5/26/2016 Cribriform Breast Lesions Cribriform Lesions of the Breast Yunn-Yi Chen, MD, PhD Professor Director of Immunohistochemistry Laboratory UCSF Uniform Cribriform Breast Lesions Cribriform � Latin cribrum : sieve � Medical definition: pierce with small holes � Pathology: sieve-like histologic pattern, sheets of epithelial cells punctuated by (rounded) gland-like spaces 1
5/26/2016 Cribriform Breast Lesions Approach for Cribriform Lesions � Lobulocentric vs diffuse pattern Cribriform DCIS � Single vs dual cell populations � Luminal contents Adenoid Cystic Invasive Cribriform Carcinoma � IHC and molecular markers Carcinoma � Myoepithelial cell (MEC) markers � LMW CK, CK5/6 � ER Collagenous � Other stains: CD117 (C-Kit), S100 Spherulosis � FISH Cribriform DCIS-- Lobulocentric Diagnostic accuracy of DCIS by pathologists (Results of ECOG Trial 5194) � 49/693 (7.1%): misclassified ADH 28 (57%) UDH 5 (10%) LCIS 5 Papilloma 2 Radial scar 2 Invasive carcinoma 3 Columnar cell lesion 2 Papillary apocrine change 1 Mucocele-like lesion 1 (Simpson J, et al: USCAP meeting abstract, 2011, 64A) 2
5/26/2016 Diagnosis of low grade Cribriform DCIS Cribriform DCIS UDH � Distinction from ADH and UDH � Criteria based on cytology, architecture and extent Cytology-- monotonous, round to oval nuclei, distinct � cell membrane Architecture-- rounder/rigid, polarized to lumen � Extent-- complete involvement of spaces, continuous � span > 2 mm (3 mm by some authors and arising in papilloma) � Inter-observer variability Monotonous Heterogeneous Share with your colleagues � Evenly spaced Crowded and overlapping � Adjunct: HMWK (CK5/6), ER Distinct cell membrane Indistinct cell membrane Nuclei polarized to lumen Nuclei lack of polarization UDH-- CK5/6 positive (mosaic pattern), variable ER � ADH and DCIS– CK5/6 negative, diffuse and strong ER � Cribriform DCIS UDH Nuclei parallel to lumen Nuclei perpendicular to lumen 3
5/26/2016 Usual Ductal Hyperplasia CK5/6 ER Atypical Ductal Hyperplasia-- Necrosis may be seen in UDH � Combined ER (brown) and CK5/6 (red) stain � Negative CK5/6, diffuse and strong ER 4
5/26/2016 UDH with necrosis Extent criteria for low-grade DCIS-- complete involvement of > 2 mm ADH ADH LG DCIS CK5/6 ER 2 mm Benign Apocrine Proliferation DCIS with apocrine features • Apocrine cells are CK5/6 and ER negative • Significant ( ≥ 3x) variation in nuclear size • Uniform nuclei, fine chromatin • Irregular nuclear membrane, coarse chromatin • No necrosis • Often with comedo necrosis CK5/6, p63 (brown)/LMW CK (red) 5
5/26/2016 SMM Cribriform DCIS Involving a Radial Sclerosing Lesion (RSL) Cribriform DCIS in RSL-- � Mimic invasion � Reduced MEC staining p63 (Hilson et al: Am J Surg Pathol 2010;34:896-900) Cribriform DCIS Collagenous Spherulosis � Lobulocentric � Benign � Single luminal type epithelial cells � Aggregates of eosinophilic fibrillar spherules or myxoid material (BM material) � Luminal contents: calcifications � Biphasic myoepithelial and epithelial proliferation � Immunophenotype � MEC around the duct space � Two types of lumens � ER: +++ � CAM5.2 +++, CK5/6 - 6
5/26/2016 Collagenous Spherulosis Arising in a Papilloma Collagenous Spherulosis: Lobulocentric 7
5/26/2016 Coll IV Collagenous Spherulosis-- two cell populations � Myoepithelial cells pseudolumen � Epithelial cells true glandular space SMM CAM5.2 p63 SMM Coll Spherulosis Cribriform DCIS Collagenous Spherulosis-- Core Biopsy for Calcifications 8
5/26/2016 Collagenous Spherulosis in Radial Scar Monomorphic cells with cribriform architecture ? DCIS 9
5/26/2016 LCIS involving collagenous spherulosis-- LCIS involving collagenous spherulosis-- Pitfall in mimicking cribriform DCIS positive E-cad staining from ME cells E-cad E-cad p63 Collagenous Spherulosis Invasive Carcinoma with Cribriform Pattern � Lobulocentric � Invasive cribriform CA � Dual MEC and epithelial cells � MEC: pseudolumens, BM material � Epithelial cells: true glandular spaces, ± eosinophilic � Adenoid cystic CA secretion � Immunophenotype � MEC markers + around pseudolumens � LMW CK (CAM5.2) + around true glandular spaces 10
