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PA30.2 | Carcinoma of the Breast — SDL Guide (Part 2)

Lobular Carcinoma In Situ (LCIS)

Lobular carcinoma in situ (LCIS) is a proliferation of small, uniform, loosely cohesive cells filling and distending the terminal duct-lobular unit (TDLU) without invading the stroma. Unlike DCIS, LCIS is almost never palpable or mammographically visible — it is most often an incidental finding in breast biopsies done for other reasons.

Three-panel diagram comparing normal TDLU histology with LCIS at medium power, showing discohesive cell filling of expanded acini with preserved myoepithelial layer, alongside E-cadherin IHC demonstrating loss of membranous staining in LCIS versus retained staining in DCIS. — **Panel A:** Normal TDLU: Terminal Duct-Lobular Unit (TDLU), luminal epithelial cells, myoepithelial layer, intralobular stroma, terminal duct. **Panel B:** LCIS TDLU: expanded and distended TDLU, monomorphic discohesive cells (with intercellular gaps), preserved myoepithelial layer at periphery, intact basement membrane, no necrosis/no calcification. **Panel C:** E-cadherin IHC split panel — Left (LCIS negative): complete loss of membranous E-cadherin staining, hematoxylin-only nuclei; Right (DCIS positive): retained brown DAB membranous ring staining; central legend: CDH1 / 16q / cell-cell adhesion.

Key molecular feature: Loss of E-cadherin expression (encoded by CDH1, chromosome 16q). E-cadherin is a cell-cell adhesion molecule; its loss explains the characteristic discohesive/non-cohesive cell morphology seen in LCIS and its invasive counterpart, invasive lobular carcinoma. IHC for E-cadherin shows complete absence of membranous staining in LCIS cells (positive in DCIS — a useful diagnostic discriminator).

Clinical significance:
• LCIS is a bilateral risk marker — risk increased ~4× in both breasts (not just the biopsy side)
• ~1–2% per year risk of developing invasive carcinoma (lobular or ductal)
• Treated with close surveillance ± chemoprevention (tamoxifen/raloxifene) rather than surgery
• Pleomorphic LCIS (rare variant with higher-grade cells, necrosis) behaves more like DCIS and may be excised

SELF-CHECK

A pathologist examining a breast biopsy performs E-cadherin immunohistochemistry. The in situ lesion shows complete loss of E-cadherin expression. Which in situ carcinoma does this confirm?

A. Ductal carcinoma in situ (DCIS), cribriform type

B. Ductal carcinoma in situ (DCIS), comedo type

C. Lobular carcinoma in situ (LCIS)

D. Atypical ductal hyperplasia (ADH)

Reveal Answer

Answer: C. Lobular carcinoma in situ (LCIS)

E-cadherin loss is the hallmark of lobular neoplasia (LCIS and invasive lobular carcinoma). It is encoded by CDH1 and its loss results in cell discohesion — the defining morphological feature. DCIS retains E-cadherin expression and is therefore E-cadherin positive on IHC. ADH also retains E-cadherin.

Invasive Ductal Carcinoma — No Special Type (NST)

Invasive ductal carcinoma of no special type (IDC NST) — also called invasive carcinoma NST in the WHO 2022 classification — is the most common breast malignancy, accounting for ~70–80% of all invasive breast carcinomas. The term "no special type" reflects that it does not show sufficient features to classify it as one of the special types.

Two-panel gross pathology illustration of invasive ductal carcinoma (NST): Panel A shows a cut breast specimen with a stellate grey-white tumour, labelled spiculated margins, chalky elastosis streaks, and surrounding fatty tissue; Panel B is a close-up schematic of the stellate architecture highlighting desmoplastic stroma and infiltrating spicules. — **Panel A:** Tumour centre (grey-white, gritty desmoplastic stroma); spiculated margin (irregular radiating projections into fat); surrounding fatty breast tissue (yellow lobulated adipose); chalky white streak / elastosis (pale linear deposits within tumour). **Panel B:** Dense desmoplastic stroma (fibrous tumour interior); elastotic collagen streaks (close-up inset, parallel pale lines); infiltrating spicule (tapering grey-white projection into adipose).

Gross features:
• Firm to hard (scirrhous) mass — due to extensive desmoplasia
• Irregular, stellate (star-shaped) margins that infiltrate surrounding fat
• Cut surface: grey-white, gritty texture (fibrotic stroma)
• Chalky white streaks represent elastosis of periductal collagen
• May show skin dimpling (tethering of Cooper's ligaments), nipple retraction

Three-panel histology diagram of IDC NST showing medium power H&E view of tumour nests and desmoplastic stroma (Panel A), high power detail of nuclear pleomorphism and mitotic figure (Panel B), and a colour-coded annotated schema (Panel C). — **Panel A:** Tumour nests (irregular clusters of malignant epithelial cells), desmoplastic stroma (dense pale fibrous background), cords and solid sheets of pleomorphic cells — medium power H&E overview. **Panel B:** Nuclear pleomorphism (enlarged, irregular, hyperchromatic nuclei with prominent nucleoli), mitotic figure (condensed chromosomal plate in dividing cell) — high power detail. **Panel C:** Colour-coded schema: coral = tumour nests and cords, blue = desmoplastic stroma, asterisk = mitotic figure sites — annotated spatial legend.

Microscopic features:
• Malignant epithelial cells arranged in nests, cords, solid sheets, or tubules — with variable patterns
• Dense desmoplastic stroma (fibroblastic reaction to tumour invasion) — this is responsible for the hard, gritty feel on gross
• Cells show nuclear pleomorphism, prominent nucleoli, variable mitoses
• May have associated DCIS ("DCIS component")
• Perineural invasion and lymphovascular invasion may be present

IHC profile: Variable — may be ER+/PR+/HER2− (most common), HER2+, or triple-negative, depending on the specific tumour.

Invasive Lobular Carcinoma

Invasive lobular carcinoma (ILC) is the second most common invasive breast carcinoma (~10–15%). It is characterised by a unique growth pattern directly attributable to loss of E-cadherin (same CDH1 deletion as LCIS).

Gross features:
• Often no discrete mass — diffuse rubbery induration of the breast
• Can be difficult to detect clinically and mammographically (low desmoplasia, no calcifications)
• May cause bilateral involvement more often than IDC

Microscopic features — classic pattern:
1. Single-file (Indian file) infiltration — cells arranged in single rows between collagen bundles
2. Targetoid pattern — concentric rings of tumour cells around a central duct
3. Minimal desmoplasia — unlike IDC NST, stroma reaction is sparse
4. Cells are small, uniform, with scanty cytoplasm and intracytoplasmic mucin vacuoles ("signet-ring" cells in variant)
5. E-cadherin negative on IHC

IHC profile: Almost universally ER+/PR+ (strongly hormone-dependent); HER2 amplification is rare; triple-negative ILC is uncommon.

Spread: ILC has a peculiar metastatic pattern — it preferentially spreads to the peritoneum, retroperitoneum, and gastrointestinal tract (particularly stomach, simulating linitis plastica), ovaries, and leptomeninges — in addition to axillary nodes and bone.

CLINICAL PEARL

Why ILC is the great mimicker: Because invasive lobular carcinoma produces minimal desmoplasia and infiltrates diffusely without forming a discrete mass, it can be mammographically occult (negative mammogram despite palpable disease). MRI is more sensitive. Histologically, the single-file pattern is sometimes subtle and can mimic a fibrous scar or chronic inflammation at low power. The stain for E-cadherin (negative in ILC, positive in IDC) is the decisive IHC test when the morphology is ambiguous.