Breast Pathology
BREAST
NORMAL
Objective
§ Normal vs physiologic changes (lactional, atrophy) vs congenital variations
§ FCC, FA, fat necrosis, duct ectasia, proliferative such as papilloma, HP, adenosis
§ DCIS, LCIS, IDC and special variants
§ Classify DCIS, understand currnet clinical implications of architectural types and nuclear grade
§ Synoptic reports for DCIS and IDC
§ Benign vs atypical and RF for subsequent cancer development
§ Phylloides, DDxx it from similar benign or malignant
§ Interpret HR studies
§ Paget’s disease
§ Understand limitations of needle core biopsies
§ Role of FNA
Structures
§ Collecting ductà lactiferous sinusà segmental ductà terminal duct lobular unit[1]
§ Lobules proliferate at menarche (ducts end blindly prior to this)
Cells and IHC
§ Epithelial cellsà LMK[2], ER/PR
Ø Luminal epithelial cells: CK7/8/18/19, MUC1, epithelial cell adhesion molecules
Ø Basal cellsà CK5/6/14, SMA, CALLA, S100, p63
Ø Precursor: CK5/6[3]
§ MEC[4]à p63, SM myosin heavy chain, SMA[5], CD10, calponin, caldesmom, maspin, S100
§ BMà collagen IV, reticulin, laminin
§ Intralobular stroma
§ Interlocular stroma
Nipple
§ SM bundles
§ Sebaceous glands
CONGENITAL
§ Hypoplasia[6]: Turner, Becker nevus
§ Congenital nipple inversion (difficult breastfeeding)
§ Macromastia
§ Supernumerary nipple: milk line from axilla to inguina
§ Axillary breast tissue: mistaken for LN and breast cancer can occur here
FROZEN SECTION
§ Limitations
Ø Benign sclerosing lesions (sclerosing adenosis, radial scar)
Ø Papillary lesions
METAPLASIA
Types
§ Apocrine[7]
§ Clear cell
§ Chondroid
§ Mucinous
§ Osseous
§ Sebaceous
§ Squamous
MICROCALCIFICATION
Types
§ Dystrophic[8]: secondary to degenerative changes, often found within fibrous stroma or inside ducts or comedonecrosis[9]
§ Metastatic:
Types by composition[10]
§ Ca phosphate (no1)
Ø Dark blue under light microscope, non polarizable
Ø Radiopaque
Ø In both benign and malignant
§ Ca oxalate
Ø Transparent under light microscope, polarizable or silver stain+
Ø Radiopaque
Ø Benign
Lesions with microcalcifications
§ FCC (no1): including fibroadenomatoid HP
§ Vascular calcification
§ FA: “heavy and coarse”
§ Duct ectasia
§ Sclerosing adenosis: “powdery”
§ Atrophic lobules
§ DCIS: “small in clusters, either linear or branching”
§ Carcinoma
Features of malignant microcalcifications
§ Clustering
§ Pleomorphism (sizes, density and shapes)[11]
§ Rod-shaped or branching
§ Ductal distribution
Limitation of imaging
§ <0.1mm not visible
Incidence
§ 1/5 of benign tissue and 1/2 of carcinomaà more in malignant
Processing
§ Have specimen radiography to confirm that calcified areas have been excised
§ Water insoluble because same composition as renal stonesà no need to use alcohol fixative
SURGICAL PROCEDURES
Name the different types of breast procedures.
§ FNA
§ Core biopsy
Ø US guided core biopsy
Ø Stereotactic needle core biopsy
§ Incisional biopsy
§ Excisional biopsy[12]
Ø Breast without skin
Ø Lumpectomy vs wide excision?
Ø +/-sentinel node biopsy
Ø +/-axillary LN dissection
§ Mastectomy[13]
Ø Simple[14]: whole breast with nipple and skin so that no breast tissue is left but no muscle or LN removal
Ø Modified radical
Ø Quadrantectomy[15]: partial mastectomy with skin, but not nipple. Also includes removal of lining over chest muscles below tumor and usually some LN. Usually for stage 1 and 2 tumors. Can combine with axillary dissection
Ø Radical: with muscles
INFLAMMATION
Types
§ Acute mastitis
§ Mammary duct ectasia
§ Fat necrosis
§ Granulomatous mastitis
§ Diabetic mastopathy
1. ACUTE MASTITIS[16] (acute purulent mastitis)
Clinical
§ Post partum women[17]
§ S aureus (more localized), Strep (more diffuse)
Micro
§ PMN in lumen of large duct up to abscess
2. DUCT ECTASIA[18]
Define
§ Large duct dilation with periductal inflammation and fibrosis
Clinical
§ Older women 40-50, mostly multiparous, tender, ill-defined subareolar nodule with cheesy secretion, nipple retraction[19]
§ Common
Micro
§ Dilated ducts filled with granular necrotic debris and lipid-laden macrophages
§ Periductal chronic inflammation[20]
§ Microcalcification common
§ Late stage: eventually obliteration of gland with garland formation (obliterated duct lumen surrounded by a ring of epithelial lined tubule structures)
§ +/-granulomas if ruptured duct
§ No: epithelial HP
Outcome
§ Completely benign
3. FAT NECROSIS
Clinical
§ History of trauma, radiation, surgery, duct rupture
§ Firm mass, skin retraction
Gross
§ Skin retraction
Micro (Steinberg, Rosai)
§ Early: hemorrhage, anucleated fat cells surrounded by foamy macrophages[21]
Ø PMN, MGC, lymphocytes, plasma cells
§ Later[22]: granulation tissue with fibrous capsule formation, calcification, hemosiderin
4. GRANULOMATOUS MASTITIS[23]
Define
§ Idiopathic granulomatous mastitis with lobulocentric distribution
Clinical
§ Young 20-40, recent pregnancy, tender mass
Etio
§ AI[24]
Micro
§ Noncaseating granulomas[25] centered on lobule
§ +/abscess
§ Diagnosis of exclusion[26]: no FB, no bugs, no duct rupture
DDX
§ Breast implant: clear spaces of varying sizes
§ Perilobular mastitis: granulomatous inflammation around a lobuleà is this duct rupture?
§ Usuals
Ø Sarcoidosis
Ø Infectious (TB, fungal, bacteria (shisto, leprosy)
Ø FB
Ø Neoplastic (HD)
Ø Vasculitis (Wegener’s, Churg, RA)
5. SCLEROSING LYMPHOCYTIC LOBULITIS[27]
Define
§ Perilobular and perivascular lymphocytic infiltrate
Etio
§ AI perhaps
Clinical
§ Older[28], multifocal painful masses
§ Other AI disorders such as DM1 (HLADRA4-5?)
Micro[29]
§ Perilobular and perivascular lymphocytes (B)
§ Very WC
§ Lobular atrophy and fibrosis
§ +/-lymphoid follicles
Complication: lymphoma?
§ No risk for lymphoma (Rosai)
DDX
§ Duct ectasia: centered on ducts, not WC
§ Granulomatous mastitis: granulomas
6. BREAST IMPLANT (silicon granuloma)
Imaging
§ Fibrous capsule, calcification
§ Snowstorm on US
Micro
§ FB giants
§ Variably sized clear spaces[30][31]à bubbly
§ Fibrosis
§ Pseudosynovium[32] on surface, fibrous capsule
Ø Sometimes pseudosynovial HP due to texture of implant
Risk: cancer?
