5/23/2015 Small Glandular Proliferative Complex sclerosing lesion - - PowerPoint PPT Presentation

5/23/2015 1 Small Glandular Proliferative Lesions of the Breast

Yunn-Yi Chen, MD, PhD Professor Director of Immunohistochemistry Laboratory Director of Breast Pathology Services UCSF Small Glandular Lesions of Breast

Complex sclerosing lesion Benign lobules in fat Microglandular adenosis Sclerosing adenosis Radial scar Tubular carcinoma Invasive ductal ca Biopsy-related changes LG adenosquamous ca Adenoid cystic ca, tubular

Distribution--

• Lobulocentric vs diffuse pattern; organized vs haphazard

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 Lesions

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

Lumen: Calcifications IHC: Positive MEC markers

5/23/2015 3 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 Adenosis

p63 CK5/6 SMM

Lobular Neoplasia Involving SA

Mimic invasive carcinoma Lobulocentric MEC markers

Apocrine Adenosis

5/23/2015 5 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 nucleoli

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

5/23/2015 6 Apocrine Adenosis

SA with apocrine cytology

Eosinophic granular or foamy cytoplasm

Mimic carcinoma Atypical apocrine adenosis

3x nuclear enlargement, prominent pleomorphic nucleoli 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 2012)

DCIS with Apocrine Features

p63

Sclerosing Adenosis with Perineural “Invasion” CNB for a Palpable Lesion

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p63 SMM

Sclerosing Lesion with Perineural “Invasion”

Peri- and Intraneural “Invasion” in Benign Breast Lesions

Ackerman: 1st 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

5/23/2015 8 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, cysts)

Radial Scar

Radial Scar Invasive Ductal CA

RS: Fibroelastotic and Hypocellular Center with 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 RSL

SMM CK5/6 p63

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, diagnose 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-- Prognosis

Diagnosis of TC on CNB?--

IDC may have focal tubular morphology 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 anastomosis (may have cribriform glands) Mild to moderate pleomorphism Minimal pleomorphism Stratified cells, loss of polarity Single layer of cells, basal nuclei Sclerotic to desmoplastic stroma Desmoplastic/elastotic stroma

Randomly distributed Hypocellular dense collagenous stroma or fat Uniform small round glands, eosinophilic secretion Cytology

• Single layer, flat to cuboidal cells, clear to amphophilic

cytoplasm, bland round nuclei

Immunophenotype

• MEC markers (p63, SMM, calponin, SMA) –; S100 diffusely +
• 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 secretion

Microglandular Adenosis

SMM calponin Laminin p63

5/23/2015 16 Microglandular Adenosis

S100 ER

Distinguishing Pathologic Features for MGA and TC MGA Tubular carcinoma

Distribution Random Infiltrative Gland size/shape Uniform, small, round Slightly irregular, angulated Lumen Open Open Cytology

Bland, flat to cuboidal Mild atypia, cuboidal to columnar

Luminal content Eosinophilic secretion Basophilic secretion; ± 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

Microglandular Adenosis

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 CA MGA 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 carcinoma

• IDC, metaplastic ca (chondroid diff), adenoid cystic ca

Management

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

Microglandular Adenosis

(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 reaction 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 Reaction

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

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LGASC-- Squamous Cyst/Nests with Comma-like Extension? 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: Histopathology 2014)

LGASC– Immunophenotype ?

p63 Calponin SMM

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p63 SMM

LGASC-- Immunophenotype?

CNB for a Palpable Mass?

Squamous Nests into Lobules Solid Tubules and Nests Cellular 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” descriptive 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 potential
• 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 ER

p63 ER Calponin

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 processing)

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 Site Squamous 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 Metaplasia at the Biopsy Site Lobulocentric

• r 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

• ne MEC marker supports a benign lesion.

A panel of MEC markers should be used. Lobulocentric

• r 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 ME markers + + + + & -

• or +
• + & -

+ & -

Approach to Small Glandular Lesions of the Breast

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Lobulocentric

• r 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 ER + + +

• or +

+++

• Approach to Small Glandular Lesions of the Breast

Thank you!