Carcinoma in Situ

Slide 1 · Carcinoma in Situ

Breast pathology: biologic boundaries and diagnostic distinctions

Ductal and lobular patterns in their clinicopathologic context

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning outcomes

Define breast carcinoma in situ using its tissue boundary.

Explain why “ductal” and “lobular” do not identify separate cells of origin.

Recognize the dominant diagnostic features of DCIS and LCIS.

Connect in situ morphology to detection, subsequent cancer risk, and management.

Slide 3 · “In situ” describes an anatomical constraint

Neoplastic epithelial cells remain within ducts and lobules.

An intact basement membrane separates involved spaces from stroma.

The term denotes a location and invasion boundary—not benignity.

The distinction is established by the relationship of tumor to surrounding structures.

Normal duct

In situ

Invasive

Schematic — not a tissue section

Slide 4 · The terminal duct–lobular unit is the shared origin

The terminal duct–lobular unit contains terminal ducts and associated acini.

Evidence indicates that both major carcinoma patterns originate here.

A ductal-type lesion may populate lobules; A lobular-type lesion may populate ducts.

Anatomic distribution should not be mistaken for the cell of origin.

Terminal duct–lobular unit

Terminal duct

Lobular acini

Schematic — simplified anatomical branching

Slide 5 · Two boundaries organize the diagnosis

Luminal epithelial proliferation forms the neoplastic component.

A basement membrane marks confinement versus invasion.

Myoepithelial cells are generally preserved around DCIS-involved spaces.

Cells beyond the boundary require assessment for invasive carcinoma.

Normal duct

In situ

Invasive

Schematic — not a tissue section

Slide 6 · Confinement does not imply molecular normality

Carcinoma in situ carries many molecular alterations seen in invasive cancer.

The lesion can be genetically neoplastic despite an intact tissue boundary.

The phrase “carcinoma in situ” therefore reflects both malignant biology and location.

Whether—and when—progression occurs varies among lesions.

Neoplastic molecular alterations

Proliferation in a duct–lobular space

Anatomically confined carcinoma

Possible later invasive carcinoma

Slide 7 · Historical “ductal” and “lobular” terminology

Historical interpretation

Current biologic interpretation

Terms originally described which normal spaces a lesion resembled.

The patterns were taken as clues to the anatomical site of origin.

This view was primarily morphological.

Most breast carcinomas arise from terminal duct–lobular epithelium.

Architectural differences reflect tumor genetics and biology.

Names remain useful diagnostic categories, not origin maps.

Slide 8 · The two major in situ patterns

Feature

DCIS

LCIS

Cohesion

Usually cohesive

Typically dyscohesive

Detectability

Often calcification-associated

Usually incidental biopsy finding

Main grade framework

Nuclear grade

Classic versus aggressive variants

Clinical pattern

Usually local recurrence concern

Risk affecting either breast

Slide 9 · The architectural relationship is diagnostic

DCIS involves ducts and lobules while generally maintaining myoepithelial cells.

LCIS also involves ducts and lobules, often with reduced cell-to-cell cohesion.

The intact boundary is shared; Patterns and molecular programs differ.

Do not infer invasiveness from the adjective “carcinoma” alone.

Normal duct

In situ

Lobular-type

Schematic — not a tissue section

Slide 10 · Detection begins before a microscopic label

DCIS most often comes to attention on mammography.

Calcification is its dominant radiologic clue.

LCIS usually lacks calcification and a stromal response.

Sampling supplies the microscopic distinction that imaging cannot establish alone.

How the lesions are encountered

DCIS → mammographic finding

LCIS → incidental biopsy finding

Morphology → final pattern recognition

Slide 11 · DCIS: A proliferation confined to epithelial spaces

Neoplastic cells remain limited to ducts and lobules.

Myoepithelial cells are generally maintained in affected structures.

Neoplastic cells may extend through connected ductal spaces.

Extensive involvement can occupy an entire breast segment.