§ No
DDX
§ LS:
§ Fat necrosis: less size variation
§ Mucinous carcinoma (signet-ring)
FIBROCYSTIC CHANGES
Clinical
§ Premenopausal[33], nodules or tenderness, due to altered hormone ratio[34]
RR
§ RR=1 for non-proliferative or mild UDH
§ RR=2 for florid UDH
Treatment
§ No need for excision when present on biopsy or resection (true even for florid UDH)
Gross
§ Fibrosis, blue dome cyst, clear cysts
Micro
1. Types of nonproliferative
§ Adenosis
§ Fibrosis
§ Apocrine metaplasia[37]
§ Fibroadenomatoid change: stromal proliferation resulting in slit-like spaces without sharp circumscription
§ +/-chronic[38] inflammation
§ +/-microcalcifcations
2. Types of proliferative
§ Adenosis
Ø Sclerosing adenosis
Ø Microglandular adenosis
Ø Radial scar
§ Omas
Ø FA
Ø Intraductal papilloma
Ø Nipple adenoma
§ HP
Ø Columnar cell lesions (CCH, FEA)
Ø Collagenous spherulosis
Ø UDH
Ø ADH
Ø ALH
2. COLUMNAR CELL LESIONS (BLUNT DUCT ADENOSIS)
Micro
§ Columnar cells (≥1 layers[39]) with perpendicular elongated nuclei
§ Apical snouts
§ Cystic dilation
§ Usually flat, occasionally luminal tufting (short micropapillae)
§ Preserved lobular architecture
§ No atypia by definition
§ +/-microcalcifications
Clinical
§ Associated with lobular neoplasia
RR
§ RR=1.5-2
DDX
§ Cystic hypersecretory change: single layer but not apical snout
ADENOSIS
Define
§ Increased number of glandsà 2x normal lobule size[40] (Farmer)
Types
§ Pregnancy-induced[41]
§ Sclerosing adenosis[42]
§ Radial scar
Etio
§ Hormonal stimulation (Steinberg)
DDx
§ UDH: thickening (>2 layers) of epithelium without glandular proliferation
RR
§ RR=1 (Steinberg)
SCLEROSING LESIONS
Types
§ Sclerosing adenosis
§ Radial scar
SCLEROSING ADENOSIS
Define
§ Benign sclerosing lesion in TDLU
§ Distorted ducts surrounded by MEC in fibrotic stroma
Imaging
§ Because of sclerosis, often contains calcifications (Steinberg)
Treatment
§ No excision needed if found on both needle core or excision specimen unless atypiaà watchful[43][44]
RR
§ RR=1 (Steinberg)
Clinical
§ Any age, incidental microcalcifications on imaging[45]
§ Caused by excess estrogen
§ Solitary or multiple[46]
Treatment
- No need to excise
Micro[47]
§ Lobulocentric[48] adenosis[49]
§ Distorted and elongated ducts[50][51][52]
§ Sclerotic stroma[53]
§ Bland cytology
§ Apocrine adenosis if apocrine metaplasia[54]
§ Nodular sclerosing adenosis if mass-forming, WC
§ Perineural pseudoinvasion[55] in 2% (Steinberg)
§ Microcalcification[56]
§ +/atypical hyperplasia, LCIS or DCIS
DDX
§ Tubular carcinoma
| Sclerosing adenosis | Tubular carcinoma |
| Lobulocentric | Haphazard |
| Fibrotic | More cellular stroma |
| Compressed up to obliterated | Angulated, always open |
| Mec | No |
| Apical snouts |
§ IDC:
RADIAL SCAR
Gross
§ Central gray-white stellate lesion with radiating streaks, hard, scirrhous[57][58]
§ Often multiple and bilateral (Steinberg)
Clinical
§ Any age, incidental mass[59]
§ Characteristic stellate with radiolucent center on imaging
§ 1/5 associated with carcinoma (steinberg)
§ Often with sclerosing adenosis (steinberg)
Incidence
§ Common 428%.
Complication: RR?
Treatment
§ Prudent to excise[62] if on biopsy
§ No reexcision if on resection
Define: when to call complex sclerosing lesion?
§ Benign sclerosing lesion
§ Fibroelastotic core with radiating ducts
§ Complex sclerosing lesion if ≥1cm (Steinberg)
Micro[63]
§ Stellate scar at low power with distorted lobular architecture
§ Central fibroelastosis[64][65], hyalinization, paucity of glands
§ Radiating compressed ducts with zonation (small in center vs dilated and more numerous in periphery[66])[67]
Ø Center sclerotic, periphery with epithelial HP
§ +/-perineural invasion
§ +/-coexists with ADH, LCIS[68], DCIS or carcinoma (usually at periphery)
DDX
§ Tubular carcinoma
§ IDC: can have fibroelastic stroma too
§ Sclerosing adenosis
ADENOMAS
1. TUBULAR ADENOMA
Micro
§ Lots of glands
§ Less fibrous stroma
§ WC
§ MEC present
Clinical
§ Variant of FA
2. LACTATING ADENOMA
Micro[69]
§ Preserved lobular architecture
§ WC
§ Hobnail cells with vacuolated cytoplasm
§ Apocrine secretion and intraluminal material
DDX
§ Lactational change (Steinberg): more diffuse
§ Carcinoma:
3. APOCRINE ADENOMA
4. PLEOMORPHIC ADENOMA
5. DUCTAL ADENOMA
Clinical
§ Perimenopausal women
§ Nipple discharge, sometimes mass
§ Variant of sclerosing papilloma (WHO)
Micro
§ Diagnosed when ductal pattern predominates over papillary pattern
§ Marked sclerosis
§ Communication with surface squamous epithelium
6. MICROGLANDULAR ADENOSIS[70]
RR
§ Entirely benign except in atypical variant (Steinberg)
§ Indolent but still with significant premalignant potential (Rosai)
Micro (Steinberg, Rosai)
§ Single cuboidal layerà no MEC[71]
§ DPAS+ intraluminal secretions
§ Small uniform rounded glands
§ Haphazard distribution[72]
§
IHC
§ Collagen IV+ or laminin+ or reticulin+
§ S100+ in 50%
§ CK+
§ EMA-
Treatment
§ Conservative (Rosai)
DDX
§ Tubular carcinoma
§ Sclerosing adenosis: MEC present, lobulocentric,
EPITHELIAL TUMORS
Types (WHO)
§ IDC
Ø Mixed
Ø Pleomorphic
Ø With osteoclastic giant cells
Ø With choriocarcinomatous features
Ø With melanotic features
§ ILC
§ Tubular
§ Invasive cribriform
§ Medullary
§ Mucinous
Ø Cystadenocarcinoma
Ø Columnar cell mucinous
Ø Signet-ring cell carcinoma
§ NE
Ø Solid NE carcinoma
Ø Atypical carcinoid
Ø Small cell NE carcinoma
Ø Large cell NE carcinoma
§ Invasive papillary
§ Invasive micropapillary
§ Apocrine
§ Metaplastic
Ø SCC
Ø Adenocarcinoma with spindle cell metaplasia
Ø Adenosquamous
Ø Mucoepidermoid
Ø Mixed epithelial/mesenchymal metaplastic
§ Lipid-rich
§ Secretory
§ Oncocytic
§ AdCC
§ Acinic cell
§ Glycogen-rich clear cell
§ Sebaceous
§ Inflammatory
§ Lobular neoplasia
Ø LCIS
§ Intraductal proliferative lesions
Ø UDH
Ø FEA
Ø ADH
Ø DCIS
§ Microinvasive
§ Intraductal papillary neoplasms
Ø Central papilloma
Ø Peripheral papilloma
Ø Atypical papilloma
Ø Intraductal papillary carcinoma
Ø Intracystic papillary carcinoma
§ Benign epithelial proliferation
Ø Adenosis
§ Sclerosing adenosis
§ Apocrine adenosis
§ Blunt duct adenosis
§ MG adenosis
§ Adenomyoepithelial adenosis
Ø Radial scar/complex sclerosing lesion
Ø Adenomas
§ Tubular
§ Lactating
§ Apocrine
§ Pleomorphic
§ Ductal
REVIEW OF CLASSIFICATIONS
Overall classification of tumours
What are the different types epithelial tumors?
