Breast Cytology

Teresa Alasio, MD

October 20, 2010

The Case for Breast Cytology

Increasing use of core needle biopsy (CNB) for breast lesions has led to diminished use of FNA in recent years

BUT….there is still a place for FNA in the evaluation of both palpable and mammographically identified breast abnormalities

Advantages of Breast FNA

Cost Minimally invasive procedure Spares patient open biopsy, especially if benign Complications are rare

Bleeding Infarction

Adequacy Are you in the lesion?

Triage Markers, lymph node assessment

Rapid diagnosis allows for pre-operative/pre-treatment discussion of therapeutic options

Specimen Types

Nipple discharge cytology Benign vs. malignant nipple secretions Patient usually does not have a palpable or

mammographic abnormality

FNA Some limitations

Accuracy of FNA is highly operator dependent IDC vs. invasive carcinoma Papilloma vs. papillary carcinoma (“papillary lesion”)

Nipple Secretions – Benign

Sparsely cellular

Ductal cells

Foam cells

Inflammatory cells

RBCs

Nipple Secretions – Malignant

Clusters and single enlarged ductal cells Variability in nuclear size and shape Stripped nuclei Nucleoli Acute inflammation Blood Necrotic debris

Reporting Terminology

Negative for malignant cellsAdequate specimens with minimum of 5-6

well preserved cell groupings

AtypicalLow probability for malignancy but needs a

biopsy to confirm

Reporting Terminology

Suspicious Probably malignant but atypical cells are too few,

poorly preserved or obscured by blood or inflammation Patient needs a biopsy

Positive for malignant cells Unequivocal features of malignancy Patient will definitely have surgery

Non-diagnostic (inadequate or unsat) Too few well-preserved cells <6 epithelial cell clusters of at least 5-10 cells or <10

intact bipolar cells per 10 medium power fields

Evaluation of the Specimen

Low powerCellularity

Benign or malignantCell arrangements

sheets, clusters, branching papillary clusters, isolated cells

Background elements

Inflammatory cells, debris, blood, mucin

High powerTypes of single cells

Epithelial vs. mesenchymal (naked nuclei)

Nuclear characteristicsLocation, size, shape,

chromatin, nucleoli

Cytoplasmic characteristics

Apocrine change, cytoplasmic vacuolization

Normal Breast

15-25 lactiferous ducts Begin at nipple, branch and then end in terminal

duct lobular unit (TDLU)

Lobule Terminal duct and many small ductules (acini)

All ducts are lined by a double layer of cells Epithelial and myoepithelial cells

Benign Conditions of Breast

Fibrocystic changes Non-proliferative Proliferative

Fibroadenoma Pregnancy and lactational changes Fat necrosis Radiation change Mastitis Subareolar abscess Gynecomastia

Fibrocystic Changes

Most common

Cysts of varying size

Apocrine metaplasia

Fibrosis

Adenosis

Non-proliferative FCC

Significant intraductal hyperplasia is not present

Lesion is predominantly fibrous

Apocrine cells

Foam cells

Small ductal cells

Non-proliferative FCC

Proliferative FCC

Variable in severity and degree of atypiaModerate and florid ductal hyperplasia,

ADH, ALHHistologic criteria, not cytologic

Crowding and nuclear atypia give clues to cytologic diagnosis of ductal proliferative lesions

Proliferative FCC

Without atypiaSheets and tight

clusters of cells without significant overlapRegular cellular

spacingFinely granular

chromatin patternInconspicuous to

small nucleoli

With atypiaSheets and tight clusters

of cells with significant nuclear overlapRegular to irregular

cellular spacingFinely to coarsely

granular chromatinProminent to multiple

nucleoli

Proliferative FCCWithout atypia With atypia

Fibroadenoma

Most common benign tumor of female breast

Seen in women of any age

Circumscribed, freely movable, rubbery masses that result from both stromal and glandular proliferation

Fibroadenoma – Cytomorphology

Hypercellular Large honeycomb sheets 3D clusters with antler-like configuration Bipolar cells and spindled or oval naked nuclei Fibrillar stromal fragments

Bluish gray with Pap stain, metachromatic with DQ

Nuclear atypia Some loss of epithelial cohesion Regular nuclear spacing Finely granular chromatin pattern Small round nucleoli

Fibroadenoma

Fibroadenoma

Pregnancy and Lactational Changes

Ductules of TDLU become hyperplastic and manifest cytoplasmic vacuolization and luminal secretion

May result in lactating adenoma

Pregnancy Associated Changes

Uniform cells Granular vacuolated cytoplasm Prominent nucleoli Proteinaceous background

Lactating Adenoma

Moderately cellular specimen

Numerous isolated epithelial cells

Nuclear enlargement without variation in size/shape

Prominent nucleoli Abundant delicate and

wispy granular or finely vacuolated cytoplasm

Lactating Adenoma

Cytoplasm easily strips awayFoamy proteinaceous

backgroundMany naked nuclei

Occasional small ductal cell clusters and portions of lobules

Do not confuse with invasive lobular carcinoma which can look similar (also NHL can look similar!)