Normal duct

In situ

Invasive

Schematic — not a tissue section

Slide 12 · Segmental ductal extension explains hidden extent

The ductal tree permits contiguous spread through branching epithelial spaces.

Imaging may underestimate how much of the system contains DCIS.

The lesion may not be grossly visible at operation.

Extent becomes relevant to complete surgical excision.

Terminal duct–lobular unit

Terminal duct

Lobular acini

Schematic — simplified anatomical branching

Slide 13 · Why mammography frequently detects DCIS

Intraductal calcifications form a conspicuous imaging clue.

Mineralization may accompany necrotic cell debris.

Secretory material can also calcify in the involved lumen.

The finding is a radiologic manifestation, not proof of stromal invasion.

Schematic — not a photomicrograph

Slide 14 · DCIS can produce a density or a palpable abnormality

Periductal fibrosis sometimes produces mammographic density.

A vaguely palpable mass is less common than calcification-only detection.

Nipple discharge occurs rarely, often with papillary patterns.

Incidental detection on biopsy is also possible.

Presentations mentioned by Robbins

Calcifications (predominant)

Density / subtle palpable mass

Discharge / incidental finding

Slide 15 · DCIS is graded chiefly by nuclear features

Nuclear size and shape are central to nuclear-grade assessment.

The architectural pattern is not the primary grading criterion.

Low-grade and high-grade groups differ in associated biology.

Report logic should not substitute “comedo” or “cribriform” for nuclear grade.

Two separate descriptive axes

Nuclear grade → cytologic features

Architecture → growth pattern

Necrosis → additional feature

Slide 16 · Grade and architecture answer different questions

Descriptor

What it captures

What it does not establish

Nuclear grade

Size and shape of nuclei

The architectural pattern

Cribriform

Punched-out intraluminal spaces

A unique grade by itself

Micropapillary

Bulbous projections, no core

The degree of nuclear atypia

Comedo necrosis

Central necrotic material

A separate cell of origin

Slide 17 · Cribriform DCIS: Rounded internal lumina

The involved space contains neoplastic epithelium with repeated rounded holes.

The “cookie-cutter” configuration describes architecture.

Secretory material within spaces may undergo calcification.

The appearance is one possible pattern of DCIS.

Schematic — not a photomicrograph

Slide 18 · Micropapillary DCIS: Projections without cores

Tumor forms bulbous intraluminal protrusions.

The projections lack fibrovascular cores.

Architecture must be distinguished from a true papillary lesion.

Micropapillary architecture may occasionally accompany nipple discharge.

Schematic — not a photomicrograph

Slide 19 · Papillary DCIS: True fibrovascular cores

True papillae have fibrovascular cores.

The cores in papillary DCIS lack a myoepithelial layer.

This is not equivalent to micropapillary protrusion.

Location and lining characteristics support correct lesion classification.

Schematic — not a photomicrograph

Slide 20 · Micropapillary versus papillary architecture

Micropapillary DCIS

Papillary DCIS

Bulbous projections of neoplastic epithelium.

No fibrovascular stalk within protrusions.

Architecture alone does not determine nuclear grade.

True projections built around fibrovascular stalks.

Papillary cores lack an associated myoepithelial layer.

Architecture alone does not determine invasive status.

Slide 21 · Comedo necrosis: Central cell breakdown

Necrotic material accumulates in the central ductal lumen.

This feature is mainly associated with high-grade DCIS.

Calcification may accompany central necrosis.

Its presence is relevant to recurrence-risk assessment.

Schematic — not a photomicrograph

Slide 22 · Calcification and necrosis are related, not synonymous

Necrotic central material can calcify.

Secretions in otherwise intact lumina may also calcify.

Calcification is the imaging signal; Microscopic examination defines the lesion.

The same mammographic clue can accompany different DCIS architectures.

Intraductal necrosis or secretion

Mineral deposition within lumen

Mammographic calcification

Biopsy and histologic classification

Slide 23 · Low-grade DCIS: A characteristic pathway

Low-grade lesions are typically estrogen-receptor positive.