Classification of papillary tumours?
Common tumours of the nipple
Mesenchymal/stromal tumours?
Benign epithelial lesions
§ Think of “Proliferative fibrocystic changes”
Precursor lesions
§ DCIS, LCIS, microinvasive ca., intraductal papillary proliferations
Malignant epithelial tumors
§ “Please act 4me pal”
Tumours of the nipple
§ Nipple adenoma, Paget disease,syringomatous adenoma
Myoepithelial and sweat gland tumours
§ Adenomyoepithelioma
§ Eg. Cylindroma, eccrine spiradenoma
§ Adenoid cystic carcinoma, pleomorphic adenoma
Fibroepithelial tumours
§ Fibroadenoma
§ Phyllodes tumor
Ø Benign
Ø Borderline
Ø Malignant
§ Periductal stromal sarcoma, low grade
§ Mammary hamartoma
Mesenchymal tumours
§ Stromal (FA, PT, PASH)
§ Vascular (hemangioma, lymphangioma, angiosarc, lymphangiosarc)
§ Neural (NF, Schw, GCT)
Lymphoma/leukemia
Metastatic diseases
Tumours in males
§ (Ductular ca)
INTRADUCTAL PROLIFERATIONS
§ UDH very different from ADH
§ ADH very similar to LG DCIS
§ LG DICS very different from HG DCIS
§ At least some FEA are neoplastic
Imaging and gross
§ May see something on imaging but nothing abnormal on gross examination[75]
1. UDH
Define
§ Increased number of epithelial layers (Steinberg)
RR
§ RR=1x in mild
§ RR=1.5-2x in florid for both breasts
Treatment
§ Regular mammography, no need for surgery (Farmer)
Micro (WHO)
§ Architecture
Ø Irregular fenestrations[76]
Ø Peripheral fenestrations
Ø Thin stretched epithelial bridges[77]
§ +/-true papillae with FV core[78]
Ø Nuclei parallel to bridge (streaming)[79]
Ø Nuclear crowding/overlapping
§ Cytology
Ø Heterogeneous cell population: epithelial, MEC,…
Ø Variation in morphology of epithelial cells[80]
Ø Indistinct cell borders
Ø Variation in morphology of nuclei
§ Not dark
§ Others
Ø No nucleoli[81], mitoses, psammoma, atypia, hemorrhage
Ø Focal apocrine metaplasia common
Ø Intranuclear round pink bodies (helioid inclusions)
Ø MEC on papillae and periphery
Ø Normal periductal stroma[82]
Ø Microcalcification and necrosis possible but rare
IHC (Goldblum)
§ CK5/6+ (Goldblum)
DDX
§ DCIS
2. FLAT EPITHELIAL ATYPIA
Clinical
§ Outcome between UDH and ADH (Farmer)
Micro
§ Mild atypia[83]: rounded nuclei, macronucleoli, apical snouts
Ø Flat to cuboidal to columnar
§ 1-5 cell layers
§ Architecture normal: no arcardes or micropapillae
Ø Can have mild distension with flocculent secretion
IHC
§ HMK (34βE12)-
Treatment
§ Controversial on biopsy; some surgeons may remove because some associated with cancers (Farmer)
§ Not reported on excision specimen (Farmer)
3. ADH
Define
§ DCIS <2mm in one duct or <2 glandular spaces
§ Must be LG
RR
§ RR=4-5 for BOTH breasts (vs ipsilateral in DCIS)à must double check ipsilateral vs bilateral
Treatment
§ Excision if on biopsy (because often coexist with DCIS or invasive cancers)
§ No re-excision if on resection, even at margin (SenGupta, Goldblum, Farmer)
Micro
§ Cytology=LG DCIS
Ø Distinct borders
Ø Monotonous population
Ø Large nuclei
Ø Dark nuclei
Ø Macronucleoli
Ø Mitoses?
Ø No nuclear overlap
Ø Necrosis should raise DCIS
§ Architecture
Ø Micropapillae[84]
Ø Arcades/roman bridges[85]
§
Ø Rigid transverse bridges
Ø Solid
Ø Cribriform
§ Very round lumens
§ ≤2mm size
§ Usually solitary lesion
§ +/-microcalcifications
§
IHC
§ HMK-: including CK5/6 or 34βE12***
§ MEC+
Treatment
§ Excision on biopsy
§ Watchful on excision (even on margin) (SenGupta, Farmer)
DDX
§ DCIS: if ADH ≥2mm or HG of any size
§ UDH
4. DCIS
Origin
§ TDLU
RR[86]
§ RR=13/4[87] cases. Ipsilateral risk (vs both in ADH and florid UDH
§ RR=8-10 (WHO)
§ 1% of nodal mets
Clinical
§ Mostly incidental on imaging but all is possible including mass[88], nipple discharge, Paget’s
§ Heterogeneous group
§ More and more common now due to better screening
Imaging
§ Visible on imaging[89]
§ Calcification[90]
Ø LG DCIS: laminatted psammoma-like, rounded, intraluminal, in clusters[91]à “fine granular”
Ø HG DCIS: different forms (either linear branching[92], rod-like[93] or coarse granules)
§ Can be very large
§ Usually segmental distribution, not multicentric[94]
EM
§ Discontinuous BM with occasional extension of tumor cells across membrane (Steinberg)
Micro[95][96]: minimal criteria for LG DCIS (WHO)***
§ Cytology
Ø Monotonous rounded cells
Ø Subtle increased N/C
Ø Evenly spaced
Ø Rounded nuclei
Ø +/-hyperchromasia
§ Architecture
Ø Arcades
Ø Cribriform (rigid and punched out)
Ø Solid
Ø +/-micropapillae
§ Other not on WHO
Ø Distinct borders
Ø Rounded lumens
Ø Dimension
§ One duct but ≥2mm[97] or
§ ≥2 glandular spaces if LG-IG
§ Any size[98] if HG
Ø No apocrine metaplasia
Ø Necrosis
Ø Periductal fibrosis (vs absent in UDH)
Ø Larger nuclei than LCIS
Ø +/microcalcification[99]
Ø Mitoses[100]
Ø No nuclear streaming[101]
Gross
§ Not visible unless calcification
Dimension: how to measure
§ Counts DCIS as separate if normal intervening breast lobules
§ Extensive DCIS defined by ≥25% of tumor areas
Patterns***
§ Solid (with pseudorosettes)
§ Comedo (>half of duct)
§ Papillary
§ Micropapillary
§ Cling (monolayer of nasty looking cells around the duct)
§ Apocrine
§ Signet-ring
Outcome
§ 20% of DCIS turn out to be invasive cancer after excision
§ Ideally must have 1cm free margin on resection
Prognosis*** (WHO)
§ Whether completely excised or not (no1)
§ Grade
§ Lesion size
§ Microcalcification
§ Microinvasion
IHC
§ HR+
§ HMK (CK5/6)[104]-
§ HMK (34βE12)-
§ E-cad+
Treatment
§ Excision if on biopsy
§ Reexcision if at margin of excision[105]
Cancerization of lobules: define
§ When ductal carcinoma spread into lobules (Steinberg).
§ Retained LOBULAR pattern but filled with neoplastic cells (Steinberg).
§ Misdiagnosed as invasive carcinoma or sclerosing adenosis (Steinberg)
§ Most importantly, this finding should prompt search for IDC in specimen (Steinberg)
DDX
§ ADH
§ Can call DCIS with only one duct if cells are high grade (2mm rule doesn’t apply)
§ What makes a high grade nucleus?
