Small Glandular Proliferative Lesions of the Breast

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Small Glandular ProliferativeLesions of the Breast

Yunn-Yi Chen, MD, PhDProfessor

Director of Immunohistochemistry LaboratoryDirector of Breast Pathology Services

UCSF

Small Glandular Lesions of Breast

Complex sclerosing lesion Benign lobules in fat Micro glandular adenosis

Sclerosing adenosis

Radial scar

Tubular carcinoma

Invasive ductal ca

Biopsy-related changes LG adenosquamous ca Adenoid cy stic ca, tubular

� Distribution--� Lobulocentric vs diffuse pattern; organized vs hapha zard

� Stromal appearance

� Glandular architecture, cytologic features

� Luminal content

� IHC markers� Myoepithelial cell (MEC) markers: p63, SMM,

Calponin, (SMA, CK5/6)� ER� S100� Cytokeratins: CK5/6, others

Approach for Small Glandular LesionsBenign Breast Lobules in Fat: “Respect” the Fat

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Radial Sclerosing Lesion: “Respect” the Fat Invasive Ductal Carcinoma: Invade the Fat

Sclerosing Adenosis (SA)

� Lobulocentric

� Stroma: collagenous, myxoid

� Glands and epithelial cells:� Glands compressed/central, open/peripheral; basemen t

membrane� Luminal epithelial and myoepithelial cells (MEC)� Epithelial cells: flat to cuboidal, bland

� Lumen: Calcifications

� IHC: Positive MEC markers

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Sclerosing Adenosis

� Incidental or mammographic calcifications

� Mimic invasion

� Nodular adenosis

� Involved by lobular neoplasia or DCIS

� Apocrine cytology

� Perineural invasion

Nodular Adenosis

� Florid sclerosing adenosis, nodular contour

� Mammographic mass or palpable lesion

� Also “adenosis tumor” (connotation of neoplasm)

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Biopsy for Mammographic Mass with Calcifications

Nodular adenosis

Sclerosing Adenosis and Nodular Adenosisp63

CK5/6SMM

Lobular Neoplasia Involving SA

� Mimic invasive carcinoma

� Lobulocentric

� MEC markers

Apocrine Adenosis

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Apocrine Adenosis Apocrine Adenosis

� SA with apocrine cytology� Eosinophic granular or foamy cytoplasm

� Mimic carcinoma� Lobulocentric, MEC markers

� Atypical apocrine adenosis

Invasive Apocrine CA Mimicking Apocrine Adenosis

SMM

Atypical Apocrine Adenosis--3x nuclear enlargement with prominent pleomorphic n ucleoli

(O’Malley FP and Bane AL. Adv Anat Pathol 2004)

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Apocrine Adenosis

� SA with apocrine cytology� Eosinophic granular or foamy cytoplasm

� Mimic carcinoma

� Atypical apocrine adenosis� 3x nuclear enlargement, prominent pleomorphic nucle oli� Long-term breast cancer risk: not well-defined� On CNB: recommend excision to exclude DCIS� On excision: regular follow-up

(Carter D et al: Mod Pathol 1991; Seidman J et al: Cancer 1996; Fuehrer N et al: Arch Pathol Lab Med 2 012)

DCIS with Apocrine Features

p63

Sclerosing Adenosis with Perineural “Invasion”

CNB for a Palpable Lesion

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p63SMM

Sclerosing Lesion with Perineural “Invasion”

Peri- and Intraneural “Invasion” in Benign Breast Lesions

� Ackerman: 1 st description in 1957

� Taylor and Norris (AFIP): series of 20 patients in 1967

� Incidence: ~2%

� Also reported in benign lesions of other anatomic sites

� In breast: SA, radial scar, sclerosing papilloma

� Pathogenesis unclear : post-traumatic, involvement by the proliferative process

Radial Scar

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Radial Scar (RS)

� Tumor-like or pseudoinfiltrative lesion

� Stellate appearance� Mimic malignancy on imaging and pathology

� Central fibroelastotic core with entrapped distorted tubules, surrounded by radiating ducts and lobules