Galactocele

Abundant foamy macrophages

Benign epithelial cells

Fat Necrosis

Can mimic carcinoma both clinically and mammographically

History very importantMany patients have had previous surgery

or trauma to the breast

Fat Necrosis

Hypocellular smears, predominantly histiocytes Fine to coarse cytoplasmic vacuoles Histiocytes can also be seen in silicone granulomas, but

the vacuoles are larger and look more like signet rings

Round to kidney-bean shaped nuclei Low N/C ratio Multinucleated and atypical cells Background of neutrophils, lymphocytes and

plasma cells

Fat Necrosis

Radiation Change

Increasing frequency due to widespread use of lumpectomy and radiation to treat patients with breast cancer

Often seen in conjunction with fat necrosis

Radiation Change

Hypocellular aspirate Nuclear and cellular

enlargement Low N/C ratio Hyperchromatic nuclei with

round, regular outline and prominent nucleoli

Coarse cytoplasmic vacuoles, some containing inflammatory cells

Binucleation and multinucleation

Mastitis

Acute mastitis = bacterial infection Lactating women

Chronic mastitis can be a sequel to acute mastitis or associated with duct ectasia Dilatation of large and intermediate-size ducts with

surrounding inflammatory infiltrate of lymphocytes and plasma cells with or without a mass

Granulomatous mastitis Infectious (tb or fungal) Presents as a firm mass

Mastitis – Cytomorphology

Acute mastitisAbundant neutrophilsOccasional groups of

reactive ductal cells with enlarged nuclei and prominent nuceloli

Chronic Mastitis

Abundant, amorphous, granular debris from inspissated ducts

Inflammatory infiltrate composed of lymphocytes and plasma cells

Granulomatous Mastitis

Clustered epithelioid histiocytes

Abundant vacuolated cytoplasm

Round or folded nuclei Dispersed chromatin

texture Large nucleoli Giant cells, lymphocytes,

plasma cells and eosinophils

Rare clusters of benign ductal cells

Subareolar Abscess

“recurring subareolar abscess”Inflammatory conditionArises in the areola

squamous metaplasia of lactiferous ducts subsequent keratin plugging and rupture of

the ducts

Can recur and form sinus tracts

Subareolar Abscess

Numerous anucleate squames admixed with neutrophils

Histiocytes and MNGs

Occasional groups of atypical reactive ductal cells

Fragments of granulation tissue

Subareolar Abscess

Gynecomastia

Resembles fibroadenoma Low, moderate or high

cellularity Groups of ductal cells

with small oval nuclei, scant cytoplasm and little variation in size and shape

Isolated bipolar cells Naked nuclei

Papillary Neoplasms

Intraductal papillomas (IDP) usually solitary Arise in subareolar lactiferous ducts

Bloody nipple discharge

Can present with subareolar mass requiring FNA

Papillary Carcinoma

1-2% of breast carcinomas

Predominant growth pattern is frond-like

Invasive or non-invasive

Cystic or solid

Favorable prognosis

Papilloma vs. Papillary Carcinoma

Impossible to establish by FNA

Call it a “papillary lesion” and leave it

Recommend excisional biopsy

Papillary Neoplasms

Favor benignModerate to highly cellular

specimens3D papillary groupsFibrovascular coresFlat sheets with myoepisRare isolated cellsPolymorphic small, cuboidal or

columnar cellsRound to oval nuclei with finely

granular chromatinNucleoli may be presentFoam cells, apocrine metaplasia

and inflammation may be present

Favor malignantModerate to marked cellularityPapillary clusters and

cribriform/tubular architecture with absence or paucity of myoepisNumerous isolated cellsUniform tall and columnar cellsElongated uniform nucleiNaked nuclei but no bipolar cellsBlood and hemosiderin-laden

macrophages common

Papillary Neoplasms

Papillary lesion on cytologyPapilloma on excision

Papillary Neoplasm

Papillary lesion on cytologyDCIS, papillary type on excision

Phyllodes Tumor

Biphasic tumors (like fibroadenomas)Epithelial and stromal proliferation

Less common than fibroadenomas<1% of all breast tumors

Benign or malignantCan’t make distinction by FNA

Phyllodes Tumor

Biphasic pattern

Cellular stroma

Phyllodes Tumor – Cytomorphology

Similar to fibroadenoma with more cellular stromal component

Sometimes marked stromal atypia with numerous mitotic figures

Pronounced epithelial atypia mimicking carcinoma

Carcinoma of Breast

Invasive ductal carcinoma

Invasive lobular carcinoma

Medullary carcinoma

Mucinous (colloid) carcinoma

Tubular carcinoma

Metaplastic carcinoma

Invasive Ductal Carcinoma

65-80% of all breast cancers

Solid tumor, palpable

Gritty consistency

Most IDCs are diagnostic on FNA

Scirrhous carcinomas have dense fibrosis and may result in non-diagnostic FNAs

Invasive Ductal Carcinoma – Cytomorphologic Features

Hypercellular Isolated cells and poorly cohesive clusters of cells Eccentric nuclei often protruding from the cytoplasm Enlarged, variably hyperchromatic nuclei, but can vary

considerably in size and shpae Fine or coarsely granular chromatin pattern Small or large and prominent, and irregularly shaped

nucleoli Usually clean background, but can see inflammation,

blood and granular debris

Invasive Ductal Carcinoma

C06-4855C06-4855

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Invasive Ductal Carcinoma

C07-621

IDC vs. DCIS

Ductal carcinoma in-situ (DCIS) is in the differential when considering IDC

Controversial as to whether true infiltration of fibrofatty tissue can be identified on smears