Ø 2.5x lymphocytes, hyperchromatic, variable size
§ Useful term if squished ducts at edge:
Ø “atypical epithelium at edge of biopsy”, can recommend rebiopsy
LOBULAR NEOPLASIA
Significance
§ Risk factor but nonobligatory precursor[106] for invasive cancer in either breast
Imaging
§ Nothing abnormal except occasional calcification within central necrosis!
Treatment
§ On biopsy: life-long follow-up +/-tamoxifenà but we recommend excision at KGH
§ Re-exicision
Ø If massive acinar distension or
Ø Pleomorphic, signet-ring or necrotic variants at or close to margins
RR
§ 7-12
Gross
§ Nothing[107]
Micro
§ Normal lobular architecture
§ Expanded lobules
§ Pagetoid extension to ducts in 75%à “necklace”
§ Intracytoplasmic lumens
§ Rare: necrosis, mitoses, calcifications
IHC
§ Similar to HG DCIS, p53+ more often in pleomorphic LCIS
§ E-cad-
§ CK5/6-
§ HWK (34bE12)+***
DDX
§ Solid DCIS
| LCIS | DCIS |
| Neg | E-cad+ |
| HWK (34bE12)+ | Neg |
| CK5/6- | |
1. ALH
Define
§ Either of the features of LCIS are lacking
§ LCIS=lobule is distended and distorted by tumour cells + at least half of acini expanded
§ Lobular HP does not exist
Complications
§ Risk marker for BOTH breasts but NOT premalignant or precursor lesion for cancers (Farmer).
Treatment
§ NO SURGERY but some aggressive surgeons will do bilateral prophylactic mastectomy, which Farmer thinks it’s overtreatment and I personally think so too (Farmer and me)
2. LCIS
Clinical
§ Multifocal, bilateral
§ Less mass-forming
§ Risk marker, not precursor lesion
Micro
§ ≥50%[108] of spaces of lobule distended and distorted
§ Discohesive
§ +/-nucleoli
§ Uniform round cells with eccentric nuclei
§ 1-2x lymphocyte size[109]
§ Mucin vacuoles: intranuclear or signet-ring
§ Pagetoid spread
§ No: mitoses, necrosis[110]
§ Pleomorphic LCIS
Ø 4x lymphocyte size
Ø Pleomorphic: macronucleoli
Ø +/-mitoses, necrosis
Ø Discohesive
Treatment***
§ Excision if found on biopsy to rule out ILC (SenGupta, Osler)
§ Watchful (long-term follow-up with mammography) if found on excision (true even on margin) (SenGupta, Osler)
Ø Prophylactic mastectomy only if family history of breast cancer (Steinberg)
Treatment*** (O’Malley)
§ No need to take out on biopsy if there is good imaging correlation. Exceptions being
Ø Concomitant higher risk lesions (ADH)
Ø Poor imaging correlation
Ø Unsure whether LCIS or ADH/DCIS
Ø Pleomorphic variant of LCIS
§ Watchful if found on resection
Evolution
§ Either ILC (more) or IDC in either breast
RR
§ RR: 8-10
§ Risk for invasive cancer for LCIS treated with biopsy alone is 20-35% for BOTH breasts (vs 25-75% for DCIS for ipsilateral breast, Steinberg)
Variants
§ Alveolar: 20 cells forming alveoli
§ Solid:
§ Pleomorphic
Ø Treatment: as DCIS (excision required on both core biopsies and resection specimen) (SenGupta, Farmer)
Ø Pleomorphic cells, more cytoplasm, hyperdiploid, resembles DCIS
Ø Apocrine change
IHC
§ Mucicarmin+
§ E-cad-
§ HR+
§ HER2- (except pleomorphic variant)
§ HMK (34βE12)+
§ HMK (CD5/6)-
DDX
§ ILC: lost normal architecture (haphazard growth)
§ Cancerization of lobules[111] (Steinberg, SenGupta): both have preserved lobular architecture but DCIS with higher nuclear grade, necrosis, more cohesive, more surrounding desmoplasia and inflammation, no signet-ring cells (Steinberg). E-cad if doubt (SenGupta)
§ Collagenous spherulosis: E-cad+
Variants with good prognosis (Osler)
§ Mucinous
§ Cribriform
§ Tubular (best of all)
§ Papillary
§ Medullary
§ AdCC
Secretory
INVASIVE CANCERS
RF (Western countries). RR. SBR (WD 3-5, MD 6-7, PD 8-9) (mainly for IDC but nuclear atypia usable for all types). BRCA1 (more common, bilateral, medullary, triple-) vs BRCA2 (male breast cancer). Gynecomastia NOT RF. Origin (all from TDLU which is lobules, not ducts). Outcome (1/3 of invasive cancer involve nodes but only <1% of PURE DCIS have nodal involvement) (20% of DCIS on needle core become invasive cancer on resection). Treatment (some protocoles require minimal total LN) (node dissection for invasive but NO CONSENSUS for DCIS) (SLN biopsy if DCIS becomes invasive after resection) (SLN biopsy only for early cancer) (always adjuvant therapy such as chemo, hormone, radiation to kill microscopic residual cancer and to prevent local recurrences EXCEPT DCIS/LCIS). Prognosis (positive LN number important). Multifocal (in same quadrant) vs multicentric (different quadrants or >5cm apart in same quadrant). FISH (when weak complete membranous staining in >10% of cells… need update!!!).
Treatment
§ Whenever have doubt on needle core biopsy, ask surgeon to take out; do not be shy because needle biopsy is screening test and a lumpectomy is not that bad compared to wait for a tumor to grow (SenGupta, Rowlands).
FNA pitfalls (Goldblum)
§ FA
§ Apocrine proliferations
§ Papillomas
§ Lactional change
§ Fat necrosis
§ Tubular and lobular carcinomas
Clinical
§ More in developed countries due to Western lifestyle (early menarche and late childbirth) (WHO)
§ Upper outer> center> rest (WHO)
§ Lump[112][113] 60-70%, pain 20%, nipple problem 10% (discharge, retraction, eczema) (WHO).
Ø
RF[114]
§ Li-Fraumeni
§ BRCA1/2
§ Cowden syndrome (multiple hamartoma syndrome)
§ Peutz-Jeghers syndrome (SenGupta)
RF***
§ Age: increasing with age
§ Alcohol: consistently linked to small increase in dose-response relationship
§ Benign breast disease[115]: ADH
§ Breastfeeding no longer protective unless long-term (>2yrs)
§ Cancer of controlateral breast or endometrium
§ Diet: high fiber/fruits/vegetables protects. Intake of high calorie, animal fat (especially red or fried meat) bad
§ Endogenous hormone: early menarche, late menopause, late childbirth, nulliparity, regular ovulation
§ Exogeneous hormone: OCP causes minimal risk increase whereas HRT causes small increase in long term use
§ Family history
§ Frist live childbirth (I guess stillbirth does not count)
§ Geography: high in North America/Europe/Australia vs low in Asia/Africa
§ Obesity: increases RR in postmenopausal women (likely from increased endogenous estrogen) and women who never used HRT. However, decreases RR in premenopausal women (Robbins)
§ Radiation
§ Sedentarity: activities decrease RR by 20-40%. Sedentarity and obesity causes insulin resistance, resulting in increased serum insulin, which in turn causes increased ovarian/adrenal synthesis of sex steroids (also via decreased liver synthesis of SHBG). Increased serum androgen, especially in postmenopausal women, causes increase peripheral formation (by fat) of estrone and estradiol.
§ Smoking: not related and even possibly protective (due to anti-estrogen effects)
RF lesions (Steinberg)
§ Yes: epithelial hyperplasia,
§ No: adenosis, apocrine metaplasia, cysts, papillomatous growth
Define multifocal vs multicentric
§ Multifocal: <5cm in same quadrant
§ Multicentric: different quadrants or >5cm apart
Origin
§ Nearly all from TDLU, NOT in ducts, making differentiating of “lobular vs ductal” historical and incorrect (Lit, WHO)
Spread
§ Lymphatics[116], blood[117] and direct
§ Unusual sites (peritoneum, RP, GI tract, reproductive organs) for ILC
Genetics
§ BRCA1
Ø >1/4 cases in <35yo but in <10% cases from >35yo (Lester).
