Fibrosis

Slide 1 · Radiation-induced fibrosis

Mechanisms, morphology and clinicopathologic consequences

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Connect radiation injury to delayed collagenous scarring.

Explain vascular injury, stem-cell loss and profibrotic signaling.

Recognize organ-specific patterns and major diagnostic pitfalls.

Slide 3 · The meaning of “fibrosis” in this topic

An adverse late tissue response within a previously irradiated field.

Dead functional cells are replaced by connective tissue.

The resulting scar may distort structures or create adhesions.

Irradiated tissue

Cell loss

Connective-tissue replacement

Scar / adhesion

Slide 4 · A local complication of cancer radiotherapy

Therapeutic irradiation targets tumor-bearing tissue.

Non-neoplastic cells and vessels inside the field may also be injured.

The same field can show both early damage and delayed fibrosis.

Irradiated

Field

Tissue inside field

SCHEMATIC — NOT A CLINICAL / HISTOLOGIC SPECIMEN

Slide 5 · Core mechanistic contributors

Parenchymal-cell death removes functioning tissue.

Vascular damage produces chronic ischemic injury.

Stem-cell depletion limits tissue restitution.

Inflammatory signals stimulate fibroblasts and matrix synthesis.

Cell death

Ischemia

Stem-cell loss

Inflammatory cues

Fibrous replacement

Slide 6 · Why radiation injury outlasts treatment

DNA injury may immediately impair vulnerable cells.

Delayed microvascular remodeling progressively restricts perfusion.

Incomplete regeneration and continuing matrix deposition reshape tissue.

Exposure

Early cellular injury

Repair failure

Fibrotic remodeling

Slide 7 · Ionizing radiation and its cellular targets

Ionization removes tightly bound electrons from atoms.

DNA injury occurs through direct events and indirect free radicals.

Tissue injury depends on which cellular compartments survive.

Direct DNA interaction

Water radiolysis → radicals

Cellular damage

Slide 8 · Direct DNA injury

Ionizing radiation can damage DNA without an intervening radical.

Double-strand breaks are a particularly important lesion.

The outcome depends on DNA repair and cell-cycle responses.

Ionization

DNA lesions

Repair response

Survival or cell loss

Slide 9 · Indirect injury through water radiolysis

Radiolysis of water produces reactive free radicals.

Radical-mediated DNA damage is a prominent radiation effect.

This pathway provides a molecular start for tissue injury.

Ionizing energy

Radiolysis of water

Free radicals

DNA injury

Slide 10 · The influence of tissue oxygen

Oxygen enhances free-radical-mediated radiation injury.

Poorly oxygenated tissues are generally less radiosensitive.

Radiobiologic sensitivity cannot be inferred from fibrosis alone.

Well oxygenated

More effective radical-associated injury

Greater radiosensitivity in this mechanism

Poorly oxygenated

Lower radiation sensitivity

Hypoxia changes initial cell injury

Slide 11 · DNA damage has several downstream outcomes

Successful repair allows cells to survive and repopulate tissue.

Extensive or unrepaired injury can stop division or cause death.

Fibrosis is a tissue-level outcome of injury and failed restitution.

Survival and reconstitution

Cell death / regeneration failure

Tissue outcome

Slide 12 · Why proliferating cells are vulnerable

DNA replication magnifies the consequences of strand damage.

Bone marrow, lymphoid tissue and gut mucosa respond early.

Late fibrosis additionally reflects effects on vessels and stem cells.

Early response

Injury in actively cycling cells

Cell loss during rapid turnover

Delayed response

Vascular remodeling

Atrophy and connective-tissue replacement

Slide 13 · Regeneration requires a viable cell pool

Surviving differentiated cells and stem cells support restitution.

Radiation-mediated stem-cell loss diminishes replacement capacity.

The greater the regenerative deficit, the more relevant scar repair becomes.

Surviving stem cells

Parenchymal replacement

Irradiation depletes progenitors

Inadequate regeneration

SCHEMATIC — NOT A CLINICAL / HISTOLOGIC SPECIMEN

Slide 14 · Structural support also determines repair

Tissue architecture depends on viable cells and extracellular matrix.

Damage to support structures makes complete restitution difficult.

Collagenous repair fills a defect but does not recreate normal parenchyma.

Regeneration

Restores functional cellular components

Requires surviving regenerative capacity

Scarring

Connective tissue substitutes for lost structure

May compromise original function

Slide 15 · Early radiation-associated vascular change

Vessels may initially show dilation.