IDC – Diagnostic Pitfalls

Well-differentiated ductal carcinomas can be a cause of false negatives Confused with fibroadenomas or phyllodes tumors Look for isolated cells with nuclear atypia and

hyperchromasia Fibroadenomas have single small uniform nucleoli Stromal fragments more often seen in fibroadenomas and

phyllodes tumors (biphasic) Pregnancy and lactational changes can also mimic

carcinoma Numerous isolated cells and prominent nucleoli Absent nuclear hyperchromasia and nuclear atypia

Invasive Lobular Carcinoma 5% of all invasive breast

cancers

Differential diagnosis is with well-differentiated ductal carcinoma

Very difficult to diagnose by FNA because of scant cellularity

Impossible to distinguish ILC from LCIS by FNA

Invasive Lobular Carcinoma – Cytomorphologic Features

Often sparsely cellular because of marked stromal fibrosis

Predominantly isolated cells with small groups or linear arrays

Small to mid sized tumor cells

Invasive Lobular Carcinoma

Cytoplasmic vacuoles (signet ring)

Hyperchromatic, often kidney bean-shaped nuclei

Usually small nucleoli, but rarely large nucleoli

Diagnosis?

Medullary Carcinoma

5-7% of all breast tumors Well-circumscribed

May be mistaken clinically for a fibroadenoma

Large, poorly differentiated cells with scant stroma and marked lymphoid infiltrate

Can be cystic because of hemorrhage and necrosis

Differential diagnosis is with chronic mastitis, intramammary lymph nodes, lymphoma or IDC

Medullary Carcinoma – Cytomophologic Features

Hypercellular smears Numerous isolated cells and loose clusters Markedly enlarged, vesicular nuclei Prominent and often irregular macronucleoli Numerous mitoses Granular scarce to abundant cytoplasm Many lymphocytes and some plasma cells

Diagnosis?

Mucinous (Colloid) Carcinoma

2% of invasive breast cancersFocal mucinous differentiation can be seen

in 2% of other breast carcinomas

Better prognosis than IDCCannot distinguish pure mucinous

carcinoma from IDC with focal mucinous change on FNA

Mucinous Carcinoma

Tightly cohesive 3D balls of cells

Mucinous background staining red-violet with Romanowsky stain and green-purple with Pap stain

Branching capillary structures

Uniform nuclei Small vacuoles in

cytoplasm

Diagnosis?

Tubular Carcinoma

<2% of breast carcinomas Well differentiated tumorwell-defined tubules

lined by single layer of neoplastic cells and surrounded by dense fibrous stroma

Dx of tubular carcinoma is reserved for cases where tubules constitute >75% of the total tumor

Better prognosis than IDC Need biopsy to make definite diagnosis

Tubular Carcinoma

Hypocellular smear because of dense fibrosis

Predominantly cohesive, often angular clusters

Some dyshesion Uniform, medium sized

tumor cells with round uniform nuclei

Finely granular chromatin Small nucleoli Occasional cells have large

cytoplasmic vacuoles

Diagnosis?

C07-5055

Granular Cell Tumor

Relatively common neoplasms derived from Schwann cells

Most common in trunk and tongue of middle aged adults

Slowly growing and more common in females

Granular Cell Tumor

Bare nuclei in granular background

Uniform cellular appearance

Small nuclei, central or eccentric

Abundant granular cytoplasm

S-100, NSE and NKI-C3 positive

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C07-5055

Diagnosis?C07--622

Diagnosis?

C07-622

C07-622

Small Cell Carcinoma

Can be primary breast or metastatic

History necessary to determine which

Cellular smears Small malignant cells

with high N/C ratio Molding and crush

artifact are evident on smears

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Diagnosis?

Adenoid Cystic Carcinoma

<0.1% of breast cancers

Morphologically and cytologically identical to salivary gland tumor of the same name

Excellent prognosis (unlike the salivary gland counterpart)

Adenoid Cystic Carcinoma

Hypercellular smears

Nests of cohesive small cells

Uniform round or oval nuclei and scant cytoplasm

Hyperchromatic nuclei with coarsely granular chromatin and small nucleoli

Round globules that stain bright red or purple with Romanowsky stain and pale green with Pap stain within the nests

Other Uncommon Breast Tumors

Non-Hodgkin lymphomaDLBCLFollicular lymphomaMALT

SarcomaRareMFHLiposarcomaOsteosarcomaRhabdoAngiosarcoma

Most common

Metastatic tumorsLungHCCMelanomaProstateRenal