Ø More likely bilateral breast cancers (Lester).
Ø “Medullary” appearance, often HG, triple negative (Lester).
§ BRCA2
Ø In 4-14% of male breast cancers (Lester, MSKCC)
Ø No specific histology (Lester).
§ Germline BRCA1 and BRCA2 in <3-5% breast cancers (Lester, Robbins).
§ HER2 amplification in 1/4 (Lester)
§ Stellate[120] mass without calcification (64%)
§ Mass with calcification (17%)
§ Calcification without mass (<20%) (WHO).
§ Cysts (mucinous carcinoma).
Prognosis (Lester, Rosai, Steinberg)***
§ Staging (no1)[121][122]: especially LN status
§ Grade
§ HR[123]: weak prognosticators but good treatment predictors (Lester)
§ HER2
§ Histology
Ø Tubular, mucinous, medullary, cribriform, adenoid cystic, papillary better***
Ø NOS worst
Ø ILC only slightly better than IDC
§ LVI
§ Gene profiling: normal-like> luminal A> luminal B> HER2+> basal-like (Sorlie 2001)
Treatment (SenGupta, Goldblum)
§ Excision: DCIS (both biopsy and resection), ADH (only biopsy), cellular FA (or if phyllodes can not be ruled out), papilloma, mucocele-like lesion (to rule out carcinoma), radial scar (because 20% has carcinoma), ALH with another high-risk lesion, pleomorphic LCIS,
§ Controversial: flat epithelial atypia but tend to excise
§ Surveillance: ADH (only specimen), LCIS/ALH, sclerosing adenosis, FA, columnar cell change/hyperplasia
§ Treatment: trastuzumab (Herceptin) is monoclonal antibody against HER2/neu receptor (Lester). A minimum of TOTAL LN (typically 6-10) MAY be needed for some treatment protocole (Lester).
What do we do if margin is <1cm in a mastectomy specimen? What about a lumpectomy?
§ Lumpectomy: if margin is <1cm or involved, patient will get re-excision (since there are still tissue left)
§ Mastectomy: if margin is <1cm or involved, patient will get radiotherapy (no more breast tissue left!) to site and axilla
Micro
§ >50% of tumor shows no special type patterns
IHC
§ Basal phyenotype or epithelium: CK5/6, CK14+. ME cells: S100, p63, SMA+
§ BM: laminin and collagen IV
§ Can LN be used for ER, PR and Her2? Yes
§ CEA+ (Archives)
§ CK7+/20-: careful that CK20+ in 1/3 of papillary and mucinous variants of breast carcinomas (Dabbs)
§ CK5/6/17: MEC markers (Livasy 2006). Pos: basal-like carcinoma
§ CK7+/CK20- (Archives)
§ EGFR
Ø Pos: basal-like carcinoma (70%, Livasy 2006), HER2-overexpressing carcinoma (60%, Livasy 2006)
§ ER
Ø No1 marker separating breast tumor into basal-like vs luminal-type based on gene expression (Kristensen 2005). Nuclear stain.
Ø Pos: normal luminal (glandular) cells,
Ø Neg: myoepithelial cells,
Ø ER controls lots of downstream genes, expression of which probably predict better response to ER-blocking agents (Robbins). Nuclear stain.
§ ER+/PR+[124]***: nuclear
Ø Negative if <1%
Ø Weakly positive if 1-10% (not 50%!)
Ø Positive if >10%
§ GCDFP+ (Archives)
Ø Any apocrine glands (breast and skin adnexa) and salivary glands (Dabbs)
Ø Pos: breast cystic diseases, apocrine carcinoma of breast, salivary glands, sweat glands, extrammary Paget’s disease (?)
Ø Detected by monoclonal antibody BRST-2
§ HER2/neu
Ø Aka ERBB2. Oncogene which regulates growth factor receptor production (by encoding HER2/neu oncoprotein which is growth factor receptor). Net result is stimulation of cell growth/division. Often amplified in ER- tumor, especially basal-like carcinoma (Kristensen 2005). Membrane stain.
Ø About 1/4 invasive carcinomas express HER2 (SenGupta)
§ Mammoglobin+ (Archives)
§ P53: Gene often mutated in ER- tumor, especially basal-like carcinoma (Kristensen 2005)
§ P63: 2 usages (SenGupta): myoepithelial marker and identify metaplastic carcinoma
§ WT1- (usually): vs + in ovarian serous and endometrioid (Archives)
1. IDC
Clinical
§ Associations: 80% with DCIS (often high grade comedo type, WHO). Comedo DCIS with poorly differentiated IDC vs low-grade DCIS with well-differentiated (Robbins).
§ Def: heterogeneous group failing to meet criteria of special types such as lobular, tubular, etc. (WHO).
§ Demo: rare before 40 (WHO). Recent increase in incidence in older women due to screening program but mortality decreases due to early detection and better treatment.
§ Etio
Ø Sporadic
Ø Hereditary: BRCA, Li-Fraumeni, Cowden (multiple hamartoma syndrome due to PTEN mutation), Peutz-Jeghers (truncating mutation of LKBI gene), ATM gene
§ Incidence: 40-75% of all breast carcinomas (WHO).
§ Origin: theory that IDC arise from ducts and ILC arise from lobules no longer true; TDLU must be regarded as single entity (WHO).
§ Prognosis: lymphatic invasion is regarded as a risk factor and clinician may do radiation or change chemo agent (SenGupta).
§ Spreads: small size IDC can metastasize (Robbins).
§ Treatment: chemokine receptors CXCR4 and CCR7 may be important for mets because blockage of CXCR4 with its receptors decreases breast cancer met to LN (Robbins).
Gross
§ Gritty feel when cut (WHO). Grey-white with yellow streaks (WHO). Small calcifications (Robbins).
Micro
§ Cords, clusters, trabeculae up to solid, syncytial[125]
§ Abundant eosinophilic cytoplasm
§ Regular up to pleomorphic nuclei[126]
§ Macronucleoli (often multiple)
§ Mitoses none up to numerous
§ DCIS in 80%
§ Stroma from highly cellular fibroblastic to marked hyalinization[127]
§ +/- focal elastosis
§ +/- focal necrosis
§ Inflammation[128] only in minority
§ Amount of IDC required for diagnosis
Ø >50%à IDC
Ø 10-50%à mixed
Ø <10%àspecial type
§ LVI: look for it outside of tumor
Is there any value looking at intraluminal content?
§ YES. If it’s eosinophilic or light pink, then it’s likely normal because cancerous ducts do not usually contain that
Why important to report signet-ring cells in IDC? When do we report?
§ If it’s >10% of the tumor, we should report its presence because it’s associated with bad prognosis. Furthermore, signet-ring cell carcinoma of the breast does exist
IHC
§ HR+ 70-80%
§ HER2+ 15-30%
DDX
§ Benign sclerosing lesions (Robbins)
What is the DDxx for entrapped breast cells within fibrous stroma beside infiltrating carcinoma?
§ ENTRAPMENT of breat acini or ducts from previous biopsy
1a. MIXED CARCINOMA
Clinical
§ 10-49% IDC mixed with other type[129]
Micro
§ Carcinoma, tubulo-lobular TLC
§ Admixture of tubular growth pattern and small uniform cells arranged in filing pattern (WHO). Accompanied by LCIS (1/3, WHO). More axillary nodal spread (43%) than tubular carcinoma (12%) (WHO)
IHC
§ Often ER+ (WHO)
1b. WITH OSTEOCLASTIC GIANT CELLS
Micro
§ Osteoclastic GC[130]
§ Inflammatory[131], fibroblastic, hypervascular stroma[132]
§ Background of WD to MD IDC
1c. PLEOMORPHIC
§ Rare variant of high grade IDC NOS (WHO).
