Malignant Lesions of Interlobular Stroma

Slide 1 · Malignant Lesions of

Interlobular Stroma

Breast stromal pathology, with emphasis on angiosarcoma

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Diagnose the problem by tissue compartment, vascular lineage, and clinical setting.

Distinguish intralobular biphasic tumours from purely stromal lesions.

Contrast primary and secondary breast angiosarcomas.

Recognize the histologic and endothelial-marker patterns.

Use MYC testing appropriately and identify major mimics.

Slide 3 · Two stromal compartments of the breast

Intralobular stroma

Interlobular stroma

Gland-associated,

Cellular specialized stroma

Connective tissue between

Lobules and ducts

Slide 4 · Stromal tumours: The two anatomical groups

Intralobular

Fibroadenoma and phyllodes tumour

Biphasic: Neoplastic stroma plus entrapped non-neoplastic epithelium

Architecture commonly incorporates ducts

Interlobular

Mesenchymal lesions analogous to those at other body sites

No required accompanying epithelial component

Includes lipoma, fibromatosis, and angiosarcoma

Slide 5 · Separating epithelial and stromal components

Breast lesion

Start with architecture

Biphasic pattern

Look for ducts in stromal proliferation

Pure stromal lesion

Classify the mesenchymal lineage

Phyllodes tumour belongs to intralobular stroma even when its stromal component is malignant.

Slide 6 · Interlobular tumour spectrum

Behaviour

Examples

Key distinguishing point

Benign

Lipoma; Myofibroblastoma

Adipocytic or myofibroblastic lesions

Locally aggressive

Fibromatosis

Infiltrative but non-metastasizing

Malignant

Angiosarcoma

Malignant endothelial neoplasm; Poor prognosis

Slide 7 · Cell lineage determines the diagnostic route

Mesenchymal breast lesion

Identify the proliferating cell population

Vascular endothelial lineage

Irregular blood-filled channels; Endothelial IHC

Angiosarcoma

Malignant endothelial growth; Infiltrative architecture

Slide 8 · What is angiosarcoma?

A malignant tumour showing vascular endothelial differentiation.

In breast, it is the most frequent sarcoma discussed under interlobular-stromal malignancy.

It may arise without prior breast therapy or develop after radiation / chronic lymphedema.

Its appearance ranges from recognizable vascular channels to high-grade solid growth.

Slide 9 · Rarity in the breast

< 0.05%

Robbins: Angiosarcoma among all breast malignancies; Exceedingly uncommon.

Slide 10 · Primary and secondary disease are distinct clinical contexts

Primary (sporadic)

No prior radiation required

Often a parenchymal mass

Usually presents at a younger age

Secondary (therapy-associated)

Occurs after breast cancer treatment

Typically affects dermis and subcutis

Prior irradiation or chronic lymphedema is important

Slide 11 · Primary angiosarcoma: Typical clinical sequence

No antecedent therapy

Sporadic setting

Parenchymal lesion

Deep breast mass

Diagnostic biopsy

Vascular architecture + endothelial immunophenotype

Slide 12 · Age profile in primary disease

Mean age: 35 years

Sporadic breast angiosarcoma mainly in young females.

Slide 13 · Primary angiosarcoma: Presentation

A parenchymal mass may be the first clue.

Reported cases may present as a palpable, sometimes enlarging breast mass.

Mammography may be nonspecific in young patients with dense breast tissue.

A bland-appearing vascular core biopsy does not automatically indicate a benign lesion.

Slide 14 · Radiation-associated angiosarcoma: Path to recognition

Treated breast cancer

Breast-conserving treatment + irradiation

Long interval

Years may pass

New skin lesion

Violaceous area, papule, plaque, or nodule

Slide 15 · Post-treatment anatomy directs clinical suspicion

The irradiated skin is often the first affected tissue.

Secondary lesions typically begin in dermis and subcutis rather than deep parenchyma.

Discoloration or a skin plaque can be the primary presentation without a dominant breast mass.

A new skin change in the radiation field requires clinicopathologic attention.

Slide 16 · Lymphedema-associated disease (Stewart–Treves)

Breast-cancer therapy

May cause chronic lymphedema

Longstanding edema

Altered lymphatic environment

Cutaneous angiosarcoma

Secondary vascular malignancy

Stewart–Treves is a clinical association, not a histologic subtype defined by one stain.

Slide 17 · Latency after radiotherapy

5–10 years

Robbins: Most radiation-associated breast angiosarcomas are diagnosed in this interval.

Slide 18 · Absolute risk after breast irradiation

~0.3%

Textbook estimate; Estimates vary across populations and studies.

Slide 19 · Cutaneous warning patterns after radiation

Bruise-like patch

A violaceous or erythematous discoloured area.

Raised papule / plaque

May be multifocal in an irradiated field.

