Fibroepithelial Lesions of the Breast

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OUTLINE

• FIBROADENOMA

• PHYLLODES TUMOR FIBROEPITHELIAL LESIONS OF THE BREAST • DIFFERENTIAL DIAGNOSIS UCSF Current Issues in – CELLULAR FIBROEPITHELIAL LESIONS Anatomic Pathology 2015 – MALIGNANT PHYLLODES TUMORS – EXCISION VERSUS CORE NEEDLE BIOPSY Gregor Krings, MD PhD – IMMUNOHISTOCHEMISTRY Assistant Professor

FIBROADENOMA FIBROADENOMA

• Very common • Solitary, mobile, “rubbery” and painless palpable mass – Most common fibroepithelial lesions – Most common benign tumors of the breast • Non-palpable, mammographically detected • Calcifications (hyalinized fibroadenomas) • Broad age group • – Incidence highest in women <30 years old Rarely pain and/or bloody nipple discharge – Can occur at any age (18.5% of women >40 years old in Breast Cancer – Infarction Surveillance Consortium) – Pregnancy, prior aspiration procedure, spontaneous • Predisposing factors – No known inherited genetic alterations but risk in some families • Often <3 cm but larger tumors not uncommon – Hormonal influence • Rare in men but associated with gynecomastia, exogenous hormones, drugs • ‘Giant fibroadenomas’ up to 20 cm – Cyclosporin A (organ transplant) – Larger tumors in adolescents (juvenile fibroadenoma) – Carney complex (myxoid fibroadenomas)

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Usual-type Hyalinized Intracanalicular Pericanalicular Mixed

Myxoid Mixed

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Myxoid FA Mucinous carcinoma Myxoid FA Mucinous carcinoma

● Myxoid fibroadenoma may mimic invasive mucinous carcinoma

● Misdiagnosis on imaging - 16/17 myxoid fibroadenomas with rapid growth or size >3 cm misdiagnosed as mucinous carcinoma on ultrasound Yamaguchi Human Pathology 2011;42:419-423 ● Misdiagnosis on FNA and core biopsy Simsir 2001 Diagn Cytopathol. 2001;25:278-284

COMPLEX FIBROADENOMA COMPLEX FIBROADENOMA

● Sclerosing adenosis, papillary apocrine metaplasia, cysts >3mm or epithelial calcifications • Managed like typical FA in absence of atypia or rad-path discordance

• We do not use this term in diagnosis

Sklair-Levy M et al. AJR 2008;190(1):214-8

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CELLULAR FIBROADENOMA

• Focal or diffuse mildly increased stromal cellularity without stromal atypia – No threshold criteria for defining hypercellularity – Stromal atypia is subjective

• Stromal mitotic figures may be present (up to 2 MF/10 HPF typically acceptable)

• Overlapping features with benign phyllodes tumors

• Uniform cellularity and epithelial:stromal distribution

JUVENILE FIBROADENOMA • More common in adolescents and women <20 years old • Usual-type fibroadenoma most common in all age groups

• May mimic phyllodes tumor – Rapid growth, large size, histologic features

• Cellular stroma with pericanalicular growth • Stromal mitotic activity may be present • No stromal cytologic atypia • Uniform cellularity and epithelial:stromal distribution • ‘Gynecomastoid’ usual ductal hyperplasia

• Excision with preservation of adjacent breast

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ALH E-cadherin

● Atypia or carcinoma may involve fibroadenomas primarily or secondarily - ALH/LCIS most common - ADH/DCIS - Invasive carcinoma

ALH E-cadherin PHYLLODES TUMORS • Rare <1% primary breast tumors <2.5% fibroepithelial lesions in tertiary centers

• Age 40-50 years (but wide range, adolescence to 90) – 15-20 years older than FA, on average ADH Tangential – Tumors in adolescents often benign

• More common in Asian and Latina women – May present at younger age in this group

• Li-Fraumeni Syndrome (p53 mutations) predisposed

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PHYLLODES TUMORS PHYLLODES TUMORS

• Present as mass lesion – Rapidly growing or accelerated growth of previously “fibroepithelial neoplasms, stable lesion histologically resembling intracanalicular fibroadenomas, characterized by a double- • 4-5 cm in size, but wide range (<3-20+ cm) layered epithelial component arranged in clefts – Smaller lesions increasingly detected by screening surrounded by a hypercellular stromal/mesenchymal component which in • Not reliably distinguished from fibroadenoma by imaging combination elaborate leaf-like structures”

