Cytology of papillary lesions of the breast

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Torill Sauer, department of Pathology, Akershus University Hospital, Norway

Papillary lesions include • Intraductal papilloma – Intraductal papilloma – Intraductal papilloma with atypical ductal hyperplasia – Intraductal papilloma with ductal carcinoma in situ – Intraductal papilloma with lobular neoplasia • (florid) papillomatosis of the nipple • Intraductal/intracystic papillary carcinoma • Encapsulated papillary carcinoma solid papillary carcinoma • Invasive papillary carcinoma • Invasive micropapillary carcinoma Torill Sauer, department of Pathology, Akershus University Hospital, Norway

Epidemiology and clinical features of intraductal papillomas • Approx 5 % of benign breast lesions • Most of them located centrally • Mean age 48 yrs, but commonly also presents in the 6th and 7th decades • Central papillomas may present with unilateral bloody or serous-bloody nipple discharge • Less common presentation as palpable mass • Mx circumscribed (retroareolar) benign appearing mass, a solitary (retroareolar) dilated duct and rarely microcalcifications • US well defined smooth-walled cystic nodule with solid components • Peripheral lesions often clinically occult, but may also cause nipple discharge and evt a mass as a result of a small cluster of papillomas • Peripheral lesions tend to be mx occult, but may present as microcalcifications • Size from a few mm up to > 5 cm

Torill Sauer, department of Pathology, Akershus University Hospital, Norway

Cytological findings in “plain” intraductal papillomas • Variable cellularity with a basic benign pattern • The epithelial cells are often seen as small groups • Complex, folded three dimensional epitehlial aggregates • Stromal fragments

Torill Sauer, department of Pathology, Akershus University Hospital, Norway

monolayer small groups benign nuclei macrophages

Torill Sauer, department of Pathology, Akershus University Hospital, Norway

Large monolayer complex folded sheets

Torill Sauer, department of Pathology, Akershus University Hospital, Norway

In PAP

Monolayer Myoepithelial benign nuclei

Torill Sauer, department of Pathology, Akershus University Hospital, Norway

Cohesive papillary clusters

Torill Sauer, department of Pathology, Akershus University Hospital, Norway

(Micro-)papillary clusters, bipolar cells

Torill Sauer, department of Pathology, Akershus University Hospital, Norway

Papillary stromal fragments

Torill Sauer, department of Pathology, Akershus University Hospital, Norway

Apocrine cells

A small amount of debris and macrophages

Torill Sauer, department of Pathology, Akershus University Hospital, Norway

Can we make a definite/confident diagnosis of benign intraductal/intracystic papilloma? • The Accuracy of the ‘Triple Test’ in the Diagnosis of Papillary Lesions of the Breast. Papeix G.a · Zardawi I.M.b · Douglas C.D.d · Clark D.A.d · Braye S.G.c . Acta Cytologica 2012;56:41–46 (DOI:10.1159/000334391)

• Background and Objective: The literature on fine-needle aspiration (FNA) cytology for papillary lesions presents a very mixed picture. Many authors advocate mandatory excision of these lesions. This recommendation is largely based on the ‘atypical’ nature of the FNA report. The aim of this work is to see if breast papillomas can be treated conservatively. Study Design: We report a retrospective study of outcomes for patients with a provisional diagnosis of a ‘papillary breast lesion’ based on assessment by palpation (no clinically suspicious features), sonography (benign or probably benign according to the Breast Imaging Reporting and Data System ‘BIRADS®’), and FNA (benign cytological category with a papillary architecture) findings from one integrated breast service. Results: Thirty-six cases were identified over a period of 6 years. Thirty-four of the patients had surgical excision. All of the 34 surgical cases were confirmed to be benign in nature on histopathology (intraduct papilloma). The remaining 2 cases were stable on follow-up. Conclusion: We believe that a policy of mandatory excision of papillary lesions of the breast is unnecessarily cautious. Torill Sauer, department of Pathology, Akershus University Hospital, Norway

Cytological findings in cellular papillary lesions • Marked epithelial proliferation • Hyperplasia with and without atypia • A mixed cell population, both benign and irregular/atypical • Threedimensional aggregates that may resemble ADH/low grade DCIS – solid – cribriform • Papillary fragments and fibrovascular stalks

Torill Sauer, department of Pathology, Akershus University Hospital, Norway

Cellular papillary lesion • Moderate to distinct cellular/nuclear pleomorphism but with a fine chromatin pattern • Nucleoli may be distinct • Usually the epithelial fragments are rather cohesive but • a population of single cells is not uncommon