� Radiating ducts and lobules: variable changes (UDH, papillomatosis, adenosis, apocrine metaplasia, cyst s)

Radial Scar

Radial Scar Invasive Ductal CA

RS: Fibroelastotic and Hypocellular Centerwith Entrapped Distorted Glands

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Entrapped Glands in Fibroelastotic Stroma

� Distorted, compressed, angulated

� Luminal epithelial cells: flat to cuboidal

� Myoepithelial layer

Radiating Ducts and Lobules

� Variable epithelial changes

� UDH, papillomatosis, adenosis, apocrine metaplasia, cysts

Radial Sclerosing Lesion (RSL)

� Include radial scar and complex sclerosing lesion

� Radial scar: Smaller ( ≤ 1 cm) lesions, stellate

� Complex sclerosing lesion: larger lesions, more complex and extensive features

Complex Sclerosing Lesion

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Complex Sclerosing Lesion Attenuated Myoepithelial (MEC) Staining in RSLSMM

CK5/6p63

Phenotypic Alterations in Myoepithelial Cells Associated with Sclerosing Lesions and DCIS

� Expression of MEC markers: reduced or focally absent in various benign sclerosing lesions and DCIS

� Frequency: � SMM > p63, calponin > SMA� Radial scar > sclerosing adensois

� Panel of MEC markers

� Avoid over-diagnosis� When in doubt about the presence of invasion, diagn ose as

non-invasive

(Hilson JB et al: Am J Surg Pathol 2009 and 2010)

Radial Sclerosing Lesions

� Organized

� Stroma: Fibroelastotic

� Glands and epithelial cells:� Distorted, compressed, angulated� Luminal epithelial and myoepithelial cells (MEC)� Epithelial cells: flat to cuboidal, bland

� Lumen: Calcifications

� IHC: Positive MEC markers� Reduced or focally absent for MEC expression

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Tubular Carcinoma--Diffuse/infiltrative growth

Tubular Carcinoma--Desmoplastic or elastotic stroma

Tubular Carcinoma with FEA

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� Infiltrative

� Desmoplastic cellular stroma, ± elastosis

� Open round, oval, or angulated tubules

� Cytology� Single layer, non-stratified, cuboidal to columnar cells,

prominent cytoplasmic apical snouts� Minimal pleomorphism, basally located round to oval nuclei� Mitosis rare

� Lack all MEC markers

� Diffusely and strongly positive for ER

Tubular Carcinoma

� > 90% with tubular morphology

� Incompatible features--� Complex architecture� Multiple layers of cells� Significant nuclear pleomorphism� Frequent mitoses

Diagnosing Tubular Carcinoma

� 10-year survival: ~100%

� LN metastasis: rare, 1 node, no significant impact on survival

� Luminal A� ER/PR +, HER2 -, low Ki-67

Tubular Carcinoma-- PrognosisDiagnosis of TC on CNB?--

� IDC may have focal tubularmorphology

� Dx: Invasive ductal ca with tubular features with a comment

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� Well-differentiated IDC

� Radial sclerosing lesions

� Microglandular adenosis

Tubular Carcinoma-- ddx Radial Sclerosing Lesion

p63

Tubular carcinoma

Radial sclerosing lesion

Distinguishing Pathologic Features for TC and RSL

Tubular carcinoma RSL

Distribution Infiltrative Lobulocentric

Gland size/shape Slightly irregular, angulated

Distorted, elongated, flattened

Lumen Open Compressed, open

Cytology Mild atypia, cuboidal to columnar

Bland, flat to cuboidal

Luminal content Basophilic secretion; ±calc

± calc

Stroma Desmoplastic, elastotic, cellular

Fibroelastotic,hypocellular

Basement memb. - to partial +, complete

ME layer Absent Present

Background FEA/ADH/DCIS, LN Benign

Biomarkers ER diffusely + ER patchy +

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Well-differentiated IDC ? Well-differentiated IDC ?