Nodular lesion

Can indicate progressively bulky disease.

Subtle early disease

Skin changes can resemble benign post-therapy effects.

Slide 20 · Gross and macroscopic features

Vascular nature helps explain hemorrhagic appearance.

Lesions may be red-purple and poorly circumscribed.

Cut surfaces can be hemorrhagic, friable, or contain blood-filled spaces.

Gross appearance alone cannot determine grade or distinguish the main vascular mimics.

Slide 21 · The underlying vasoformative architecture

Conceptual schematic — not a histologic specimen

Recognizable channels

Irregular vasoformation

Invasive growth still matters

Slide 22 · Anastomosing vascular channels dissect tissue

Conceptual schematic — not a histologic specimen

Branching and anastomosis

Stromal and fat infiltration

Endothelial lining is abnormal

Slide 23 · Endothelial atypia: What the pathologist assesses

Nuclear change

Hyperchromasia, pleomorphism and conspicuous nucleoli.

Growth organisation

Single layers versus stratified endothelial cells.

Mitotic activity

Proliferation supports malignancy in context.

Infiltrative pattern

Dissection through breast stroma and fat is a major clue.

Slide 24 · Tufting and endothelial multilayering

Conceptual schematic — not a histologic specimen

Intermediate morphology

Endothelial stratification

Tufting and nuclear atypia

Slide 25 · High-grade angiosarcoma can appear solid

Conceptual schematic — not a histologic specimen

Poorly differentiated

Solid or spindle-cell growth

Endothelial IHC may be essential

Slide 26 · A spectrum of endothelial differentiation

Well-formed channels

Irregular lumina remain recognizable

May show only modest cytologic atypia

Deep infiltration remains critical

Intermediate architecture

Layering and tufting become conspicuous

Increasing atypia and mitotic activity

Both vascular and solid areas may coexist

Poorly differentiated

Sheets of epithelioid or spindle cells

Blood lakes, hemorrhage and necrosis

Endothelial IHC is often decisive

Slide 27 · Features that favour aggressive biology

Tissue invasion

Growth penetrates adjacent stroma or adipose tissue.

Cellular atypia

Pleomorphism beyond a reactive endothelial response.

Mitotic figures

Cell division may be numerous in high-grade areas.

Necrosis or blood lakes

Often encountered in less differentiated tumours.

Slide 28 · Primary versus secondary: Morphologic tendency

Primary angiosarcoma

Broader morphologic spectrum

Low-, intermediate-, and high-grade differentiation

Often centred in breast parenchyma

Radiation-associated

Often high-grade and multifocal

Dermal / subcutaneous distribution

Prominent solid, spindle, or hemorrhagic foci

Slide 29 · Secondary lesions may be multicentric

Sample beyond the dominant visible focus.

Small lesions or peripheral regions may look less atypical than the main tumour.

Diffuse cutaneous involvement may exceed the area visible clinically.

Patchy vasoformation requires thoughtful tissue sampling.

Slide 30 · Core-biopsy pitfall in primary angiosarcoma

Small fragment

Only bland-looking channels sampled

Missed architecture

Infiltrative interface absent

Need integration

Imaging, deeper levels, IHC and multidisciplinary review

A low-grade-looking vascular core is not proof of benignity.

Slide 31 · Features to report in a vascular biopsy

Feature

Diagnostic meaning

Infiltrative interface

Evaluate dissection of native stroma or fat

Vasoformation

Describe anomalous anastomosing channels

Endothelial atypia

Note distribution and degree

Cellularity / mitoses

Document foci of increased proliferation

Solid / necrotic foci

May indicate high-grade component

Slide 32 · Immunophenotype: Establish endothelial differentiation

Suspicious lesion

Vascular spaces or solid tumour

Endothelial stains

CD31 and nuclear ERG

Integrated diagnosis

Interpret alongside growth pattern and clinical setting

Marker positivity is supportive; It is not sufficient to establish malignancy.

Slide 33 · CD31: An endothelial-lineage marker

Membranous and cytoplasmic CD31 helps identify tumour endothelial cells.

Useful in vasoformative and poorly differentiated areas.

Interpret distribution and morphology rather than staining alone.

A confirmed endothelial phenotype does not distinguish benign from malignant vascular growth.

Slide 34 · ERG: A nuclear endothelial marker

ERG complements CD31 in difficult lesions.

Nuclear labelling helps localize the neoplastic endothelial population.

Particularly helpful when vasoformation is subtle.

A panel and morphologic review remain necessary; ERG is not a malignancy-specific stain.

Slide 35 · Auxiliary endothelial markers and their limits

CD34

Can highlight vascular differentiation

Sensitivity varies by tumour area and grade

Not specific to angiosarcoma

FLI1 / factor VIII

Can support endothelial lineage

May be used with CD31 and ERG

No single stain substitutes for morphology

Slide 36 · Cytokeratin is not an absolute exclusion test

A subset of angiosarcomas may express cytokeratin.