PHYLLODES TUMOR DIAGNOSIS BASED LEAF-LIKE GROWTH ON A CONSTELLATION OF FEATURES • Increased stromal cellularity* • Leaf-like growth ± periductal stromal condensation • Stromal heterogeneity • +/- mitotic activity* • +/- infiltrative border* • +/- stromal overgrowth* • +/- stromal cytologic atypia* • +/- malignant heterologous stroma*

* Used to establish grade

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LEAF-LIKE GROWTH LEAF-LIKE GROWTH

SUBEPITHELIAL STROMAL CONDENSATION SUBEPITHELIAL STROMAL CONDENSATION

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INTRALOBULAR STROMAL STROMAL HETEROGENEITY COMPRESSION OF FIBROADENOMA

BENIGN PHYLLODES TUMOR GRADING PHYLLODES TUMORS

Adapted from WHO Classification of Tumours of the Breast, 4 th ed. 2012

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MALIGNANT PHYLLODES TUMOR

INFILTRATIVE BORDERS

Stromal overgrowth (4x low power field) often diffuse

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MALIGNANT HETEROLOGOUS STROMA

Most commonly liposarcomatous

SATB2 is a useful marker of osseous differentiation SATB2

BORDERLINE PHYLLODES TUMOR

SATB2

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Phyllodes tumor histologic grade FEATURES PREDICTIVE OF PHYLLODES predicts local recurrence TUMOR RECURRENCE

- 605 phyllodes tumors (diagnosed over 18 years, 1992-2010) - 552 patients with clinical follow-up - 29.8/24.6 months mean/median time to recurrence ‘A.M.O.S.’ criteria

Tan PH et al J Clin Pathol 2012;65:69-76

NOMOGRAM FOR PREDICTING PHYLLODES NOMOGRAM FOR PREDICTING PHYLLODES TUMOR RECURRENCE FREE SURVIVAL TUMOR RECURRENCE FREE SURVIVAL

A. A. M. M. O. * Positive O. REQUIRES ADDITIONAL margin status S. best predictor S. VALIDATION IN OTHER of recurrence* POPULATIONS

Tan PH et al J Clin Pathol 2012;65:69-76 Tan PH et al J Clin Pathol 2012;65:69-76

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PHYLLODES TUMOR: HISTOLOGIC GRADE AND PROGNOSIS 21/48 (43.8%) 4/48 (8.3%) initially benign Benign Borderline Malignant benign tumors recurred tumors as higher grade recurred as malignant 2/16 (12.8%) initially borderline Local recurrence* 4-17% 14-25% 23-30% tumors recurred as malignant Tan PH et al J Clin Pathol 2012;65:69-76 * Margin status remains the best predictor of local recurrence

Hart WR et al. Am J Clin Pathol 1978;70(2):211-6 ● Other studies with similar results Moffat CJ et al. Histopathology 1995;27(3):205-18 - 6-19% benign tumors reported to recur as malignant De Roos WK et al. British J Surg 1999;86(3):396-9 Tan PH et al. J Clin Pathol 2012;65:69-76 Barth RJ Jr. Breast Cancer Res Treat 1999;57(3):291-5 ● Highlights importance of preventing local tumor recurrence Kim S et al. Breast Cancer Res Treat 2013 141;353-363 WHO 2012

DISTANT PHYLLODES TUMOR METASTASIS PHYLLODES TUMOR: • Stromal overgrowth and malignant HISTOLOGIC GRADE AND PROGNOSIS heterologous stromal elements are best predictors of distant spread Benign Borderline Malignant

% of phyllodes 65-70% 15-20% 10-20% • Metastasis essentially always stromal Metastasis** component only (<10% overall) 0% 0-4% 13-29%

** Essentially only malignant tumors metastasize • Lung/pleura (>75%) and skeletal system most common sites Tan PH et al. J Clin Pathol 2012 65(1):69-76 Kim S et al. Breast Cancer Res Treat 2013 141;353-363 WHO 2012

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Lung Vulva PHYLLODES TUMOR TREATMENT

• Excision with negative margins to minimize recurrence risk – 1 cm normal rim preferable (but no data to support this arbitrary margin width) – Rationale • Margin status primary predictor of recurrence • Recurrences may be of higher grade • Metastatic tumors may be preceded by local recurrences

