04/10/2018. Intraductal Papillary Neoplasms Of Breast INTRADUCTAL PAPILLOMA

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1 Intraductal Papillary Neoplasms Of Breast Savitri Krishnamurthy MD Professor of Pathology Deputy Division Head The University of Texas MD Anderson Cancer Center 25 th Annual Seminar in Pathology Pittsburgh, 2018 INTRADUCTAL PAPILLARY NEOPLASMS OF BREAST Presence of fibrovascular cores surrounded by epithelial proliferation BENIGN ATYPICAL MALIGNANT PAPILLOMA ATYPICAL PAPILLOMA PAPILLARY CARCINOM A Clinical history Imaging findings Gross and microscopic findings FINAL PATHOLOGIC DIAGNOSIS INTRADUCTAL PAPILLOMA Benign tumors characterized by fibrovascular cores surrounded by an inner layer of myoepithelial cells and an outer layer of epithelial cells Central Arise from larger ducts Subareolar location Large duct papilloma Peripheral Arise from TDULs Anywhere in breast Microscopic papilloma ~5% of all breast biopsies Age: between 30 and 50 years Preoperative diagnosis: CNB, FNA 1

2 INTRADUCTAL PAPILLOMA CLINICAL AND IMAGING FINDINGS Unilateral nipple discharge - sanguineous or sero-sanguineous Non-palpable mass found on imaging Palpable mass Mammography: circumscribed mass, dilated duct, microcalcifications Ultrasound: Dilated ducts, solid hypoechoic nodule, solid and cystic mass MRI: Enhancing mass IMAGING FINDINGS OF PAPILLOMA ULTRASOUND DOPPLER ULTRASOUND MAMMOGRAM Well circumscribed mass in retroareolar region or in breast parenchyma Dilated duct with smooth walled hypochoic nodule DUCTOGRAM Filling defect in ductogram caused by a smooth walled mass INTRADUCTAL PAPILLOMA 2

3 INTRADUCTAL PAPILLOMA INTRADUCTAL PAPILLOMA p63 I CALPONIN 3

4 / KER5/6 INTRADUCTAL PAPILLOMA INTRADUCTAL PAPILLOMA CALPONIN 4

5 INTRADUCTAL PAPILLOMA ISSUES AND PROBLEMS Florid hyperplasia without atypia Areas of hemorrhage and infarction Torsion of fibrovascular core Biopsy procedures Stromal fibrosis, significant Obscure papillary nature Sclerosing papilloma Intact myoepithelial cells Displacement of epithelial cells in the biopsy tract ' INTRADUCTAL PAPILLOMA WITH FLORID DUCTAL EPITHELIAL HYPERPLASIA WITHOUT ATYPIA CK5/6 INTRADUCTAL PAPILLOMA WITH FLORID DUCTAL EPITHELIAL HYPERPLASIA WITHOUT ATYPIA ER 5

6 INTRADUCTAL PAPILLOMA INTRADUCTAL PAPILLOMA Ductal epithelial hyperplasia Apocrine Metaplasia Collagenous spherulosis Squamous Metaplasia Mucinous Metaplasia Clear Cell Metaplasia Sebaceous Metaplasia INTRADUCTAL PAPILLOMA WITH INFARCTION 6

7 INTRADUCTAL PAPILLOMA WITH SCLEROSIS DISPLACED EPITHELIAL CELLS FROM INTRADUCTAL PAPILLOMA SQUAMOUS METAPLASIA OF DISPLACED EPITHELIUM FROM PAPILLOMA 7

8 ; '/ l I ' I 04/10/2018 SQUAMOUS METAPLASIA OF DISPLACED EPITHELIUM FROM PAPILLOMA ,. J -...'Ī '... J ; ' ' : o, "!'.. ' ( " _ ' "' \ '::'\,. - I ;.. I c t"" / -... f -,_.,... I 1,.'... -,, tf,- - -.,.-. -.: ' ',,... " \ -.. ' '.. '.J I ',,. ""--....,..; / "' ;,.' ; '.,, ;. ',,.,,,....,,.,,,1 (, ;..., ',4 I ',J' " I PAPILLOMA WITH ADH AND DCIS Papilloma with focal population of monotonous cells with cytological and architectural features of low-grade ductal neoplasia Myoepithelial cells intact, scant, absent CK 5/6, CK5, CK14 negative ER: uniform, strong, positive Papilloma involved by ADH ATYPICAL PAPILLOMA Papilloma involved by DCIS PAPILLARY CARCINOMA PAPILLOMA WITH ADH/DCIS CRITERIA Size/Extent Based Criteria for the distinction of papilloma with ADH vs DCIS < 3mm area of low grade atypical cells - ADH 3mm area of low grade atypical cells- DCIS Papillomas with intermediate or high grade atypical cells- Papillomas with DCIS irrespective of extent of involvement 8