Solid/epithelioid angiosarcoma can mimic carcinoma.

A broad epithelial panel may be positive in a minority of cases.

Endothelial markers and the spatial growth pattern resolve the differential.

Slide 37 · Diagnostic IHC: Clinical question versus interpretation

Marker / method

Main use

Important limitation

CD31; ERG

Confirm endothelial differentiation

Also mark non-malignant endothelium

CD34; FLI1

Additional vascular support

Not diagnostic in isolation

Pan-cytokeratin

Assess epithelial differentiation

Some angiosarcomas express keratin

MYC IHC / FISH

Support radiation-associated disease

Negative result does not exclude all cases

Slide 38 · Secondary angiosarcoma: Hallmark alteration

MYC amplification

High-level MYC amplification in >90% of secondary cases.

Slide 39 · How MYC amplification may be demonstrated

Suspicious irradiated skin lesion

History + morphology

MYC protein IHC

Supportive screening adjunct

MYC FISH

Interrogate gene amplification in tissue

MYC amplification supports the diagnostic context but does not replace histologic assessment.

Slide 40 · MYC: The crucial interpretive nuance

High-level amplification is strongly associated with secondary angiosarcoma.

Use the result as diagnostic support in a lesion arising after radiation or lymphedema.

Strong diffuse MYC IHC is more convincing than isolated weak staining.

Primary tumours may show variable MYC expression; Clinical history is essential.

Slide 41 · A MYC-negative sample cannot rule out angiosarcoma

Morphology and sampling can override a negative ancillary result.

Not all secondary cases show the classic amplified profile in every published series.

Biopsy may undersample heterogeneous or invasive components.

Reassess tumour extent and degree of atypia if clinical concern persists.

Slide 42 · Postradiation atypical vascular lesion (AVL)

Typical setting

Arises in irradiated breast skin

Can appear as a small vascular proliferation

May mimic an early angiosarcoma

Reasons for caution

Limited biopsy may miss infiltrative tumour

Cytologic atypia may overlap

MYC supports, but does not replace, morphology

Slide 43 · AVL versus radiation-associated angiosarcoma

Criterion

Atypical vascular lesion

Angiosarcoma

Depth

Usually superficial dermal

May infiltrate deeply / subcutis

Atypia

Limited or focal

More pronounced, possibly variable

Growth

More restricted architecture

Infiltrative / anastomosing channels

MYC status

Usually no amplification

Frequently amplified

Slide 44 · Primary versus secondary breast angiosarcoma

Domain

Primary

Secondary

Typical patient

Younger; No prior therapy

Older; Breast therapy / lymphedema

Usual focus

Breast parenchyma

Skin and subcutaneous tissues

Morphology

Variable differentiation

Often high-grade and multifocal

Molecular clue

No characteristic MYC amplification pattern

Frequent high-level MYC amplification

Slide 45 · Malignant phyllodes versus breast angiosarcoma

Diagnostic domain

Malignant phyllodes

Angiosarcoma

Compartment

Intralobular

Interlobular

Epithelial component

Present, possibly focally sampled

No intrinsic biphasic epithelium

Stromal pattern

Leaf-like fibroepithelial lesion

Vasoformative endothelial lesion

Diagnostic strategy

Extensive search for epithelial clefts

Vascular morphology + endothelial IHC

Slide 46 · Other interlobular lesions are not angiosarcoma

Fibromatosis

Clonal fibroblast–myofibroblast proliferation

May infiltrate muscle

Locally aggressive but does not metastasize

Myofibroblastoma

Myofibroblastic interlobular tumour

Not a vascular endothelial neoplasm

Can occur in either sex

Lipoma

Mature adipocytic lesion

Can be palpable or radiologically apparent

Vascular atypia is not the defining pattern

Slide 47 · Angiosarcoma versus epithelial carcinoma

Consider carcinoma when

Definitive ductal/glandular epithelial architecture

Epithelial immunophenotype dominates

No convincing malignant endothelial network

Consider angiosarcoma when

Dissecting, atypical blood-filled spaces

Tumour cells express CD31 / nuclear ERG

Skin lesion follows irradiation or lymphedema

Slide 48 · Practical diagnostic workflow

Clinical map

Prior radiotherapy? Skin or parenchymal lesion?

Microscopic map

Invasion, vasoformation, atypia, necrosis

Ancillary tests

CD31/ERG ± MYC IHC and FISH

Expert review and sampling adequacy remain crucial when stains and morphology are discordant.

Slide 49 · Imaging findings: Supportive, not pathognomonic

Imaging determines site and extent; Histology establishes the diagnosis.

Primary lesions may be mammographically nonspecific or occult.

