak incidence for luminal-type breast cancer
• Needle biopsy confirms malignancy histologically

Classification of the Lesion

A. Histological/Morphological Classification (WHO)

B. Molecular/Biomarker Classification (Clinical Groups)

C. Histologic Grade (Nottingham Score - Bloom-Richardson)

1. Tubule formation (glandular differentiation)
2. Nuclear pleomorphism
3. Mitotic rate

• Grade 1 (well differentiated): tubular/cribriform pattern, small uniform nuclei, low mitoses
• Grade 2 (moderately differentiated): solid clusters, moderate nuclear pleomorphism
• Grade 3 (poorly differentiated): ragged nests/sheets, enlarged irregular nuclei, high mitotic rate, necrosis common

Morphology

• Hard, irregular mass (typically 2-3 cm at presentation without screening)
• Irregular margins on imaging and gross examination (Fig. 23.20A, B)
• Chalky-white desmoplastic stroma; produces a characteristic grating sound when cut or scraped
• Occasional foci of calcification

Fig. 23.20: Invasive breast carcinoma NST. (A) Mammogram showing irregular radiodense mass. (B) Gross specimen with irregular margins. (C) Exuberant desmoplastic stromal response on histology.

• Irregular nests, cords, and sheets of malignant epithelial cells invading stroma
• Desmoplastic stromal reaction (key feature)
• Varying degrees of glandular differentiation depending on grade
• Tumor cells with enlarged nuclei, mitoses, and necrosis (in high-grade tumors)

Fig. 23.21: Histologic grading. (A/D) Grade 1 - well-formed tubules, uniform nuclei. (B/E) Grade 2 - mixed tubular and solid areas, moderate pleomorphism. (C/F) Grade 3 - sheets of poorly differentiated cells, high mitotic rate, necrosis.

Prognostic Factors

Major Prognostic Factors (Table 23.5)

• The single most important prognostic factor. Once present, cure is unlikely.

• Most important factor in the absence of distant metastases
• 10-year disease-free survival: 70-80% with no nodal involvement → drops to 35-40% with 1-3 positive nodes → 10-15% with >10 positive nodes

• Node-negative tumors <1 cm: 10-year survival >90%
• Node-negative tumors >2 cm: survival drops to 77%

• Higher grade = worse prognosis at each stage level

• Best prognosis: high ER + high PR + HER2-negative
• Worst prognosis: ER/PR/HER2-negative (triple negative - TNBC)
• HER2 overexpression indicates aggressive behavior but responds to targeted therapy (trastuzumab)

• Lymphovascular invasion: found in ~50% of invasive carcinomas; poor prognostic factor for recurrence
• Inflammatory carcinoma presentation: 3-year survival only 3-10%
• Tumor-infiltrating lymphocytes (TILs): high TILs = better prognosis in HER2 and TNBC
• Gene expression profiling (Oncotype DX, MammaPrint): identifies patients who can be spared chemotherapy
• Response to neoadjuvant chemotherapy: pathologic complete response (especially in TNBC/HER2) correlates with better survival

Source: Robbins, Cotran & Kumar Pathologic Basis of Disease, blocks 10-11

Case 2: 46-Year-Old Female with Left Breast Mass, Nipple Retraction, and Axillary Lymphadenopathy

Probable Diagnosis

• Nipple retraction - occurs when the central breast is involved and tumor invades toward the nipple via Cooper's ligaments
• Axillary lymphadenopathy - regional nodal spread
• ILC typically infiltrates the breast insidiously with minimal desmoplasia, making it difficult to detect on imaging, and may present as diffuse thickening rather than a discrete hard lump

Etiology

• CDH1 gene mutation/deletion (chromosome 16q22.1) - the foundational molecular event; CDH1 encodes E-cadherin
• Males and females with heterozygous germline CDH1 mutations are at increased risk for both lobular breast carcinoma and signet ring carcinoma of the stomach
• Most ILCs are ER-positive/HER2-negative (luminal subtype), driven by estrogenic stimulation
• Risk factors overlap with breast cancer generally: nulliparity/delayed childbearing, hormone replacement therapy, increasing age (peak 40s-60s)
• ILC shares the low-grade breast neoplasia pathway genomic alterations, including 16q deletion, with LCIS (its non-invasive precursor)

Pathogenesis

1. E-cadherin is a transmembrane cell adhesion protein expressed by epithelial cells; it acts as a tumor suppressor
2. Loss-of-function mutations or deletion of the CDH1 gene → loss of E-cadherin expression
3. Rarely, other components of the E-cadherin complex (e.g., beta-catenin) are dysfunctional instead
4. Loss of E-cadherin disrupts cell-cell adhesion → dyscohesive tumor cells that cannot form glands or tubules
5. These dyscohesive cells infiltrate the stroma individually or in single-file "Indian file" cords
6. The lack of desmoplastic reaction explains why ILC is difficult to detect on imaging
7. LCIS (lobular carcinoma in situ) represents the precursor in-situ phase; cells are morphologically identical to ILC and also lack E-cadherin

Morphology

• Often no discrete, well-defined mass - instead a diffuse, rubbery induration or ill-defined thickening
• Minimal desmoplasia (unlike IDC-NST) - hence soft/subtle
• May be almost imperceptible on gross examination

1. Dyscohesive single infiltrating cells - due to E-cadherin loss
2. "Indian file" or single-cell linear cords - the pathognomonic pattern; tumor cells line up in single file through stroma
3. Targetoid (concentric) pattern - cells encircle normal ducts and lobules in a bull's-eye pattern
4. Signet ring cells - mucin-positive intracytoplasmic vacuoles displacing the nucleus
5. Cells are small, uniform, with round-to-oval nuclei and inconspicuous nucleoli
6. Absent or minimal desmoplasia
7. Almost always ER-positive, HER2-negative

Fig. 23.22A: Invasive lobular carcinoma - note the single-file (Indian file) infiltration pattern of dyscohesive small cells through the stroma. Compare with the other special histologic types.

Lab Diagnosis

1. Fine Needle Aspiration Cytology (FNAC) / Core Needle Biopsy

• FNAC: Dyscohesive, small uniform cells; Indian-file arrangement; signet ring cells with intracytoplasmic mucin; absence of tubule formation
• Core needle biopsy (preferred): Histologic sections showing the classic single-file infiltrating pattern; IHC can be performed

2. Immunohistochemistry (IHC) - Key Panel

E-cadherin loss is the defining diagnostic marker for ILC. In IDC-NST, E-cadherin is retained (membrane positivity).

3. Imaging

• Mammography: May appear as architectural distortion rather than a discrete mass (low sensitivity ~60-70% due to minimal desmoplasia)
• MRI: Superior sensitivity; better characterizes extent of disease
• Ultrasound: May show heterogeneous hypoechoic area with shadowing

4. Additional Investigations

• Tumor markers: CA 15-3, CEA (not diagnostic alone; used for monitoring)
• Sentinel lymph node biopsy/axillary dissection: For staging nodal disease
• Gene expression profiling: Oncotype DX or MammaPrint if ER-positive, node-negative, to guide chemotherapy decision
• Germline CDH1 testing: Consider in cases with family history or signet ring gastric cancer history

5. Histologic Grading

• Most ILCs are Grade 1 or 2 (well-to-moderately differentiated) despite their invasive behavior
• Grade determined by Nottingham Histologic Score

Sources: Robbins, Cotran & Kumar Pathologic Basis of Disease (9780443264528), blocks 10-11; Robbins & Kumar Basic Pathology (9780323790185), block 7