They are commonly HER2 negative.

Loss of 16q and gain of 1q exemplify the low-grade molecular pathway.

These features connect in situ lesions with related invasive carcinomas.

Low-grade neoplasia pathway

Often ER positive / HER2 negative

16q loss; 1q gain

Low-grade DCIS / related lesions

Simplified source-grounded relationship

Slide 24 · High-grade DCIS: A different biological program

High-grade DCIS may lack ER expression.

HER2 positivity is possible in this group.

Greater genomic instability and chromosomal alterations occur.

Molecular patterns resemble those of high-grade invasive carcinomas.

High-grade neoplasia pathway

ER negative and/or HER2 positive possible

Genomic instability; Chromosome changes

High-grade DCIS / related lesions

Simplified source-grounded relationship

Slide 25 · Biologic contrast between DCIS grades

Property

Low-grade DCIS

High-grade DCIS

ER

Typically positive

May be negative

HER2

Typically negative

May be positive

Molecular changes

16q loss; 1q gain

Genomic instability

Pathway

Low-grade neoplasia

High-grade neoplasia

Slide 26 · DCIS progression is not a single uniform sequence

Low- and high-grade DCIS appear biologically distinct.

They may follow separate pathways toward invasive carcinoma.

A subsequent invasive lesion often resembles the associated DCIS phenotype.

Neither histology nor receptors alone predicts an exact date of invasion.

Parallel source-described pathways

Low-grade DCIS → related invasion

High-grade DCIS → related invasion

Timing in an individual remains uncertain

Slide 27 · Natural history: Treatment obscures observation

Most diagnosed DCIS is treated, limiting untreated follow-up.

The full untreated trajectory cannot be observed directly in most cases.

Source estimates apply to groups, not a particular patient.

Higher-grade and extensive lesions are believed to progress faster.

Question for interpretation

Interpret rates as cohort estimates.

Do not imply every DCIS becomes invasive.

Distinguish biological risk from observed outcomes.

Slide 28 · Small low-grade DCIS: Reported invasive risk

Invasive cancer development of approximately 1% per year.

The estimate refers specifically to small low-grade DCIS.

Invasive disease often emerges in the same breast quadrant.

Grade and ER/HER2 pattern commonly resemble antecedent DCIS.

Clinical distribution

DCIS: Usually same site

LCIS: Risk in either breast

Slide 29 · DCIS recurrence risk: Three major features

High nuclear grade with associated necrosis increases recurrence concern.

Extensive intraductal distribution increases the chance of residual disease.

A positive surgical margin indicates incomplete local clearance.

These are source-described recurrence factors, not an individual risk calculator.

Nuclear grade and necrosis

Lesion extent

Margin status

Risk of ipsilateral recurrence

Slide 30 · DCIS treatment logic is primarily local

Mastectomy cure in more than 95% of patients with DCIS.

Complete excision can be difficult when extent is not grossly apparent.

Postoperative radiation reduces recurrence risk.

Tamoxifen also reduces recurrence in appropriate circumstances.

What local therapy targets

Remove anatomically confined lesion

Reduce residual-local recurrence

Consider future ipsilateral disease risk

Slide 31 · Clinical decisions must preserve uncertainty

Confinement does not guarantee the absence of occult invasion.

Metastatic deaths after an initial DCIS diagnosis are uncommon.

Possible origins include later invasive carcinoma or initially occult invasion.

Active investigation of surveillance for selected DCIS.

Question for interpretation

Pathologic diagnosis ≠ certainty of future course.

Sampling limitations remain important.

Management trials were ongoing in source edition.

Slide 32 · Paget disease: Extension to the nipple epidermis

Tumor cells can move from DCIS along lactiferous ducts.

They reach the nipple epidermis without crossing the basement membrane.

The resulting epithelial disruption permits fluid leakage.

An in situ ductal process can therefore generate a visible skin lesion.