Micro
§ >50% of tumor composed of pleomorphic or bizzare giant cells
§ Background of adenocarcinoma or adenocarcinoma with spindle and squamous differentiation
§ >20/10 mitoses
§ Grade 3 by definition
IHC
§ P53+ in 2/3
§ CK markers often+ despite ugliness
§ HR-
DDX
§ Sarcoma (WHO): often misinterpreted this way
1d. WITH CHORIOCARCINOMATOUS FEATURES
Clinical
§ High serum HCG
1e. WITH MELANOTIC FEATURES
§ Rare
2. ILC[133]
Gross
§ Ill-defined mass
§ More bilateral[134] and multicentric
Micro
§ Uniform small cells[135]
§ Thin rim of cytoplasm
§ Indian file
§ Targetoid around normal ducts
§ Signet ring
§ Intracytoplasmic lumens[136]
§ Rare: mitoses, inflammation, desmoplasia[137]
§ Discohesive
§ Even chromatin
§ No nucleoli
§ No tubule or papillary formation (Robbins)
§ Coexisting LCIS in >90% cases
§ Periductal and perivascular elastosis common
§ No: necrosis
§ Difficult to see in LN
§ Less calcification than IDC
Variants
§ Solid
Ø Sheets
Ø More mitoses
§ Alveolar
Ø Globular aggregates of >20 cells
§ Pleomorphic
Ø More pleomorphism
§ Tubulolobular
Ø Mixed
IHC
§ E-cadherin- in 80-100%[138]: vs always present in IDC
§ HR+ in 70-95%: higher than IDC but may be- in HG[139]
§ GCDFP-15+: useful to determine origin of mets (WHO)
§ HER2-[140]: very rarely+ unless pleomorphic variant
§ Mucicarmine+
Clinical
§ Same age as IDC (45-55), palpable mass or radiographic density
Genetics
§ Loss of 16q[141]
EM
§ Intracytoplasmic lumen with targetoid body[142]
Outcome
§ Same as IDC if matched by stage and grade (Robbins).
Spread
§ Less nodal mets
§ More to CSF, ovary, pleura, peritoneum, marrow
Treatment
§ Same as IDC
§ What to do if positive marign on resection?
3. TUBULAR CARCINOMA
Micro
§ >90% tubules[143]
§ Angulated glands
§ Apical snouts
§ Single layered
§ No eosinophilic content
§ Cellular (desmoplastic) stroma
§ Commonly associated with FEA
§ WD by definition
§ May have coexisting LG DCIS, columnar cell change
§ Often in radial scar
Clinical: associations?
§ Same age
§ Quite common 1/20
Outcome
IHC: complete opposite to MG adenosis
§ HR+
§ HER2-
§ GCDFP+
§ EMA+? (Rowlands)
DDX
§ MG adenosis
§ Sclerosing adenosis
4. INVASIVE CRIBRIFORM CARCINOMA
Micro
§ Like cribriform DCIS pattern
§ >90% tumor
§ Apical snouts
§ LG nuclei
§ Mitoses rare
Outcome
§ Good prognosis because nodal mets about 15%
IHC
§ Same as tubular carcinoma
DDX
§ AdCC: AB+/PAS+, ER-, lamin+[146]
§ Cribriform DCIS: MEC present, normal architecture and distribution
§ Carcinoid: intracytoplasmic silver+ granules
5. MEDULLARY CARCINOMA
Clinical
§ BRCA1* in 15%
§ Younger
Gross
§ Soft, WC[147]
Outcome
§ Better[148] despite aneuploidy, HG nuclei, mitoses, HR-
Spread
§ Nodal mets in <10%!
Micro: 5 criteria[149]*** (outside to inside)
1. Pushing border[150]
2. Stromal lymphoplasmacytic infltrate[151][152]
3. No glands[153]
4. Synctial cells in >75%[154][155]à most important
5. Marked atypia (score 2-3)[156]
§ Numerous mitoses and can be atypical
§ Little desmoplasia[157]
§ NO DCIS
§ Never LVI
IHC
§ Triple-
§ P53+*
6. MUCIN-PRODUCING CARCINOMAS
6a. MUCINOUS CARCINOMA
Clinical
§ Slightly older women
§ Mucin can embolize to brainà death by stroke
Outcome
§ Good prognosis[158]
Gross
§ WC
§ Extremely soft, lobulated
§ Pale gray-blue
Micro
§ Uniform smalls cells floating in mucin[159]
§ LG-IG[160]
§ Pushing borders
§ Minimal pink cytoplasm
§ Dividing fibrous septa
§ Rare: atypia, mitoses, papillae
§ NE differentiation quite common
Variants
§ Pure: must be 100% mucinous carcinoma (not 90%)!
Ø Cellular: more intracytoplasmic mucin, silver+ granules[161]
Ø Hypocellular
§ Mixed
IHC
§ HR+
§ HER2-
§ NE markers sometimes+[162]
§ Mucicarmine+ in mucin lake but neg within cells!
DDX
§ Myxoid FA: mast cells, MEC+
§ Mucocele: MEC+ on floating cells
6b. MUCINOUS CYSTADENOMA
6c. COLUMNAR CELL MUCINOUS CARCINOMA
6d. SIGNET-RING CELL CARCINOMA
Variants
§ Related to ILC
§ Related to IDC[163]
7. NEUROENDOCRINE TUMORS
Variants
§ Solid NE carcinoma
§ Atypical carcinoid
§ Small cell NE carcinoma
§ Large cell NE carcinoma
8. INVASIVE PAPILLARY CARCINOMA
Gross
§ WC
Outcome
§ Relatively good
Clinical
§ When intraductal papillary carcinoma invades, it loses its papillary architecture
Micro
§ In situ component
Ø Expansile WC nests with papillae
§ Invasive component
Ø Lost papillae
Ø Mostly Grade 2
§ Calcification
§ DCIS common
§ Tumor size=only invasive component
9. INVASIVE MICROPAPILLARY CARCINOMA
§ Clusters of neoplastic cells present in clear spaces separated by FV tissue “inside out“ arrangement
Micro
§ Small tubules[164], surrounded by clear artifactual spaces
§ LVI very common
§ Axillary LN often+[165]
Prognosis (WHO)
§ No value when matched stage for stage despite more LVI invasion (WHO, Goldblum)
10. APOCRINE CARCINOMA
Clinical
§ Same outcomeà academic interest only
§ Apocrine LCIS and apocrine DCIS both exist
Micro[166]
§ >90% tumor with apocrine morphology and IHC
§ Large cells with abundant pink granular cytoplasm
§ Large nuclei with macronucleoli
§ Apical snouts
IHC: apocrine marker?***
§ GCDFP15+
§ HR- (interesting)
§ BCL2-
§ AR+
IHC
DDX
§ Granular cell tumor (SenGupta)
11. METAPLASTIC CARCINOMA
Define[167]
§ Adenocarcinoma with dominant[168] areas of spindle, squamous, +/-heterologous differentiation
Clinical
§ Same
Treatment
§ Same as IDC/ILC
Outcome
§ Depends on subtypes
Ø Pure SCC, with heterologous elementsà good
Ø Carcinosarcomaà bad
Micro
§ Adenocarcinomatous component may be absent
§ Squamous or spindle[169] cells or mixed
§ +/-heterologous element[170]
§ Grading mainly based on nuclear features and cytopalsmic differentiation
Variants***
§ Purely epithelial
Ø Squamous
§ Large cell keratinizing[171]
§ Spindle cell[172]
§ Acantholytic
Ø Adenocarcinoma with spindle cell differentiation
Ø Adenosquamous[173] including mucoepidermoid carcinoma
§ Mixed
Ø With chondroid metaplasia
Ø With osseous metaplasia
Ø Carcinosarcoma
IHC:
§ P63+
§ VIM+
§ CK+: even focal+ in spindle cells
§ Triple-
DDX for sarcomatoid metaplastic carcinoma
§ Phyllodes (SenGupta): submit more blocks to look for clef-like spaces (Goldblum)
§ Sarcoma (Robbins, SenGupta): vimentin+. Spindle cell carcinoma in breast is much more likely metaplastic carcinoma than true sarcoma (Goldblum, SenGupta). More a diagnosis of exclusion after exclusion of metaplastic carcinoma, phyllodes and melanoma (Goldblum).