Torill Sauer, department of Pathology, Akershus University Hospital, Norway

Cytological immunophenotype benign papillary tumours • benign intraductal/intracystic papilloma, including cellular due to adenosis, UDH etc – p63 positive cells in papillary fronds – HMW cytokeratins (5/6 and 14) positive in myoepithelial cells and in UDH – ER/PgR patchy positive • Intraductal/intracystic papilloma with ADH/DCIS – In the benign cell population as above – In aggregates of ADH/DCIS • p63 and HMW cytokeratin are negative • ER/PgR uniform positive

Torill Sauer, department of Pathology, Akershus University Hospital, Norway

Reporting strategy cellular papillary lesion • C2-C3-C4 • In text: – cellular papillary lesion with/without atypia; favor ……. – cellular papillary lesion with low grade atypia/population of low grade atypical cells; uncertain benign or low grade malignant

• Recommendation: histological confirmation/local excision

Torill Sauer, department of Pathology, Akershus University Hospital, Norway

Florid papillomatosis of the nipple (subareolar papillomatosis) • A benign epithelial proliferation localized within and around the collecting ducts of the nipple • < 1 % of breast specimens • Age range 20-87 yrs with a mean of 43 yrs • About 2/3 present with nipple discharge • About 1/3 present with nipple erosion or a nodule • Clinical impression might mimic Paget’s disease of the nipple

Torill Sauer, department of Pathology, Akershus University Hospital, Norway

Cytologic findings in subareolar papillomatosis • Moderate or high cellularity with a basic benign pattern • Adenosquamous nests may be apparent • Small amount of debris, inflammatory cells and siderophages may be found

Torill Sauer, department of Pathology, Akershus University Hospital, Norway

Aggregates and smaller groups, background debris

Torill Sauer, department of Pathology, Akershus University Hospital, Norway

Basically cohesive, irregular aggregates

Torill Sauer, department of Pathology, Akershus University Hospital, Norway

Irregular shapes

Torill Sauer, department of Pathology, Akershus University Hospital, Norway

Micropapillary, macrophages, naked nuclei

Torill Sauer, department of Pathology, Akershus University Hospital, Norway

Uniform nuclei with finely distributed chromatin and small nucleoli

Torill Sauer, department of Pathology, Akershus University Hospital, Norway

Little anisonucleosis, occasional hyperchromatic nuclei possible

Torill Sauer, department of Pathology, Akershus University Hospital, Norway

(Occasional) dispersed epithelial cells

Torill Sauer, department of Pathology, Akershus University Hospital, Norway

Apocrine cells may be present

Torill Sauer, department of Pathology, Akershus University Hospital, Norway

Intraductal/intracystic papillary carcinoma (in situ) • Non-invasive • Clear or blood stained nipple discharge • More peripheral lesion may present as a mass • Mx microcalcifications • Ducts or TDLU with slender, branching fibrovascular stalks covered by a single cell population of neoplastic cells • Micropapillary, cribriform and solid growth patterns also • Neoplastic, columnar cells in one or several layers • Cells deceptively bland; low grade atypia • ER/PgR positive; HER2 negative Torill Sauer, department of Pathology, Akershus University Hospital, Norway

Cytological findings 1 • Cystic • Micropapillary groups • True papillary fragments with a fibrovascular core • Denuded fibrovascular core

Torill Sauer, department of Pathology, Akershus University Hospital, Norway

Cytological findings 2 • Monotonous tumour cell population, usually with a very discrete nuclear/cellular atypia • Variable single cell population

Torill Sauer, department of Pathology, Akershus University Hospital, Norway

Intracystic papillary carcinoma in situ grade 3

Torill Sauer, department of Pathology, Akershus University Hospital, Norway

Encapsulated papillary carcinoma • A variant of papillary carcinoma characterized by fine fibrovascular cores covered by neoplastic cells of low or intermediate grade and surrounded by a fibrous capsule • In the majority of cases there are no myoepithelial cell layer within the papillae or at the periphery of the lesion • Circumscribed round mass • With or without nipple discharge • frank invasive part is usually IDC • ER/PgR positive; HER2 negative

Torill Sauer, department of Pathology, Akershus University Hospital, Norway

Cytological findings • Few macrophages • Abundant cell material • Single cell population • Fibrovascular cores