DCIS in breast ductal system

Extension along lactiferous ducts

Malignant cells in nipple epidermis

Crusting and erythematous eruption

Slide 33 · Paget disease can mimic unilateral eczema

Clinical appearance includes erythema and a scaling crust.

Itching is common.

The unilateral nipple pattern should prompt pathologic evaluation.

Paget cells may be identified on nipple biopsy or exudate cytology.

Clinicopathologic reasoning

Unilateral itchy, crusted nipple

Paget cells within epidermis

Evaluate underlying breast lesion

Slide 34 · An underlying mass changes the Paget scenario

Without a palpable mass, Paget disease frequently accompanies DCIS.

With a palpable mass, invasive carcinoma is often present.

Prognosis reflects the invasive component if one is identified.

The presence of Paget disease itself is not the key prognostic driver.

Clinical distribution

DCIS: Usually same site

LCIS: Risk in either breast

Slide 35 · LCIS: In situ growth with cellular dyscohesion

Neoplastic epithelial cells grow within ducts and lobules.

Unlike typical DCIS, the cells are loosely cohesive.

The lesion is usually detected incidentally on biopsy.

This phenotype is linked to impaired E-cadherin-mediated adhesion.

Normal duct

Lobular-type

Lobular-type

Schematic — not a tissue section

Slide 36 · E-cadherin helps adjacent epithelial cells adhere

E-cadherin is a transmembrane epithelial adhesion protein.

It contributes to cell-to-cell attachment in glandular tissues.

Functional loss permits the rounded, separate-cell pattern of LCIS.

Loss of cohesion is biological, not proof of stromal invasion.

Cell–cell cohesion

Adhesion retained

Adhesion lost

Conceptual cell diagram

Slide 37 · CDH1 is a major route to E-cadherin loss

The E-cadherin gene is CDH1 on chromosome 16q22.1.

Mutation or deletion is a common cause of its loss in lobular lesions.

Adhesion failure helps explain dyscohesive morphology.

The pathway overlaps with low-grade breast neoplasia alterations.

CDH1 alteration

Reduced functional E-cadherin

Loss of epithelial cohesion

Dyscohesive lobular proliferation

Slide 38 · Not every lobular lesion loses CDH1 itself

Other adhesion-complex proteins are sometimes dysfunctional.

Robbins specifically mentions β-catenin as an alternative.

The diagnostic phenotype reflects compromised adhesion.

A single protein result must be interpreted with morphology and context.

Alternative molecular routes

E-cadherin loss (commonly CDH1)

Other adhesion component dysfunction

Shared effect: Cellular dyscohesion

Slide 39 · Classic LCIS: Uniform cells within lobular units

Rounded or oval nuclei with small nucleoli are characteristic.

Cells tend to be monomorphic and loosely connected.

Affected acini become filled and expanded.

The source describes more than half of acini in a unit involved.

Classic LCIS: Expanded acini

Rounded, separated cells expand multiple acini

Schematic — not a photomicrograph

Slide 40 · Classic LCIS may contain signet-ring cells

Intracytoplasmic mucin can create a signet-ring appearance.

Signet-ring cells may occur within otherwise classic LCIS.

The observation does not by itself establish invasive carcinoma.

Interpret individual cells in the architecture of the involved unit.

Question for interpretation

Cell morphology and compartment are separate questions.

Mucin positivity can occur in classic LCIS.

Preserve the in situ/invasive distinction.

Slide 41 · Pagetoid lobular spread is not nipple Paget disease

Lobular neoplastic cells may extend beneath the luminal duct epithelium.

This distribution is termed pagetoid spread.

It occurs between basement membrane and overlying luminal cells.

Nipple epidermal Paget disease is a different phenomenon.

Two unrelated uses of “Paget”

LCIS pagetoid spread: Duct wall

Paget disease: Nipple epidermis

Do not equate the two diagnoses

Slide 42 · LCIS is usually occult on breast imaging

Classic LCIS rarely produces calcifications.