Endothelial swelling, vacuolation and degeneration can follow.

More severe injury may cause wall necrosis, rupture or thrombosis.

Open lumen

Early endothelial injury

Dilation → endothelial swelling → wall injury

SCHEMATIC — NOT A CLINICAL / HISTOLOGIC SPECIMEN

Slide 16 · Late vascular remodeling

Endothelial proliferation and intimal collagenous thickening develop.

Hyalinization narrows small-vessel lumens.

Marked narrowing or obliteration compromises local perfusion.

Thick intima

Chronic intimal sclerosis

Progressive lumen restriction

SCHEMATIC — NOT A CLINICAL / HISTOLOGIC SPECIMEN

Slide 17 · The vascular lumen is the decisive variable

Intimal collagen accumulates between endothelium and vessel wall.

The remaining lumen becomes smaller despite a thickened wall.

Less perfusion increases the vulnerability of irradiated parenchyma.

Open lumen

Thick intima

Before

Sclerotic

SCHEMATIC — NOT A CLINICAL / HISTOLOGIC SPECIMEN

Slide 18 · From vessel sclerosis to tissue ischemia

Vascular lumen loss restricts blood supply.

Chronic ischemia aggravates parenchymal atrophy and cell death.

Replacement fibrosis can then accumulate in the affected field.

Vessel narrowing

Reduced blood flow

Chronic ischemia

Parenchymal loss

Fibrosis

Slide 19 · Three injury routes converge

Direct parenchymal injury reduces cellular mass.

Microvascular sclerosis produces ischemic cell loss.

Stem-cell injury blocks effective restitution.

Direct cell loss

Ischemic loss

Poor regeneration

Scar-forming repair

Slide 20 · Time course: Early injury versus late injury

Cellular injury may appear hours to weeks after irradiation.

Fibrosis can emerge weeks or months after treatment.

Progressive vascular change and organ scarring may persist for years.

Hours–weeks

Weeks–months

Months–years

Slide 21 · Why scar tissue forms

Mammalian organs often cannot fully recreate damaged parenchyma.

Fibroblasts deposit extracellular matrix to stabilize a defect.

Structural repair is achieved at the expense of original architecture.

Nonrestorable defect

Fibroblast recruitment

Extracellular matrix

Scar

Slide 22 · Fibrosis is not synonymous with regeneration

Regeneration replaces lost tissue with appropriate cells.

Fibrosis replaces tissue with connective tissue.

The two responses can occur together but have different consequences.

Regeneration

Restitution of parenchyma

Closer to original tissue organization

Fibrosis

Collagen-rich replacement

May create contracture or impaired function

Slide 23 · Inflammatory cells recruit fibroblasts

Injury-associated inflammatory cells generate growth factors.

Macrophages are major sources of profibrotic mediators.

These signals promote fibroblast migration, proliferation and activation.

Tissue injury

Inflammatory cells

Growth factors

Fibroblast activation

Slide 24 · Recruitment precedes matrix production

Fibroblasts first migrate into the injured site and multiply.

Activated fibroblasts synthesize collagen and other matrix proteins.

Accumulation of these products creates the physical scar.

Recruitment

Proliferation

ECM secretion

Fibrous scar

Slide 25 · Growth factors organize connective-tissue repair

PDGF and FGF-2 contribute to fibroblast recruitment and proliferation.

TGF-β strongly promotes extracellular-matrix deposition.

The result is a coordinated but potentially excessive repair response.

PDGF

FGF-2

TGF-β

Fibroblast / ECM response

Slide 26 · TGF-β is central to connective-tissue deposition

Stimulates fibroblast migration and proliferation.

Increases synthesis of collagen and fibronectin.

Also reduces extracellular-matrix degradation.

Increased matrix synthesis

Reduced matrix clearance

Matrix accumulation

Slide 27 · Matrix accumulation is a balance

Fibrosis depends on more than collagen production alone.

Extracellular matrix is simultaneously synthesized and remodeled.

Disproportionate deposition favors persistent scarring.

Synthesis

Fibroblasts deposit collagen and fibronectin

TGF-β supports production

Degradation

Matrix metalloproteinases remodel ECM

TIMPs restrain metalloproteinases

Slide 28 · Myofibroblasts generate contraction

Some fibroblasts acquire actin-rich contractile features.

These myofibroblasts contribute to wound contraction.

In fixed anatomic spaces, contraction may distort local structures.