• No routine role for radiation or chemotherapy

DIFFERENTIAL DIAGNOSIS OF Benign phyllodes Fibroadenoma FIBROEPITHELIAL LESIONS Mean age ~45-50 (but any age) ~30 y (but any age) OVERLAP Size Few cm up to 20 cm <3 cm; rarely up to 20 cm OVERLAP benign borderline malignant Growth May be rapid; rapid growth of previously Stable stable mass NOT RELIABLE

Clinical and radiologic features do not reliably distinguish between phyllodes tumor and fibroadenoma

MAY BE PROBLEMATIC IN Jacobs et al Am J Clin Pathol. 2005 Sep;124(3):342-54 EXCISIONS AND CORE BIOPSIES WHO 2012

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BENIGN FIBROADENOMA PHYLLODES CELLULAR FIBROADENOMA BENIGN PHYLLODES TUMOR Present, well-developed Leaf-like architecture ± periductal condensation Usually absent, may be focal

Stromal heterogeneity May be present Absent

Distribution of epithelium and stroma Often non-uniform Uniform

Hypocellular or Stromal cellularity Mild Mild (*cellular and juvenile fibroadenoma) Rare-up to 2/10 HPF allowed Stromal mitoses Few (0-4/10 HPF) (*cellular and juvenile fibroadenoma) Cellular atypia Mild Absent (*stromal giant cells)

Squamous metaplasia Rarely present Virtually absent

BENIGN FIBROADENOMA PHYLLODES Present, well-developed Leaf-like architecture ± periductal condensation Usually absent, may be focal

Stromal heterogeneity May be present Absent

Distribution of epithelium and stroma Often non-uniform Uniform

Squamous metaplasia Rarely present Virtually absent

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PITFALLS PITFALLS

1. Fibroadenomas may have focal leaf-like growth. 1. Fibroadenomas may have focal leaf-like growth.

2. Phyllodes tumors may lack leaf-like growth. 2. Phyllodes tumors may lack leaf-like growth.

3. Phyllodes tumors may be less cellular or mimic 3. Phyllodes tumors may be less cellular or mimic fibroadenomas in some areas due to heterogeneity. fibroadenomas in some areas due to heterogeneity. 4. Benign multinucleated stromal giant cells in 4. Benign multinucleated stromal giant cells in fibroadenomas should not be mistaken for atypia. fibroadenomas should not be mistaken for atypia. 5. Mitotic activity does not equate with phyllodes tumor. 5. Mitotic activity does not equate with phyllodes tumor.

FIBROADENOMA WITH FOCAL FIBROADENOMA WITH FOCAL LEAF-LIKE GROWTH LEAF-LIKE GROWTH

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Juvenile fibroadenoma with focal PITFALLS leaf-like growth 1. Fibroadenomas may have focal leaf-like growth.

2. Phyllodes tumors may lack leaf-like growth.

3. Phyllodes tumors may be less cellular or mimic fibroadenomas in some areas due to heterogeneity. 4. Benign multinucleated stromal giant cells in fibroadenomas should not be mistaken for atypia. 5. Mitotic activity does not equate with phyllodes tumor.

PHYLLODES TUMOR WITHOUT PHYLLODES TUMOR WITHOUT LEAF-LIKE GROWTH LEAF-LIKE GROWTH

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PITFALLS PHYLLODES TUMOR HETEROGENEITY

1. Fibroadenomas may have focal leaf-like growth.

2. Phyllodes tumors may lack leaf-like growth.

PHYLLODES TUMOR HETEROGENEITY PHYLLODES TUMOR HETEROGENEITY

CNB DIAGNOSIS: FIBROADENOMATOUS CHANGE

* Adequate sampling required

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PHYLLODES TUMOR HETEROGENEITY PITFALLS

1. Fibroadenomas may have focal leaf-like growth.

2. Phyllodes tumors may lack leaf-like growth.

Benign multinucleated stromal giant cells PITFALLS

1. Fibroadenomas may have focal leaf-like growth.

2. Phyllodes tumors may lack leaf-like growth.

CD34 3. Phyllodes tumors may be less cellular or mimic fibroadenomas in some areas due to heterogeneity. Atypical stromal cells of phyllodes tumor 4. Benign multinucleated stromal giant cells in fibroadenomas should not be mistaken for atypia. 5. Mitotic activity does not equate with phyllodes tumor. - Overlap with cellular/juvenile fibroadenomas

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• SOME FIBROEPITHELIAL LESIONS CANNOT BE EASILY CLASSIFIED AS FIBROADENOMA OR PHYLLODES TUMOR