Necrosis and secretory activity are generally absent.

There is usually no stromal reaction causing a density.

Diagnosis commonly follows biopsy obtained for another reason.

No usual necrosis / secretion

Calcifications usually absent

No strong imaging target

Incidental tissue diagnosis

Slide 43 · Pleomorphic LCIS is an important exception

Aggressive lobular in situ variants can show necrosis.

Associated calcifications may make these lesions image-detectable.

Their behavior and management differ from classic LCIS.

“Lobular” does not automatically mean indolent morphology.

Question for interpretation

Classic phenotype ≠ all variants.

Assess necrosis, nuclear appearance, and context.

Variant recognition changes management.

Slide 44 · LCIS receptor phenotype

LCIS almost always expresses estrogen receptor.

Progesterone-receptor expression is also usual.

Most lesions are HER2 negative.

This phenotype is consistent with a low-grade neoplasia pathway.

Low-grade neoplasia pathway

Often ER positive / HER2 negative

16q loss; 1q gain

Low-grade DCIS / related lesions

Simplified source-grounded relationship

Slide 45 · LCIS can occur in both breasts

Bilateral LCIS in 20%–40% when both breasts are biopsied.

The analogous reported proportion for DCIS is 10%–20%.

These are observed biopsy-distribution figures, not population prevalences.

Bilateral potential is relevant to future risk assessment.

Clinical distribution

DCIS: Usually same site

LCIS: Risk in either breast

Slide 46 · Classic LCIS indicates bilateral invasive-cancer risk

The risk applies to either breast, somewhat higher ipsilaterally.

An 8- to 10-fold increased relative risk.

A subsequent invasive cancer occurs at about 1% per year.

This is not the same clinical model as local DCIS recurrence.

Relative risk intervals reported in source

Nonproliferative

1×

Proliferative

1.5–2×

With atypia

4–5×

In situ

8–10×

0

2

4

6

8

10

Relative risk (× reference group)

Slide 47 · Classic and aggressive LCIS variants are managed differently

Classic LCIS on a concordant core biopsy may be surveilled.

The source associates concordance with a low chance of missed invasive disease.

Pleomorphic LCIS and other aggressive variants merit surgical excision.

Endocrine strategies or mastectomy are options in selected circumstances.

Risk-adapted source framework

Classic + concordant → surveillance possible

Aggressive variants → excision

Individualized risk-reduction options

Slide 48 · Relative risk across breast epithelial lesions

Lesion category

Relative risk of invasive breast carcinoma

Nonproliferative change

1.0

Proliferation without atypia

1.5–2

Proliferation with atypia

4–5

Carcinoma in situ (DCIS / LCIS)

8–10

Slide 49 · Atypical ductal hyperplasia is not automatically DCIS

Atypical ductal hyperplasia can partly involve a duct.

The Robbins figure describes cytologically monotonous cells and cribriform spaces.

Architectural resemblance does not by itself establish full DCIS.

Lesion extent and diagnostic assessment must be integrated.

Source-illustrated relationship

ADH: Partial duct involvement

DCIS: Defined in situ neoplastic lesion

Avoid diagnosis from one motif alone

Slide 50 · Atypical lobular hyperplasia and LCIS share a phenotype

Atypical lobular hyperplasia contains monomorphic dyscohesive cells.

LCIS cells are morphologically identical to cells in ALH.

Extent of lobular-unit involvement distinguishes diagnostic categories.

Adhesion biology supports their relationship.

Cell–cell cohesion

Adhesion retained

Adhesion lost

Conceptual cell diagram

Slide 51 · Microscopic differentiation: DCIS versus LCIS

Criterion

DCIS

Classic LCIS

Cell arrangement

Usually cohesive

Dyscohesive

Dominant classification

Nuclear grade

Lobular phenotype / variant

Necrosis

Comedo necrosis possible

Typically absent

Calcifications

Common

Usually absent

E-cadherin

Generally retained

Usually lost

Slide 52 · Clinical interpretation: DCIS versus LCIS

Question

DCIS

Classic LCIS

How found?