Fibroblast

Myofibroblast

Contractile force

Scar contraction

Slide 29 · Connective-tissue remodeling persists

Matrix metalloproteinases degrade selected ECM components.

Tissue inhibitors of metalloproteinases limit their activity.

Scar architecture reflects the balance between both systems.

MMP-mediated cleavage

TIMP-mediated inhibition

ECM remodeling balance

Slide 30 · Maturation produces a collagen-rich scar

Granulation tissue becomes less vascular as healing progresses.

Collagen persists while the vascular network regresses.

The resulting dense scar differs from the lost normal tissue.

Cell-rich repair

ECM deposition

Vascular regression

Mature scar

Slide 31 · Integrated pathogenesis of radiation fibrosis

Initial cell and endothelial injury initiate tissue loss.

Defective regeneration and cytokine signaling shift repair toward scar.

Collagen accumulation and contraction generate functional injury.

Cell damage

Microvascular injury

Inflammation

Fibroblasts → ECM → fibrosis

Slide 32 · The two major structural hallmarks

Thickened, narrowed or obliterated vessels.

Increased interstitial collagen with loss of normal parenchyma.

The two alterations reinforce impairment of tissue function.

Open lumen

Thick intima

Before

Sclerotic

SCHEMATIC — NOT A CLINICAL / HISTOLOGIC SPECIMEN

Slide 33 · Fibrosis changes the geometry of tissues

Scar tissue fills spaces previously occupied by functioning cells.

Contraction can pull neighboring structures together.

Adhesions may develop where surfaces heal through connective tissue.

Collagen-rich

Replacement

Schematic tissue remodeling

SCHEMATIC — NOT A CLINICAL / HISTOLOGIC SPECIMEN

Slide 34 · Microscopic radiation injury is not only fibrosis

Radiation may produce pleomorphic or multinucleated giant cells.

Nuclear swelling, chromatin changes and atypical mitoses can occur.

These features can resemble neoplastic atypia.

Radiation effect

Nuclear atypia and giant cells

Abnormal mitotic appearances

Diagnostic risk

Changes can mimic residual tumor

Clinical treatment history is essential

Slide 35 · The pathologist must integrate treatment history

Know whether the sampled tissue lies inside the radiation field.

Distinguish therapy-related atypia from persistent neoplasia.

Interpret scar, atypical cells and vascular injury together.

Prior irradiation

Field localization

Microscopic pattern

Contextual diagnosis

Slide 36 · Skin: Chronic radiation dermatitis

The textbook illustration describes epidermal atrophy.

Dermal fibrosis and subcutaneous vascular telangiectasia coexist.

The triad links epithelial, stromal and vascular damage.

Atrophic epidermis

Fibrotic dermis

Subcutaneous vessel change

SCHEMATIC — NOT A CLINICAL / HISTOLOGIC SPECIMEN

Slide 37 · Skin: Why the changes occur together

Epidermal loss reflects failure of epithelial maintenance.

Collagen deposition thickens the supporting dermal compartment.

Vascular abnormalities persist in damaged tissue.

Epidermal atrophy

Dermal fibrosis

Telangiectasia

Chronic radiation dermatitis

Slide 38 · Mediastinum: An example of extensive fibrosis

Radiotherapy can produce dense fibrous tissue in the mediastinum.

The Robbins illustration includes a markedly thickened pericardium.

Tissue planes may be replaced by constricting scar.

Collagen-rich

Replacement

Schematic tissue remodeling

SCHEMATIC — NOT A CLINICAL / HISTOLOGIC SPECIMEN

Slide 39 · Pericardial thickening is a structural clue

The mediastinal example places the pericardium within the scarred field.

Thickening reflects replacement or encasement by fibrous tissue.

Functional effects require organ-specific clinical evaluation.

Thoracic irradiation

Mediastinal repair

Pericardial thickening

Possible restriction

Slide 40 · Lung: A clinically important radiation target

Thoracic radiotherapy may involve lung, esophageal, breast or mediastinal tumors.

Injury typically affects lung tissue within the irradiated field.

Acute pneumonitis and chronic fibrosis are related patterns.

Irradiated

Field

Tissue inside field

SCHEMATIC — NOT A CLINICAL / HISTOLOGIC SPECIMEN

Slide 41 · Acute radiation pneumonitis

Presentation 1–6 months after irradiation.

Symptoms may include fever, dyspnea and pleural effusion.

Pulmonary infiltrates are part of the described clinical pattern.