• “DIAGNOSIS OF FIBROADENOMA IS PREFERABLE WHEN THERE IS HISTOLOGICAL AMBIGUITY TO AVOID OVERTREATMENT”. WHO 2012 ● 21 pre-selected challenging cellular fibroepithelial lesions separately reviewed by 10 breast pathologists (1-2 slides per case) OUR APPROACH: ● Uniform agreement in only 2 cases (9.5%): 1 fibroadenoma, 1 phyllodes “CELLULAR FIBROEPITHELIAL LESION; SEE COMMENT.” ● 4 (19%) cases equally split between cellular fibroadenoma and phyllodes - Describe features and diagnostic difficulty/ambiguity ● 43% of cases, diagnoses ranged from fibroadenoma to borderline - Relate low recurrence potential, especially if margins phyllodes frankly positive

CORE BIOPSY OF CELLULAR FIBROEPITHELIAL LESIONS

Cellular FA Benign PT

benign borderline malignant

Cellular FA Benign PT

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Features of cellular fibroepithelial lesions on core biopsy that may predict phyllodes tumor???

• Increased stromal cellularity (marked>moderate) PHYLLODES TUMOR FIBROADENOMA • Increased mitotic activity (>2 MF/10 HPF) • Excision with rim of normal • Enucleation • Stromal heterogeneity tissue • No (?) recurrence potential • Tissue fragmentation • Recurrence potential • Adipose tissue within lesional stroma • Stromal expansion (no epithelium in 100x field) • Ill-defined borders • Stromal cell atypia • Ki-67 index ≥5% • Ki-67 6% (range 10-18%) in PT versus 1.6% (range

0-4.4%) in FA Jacobs TW et al Am J Clin Pathol 2005;124:342-354 Lee AHS et al Histopathology 2007; 51; 336-244 Optimize cosmesis and avoid additional surgery Jara-Lazaro et al Histopathology 2010; 57:220-232 Tsang AK et al Histopathology. 2011;59(4):600-8 Yasir S et al Am J Clin Pathol 2014;142:362-369

Features of cellular fibroepithelial lesions on core biopsy that may predict phyllodes tumor???

• Increased stromal cellularity (marked>moderate) • Increased mitotic activity (>2 MF/10 HPF) • Stromal heterogeneity • Tissue fragmentation • Adipose tissue within lesional stroma • Stromal expansion (no epithelium in 100x field) • Ill-defined borders • Stromal cell atypia • Ki-67 index ≥5% (favor phyllodes tumor) • Ki-67 6% (range 10-18%) in PT versus 1.6% (range

0-4.4%) in FA Jacobs TW et al Am J Clin Pathol 2005;124:342-354 Lee AHS et al Histopathology 2007; 51; 336-244 Jara-Lazaro et al Histopathology 2010; 57:220-232 Tsang AK et al Histopathology. 2011;59(4):600-8 Yasir S et al Am J Clin Pathol 2014;142:362-369

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Features of cellular fibroepithelial lesions on core Stromal heterogeneity of cellular fibroepithelial lesions on CNB biopsy that may predict phyllodes tumor???

• Increased stromal cellularity (marked>moderate) • Increased mitotic activity (>2 MF/10 HPF) • Stromal heterogeneity • Tissue fragmentation • Adipose tissue within lesional stroma CNB Excision • Stromal expansion (no epithelium in 100x field) • Ill-defined borders • Stromal cell atypia • Ki-67 index ≥5% • Ki-67 6% (range 10-18%) in PT versus 1.6% (range

● No histologic features can reliably predict phyllodes DIFFERENTIAL DIAGNOSIS OF tumor over cellular fibroadenoma on CNB - Cellularity and mitotic activity most useful FIBROEPITHELIAL LESIONS - Stromal heterogeneity

● Constellation of features may favor phyllodes tumor in some cases benign borderline malignant

DESCRIPTIVE DIAGNOSIS: FIBROEPITHELIAL LESION WITH CELLULAR STROMA – Recommend excision for final classification – 41% probability of PT on excision Jacobs TW et al Am J Clin Pathol 2005;124:342-354 MAY BE PROBLEMATIC IN EXCISIONS AND CORE BIOPSIES