Usually mammography

Usually incidental biopsy

Later risk

Often same region of breast

Either breast

Local therapy?

Commonly treated locally

Concordant lesions may be observed

Important exception

High-grade / extensive disease

Pleomorphic variants

Slide 53 · Histologic boundaries depend on adequate sampling

Imaging cannot demonstrate a basement membrane directly.

Involvement may extend beyond the radiologic abnormality.

When invasion is suspected, the sampled tissue must be examined carefully.

An initial in situ diagnosis does not eliminate the possibility of unsampled invasion.

Normal duct

In situ

Invasive

Schematic — not a tissue section

Slide 54 · Case 1 — mammographic calcifications

Clinical / pathology vignette

Screening detects branching calcifications in one segment of the breast.

Core biopsy shows enlarged atypical nuclei in ducts with central necrosis.

The involved duct periphery remains bounded; No definite stromal invasion is sampled.

Question: Which in situ phenotype is most strongly suggested?

Slide 55 · Case 1 — interpret the full feature set

Intraductal cells with comedo necrosis support DCIS.

High nuclear grade is compatible with prominent atypia and necrosis.

Calcification helps explain the mammographic presentation.

Sampling still determines whether an invasive component is identified.

Schematic — not a photomicrograph

Slide 56 · Case 2 — incidental lobular epithelial proliferation

Clinical / pathology vignette

Biopsy for an unrelated imaging finding shows expanded acini.

Small monomorphic cells are round, separated, and lack strong cohesion.

No significant necrosis or calcifications are identified within the proliferation.

Question: What molecular change would explain the phenotype?

Slide 57 · Case 2 — connect cell shape to adhesion

A lobular in situ proliferation is favored by dyscohesive cell morphology.

E-cadherin function is commonly lost through CDH1 alteration.

Other adhesion-component defects can yield a similar phenotype.

Morphology and specimen context remain necessary for classification.

Cell–cell cohesion

Adhesion retained

Adhesion lost

Conceptual cell diagram

Slide 58 · Case 3 — persistent unilateral nipple eruption

Clinical / pathology vignette

A patient reports unilateral nipple pruritus with a recurrent scaly crust.

Biopsy finds malignant cells among squamous epidermal cells.

Breast sampling identifies an associated ductal in situ lesion.

Question: How can an in situ breast carcinoma affect nipple skin?

Slide 59 · Case 3 — epidermal spread without stromal invasion

Paget cells can track along lactiferous ducts to the nipple epidermis.

Disruption of the epidermal barrier produces ooze and crusting.

A palpable mass should raise concern for underlying invasive disease.

The prognosis is determined by any invasive component.

Ductal carcinoma in situ

Upward intraductal extension

Tumor cells in nipple epidermis

Eruption with crust and pruritus

Slide 60 · Three critical distinctions prevent category errors

In situ versus invasive refers to the basement membrane boundary.

Ductal versus lobular describes growth phenotype and tumor biology.

Nuclear grade versus architecture are different DCIS descriptors.

Classic LCIS versus pleomorphic variants changes clinical interpretation.

Four questions at diagnosis

Is tumor confined?

Ductal or lobular phenotype?

Nuclear grade and architecture?

Variant and lesion extent?

Slide 61 · Synthesis: What the pathologist must establish

Identify a neoplastic epithelial proliferation within the duct–lobular unit.

Evaluate confinement by the basement membrane and epithelial boundary.

Classify the ductal or lobular pattern with morphology and biology.

Communicate lesion grade/variant, extent, and clinically relevant risk.

Slide 62 · Recommended reading

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th edition (2026).

Chapter “The Breast”: introductory section, “Carcinoma in Situ.”

“Ductal Carcinoma In Situ”: morphology, molecular distinctions, and clinical course.

“Lobular Carcinoma In Situ”: cohesion biology, morphology, and clinical course.