§ Melanoma (SenGupta): S100 and HMB45
§ Skin tumors sucha as dermatofibrosarcoma protuberans (Goldblum): storiform pattern without significant pleomorphism
§ Inflammatory myofibroblastic tumor (Goldblum): usually low grade spindle cell neoplasm
§ Fibromatosis of the breast (Goldblum): usually low grade, composed of fascicle of infiltrating fibroblasts in collagenous matrix (same morphology as fibromatosis elsewhere in body, Goldblum). Rare mitoses can be present (Goldblum)
12. LIPID-RICH CARCINOMA
Micro
§ Morphologically similar to glycogen-rich carcinoma because clear cytoplasm
§ ≥90% of tumor
Outcome
§ Unknown yet
13. SECRETORY CARCINOMA
Clinical
§ Kids[174] and adults
Micro
§ Irregular epithelial islands containing glandular lumina with PAS+ secretions (Steinberg). Low nuclear grade and no mitoses (Steinberg)
§ WC
§ 3 patterns
Ø Solid
Ø Microcystic (honeycomb): mimics thyroid follicles
Ø Tubular: tubules containing secretions
§ Abudnant intracellular and extracellular pink colloid-like[175] material[176]
§ Oval nuclei, small or indistinct nucleoli
§ Abundant pink cytoplasm
§ Intracytoplasmic lumens common
Outcome
§ Extremely favorable
14. ONCOCYTIC CARCINOMA
15. ADENOID CYSTIC CARCINOMA
Gross
§ WC
§ Solid with microcysts on cut surface
Micro
§ 3 patterns[177]
Ø Trabeculae-tubular
Ø Cribriform
Ø Solid
§ Pseudocysts[178]: mostly round, Alcian blue+ BM material (hyaluronate)[179], surrounded by basaloid cells[180], more in center
§ True lumens: smaller and more difficult to see, PAS+ neutral mucin, surrounded by larger cells with abundant pink cytoplasm, more at periphery
§ Perineural invasion common
Outcome
§ Good (vs bad in salivary glands)
IHC
§ AB+ in pseudocysts (BM)
§ PAS+ in true lumens (hyaluronate)
§ LMK+ in epithelium
§ MEC+
§ HR- (never+)
DDX
§ Collagenous spherule:
§ Cribriform carcinoma: one cell type, one mucosubstance, HR+
16. ACINIC[181] CELL CARCINOMA [182]
Clinical
§ Same
§ 9 cases reported
Micro
§ Abundant, DPAS+, amphophilic to pink granules
§ Mitoses can be high
EM*
§ Electron-dense zymogen granules (0.08-0.9µm)
IHC
§ HR-
§ GCDFP15-
§ S100+
§ Amylase+, lysozyme+, chymotrypsin+, EMA+
17. GLYCOGEN-RICH CLEAR CELL CARCINOMA
Outcome
§ Same as IDC
Micro
§ Remember it’s clear cell carcinoma[183]
§ ≥90% of tumor
18. SEBACEOUS CARCINOMA
19. INFLAMMATORY CARCINOMA
Clinical
§ T4d
§ Typically not mass-forming
Micro
§ Clinicopathologic diagnosis[184]
§ Invasive cancer of ANY histologic type
§ Not much inflammation despite its name
Outcome
§ Bad
Prognosis
§ Response to neoadjuvant chemoradiation
20. MICROINVASIVE CARCINOMA
Microinvasion: define. What to do if doubt?
§ <1mm into non-specialized interlobular stroma
§ If doubt, classify as DCIS (WHO)
Micro***
§ Desmoplasia
§ Lymphoplasmacytic inflammation
§ Paradoxical maturation
§ Loss of BM (often only focal)
§ Loss of MEC (often only focal)
Treatment
§ Same as DCIS
BILATERAL BREAST CARCINOMA
Define
§ Synchronous tumor within 2 months of initial tumor
BASAL-LIKE CARCINOMA
Define
§ Defined by gene expression microarray as tumor having gene expression pattern similar to normal basal/myoepithelial cells (Livasy 2006). Associated with poor clinical outcome. Often triple negative but EGFR overexpressed (Lit). Appears to have higher incidence in BRCA1 carriers (Lit). 20% of all invasive carcinomas (Livasy 2006). Histologically, described as mainly ductal type (NOS) or metaplastic (Livasy 2006)
§ Mostly solid mass with no tubule formation. Very densely packed with nuclear crowding/overlapping. Tumor cells containing round/oval, sometimes vesicular nuclei, sometimes prominent nucleoli and very scant cytoplasm (therefore high N/C ratio, Livasy 2006). Very scant intervening stroma. Geographic necrosis (70%) with apoptotic figures. Pushing border (60%). Very high mitoses (100%). Strong lymphocytic response (60%) (Livasy, 2006). Pushing border and high mitoses are features of medullary carcinoma (Livasy called it atypical medullary features). Virtually all high grade (100%).
Immuno (Livsay, 2006; careful, not gene expression but truly protein expression)
§ Vimentin+ (95%; very specific to basal-like carcinoma, Livasy 2006), luminal CK+ (CK8/18, 83%, Livasy 2006), EGFR+ (70%, Livasy 2006), basal CK+ (CK5/6, 60%; quite specific to basal-like carcinoma, Livasy 2006), ER-/PR-/HER2- (always). Only a small proprtion (<20%) express myoepithelial markers (SMA, p63, CD10), HER1+ (Nielsen 2004), c-KIT? (Nielsen 2004), CK17+ (WHO), laminin+ (WHO)
§ Careful that not all basal-like carcinomas, identified by gene microarray, demonstrate basal cytokeratin immunoreactivity (requires more immunomarkers to better define this new cluster, Livasy 2006)
§ P53 often mutated in basal-like carcinoma but not yet tested by immunohistochemistry
§ Unlikely myoepithelial origin (Livasy, 2006). ER-. Expresses basal keratins, p-cadherin, laminin (Robbins). Likely associated with BRCA1 (Robbins). CK5/6/14+ basaloid carcinoma is being more recognized and more often in BRCA1
§
INTRADUCTAL PAPILLARY NEOPLASMS
Name the different types of papillary lesions and describe the micro characteristics.
§ Papilloma (small duct or peripheral)[185]
Ø In TDLU. Term “papillomatosis” should be avoided (WHO). Same age as central papillomas. Often clinically occult with less nipple discharge. Sometimes peripheral microcalcifications. Usually multiple. Arising from tdlus, extending into larger ducts.
Ø Very often associated with usual type epithelial hyperplasia, ADH, DCIS and IDC, sclerosing adenosis, radial scar (more than central papillomas).
§ Papilloma (large duct or central)[186]
Ø Can extend for cm long (WHO)
Ø Any age but mostly 4050
Ø Nipple sanguinous discharge (75%), mass uncommon (WHO). Calcifications rare.