5/26/2016 Invasive Cribriform Carcinoma-- Diffuse Invasive Cribriform Carcinoma � Excellent prognosis � Luminal A molecular type � Cribriform pattern invading stroma � Often mixed with other invasive (tubular carcinoma in 17-23%) � Diagnosis-- � > 90% cribriform pattern or � >50% cribriform + tubular as the second component Inv cribriform CA-- irregular contours, desmoplastic stroma Cribriform DCIS: Lobulocentric 11
5/26/2016 DCIS: Smooth Contours, Myoepithelial Cells Cribriform DCIS Inv Cribriform CA Irregular contour Desmoplastic stroma Inv cribriform CA-- smooth contours, mimic cribriform DCIS p63 12
5/26/2016 p63 Invasive and in situ cribriform carcinoma Smooth ME-like cells Invasive SMM p63 Irregular In situ Invasive Cribriform Carcinoma Invasive Cribriform CA Cribriform DCIS � Diffuse pattern Infiltrate between normal Normal ductal and lobular lobules and ducts architecture preserved � Single luminal type epithelial cells Irregular, sharp, angulated Smooth, rounded contours � Luminal contents: - /+ calcifications, mucin edges � Immunophenotype Desmoplastic Normal stroma � MEC markers: - � ER: +++ � CAM5.2 +++; CK5/6 - No myoepithelial cells Intact myoepithelial cells 13
5/26/2016 Adenoid Cystic Carcinoma-- Diffuse Adenoid Cystic Carcinoma � Histology similar to salivary gland counterpart � Various architectural patterns Cribriform � Tubular/trabecular, solid/basaloid � � Triple negative, basal-like molecular type Lower mutation rate compared to TN IDC � � t(6;9) MYB-NFIB translocation � Favorable prognosis Adenoid Cystic CA Adenoid Cystic Carcinoma Adenoid Cystic CA * * pseudolumen true lumen * 14
5/26/2016 Adenoid Cystic Carcinoma Immunophenotype * Adenoid cystic carcinoma biphasic differentiation * * Epithelial-like Myoepithelial-like May demonstrate an “aberrant/variable” phenotype * Adenoid Cystic Carcinoma Adenoid Cystic CA p63 CK7 SMM 15
5/26/2016 Adenoid cystic carcinoma-- dual cell populations Adenoid Cystic Carcinoma Myoepithelial-like/basaloid cells: p63 +, calponin – (brown) Epithelial cells: CAM5.2 + (red) breast triple stain � Diffuse pattern � Dual cell types-- � Myoepithelial-like/basaloid cells: pseudolumens with BM material � Epithelial cells: true glandular spaces ± secretion � Immunophenotype � MEC markers: variable; usually p63 +, SMA +/ - & SMM/calponin - /+ in basaloid cells � LMW CK (CK7) + in epithelial cells � ER/PR/HER2 - ; CD117 & CK5/6 + (basal-like) � MYB + Adenoid Cystic Carcinoma Adenoid Cystic Carcinoma-- Excellent Prognosis on population-based studies CK5/6 Study Population Year # LN met Survival* patients Ghabach Surveillance, 1977- 338 14/335 5 y RS: 98.1% Epidemiology 2006 (4.2%) 10 y RS: 94.9% and End Results 15 y RS: 91.4% Program (SEER) Thompson California 1988- 244 12/244 5 y RS: 95.6% Cancer Registry 2006 (4.9%) 10 y RS: 94.9% (CCR) CD117 MYB Kulkarni National Cancer 1998- 933 36/703 5 y OS: 88% Data Base 2008 (5.1%) (*RS: relative survival; OS: overall survival) ( Ghabach: Breast Cancer Res 2010; Thompson: Breast J 2011; Kulkarni: Ann Surg Oncol 2013 ) 16
5/26/2016 56 y F with a breast lesion 56 y F with a breast lesion 56 y F with a breast lesion Secretory Carcinoma � Rare histologic subtype of breast cancer: 0.02% � Originally as “Juvenile secretory carcinoma” in 1966 Most common childhood breast ca � � Renamed “secretory carcinoma” in 1980s ~2/3 pts > 50 y, mean age 53-56 (range 3 to 89) � � Various growth patterns Microcystic/cribriform � Papillary, solid, tubular � 17
5/26/2016 Secretory Carcinoma-- Diffuse Secretory Carcinoma � Triple negative or low hormonal receptor expression, basal-like molecular type � t(12;15) ETV6-NTRK3 translocation � Favorable prognosis Lower mutation rate than TN IDC � Simplex genomic profile by chromosomal analysis � Secretory Carcinoma-- Secretory Carcinoma-- Abundant eosinophilic vacuolated cytoplasm Abundant eosinophilic to amphophilic secretion � Medium-sized oval nuclei, small nucleoli; low mitotic activity � SBR grade 1 and 2 � 18
5/26/2016 Secretory Carcinoma Secretory Carcinoma PASD stain � Secretory material: PASD and Alcian blue + � S100 and mammaglobin +++ � ER/PR/HER2 - or low ER/PR � CK5/6 + Secretory Carcinoma Secretory Carcinoma S100 Stain Mammaglobin Stain ER/PR/HER2 – or low ER/PR � CK5/6 + � Basal-like � ER CK5/6 19
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