Chest irradiation

1–6 months

Pneumonitis symptoms

Possible resolution

Slide 42 · Morphology of the pneumonitis phase

The described pattern includes diffuse alveolar damage.

Hyperplastic type II pneumocytes and fibroblasts may be atypical.

Epithelial atypia and vascular-wall foam cells support radiation effect.

Alveolar wall injury (simplified)

SCHEMATIC — NOT A CLINICAL / HISTOLOGIC SPECIMEN

Slide 43 · Some injured lungs progress to fibrosis

Acute inflammatory lung injury may resolve.

Other cases evolve into chronic radiation pneumonitis with fibrosis.

Fibrosis may also arise without a clinically recognized acute phase.

Resolution after pneumonitis

Progression / delayed fibrosis

Different clinical courses

Slide 44 · Fibrosis replaces functional alveolar architecture

Interstitial collagen increases as injury becomes chronic.

The simplified schematic shows loss of thin gas-exchange septa.

Reduced compliant lung tissue explains progressive functional limitation.

Thickened interstitium; Fewer thin septa

SCHEMATIC — NOT A CLINICAL / HISTOLOGIC SPECIMEN

Slide 45 · Severe chronic lung consequences

Chronic progressive fibrosis may cause cyanosis.

Pulmonary vascular consequences can include pulmonary hypertension.

Advanced disease may lead to cor pulmonale.

Pulmonary fibrosis

Vascular / gas exchange burden

Pulmonary hypertension

Cor pulmonale

Slide 46 · Acute and chronic lung injury differ

Feature

Acute radiation pneumonitis

Chronic radiation fibrosis

Timing

Usually 1–6 months

Delayed / progressive

Dominant process

Inflammatory alveolar injury

Interstitial collagen deposition

Morphology

DAD, type II cell atypia

Architectural scarring

Course

May resolve or progress

May be persistent / progressive

Slide 47 · Salivary glands: A recognized site

Head and neck radiotherapy may include salivary glands.

Radiation-related fibrosis can follow loss of glandular parenchyma.

Residual tissue function depends on the surviving compartments.

Head / neck field

Gland injury

Reduced regeneration

Glandular fibrosis

Slide 48 · Colorectal and pelvic irradiation

Radiotherapy for prostate, rectal or cervical cancer exposes pelvic tissues.

Fibrotic healing can occur within the irradiated pelvic field.

Scars and adhesions can alter normal relationships between structures.

Collagen-rich

Replacement

Schematic tissue remodeling

SCHEMATIC — NOT A CLINICAL / HISTOLOGIC SPECIMEN

Slide 49 · Gastrointestinal wall fibrosis is delayed

Early intestinal radiation injury primarily involves mucosal cells.

Late injury may produce fibrosis of the bowel wall.

This illustrates sequential epithelial loss and stromal replacement.

Mucosal injury

Impaired restitution

Wall fibrosis

Tissue distortion

Slide 50 · Obstructed lymphatics can follow irradiation

Postradiation fibrosis is a listed cause of secondary lymphedema.

Fibrosis can impair lymphatic drainage through obstructed channels.

Chronic edema may itself be followed by further ECM deposition.

Postradiation scar

Lymphatic obstruction

Distal edema

Tissue induration

Slide 51 · Organ pattern follows the treated field

Site

Recognized fibrotic change

Context

Lung

Interstitial pulmonary fibrosis

Thoracic radiotherapy

Salivary tissue

Gland fibrosis

Head and neck therapy

Mediastinum

Dense scar; pericardial thickening

Thoracic field

Colorectal / pelvis

Fibrosis; scars and adhesions

Prostate, rectal, cervical therapy

Slide 52 · Rate of radiation delivery modifies damage

Subdividing a total dose permits repair between exposures.

Fractionation limits injury when surviving normal cells recover.

Incomplete recovery may still lead to delayed tissue effects.

Single concentrated exposure

Less inter-fraction repair opportunity

Greater immediate injury at comparable context

Fractionated course

Intervals allow partial normal-tissue repair

Residual effects may accumulate

Slide 53 · Field size changes tissue consequences

The irradiated volume is a major determinant of biologic effects.

Smaller, shielded fields confine injury to less tissue.

Organ-specific consequences depend on what lies inside the field.

Irradiated

Field

Tissue inside field

SCHEMATIC — NOT A CLINICAL / HISTOLOGIC SPECIMEN

Slide 54 · Cell turnover and vascular injury act on different clocks

Rapidly dividing populations can show early tissue depletion.

Delayed vascular stenosis can appear months or years later.