Well-diff IDC Tubular carcinoma

Irregular glands Slightly irregular, angulated glands

± Trabeculae and ribbons Open glands

Branching and anastomosis No branching or anastomosi s (may have cribriform glands)

Mild to moderate pleomorphism Minimal pleomorphism

Stratified cells, loss of polarity Single layer of c ells, basal nuclei

Sclerotic to desmoplastic stroma Desmoplastic/elasto tic stroma

� Randomly distributed

� Hypocellular dense collagenous stroma or fat

� Uniform small round glands, eosinophilic secretion

� Cytology� Single layer, flat to cuboidal cells, clear to amph ophilic

cytoplasm, bland round nuclei

� Immunophenotype� MEC markers (p63, SMM, calponin, SMA) –; S100 diffu sely +� ER -� Laminin and type IV collagen +

Microglandular Adenosis (MGA)

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Microglandular Adenosis--

Haphazard distribution

Microglandular Adenosis--Hypocellular collagenous stroma

PAS stain

Microglandular Adenosis--Uniform small glands, open lumen, eosinophilic secr etion

Microglandular AdenosisSMMcalponin

Lamininp63

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Microglandular Adenosis

S100ER

Distinguishing Pathologic Features for MGA and TC

MGA Tubular carcinoma

Distribution Random Infiltrative

Gland size/shape Uniform, small, round Slightly irregul ar, angulated

Lumen Open Open

Cytology Bland, flat to cuboidal Mild atypia, cuboidal to columnar

Luminal content Eosinophilic secretion Basophilic sec retion; ± calc

Stroma Collagenous to fatty Desmoplastic, elastotic, cellular

Basement memb. +, complete - to partial

ME layer Absent Absent

Background Benign FEA/ADH/DCIS, LN

Biomarkers ER -, S100 + ER diffusely +

(Courtesy of Dr. Timothy Jacobs)

CNB for a Palpable Mass


Follow-up Lumpectomy

Regular MGA

Atypical MGA

Metaplastic ca

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Regular MGA Atypical MGA Atypical MGA Metaplastic Carcinoma

Metaplastic CA Arising in MGA and Atypical MGA--

Atypical MGA Metaplastic CAMGA

S100 Stain � Presentation: mass, mammographic calcifications or an incidental microscopic finding

� Spectrum of MGA, atypical MGA, invasive carcinoma� Share immunophenotype and genetic alterations

� Non-obligate precursor for triple negative carcinom a� IDC, metaplastic ca (chondroid diff), adenoid cysti c ca

� Management� CNB: excision� Excision: negative margin, careful clinical follow -up


(Wen YH et al: Histol Histopathol 2013; Shin SJ et al: AJSP 2009; Khlifeh IM et al. AJSP 2008)

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Low-grade Adenosquamous Carcinoma (LGASC)

� Infiltrative (may resemble RS in some cases)

� Spindle cellular stroma, prominent lymphoid reactio n

� Glands (long, irregular) and solid squamous nests (comma shaped extension), ± squamous cysts

� Cytology: bland� Glands: some with epithelial and myoepithelial cells ; variable

squamous diff.� Solid nests: squamous cells

Low-grade Adenosquamous CA (LGASC)

LGASC-- Infiltrative Growth ? LGASC– Cellular Stroma and Prominent Lymphoid Reacti on

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LGASC-- Glands and Squamous Nests ? LGASC-- Squmous Cysts ?

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LGASC-- Squamous Cyst/Nests with Comma-like Extensio n? LGASC-- Infiltrating Between and Into Lobules

� MEC markers (p63, SMM, calponin, SMA): consistently variable pattern� Continuous, discontinuous or absent staining around

glands/epithelial nests in the same lesion� No tumor shows complete absence of staining by any of the

MEC markers

� Squamous cells: p63 and CK5/6 +

� ER/PR/HER2 negative

LGASC-- Immunophenotype

(Kawaguchi and Shin: AJSP 2012; Boecher W et al: Hi stopathology 2014)

LGASC– Immunophenotype ?p63

CalponinSMM

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p63 SMM

LGASC-- Immunophenotype ?

CNB for a Palpable Mass ?