9 ATYPICAL PAPILLOMA Papilloma involved by low grade atypical cells measuring less than 3 mm INTRADUCTAL PAPILLOMA WITH ADH INTRADUCTAL PAPILLOMA WITH ADH 9

10 INTRADUCTAL PAPILLOMA Involvement by atypical apocrine cells Criteria to identify ADH/DCIS : similar to nonapocrine ADH/DCIS Cytological and architectural atypia Nuclear atypia, prominent nucleolus, mitosis, necrosis Cribriform, solid IMMUNOPHENOTYPE CK5/6 : Negative ER : Negative p63: Present or decreased APOCRINE DCIS INVOLVING A PAPILLOMA APOCRINE DCIS INVOLVING PAPILLOMA P63 ER 10

11 INTRADUCTAL PAPILLOMA GENOMIC CHANGES Higher frequency of point mutations of P1K3CA, AKT1, and RAS LOH on 16p13 in the TSC2/PK01 location RISK Central papilloma - 2 fold increase in risk Peripheral papilloma - 3 fold increase in risk Peripheral papillomas more often show ADH MANAGEMENT OF INTRADUCTALPAPILLOMA With nipple discharge Without nipple discharge Duct excision Benign Atypical Small well sampled Large incompletely sampled Surgical excision Follow up Vacuum assisted CNB Surgical excision INTRADUCTAL PAPILLARY CARCINOMA Malignant non-invasive neoplastic epithelial proliferation with a papillary architecture restricted to the lumen of ductal system Papillary DCIS DCIS, papillary type Papillary carcinoma, non-invasive Entire intraductal lesion is malignant No evidence of a benign papilloma 11

12 I 04/10/2018 INTRADUCTAL PAPILLARY CARCINOMA INTRADUCTAL PAPILLARY CARCINOMA INTRADUCTAL PAPILLARY CARCINOMA ' " -...'.. * '..s \.. ".. \ I,, f" ' I ' t

13 INTRADUCTAL PAPILLARY CARCINOMA ER INTRADUCTAL PAPILLARY CARCINOMA Absent or scant myoepithelial cells at the base Periphery of ducts - myoepithelial cells present - attenuated Neoplastic cells: ER - strongly positive CK 5/6 - negative INTRADUCTAL PAPILLARY CARCINOMA Genetics LOH on 16p13 in the TSC2/PKD1 gene region LOH on 16q23 Treatment, prognostic and predictive factors Segmental mastectomy/mastectomy Radiation therapy Hormonal therapy 13

14 Variant of papillary carcinoma Papillary proliferation of neoplastic epithelial cells surrounded by a fibrous capsule Intracystic papillary carcinoma Encysted papillary carcinoma Older women ~ 65 years (34-92 years) Usually solitary tumor Subareolar location Palpable/Nonpalpable mass Nipple discharge Circumscribed subareolar mass Clinical and imaging findings similar to papillomas except that they are generally larger in size 14

15 15

16 & I P 04/10/2018 I, - ( I I I I # #.. rl,., #,, /.., I,,

17 Friable mass within a cystic cavity Thick capsule surrounding tumor cells Fibrovascular cores covered by neoplastic cells - solid, cribriform or papillary pattern Low or intermediate grade nuclei Lacks myoepithelial cells within the tumor and at the periphery. DIFFERENTIAL DIAGNOSIS Large duct Papilloma Myoepithelial cells present in fronds and periphery Solid Papillary DCIS Multinodular vs Solitary dominant mass Papillary DCIS Diffuse, multiductal neoplasm Intact peripheral myoepithelial cells ISSUES FOR INTERPRETATION Entrapment of tumor cells into capsule Epithelial displacement into biopsy site can mimic invasion? Expansile pattern of growth of invasive carcinoma Measurement of invasive carcinoma Displacement vs true metastasis in lymph nodes 17