Both mechanisms can contribute to the final fibrotic state.

DNA injury

Cell turnover effects

Vascular sclerosis

Late fibrosis

Slide 55 · The field and chronology support recognition

Confirm a compatible history of radiotherapy.

Map the abnormality to the treated anatomic territory.

Combine delayed timing with collagenous and vascular changes.

Treatment history

Spatial concordance

Temporal concordance

Tissue morphology

Slide 56 · Morphology must be interpreted as a pattern

Scar alone is not specific for radiation as the cause.

Atypical nuclei alone do not prove residual carcinoma.

Concordant vessel, parenchymal and stromal injury is more informative.

Insufficient alone

Collagen deposition

Radiation-like cytologic atypia

Better interpretation

Treatment field and timing

Vascular + stromal + cell findings

Slide 57 · Radiation fibrosis is distinct from carcinogenesis

Fibrosis follows tissue loss and connective-tissue repair.

Carcinogenesis results from persisting genomic alterations.

They are different late consequences of radiation exposure.

Cell death → scarring

Mutation persistence → tumor risk

Distinct late pathways

Slide 58 · Case: Dyspnea after thoracic radiotherapy

A patient develops dyspnea several months after chest irradiation.

Imaging shows abnormalities predominantly in the irradiated lung.

Which acute radiation-associated process is suggested?

CLINICAL REASONING

Which mechanism or diagnosis best fits the exposure, timing and tissue findings?

Answer and rationale in presenter notes

Slide 59 · Case interpretation: Pneumonitis is not fibrosis

Acute pneumonitis reflects an inflammatory/alveolar injury phase.

Some cases resolve; Others progress to chronic fibrosis.

Do not label every postradiotherapy opacity as established scar.

Pneumonitis

Inflammatory lung injury

Potentially reversible

Fibrotic sequela

Collagenous architectural replacement

May be persistent

Slide 60 · Case: Thickened tissue after thoracic radiation

A post-treatment specimen shows fibrous mediastinal tissue.

The pericardium is markedly thickened.

Which tissue-level mechanisms explain this pattern?

CLINICAL REASONING

Which mechanism or diagnosis best fits the exposure, timing and tissue findings?

Answer and rationale in presenter notes

Slide 61 · Case interpretation: Mediastinal fibrosis

Location within the treated field supports therapy-related injury.

Vascular sclerosis and collagen deposition account for the scar.

Any functional consequence should be assessed clinically.

Past radiation

Vascular / tissue damage

Fibrous replacement

Pericardial thickening

Slide 62 · Case: Atypical cells in an irradiated specimen

A biopsy contains bizarre enlarged and multinucleated cells.

The tissue was previously treated with ionizing radiation.

Why is tumor persistence not inferred from atypia alone?

CLINICAL REASONING

Which mechanism or diagnosis best fits the exposure, timing and tissue findings?

Answer and rationale in presenter notes

Slide 63 · Case interpretation: Avoid an attribution error

Recognize radiation-associated cellular atypia as a mimic.

Search for an adequately supported neoplastic pattern.

Treatment history changes interpretation of cellular morphology.

Observed atypia

Pleomorphism or giant cells

Unusual nuclear appearances

Additional information needed

Prior radiation field and timing

Architecture and other tumor evidence

Slide 64 · Synthesis: Tissue injury becomes scar

Parenchymal loss and blocked regeneration create a defect.

Damaged vessels sustain ischemia and impair repair.

Profibrotic signaling promotes fibroblasts, collagen and contraction.

Cellular loss

Microvascular ischemia

Profibrotic signaling

Radiation-induced fibrosis

Slide 65 · High-yield distinctions

Distinction

Interpretive principle

Fibrosis vs regeneration

ECM replacement vs restoration of tissue-specific cells

Early vs late radiation effects

Cell loss often precedes sclerosis and interstitial scar

Pneumonitis vs lung fibrosis

Acute alveolar injury vs chronic architectural replacement

Radiation atypia vs tumor

Microscopy requires treatment and tissue-context correlation

Slide 66 · Final learning check

What three injury processes promote delayed radiation fibrosis?

How does TGF-β influence extracellular matrix?

Why can radiation-related cellular atypia complicate diagnosis?

Slide 67 · Selected textbook sources

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

Chapter 9: radiation injury and fibrosis (pp. 390–394).

Chapter 3: connective-tissue deposition and remodeling (pp. 93–97).

Chapter 15: radiation-induced lung diseases (p. 634).