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
C07-621 C07-621
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
S07-6169
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
S07-977
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