Fibrous Tumors

Slide 1 · Fibrous Tumors

Pediatric fibromatosis and infantile fibrosarcoma

Morphology · molecular pathogenesis · clinicopathologic reasoning

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Distinguish fibromatosis from infantile fibrosarcoma.

Connect spindle-cell morphology to biologic behavior.

Explain ETV6::NTRK3–driven kinase signaling.

Integrate morphology, molecular findings, prognosis, and treatment relevance.

Slide 3 · Fibrous lesions in childhood

Pediatric soft-tissue masses commonly arise from mesenchymal tissues.

Fibrous tumors are thought to derive from fibroblasts or myofibroblasts.

The category spans relatively hypocellular lesions and cellular sarcomatous tumors.

Tumor name, age, and biologic context modify morphologic interpretation.

Slide 4 · Cell lineage and lesion spectrum

Mesenchymal tissue

Fibroblastic / myofibroblastic proliferation

Fibrous tumor phenotype

Cell lineage provides context; It is not sufficient for a specific diagnosis.

Slide 5 · What do fibroblasts and myofibroblasts imply?

Fibroblast-associated features

Spindle-shaped stromal cells

Synthesis and organization of fibrous matrix

Collagen-rich lesions may appear hypocellular

Myofibroblast-associated features

Fibroblastic lineage with contractile phenotype

Contributes to tissue remodeling

Myofibroblastic proliferations may resemble scars

Slide 6 · The pediatric fibrous tumor spectrum

Feature

Fibromatosis

Infantile fibrosarcoma

Cellularity

Relatively sparse

Relatively rich

Cell shape

Spindle shaped

Spindle shaped

Histology

Fibroblastic proliferation

Adult-fibrosarcoma-like

Interpretation

Context-dependent behavior

Often excellent prognosis despite appearance

Slide 7 · Low cellularity: Conceptual architecture

Schematic—not an H&E photomicrograph

Relatively few spindle cells

Prominent intervening fibrous matrix

Illustrates low cellularity—not a diagnostic image

Slide 8 · High cellularity: Conceptual architecture

Schematic—not an H&E photomicrograph

Numerous spindle-shaped cells

Less matrix between neighboring cells

Cellularity alone does not establish clinical risk

Slide 9 · Morphologic resemblance is not equivalence

Observed on a slide

Spindle-cell density

Fascicular arrangement

Amount of extracellular matrix

Beyond the slide

Patient age and anatomic site

Clinical course and growth behavior

Entity-defining molecular alterations

Slide 10 · Why histology alone can mislead

A fibrous lesion in an infant appears strikingly cellular and resembles an adult fibrosarcoma. What can be concluded from the resemblance?

Morphologic similarity alone does not establish adult-type clinical prognosis.

Slide 11 · Fibromatosis: Defining pattern

A sparsely cellular spindle-cell proliferation under the fibromatosis label.

The fibrous matrix forms a conspicuous component of the lesion.

Different anatomic and clinical forms of fibromatosis have distinct natural histories.

The term fibromatosis does not automatically mean a clinically insignificant lesion.

Slide 12 · Fibromatosis: Spindle cells within matrix

Schematic—not an H&E photomicrograph

Relatively few spindle cells

Prominent intervening fibrous matrix

Illustrates low cellularity—not a diagnostic image

Slide 13 · Why collagen matters to morphology

Fibroblastic proliferations may elaborate abundant dense collagen.

In collagen-rich lesions, the cell-to-matrix ratio is low.

A bland spindle-cell lesion may resemble a scar.

Tissue architecture and growth interface aid interpretation.

Slide 14 · Fibromatosis: Anatomic and clinical forms

Form

Typical description

Clinical behavior

Superficial

Fascial / subcutaneous; collagenous

Usually indolent

Deep (desmoid)

Musculoaponeurotic or mesenteric

Infiltrative and locally recurrent

Slide 15 · Superficial fibromatosis: Named syndromes

Name

Anatomic site

Key consequence

Dupuytren

Palmar fascia

Progressive flexion contracture

Ledderhose

Plantar fascia

Nodularity; typically no contracture

Peyronie

Penile fascia

Curvature or urethral narrowing

Slide 16 · Palmar fibromatosis: Fascial contracture

Irregular or nodular thickening arises in palmar fascia.

Adherence to overlying skin may cause puckering or dimpling.

Progressive flexion contracture reflects tissue distortion.

This is contextual fibromatosis morphology, not a claim of pediatric predominance.

Slide 17 · Plantar fibromatosis in younger patients

Ledderhose disease occurs from childhood into adolescence.

Robbins specifically describes boys younger than 10 years through adolescence.

Lesions are often unilateral and do not cause contractures.

Association with palmar or penile fibromatosis may occur.

Slide 18 · Penile fibromatosis: Structure and effect

Peyronie disease produces palpable induration or a mass.