Radiation-associated lesions can manifest as skin thickening and abnormal enhancement.

Ultrasound or magnetic resonance imaging may help target suspicious tissue for biopsy.

Slide 50 · Why diagnosis may be delayed

Low prior probability

Angiosarcoma accounts for a tiny fraction of breast malignancies.

Post-therapy mimic

Discoloration can resemble bruising or radiation skin change.

Heterogeneous histology

A small fragment may sample only mild-looking vasoformation.

Disparate tests

Negative/weak MYC or focal cytokeratin requires contextual review.

Slide 51 · Pathology informs clinical management

Confirm diagnosis

Separate angiosarcoma from vascular mimics

Map disease extent

Consider skin field, multifocality, margins

Multidisciplinary planning

Local treatment and systemic evaluation

Treatment choice is individualized; This lecture emphasizes pathology rather than prescribing a regimen.

Slide 52 · Local recurrence is a central clinical problem

Secondary angiosarcoma often demonstrates diffuse cutaneous spread.

Multifocal or microscopic peripheral extension complicates complete excision.

Negative margins and careful assessment of distribution are clinically important.

Published recurrence estimates vary substantially because series are small and heterogeneous.

Slide 53 · Distant spread and prognosis

Angiosarcoma has aggressive malignant potential.

Hematogenous spread is an important metastatic route.

Pulmonary metastases are reported; Atypical metastatic sites also occur.

Prognostic assessment requires disease extent and the full clinical context.

Slide 54 · Case 1: A young patient with a vascular mass

A 34-year-old woman has a growing deep breast mass; No previous breast irradiation.

Clinical–pathological information

Core biopsy contains irregular blood-filled spaces.

Channels dissect between native ducts and adipose tissue.

Tumour cells express CD31 and nuclear ERG.

Which feature most strongly supports angiosarcoma?

Slide 55 · Case 1: Interpret the infiltrative interface

The key clue is dissection through native breast tissue.

Unusual anastomosing channels invading adipose tissue support a malignant vascular process.

CD31 / ERG substantiate endothelial differentiation.

Absence of radiation history favours a primary clinical context, not benignity.

Slide 56 · Case 2: A skin plaque years after radiotherapy

A 70-year-old woman develops expanding violaceous patches in a previously irradiated breast.

Clinical–pathological information

Radiotherapy was administered 7 years earlier.

Dermal biopsy shows atypical endothelial channels with tufting.

High-level MYC amplification is found by FISH.

Which diagnosis best integrates the findings?

Slide 57 · Case 2: Radiation-associated angiosarcoma

Prior irradiation, dermal distribution, and MYC amplification converge.

A 5–10 year latency fits the textbook pattern.

The skin-centred appearance matches the usual secondary presentation.

MYC amplification is strong ancillary support for secondary angiosarcoma.

Slide 58 · Case 3: Small postradiation vascular proliferation

A small superficial vascular papule is biopsied from irradiated breast skin.

Clinical–pathological information

Mild endothelial atypia without unequivocal deep invasion.

MYC immunostaining is negative.

The biopsy is shallow and fragmented.

What is the most defensible next interpretation?

Slide 59 · Case 3: Do not overcall or exclude malignancy

Atypical vascular lesion remains possible, but sampling limits are real.

MYC negativity supports AVL in the correct architecture; It cannot independently rule out angiosarcoma.

Reassess depth, infiltrative edges and clinical enlargement.

Additional tissue or expert consultation may be needed for persistent suspicion.

Slide 60 · Diagnostic synthesis

Domain

Primary angiosarcoma

Secondary angiosarcoma

Topography

Often parenchymal

Often cutaneous

Clinical association

Sporadic; Younger patients

Radiation / lymphedema; Older patients

Histological hallmark

Infiltrative malignant endothelial growth

Same lineage, often high-grade

Useful tests

CD31 / ERG

CD31 / ERG; MYC testing

Most important pitfall

Bland vascular areas on core biopsy

Misclassification as AVL or benign skin change

Slide 61 · Four principles to carry into practice

A vascular lesion must be classified by site, invasion, cytology and clinical context.

Interlobular stromal malignancy is rare; Angiosarcoma is the key entity.

Primary parenchymal and secondary cutaneous disease are distinct settings.

CD31/ERG support endothelial lineage; MYC aids secondary/AVL distinction.

No stain substitutes for adequate sampling and evaluation of infiltrative growth.

Slide 62 · Selected source readings

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed.; Ch. 23.

Cozzi S, et al. J Pers Med. 2024;14:859. doi:10.3390/jpm14080859.

Yang Y, et al. Int J Surg Pathol. PMID:37231624.

Udager AM, et al. Pathology. 2016;48:697–704.

Breast Angiosarcoma: Imaging Features With Histopathologic Correlation. PMID:38416884.