Squamous Nests into LobulesSolid Tubules and NestsCellular Stroma

Prominent Perineural Invasion, Squamous Atypia

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Triple Stain: p63 +, calponin -, LMWK -

Low-grade adenosquamous carcinoma

mimicking a sclerosing lesion

� Benign fibrosclerosing lesions (SA, radial scar)� CNB: “low-grade or atypical sclerosing lesion” descr iptive dx for

unusual morphologic features or IHC pattern for MEC markers

� Syringomatous tumor of the nipple (SyT)� Similar morphology and immunophenotype� Location: SyT in superficial skin of nipple/areola; LGASC in

peripheral breast parenchyma

� Reactive squamous metaplasia

� Tubular carcinoma

LGASC-- ddx

� An uncommon variant of metaplastic ca

� May arise de novo or in association with benign sclerosing lesions (RS, sclerosing papilloma)

� Triple negative

� Indolent behavior with excellent prognosis� Local aggressive growth, extremely low metastatic p otential� Rare cases: transition to higher grade ca (spindle cell ca)� Complete surgical excision; chemotherapy likely not indicated

Low-grade Adenosquamous Carcinoma Tubular Pattern of ACC: Mimic Benign Glands or IDC

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Adenoid Cystic Carcinoma (ACC)

Cribriform Pattern Tubular Pattern

Tubular ACC-- Biphasic Epi-Myoepithelial Diff.

ACC– Aberrant MEC Expression and Negative ERp63

ERCalponin

� Diffuse pattern

� Dual cell types--� Myoepithelial-like/basaloid cells� Epithelial cells

� Immunophenotype

� MEC markers: p63/SMA + & SMM/calponin - in basaloid cells

� LMW CK (CK7) + in epithelial cells

� ER/PR/HER2 -

Adenoid Cystic Carcinoma

(Rabban Mod Pathol 2006;19:1351; Foschini Semin Diagn Pathol 2010;27:77)

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� Problem with IHC stains

� Special types of breast tumors� Microglandular adenosis� Low-grade adenosquamous carcinoma� Adenoid cystic carcinoma

� Metastatic carcinoma

When a Low-grade “Infiltrative” Epithelial Lesion is ER Negative--

� Morphologic alterations secondary to procedures� Prior needling (CNB, FNA)� Current procedure (injection for SLN, tissue proces sing)

� Various changes� Mimic stromal invasion� Mimic LVI� Mimic LN metastasis

� Factors� Time interval� Lesion type: papillary lesion

� MEC markers often not helpful

Iatrogenic Small Glandular Lesions

(Phelan S et al: J Clin Pathol 2007)

Mechanical Displacement of DCIS Cells--

Bx tracts

Mechanical Displacement of DCIS Cells--Tumor cells associated with biopsy site changes

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Mechanical Displacement of DCIS Cells--Tumor cells associated with biopsy site changes

Epithelial Displacement s/p FNA--Epithelial cells in stoma and vascular space

Epithelial Displacement s/p CNB Re-excision for Extensive HG DCIS with + Margin

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SMM

Squamous Metaplasia at Biopsy SiteSquamous Metaplasia at Biopsy Site

SMM p63

Squamous Metaplasia at Biopsy Site Squamous Metaplasia at Biopsy Site

Prior DCIS Current Epithelial Lesion

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CK5/6

Re-excision for DCIS

Squamous Metaplasiaat the Biopsy Site

Lobulocentric or organized

Diffuse and haphazard

� Sclerosing adenosis� Nodular adenosis� Radial sclerosing lesion� Squamous metaplasia

� Epithelial displacement

� Tubular ca & well-diff IDC� Microglandular adenosis� Low grade adenosquamous ca� Adenoid cystic ca

Approach to Small Glandular Lesions of the Breast

� Benign sclerosing lesions may exhibit reduced or absent expression in one 1 or more MEC markers

� MGA lacks expression of multiple MEC markers

� Some invasive carcinomas (LGASC, ACC) express 1 or more MEC markers

Myoepithelial cell (MEC) markers

� It cannot necessarily be concluded that lack of one MEC marker indicates invasion or that expression of one MEC marker supports a benign lesion.

� A panel of MEC markers should be used.






ME markers+++

+ & -

- or +

--

+ & -+ & -


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ER+++-

- or +

+++---


Thank you!

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Small Glandular Proliferative Lesions of the Breast