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AMPLE TUMOR SAMPLING TO IDENTIFY EPITHELIAL COMPONENT

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DIFFERENTIAL DIAGNOSIS DIFFERENTIAL DIAGNOSIS Potential neoadjuvant Metaplastic carcinoma chemotherapy Metaplastic carcinoma Sentinel lymph node Phyllodes tumor Surgical management Phyllodes tumor No sentinel lymph node Sarcoma Sarcoma

KERATIN AND p63 EXPRESSION IN PHYLLODES TUMORS

Auger M et al. Arch Pathol Lab Med 1989 Nov;113(11):1231-5 Aranda FI et al. Path Res Pract 1994;190(5):474-81 Focal (1-5% of stromal cells) CK and Barbareschi M et al . Am J Surg Path. 2001;25(8):1054-60 p63 staining in all cases Dunne B et al. Human Pathology 2003;34(10):1009-15 Koker MM et al. Am J Surg Path 2004;28(11):1506-12 Leibl S et al. Am J Surg Path 2005;29(3):347-53 Cytokeratin Chia Y et al. J Clin Pathol 2012;65(4):339-47 Cimino-Mathews A et al. Am J Surg Path 2014;38(12):1689-96

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Sarcomatoid carcinoma MALIGNANT PHYLLODES TUMOR Malignant PT Borderline PT Benign PT Fibroadenoma

8/14 (57%) malignant PT were p63 positive 3/14 (21%) malignant PT were CK positive - Most (63%) focal (1-5%) - Cytokeratins AE1/3, 34βE12 and CK8/18 - None with >30% p63+ stromal cells - All focal (1-5%) - p40 more specific but less sensitive for sarcomatoid carcinoma cytokeratin

MALIGNANT PHYLLODES TUMOR

• Phyllodes tumors may express cytokeratins and/or p63 - Expression is typically focal or patchy (<5%)

• Cytokeratin or p63 expression, especially in core biopsies, cannot be used to exclude phyllodes tumor – Strong, diffuse CK staining may favor metaplastic carcinoma

p63 cytokeratin

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CD34 in Fibroepithelial Lesions

* alternate grading scheme ** patchy staining in all PT; median 40% cells staining in malignant PT vs 80% cells staining in benign/borderline PT Strong diffuse CD34 *** TMA † Focal staining only (<5% cells) expression essentially Spindle cell carcinoma are essentially excludes metaplastic carcinoma always CD34 negative

Silverman JS et al. Histopathology. 1996;29(5):411-9 Chia Y et al. J Clin Pathol. 2012;65(4):339-47 Chen et al. J Surg Res. 2000;94(2):84-91 Ho SK et al. Histopathology. 2013;63(3):393-406 CD34 EXCISION – MALIGNANT PT Moore T and Lee AH. Histopathology. 2001;38(1):62-7 Cimino-Mathews A et al. Am J Surg Path. 2014;38(12):1689-96 Noronha Y et al. Int J Surg Path. 2011;19(2): 152 -8 Lee AHS. Histopathology 2008;52:45 -57

MALIGNANT PHYLLODES TUMOR

CD34 pankeratin p63

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Aberrant nuclear β-catenin can be seen in both • CD34 positivity essentially excludes phyllodes tumor and metaplastic carcinoma metaplastic carcinoma – 82-100% of mammary fibromatosis • Malignant phyllodes tumors are often CD34 – 23% metaplastic carcinomas negative – 72-83% of phyllodes tumors – CD34 expression is negatively correlated with • More common in benign than malignant PT phyllodes tumor grade – 94% benign vs 57% malignant PT (Lacroix-Triki et al 2010) – If positive, staining in malignant tumors is often – 12.5% malignant PT (Sawyer et al 2002) focal or patchy (<5%)

Sawyer EJ et al. J Pathol 2002;196(4):437-44 Lacroix-Triki M et al. Modern Pathology;2010;23(11):1438-48 Abraham SW et al. Hum Pathol; 2002:33:39-46

Excision – Malignant phyllodes tumor

CD34 β-catenin

Multiple keratins (AE1/3, Cam 5.2, MNF116, CK5/6) negative

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SUMMARY

• Fibroadenoma and variants

• Phyllodes tumor – Diagnosis requires constellation of features – Pitfalls in diagnosis – Diagnosis and categorization has clinical significance – Some lesions may defy accurate categorization: err on conservative side

• Core biopsy of cellular fibroepithelial lesions requires excision for definitive classification

• Malignant phyllodes tumor may mimic metaplastic carcinoma – Additional sampling and/or immunohistochemistry may be useful – Core biopsy diagnosis of spindle cell neoplasm

Questions?