18 I 18

19 II'' ( 04/10/2018 LYMPH NODE METASTASIS IN DISPLACED EPITHELIUM vs METASTATIC CARCINOMA \,,',;. I I,.... l.,.\ GENOMICS Numerical alterations in chromosomes 3, 7, 17 and x Array CGH : 16p gain, 16q loss, 1q gain Complex copy number alterations Markers E-cadherin, TGF-β1 more than DCIS 19

20 CONTROVERSIAL ISSUES Minimally invasive low/intermediate grade Invasive carcinoma In transition from in situ to invasive carcinoma Invasive carcinoma - tumor cells extending beyond the confines of the lesion - conventional criteria Measure invasive tumor that is present beyond the fibrous capsule STAGING Presence of conventional invasive carcinoma - staged based on the size of invasive carcinoma In the absence of conventional invasive carcinoma, staged as Tis 20

21 Behavior similar to low-grade DCIS If EPC is associated with invasive carcinoma, behavior Size Grade Biomarker status Segmental mastectomy with clear margins SLN Bx performed for? All EPC EPC - > 2 cm, high grade Radiation therapy Controversial Endocrine Therapy Chemotherapy - based on size of invasive component California Cancer registry Study 10 - year survival EPC : 96.8% EPC + Invasive Carcinoma % Favorable prognosis with solitary lesion and absence of DCIS in surrounding parenchyma Lymph node metastasis - rare DCIS in surrounding breast - risk of local recurrence Sampling of surrounding tissue important SOLID PAPILLARY CARCINOMA A variant of papillary carcinoma characterized by closely placed expansile - nodules with solid proliferation of tumor cells around fibrovascular cores Neuroendocrine differentiation is commonly noted Neuroendocrine breast carcinoma Spindle cell DCIS Neuroendocrine DCIS Endocrine DCIS < 1% of breast carcinomas Mean age: seventh decade Palpable mass or non-palpable detected on imaging 21

22 SOLID PAPILLARY CARCINOMA SOLID PAPILLARY CARCINOMA SOLID PAPILLARY CARCINOMA 22

23 SOLID PAPILLARY CARCINOMA SYNAPTOPHYSIN KER 5/6 ER SOLID PAPILLARY CARCINOMA.. SOLID PAPILLARY CARCINOMA Abnormal calcifications, solid nodules Nipple discharge Palpable multinodular mass Aggregated solid nodules with smooth borders Nodules can be placed close to one another - jigsaw pattern Low grade nuclei - oval/spindle Scattered mitosis Margins of the ductal spaces can be irregular Extracellular mucin - common Invasive component Mucinous, neuroendocrine differentiation 23

24 SOLID ENCAPSULATED CARCINOMA IMMUNOPHENOTYPE 50% of cases - positive for chromogranin and/or synaptophysim ER strongly and diffusely positive CK 8/18 positive, CK 5/6 negative Myoepithelial cells - may or may not be present SOLID PAPILLARY CARCINOMA DIFFERENTIAL DIAGNOSIS DCIS, solid pattern: Absence of papillary architecture Usually high grade Florid ductal hyperplasia CK5/6 positive ER heterogeneous expression Neuroendocrine markers negative Encapsulated Papillary Carcinoma: Single mass within a cystic space vs multinodular solid mass Papillary DCIS Papillary architecture in open ductal spaces Myoepithelial cells intact in periphery more than SPC SOLID PAPILLARY CARCINOMA GENOMICS Gene expression - Luminal A pattern similar to mucinous and neuroendocrine carcinomas Copy number alterations : Similar to Luminal A invasive tumors 16q loss, absence of p53 mutation PIK3CA Mutation - Similar to luminal A tumors 24

25 SOLID PAPILLARY CARCINOMA Low grade carcinoma with good prognosis When multinodular with smooth margins - low grade DCIS staged as Tis Adjuvant Radiation Therapy and endocrine therapy SPC with associated invasive ductal carcinoma - staged based on size of invasive tumor - behave like IDC, low grade Chemotherapy based on features of the invasive component SOLID PAPILLARY CARCINOMA Distinction between in situ and invasive carcinoma For staging purposes - in situ carcinoma Geographic jigsaw pattern with irregular margins - absence of myoepithelial cells -? invasive IMMUNOHISTOCHEMICAL FEATURES OF PAPILLARY LESIONS p63 CK 5/6 ER/PR Papillae Periphery Intraductal Papilloma + + Patchy + Patchy + Papilloma with ADH/DCIS diffuse, strong Papillary DCIS diffuse, strong Encapsulated Papillary Ca Solid Papillary Carcinoma diffuse, strong - ± - + diffuse, strong 25

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