It affects the dorsolateral penile region.

Fibrosis may cause shaft curvature or urethral constriction.

The example illustrates structure–function consequences of collagenous proliferation.

Slide 19 · Superficial fibromatosis: Sweeping fascicles

Schematic—not an H&E photomicrograph

Fascicular organization

Bland spindle-cell appearance

Architectural pattern requires clinical context

Slide 20 · Clinical course of superficial fibromatoses

Some palmar and plantar fibromatoses progressively enlarge.

Others stabilize or may regress spontaneously.

Anatomic location determines functional consequences.

Histologic blandness should not be confused with absence of morbidity.

Slide 21 · Deep fibromatosis: Local aggression without metastasis

Infiltrative fibrous growth

Entrapment of adjacent tissues

Local pain / dysfunction / recurrence

Desmoid-type fibromatosis can recur without acquiring metastatic potential.

Slide 22 · Deep fibromatosis: Clinical context

Deep lesions arise in musculoaponeurotic structures.

Adolescents and young adults, particularly females.

Common locations include abdominal wall, limb girdles, and mesentery.

This entity broadens the fibromatosis differential beyond the infantile subset.

Slide 23 · Deep fibromatosis: Macroscopic appearance

Firm, gray-white, collagen-rich mass.

Poorly demarcated margins suggest infiltration.

The lesion may involve skeletal muscle, fat, or nerve.

Gross appearance correlates with difficult complete excision.

Slide 24 · Deep fibromatosis: Collagen and bland spindle cells

Schematic—not an H&E photomicrograph

Fascicular organization

Bland spindle-cell appearance

Architectural pattern requires clinical context

Slide 25 · Infiltration explains local recurrence

Bland-appearing spindle cells

Growth through muscle and fat

Residual microscopic disease may remain

The key aggressive feature is local extension rather than distant spread.

Slide 26 · Locally aggressive versus metastatic behavior

Feature

Desmoid-type fibromatosis

Metastatic sarcoma

Growth

Infiltrative

May infiltrate

Recurrence

Can recur after local treatment

May recur

Metastasis

Does not metastasize

May metastasize

Primary danger

Local morbidity

Local and distant disease

Slide 27 · Deep fibromatosis: Wnt pathway context

APC or CTNNB1 alteration

Increased Wnt signaling

Fibroblastic tumor growth

Most deep fibromatoses are associated with sporadic CTNNB1 alterations.

Slide 28 · CTNNB1 and APC: Genetic settings

Sporadic deep fibromatosis

CTNNB1 mutation described in most lesions

Increased Wnt signaling

Molecular context differs from infantile fibrosarcoma

Hereditary predisposition

Germline APC variants underlie familial adenomatous polyposis

Associated desmoid susceptibility

Gardner syndrome is the relevant phenotype

Slide 29 · Why a desmoid tumor is not simply a scar

A desmoid is a clonal fibroblastic neoplasm.

It may be poorly circumscribed and infiltrate adjacent structures.

Local recurrence is a clinically significant feature.

Its bland collagen-rich histology can overlap with scar-like tissue.

Slide 30 · Scar, nodular fasciitis, and desmoid

Feature

Excessive scar

Nodular fasciitis

Desmoid

Process

Repair-related

Self-limited clonal proliferation

Infiltrative neoplasm

Architecture

Dense collagen

Loose / tissue-culture-like

Long fascicles; dense collagen

Course

May stabilize

Typically self-limited

Locally recurrent

Slide 31 · Nodular fasciitis: Diagnostic comparator

A fibroblastic and myofibroblastic proliferation.

Often rapidly enlarges over weeks to months.

Generally self-limited despite brisk growth.

May be mistaken for a more aggressive spindle-cell neoplasm.

Slide 32 · Nodular fasciitis: Microscopic cues

Feature

Reported appearance

Cells

Plump spindle-shaped fibroblasts / myofibroblasts

Pattern

Loose tissue-culture-like growth

Mitoses

Can be frequent, but atypical forms absent

Stroma

Myxoid regions with zonation to fibrous areas

Slide 33 · MYH9::USP6 supports clonality

Acquired MYH9::USP6 fusion

Clonal spindle-cell proliferation

Self-limited clinical course

Clonality does not necessarily imply a highly aggressive clinical phenotype.

Slide 34 · Three fibrous patterns to distinguish

Entity

Cellularity / matrix

Behavioral clue

Fibromatosis

Bland spindle cells, fibrous matrix

Superficial indolence or deep infiltration

Nodular fasciitis

Plump spindled cells, often myxoid

Rapidly growing yet self-limited

Infantile fibrosarcoma

Cell-rich spindle-cell lesion

Favorable pediatric outcome despite sarcomatous morphology

Slide 35 · Infantile fibrosarcoma: Defining contrast

A richly cellular spindle-cell neoplasm of infancy and childhood.