Torill Sauer, department of Pathology, Akershus University Hospital, Norway

Monolayer sheets

Torill Sauer, department of Pathology, Akershus University Hospital, Norway

Siderophages, irregular groups

Torill Sauer, department of Pathology, Akershus University Hospital, Norway

Discrete nuclear/cellular atypia

Torill Sauer, department of Pathology, Akershus University Hospital, Norway

Solid papillary carcinoma • Closely apposed expansile nodules • Delicate fibrovascular cores within the nodules • Frequent neuroendocrine differentiation • Conventional invasive growth may be present, often having mucinous or neuroendocrine features • < 1 % of breast carcinomas (???) • Occurs usually in menopausal women, mean in the seventh decade • Bloody discharge in 20-25 % • Mx “abnormality”, may be palpable • Size from few mm to several cm • ER/PgR positive; HER2 negative Torill Sauer, department of Pathology, Akershus University Hospital, Norway

Cytological findings • Few if any macrophages • Abundant cellularity • Often columnar • Intracytoplasmic vacuoles are not rare • neuroendocrine differentiation common

Torill Sauer, department of Pathology, Akershus University Hospital, Norway

(pseudo)-papillary arrangement of cells

Torill Sauer, department of Pathology, Akershus University Hospital, Norway

Low grade nuclear/cell atypia

Torill Sauer, department of Pathology, Akershus University Hospital, Norway

Often extensive dissociation in single cells In this case also neurendocrine differentiation

Torill Sauer, department of Pathology, Akershus University Hospital, Norway

Cytological features of papillary carcinomas (cystic in situ, encapsulated and solid) • May be cystic on aspiration • Cell material is usually abundant • Epithelial cells are monotonous and appear “monoclonal” • Anisonucleosis, hyperchromasia, coarse chromatin and prominent nucleoli are uncommon • Benign bipolar cells are absent from the background and myoepithelial cells are not seen within the groups • Large papillary cell clusters forming arborising arrays bearing overlapping, palisaded cells on a fibrovascular core may be present (as in papilloma) • Cells may be dispersed and the fibrovascular cores denuded • Cells are often distinctly columnar in appearance • Evaluation of invasive component not possible • Usually G1, but occasionally G2 or G3 • Microcalcifications are common findings Torill Sauer, department of Pathology, Akershus University Hospital, Norway

Reporting categories papillary carcinomas • C3-C4 • In text

– Cell material consistent with/ suspicious of papillary carcinoma; cannot evaluate invasiveness

Torill Sauer, department of Pathology, Akershus University Hospital, Norway

Invasive papillary carcinoma (WHO definition) • Predominantly papillary morphology (> 90 %) in the invasive component • No specific known clinical characteristics • Rare • No specific epidemiological data available • Main differential diagnosis is a papillary carcinoma metastatic from another organ site, particularly ovary and lung

Torill Sauer, department of Pathology, Akershus University Hospital, Norway

Diagnostic considerations cellular (benign) papillary lesions vs papillary carcinoma (1) Cellular papillary lesion

Papillary carcinoma

• Heterogeneous (“polyclonal”) cell population • Basic benign pattern, but may have a population of cells showing low grade nuclear atypia/anisonucleosis • Straight or curved tubular structures representing adenosis in papilloma • Mostly cohesive, but with single cells

• Monomorphous (“monoclonal”) cell population

• More discohesive, often extensive

Torill Sauer, department of Pathology, Akershus University Hospital, Norway

Diagnostic considerations cellular (benign) papillary lesions vs papillary carcinoma (2) • Threedimensional cells aggregates representing/resembling low grade DCIS, solid and/or cribriform can be found in both lesions • Papillary and micropapillary groups in both lesions • Fibrovascular stalks in both lesions • Debris and macrophages in both lesions • A distinct population of cells epithelial groups with positivity for p63 and HMW cytokeratins speak in favor of a benign lesion • Uniform and distinct positivity for ER/PgR speak in favor of a papillary carcinoma Torill Sauer, department of Pathology, Akershus University Hospital, Norway

Invasive micropapillary carcinoma • Composed of small, hollow and morula-like clusters of cancer cells and surrounded by clear stromal places • Usually a reversed polarity, a “in side out” growth pattern whereby the apical pole of the cells faces the stroma and not the luminal surface • 0.9-2 % of invasive breast cancers • Up to 7.4 % may show invasive breast cancers may have partial micropapillary growth pattern • Mean age as IDC • Usually present as a palpable mass • 75 % are grade 2 and 3 • ER/PgR positive; HER-2 +/- (Luminal A/Luminal B) Torill Sauer, department of Pathology, Akershus University Hospital, Norway

You will see a number of papillary lesions in the workshop

Torill Sauer, department of Pathology, Akershus University Hospital, Norway