Can be histologically indistinguishable from adult fibrosarcoma.

Nevertheless, it generally has an excellent prognosis.

The contrast exemplifies why age and molecular context matter.

Slide 36 · Infantile fibrosarcoma: Cellular spindle cells

Schematic—not an H&E photomicrograph

Numerous spindle-shaped cells

Less matrix between neighboring cells

Cellularity alone does not establish clinical risk

Slide 37 · Interpreting a cellular spindle-cell lesion

Identify elongated spindle-shaped tumor cells.

Assess cellularity relative to collagenous matrix.

Describe arrangement and cytologic features without overclaiming risk.

Integrate clinical and molecular evidence before final classification.

Slide 38 · Adult-like appearance, different outcome

Histologic correspondence

Both may show densely cellular spindle-cell areas

Microscopy alone can appear similar

A malignant-looking pattern raises a diagnostic question

Biologic divergence

Infantile fibrosarcoma generally has a favorable prognosis

Clinical course cannot be extrapolated from adult histology

Fusion status provides entity-specific evidence

Slide 39 · The diagnostic paradox

A pathologist sees a highly cellular fascicular tumor in an infant. Its microscopic appearance resembles adult fibrosarcoma. What additional evidence is particularly informative?

Evaluate the possibility of ETV6::NTRK3-driven infantile fibrosarcoma.

Slide 40 · Chromosomal rearrangement creates a fusion

T(12;15) rearrangement

ETV6::NTRK3 fusion transcript

Chimeric kinase protein

Fusion identity is the central diagnostic concept; Band-level notation is secondary.

Slide 41 · ETV6: The transcription-factor partner

ETV6 normally encodes a transcription factor.

The chromosomal rearrangement brings ETV6 into a fusion transcript.

This alters the functional context of the partnered kinase.

The relevant oncogenic entity is the fusion, not ordinary ETV6 expression.

Slide 42 · NTRK3: A tyrosine-kinase partner

NTRK3 encodes the kinase also called TRKC.

Tyrosine-kinase signaling ordinarily depends on regulated activation.

The ETV6::NTRK3 fusion generates a constitutively active kinase.

The kinase moiety supplies a pharmacologically targetable vulnerability.

Slide 43 · From gene fusion to protein function

ETV6 and NTRK3 gene segments

ETV6::NTRK3 fusion protein

Persistent oncogenic kinase activity

A fusion product acquires properties not conveyed by either normal gene name alone.

Slide 44 · ETV6::NTRK3 activates two signaling branches

ETV6::NTRK3 fusion

Constitutive tyrosine kinase signaling

RAS → MAPK

PI3K → AKT

Both branches transmit oncogenic growth signals

Slide 45 · RAS–MAPK branch of the fusion signal

ETV6::NTRK3 kinase activity

RAS–MAPK signaling

Pro-oncogenic signaling output

This is a pathway-level schematic, not an exhaustive reaction mechanism.

Slide 46 · PI3K–AKT branch of the fusion signal

ETV6::NTRK3 kinase activity

PI3K / AKT signaling

Pro-oncogenic signaling output

The Robbins excerpt identifies pathway activation but not a complete molecular cascade.

Slide 47 · Fusion biology: What is and is not established

Supported by the source

The fusion is a characteristic molecular event

The chimeric kinase is constitutively active

RAS–MAPK and PI3K/AKT pathways are stimulated

Do not infer without evidence

Every spindle-cell tumor carries this fusion

Morphology predicts targetable mutation status

A particular response percentage applies to all patients

Slide 48 · Diagnostic value of ETV6::NTRK3

Finding

Interpretation

Compatible pediatric spindle-cell tumor

Raises suspicion for infantile fibrosarcoma

ETV6::NTRK3 identified

Strong molecular support in appropriate context

Cellularity without fusion information

Does not resolve the entity by itself

Fusion in an unexpected setting

Requires site-specific diagnostic correlation

Slide 49 · Fusion testing: Evidence from an open case report

A published neonatal case used ETV6 break-apart FISH.

Fusion testing by sequencing demonstrated ETV6::NTRK3.

The molecular result was interpreted alongside biopsy morphology.

An ETV6 rearrangement is not identical to full fusion-partner identification.

Slide 50 · Integrated interpretation of a pediatric mass

Clinical age / site

Spindle-cell morphology

Molecular characterization

Clinicopathologic classification

The sequence is conceptual; Local diagnostic workflows vary.

Slide 51 · Fibromatosis versus infantile fibrosarcoma

Feature

Fibromatosis spectrum

Infantile fibrosarcoma

Dominant structure

Spindle cells + collagenous matrix

Densely cellular spindle cells

Risk inference

Depends on subtype and location

Adult-like histology may overstate risk

Molecular context

Wnt alterations in desmoid subset

Characteristic ETV6::NTRK3 fusion

Distinctive issue

Local infiltration in desmoid

Targetable kinase fusion

Slide 52 · Prognosis requires pediatric context

Infantile fibrosarcoma generally has an excellent prognosis.

Adult fibrosarcoma resemblance should not be used as a prognostic shortcut.

The diagnostic distinction has direct clinical implications.

A molecularly grounded diagnosis helps avoid misleading assumptions.

Slide 53 · Kinase dependence suggests targeted treatment

ETV6::NTRK3 oncoprotein

NTRK-directed pharmacologic inhibition

Antitumor response

Dramatic responses in previously unresectable ETV6::NTRK3-positive disease.

Slide 54 · NTRK inhibitors: Disease-specific relevance

The oncogenic fusion encodes an active tyrosine kinase.

Selective NTRK inhibition targets this molecular mechanism.

Dramatic antitumor responses in selected unresectable cases.

A fusion-directed therapy illustrates the link from pathology to treatment.

Slide 55 · Molecular finding changes clinical reasoning

Without fusion information

Histologic spindle-cell neoplasm may be ambiguous

Cellularity may suggest adult-type risk incorrectly

A therapeutic vulnerability may remain unrecognized

With ETV6::NTRK3 evidence

Supports an appropriate infantile fibrosarcoma diagnosis

Defines a kinase-driver mechanism

Provides a rationale for NTRK inhibitor consideration

Slide 56 · Why unresectable disease matters

Mass location and local extension can limit surgical options.

Robbins specifically describes previously unresectable infantile fibrosarcoma.

Targeted treatment offers a biologically rational alternative in fusion-positive tumors.

Treatment selection requires multidisciplinary clinical assessment.

Slide 57 · Treatment does not redefine morphology

An infantile fibrosarcoma responds dramatically to an NTRK inhibitor. Does treatment response mean that the original lesion was histologically benign?

No. Treatment response reflects the actionable oncogenic driver, not reclassification as a benign lesion.

Slide 58 · Case exercise: Collagen-rich lesion

A patient has a firm, poorly demarcated lesion with bland spindle cells and abundant dense collagen infiltrating skeletal muscle. What biologic behavior is especially important?

Consider deep fibromatosis: Locally infiltrative behavior and risk of recurrence.

Slide 59 · Case exercise: Rapidly growing spindle mass

A rapidly enlarging soft-tissue nodule has plump spindle cells, a loose myxoid background, frequent nonatypical mitoses, and zonation. Which comparator is important?

Nodular fasciitis; Correlate with clinical behavior and MYH9::USP6-related clonality.

Slide 60 · Case exercise: Tumor in an infant

A neonatal mass has highly cellular spindle-cell morphology and molecular testing identifies ETV6::NTRK3. What entity best fits this combined profile?

Infantile fibrosarcoma, in the appropriate anatomic and clinicopathologic context.

Slide 61 · Case exercise: Treatment linkage

A molecularly confirmed ETV6::NTRK3-positive infantile fibrosarcoma is not amenable to resection. What mechanism supplies a therapeutic rationale?

Constitutive NTRK kinase signaling creates a target for selective NTRK inhibition.

Slide 62 · Final diagnostic synthesis

Observation

Key question

Useful evidence

Hypocellular / collagen-rich

Which fibromatosis subtype?

Site, margins, clinical behavior

Bland but infiltrative

Could this be desmoid?

Growth interface; CTNNB1/APC context

Rapidly growing myxoid

Could this be nodular fasciitis?

Zonation; MYH9::USP6 context

Cell-rich infantile tumor

Could this be infantile fibrosarcoma?

Age, histology, ETV6::NTRK3

Slide 63 · Core distinctions for practice

Fibromatoses

Spindle-cell proliferations with variable collagen

Superficial lesions may remain indolent

Deep desmoids infiltrate and recur but do not metastasize

Infantile fibrosarcoma

Histologically resembles adult fibrosarcoma

Generally much better prognosis

ETV6::NTRK3 provides molecular support and an actionable target

Slide 64 · Five clinical–pathologic checkpoints

Identify the patient’s age and lesion site.

Describe spindle cells, cellularity, collagen, and tissue interface.

Distinguish locally aggressive growth from metastatic risk.

Use entity-specific molecular alterations for classification.

Link a verified kinase fusion to treatment relevance.

Slide 65 · Selected references

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed. Elsevier; 2026.

Source scope: pediatric soft-tissue neoplasms, fibromatosis, infantile fibrosarcoma, and related fibrous lesions.

Wang D, Zhang F, Feng W, Pan J, Yuan T. Front Oncol. 2023;13:1206833. doi:10.3389/fonc.2023.1206833.

The lecture includes original schematic morphology diagrams; these are not authentic histopathology images.