Ø Sometimes duct formation (WHO)
§ Nipple adenoma
§ Papilloma with ADH/DCIS
§ Intracystic papillary carcinoma
§ Invasive papillary carcinoma
§ Micropapillary carcinoma
FS
§ Notoriously difficult for papillary lesions of breast
1. PAPILLOMA
Define
§ Lesions of true ducts with FV cores
§ Monoclonal (truly neoplastic)
Related lesions and location
§ Central papilloma: near nipple, solitary
§ Peripheral papillomas: periphery, multiple, more associated with UDH, ADH, DCIS, cancer, sclerosing lesions
§ Ductal adenoma[187]: large duct, aka sclerosed papilloma
§ Nipple adenoma[188]
Clinical
§ Perimenopausal, bloody discharge[189], maybe mass[190]
§ Solitary: age 40-50, subareolar, nipple discharge, less often clinically occult (Goldblum).
§ Multiple: younger than solitary form, peripherally located, nipple discharge, more often clinically occult (Goldblum). Much higher risk for carcinoma than solitary (Goldblum)
Micro
§ Branching papillae with broad FV cores[191] and secondary lumens
§ Bland cuboidal lining with MEC[192]
§ +/-UDH[193], ADH/DCIS[194], metaplasia (apocrine, squamous[195], sebaceous, mucinous, osseous, chondroid)
§ +/-pseudoinvasion at base because often sclerosis there[196]
§ +/-necrosis, hemorrhage, infarct[197][198], stromal sclerosis
Variants
§ Solid
Malignant criteria (ADH, DCIS, carcinoma)
§ Back to back glands with LOSS of FV CORE (micropapillae), perpendicular nuclei, columnar cell atypia, monomorphism (no MEC), mitoses (Goldblum, Steinberg).
§ 2 most distinguishing features between benign and malignant papillary lesions are MEC and FV cores (Steinberg)
RR
§ RR=2[199][200] in ipsilateral breast (WHO)
DDX
§ Other breast adenomas[201]
§ IDC
§ Micropapillary DCIS: no MEC within papillae but present at periphery, no FV core, atypia, pseudostratification, NO apocrine metaplasia
§ UDH: no FV core, ME cell continuous, APOCRINE metaplasia
§ Intracystic papillary carcinoma: increased discohesiveness, mitoses
Treatment
§ Excision recommended on biopsy to R/O atypia arising in papillary lesion[202] (farmer)
2. ATYPICAL PAPILLOMA
PAPILLOMA WITH ADH[203]
Micro (Goldblum, Steinberg)
§ Approaches DCIS but are not diagnostic OR
§ DCIS-like[204] area <3mm[205]
§ MEC absent only at foci of ADH (Goldblum)
Treatment
§ Complete excision despite still being considered benign (Schnitt)
PAPILLOMA WITH DCIS
Micro
§ MEC absent at foci of DCIS
§ DCIS-like[206] changes >3mm[207] but not entirely
§ FV cores still present[208]
§ Must be LG DCIS?
DDX
§ Papillary DCIS[209]: complete replacement of papilloma by DCIS (Steinberg). MEC present at periphery but not on papillae (Goldblum).
§ Intraductal papillary carcinoma
| Papilloma | Intraductal papillary carcinoma |
| MEC | Absent (may be present at periphery of duct wall) |
| -Not dark
-Vesicular -Variable size and shape |
-May be dark
-Diffuse chromatin -Uniform size and shape |
| Apocrine metaplasia | No |
| -Broad FV cores
-Sclerosis common |
-Fine FV cores
-Sclerosis rare |
§ Encysted[210] non-invasive papillary carcinoma: same as papillary DCIS except with loss of MEC at periphery[211] (Goldblum).
3. INTRADUCTAL PAPILLARY CARCINOMA
Micro (WHO)
§ >90% papillae devoid of MEC
§ Epithelial proliferation not required
§ +/-LG DCIS occupying >90% of lesion
§ Central≡intracystic papillary carcinoma
§ Peripheral≡papillary DCIS
4. ENCYSTED[212] NON-INVASIVE PAPILLARY CARCINOMA[213]
Define
§ Non-invasive with papillae[214] within large cystic duct
§ Intraductal if within non-dilated duct vs intracystic if within cystically dilated duct (SenGupta)
Clinical
§ Elderly[215], bloody discharge
Micro: define invasion
§ Needs to be in a cyst
§ Thin papillae
Ø Cribriform, micropapillary areas[216]
§ FV cores[217] lined completely by DCIS[218] or tall cell atypia
§ No MEC on papillae
§ At least focal but often complete loss of MEC at periphery[219]
§ +/-invasion (must be completely outside fibrous capsule)[220]
§ Same patterns as LG DCIS including solid, cribriform, micropapillary, stratified spindle
Variants
§ Transitional
§ Solid: often with NE differentiation
IHC
§ MEC lost completely on papillae but at least focally at periphery[221]
§ HR+
§ HER2?
Outcome
§ Favorable, cured if completely excised
Prognosis***
§ Complete excision
§ Extracapsular invasion (no1)
DDX (WHO has good table)
§ Papilloma: MEC present everywhere, nuclei not dark, nuclei more pleo, apocrine metaplasia frequent, broader FV stalks
ENCAPSULATED IDPC
Probably circumscribed invasive carcinoma (not DCIS) but same prognosis and management as DCIS, subareolar mass in elderly +/- nipple discharge, no MEC on papillae and at periphery, must have imaging correlation, BIGGER,
§ Aka “encysted”/”intracystic” papillary carcinoma (Schnitt, Goldblum). Encapsulated is better term because not always in a cyst (SenGupta). Schnitt on his paper from 2008 says that should be called encapsulated papillary carcinoma (Lit).
§ Associations: DCIS or microinvasive carcinoma outside of capsule (Goldblum)
§ Def: variant marked by striking fibrous CAPSULE and radiographic finding of CYSTIC SPACE (WHO, Schnitt, SenGupta). MuDDxy area on nomenclature but Schnitt now call this cancer (not DCIS) because absence of peripheral MEC (SenGupta).
§ Grade: LG cancer (SenGupta).
§ Caveat: previously viewed as DCIS, now may be LG invasive carcinoma with expansile growth given absence of peripheral MEC (Schnitt). Due to complete absence of MEC, whether this tumor should be considered as DCIS or circumscribed INVASIVE carcinoma is debatable (DCIS by definition should have a rim of MEC around, SenGupta). Bottomline is no matter whether defined as in situ or invasive, clinical outcome is excellent (Schnitt)
§ Caveat: formerly thought to be in situ but now believed to be borderline lesion transiting from DCIS to invasive carcinoma because peripheral MEC can be either positive or negative (Goldblum). Schnitt calls encapsulated papillary carcinoma if peripheral MEC is absent and papillary DCIS if peripheral MEC is present (Schnitt).
§ Caveat: bottomline is that whenever there is absence of peripheral MEC, it’s a circumscribed invasive carcinoma rather than DCIS (DCIS by definition must have peripheral MEC) (Goldblum).
§ Imaging: quite specific radiographic and gross finding with tumor within a cystic space (SenGupta)
§ Incidence: up to 2% of breast cancers (Goldblum)
§ Locations: in large cystic duct. Mostly located centrally (Goldblum)
§ Outcome: similar to DCIS, therefore excellent with 100% 10-year survival (Goldblum, SenGupta). Cases with nodal mets exist further supporting this to be an invasive but circumscribed carcinoma (Schnitt)
§ Ssx: palpable subareolar mass (9/10) +/- (Schnitt, Goldblum).
§ Treatment: local excision (no need for axillary dissection) (Schnitt). Best manage it as DCIS and NOT invasive papillary carcinoma (Schnitt). Should not get chemotherapy because of good prognosis despite usually large size (SenGupta)
Gross
§ BIGGER than intraductal papillary carcinoma (WHO); often quite large (SenGupta).
Micro
§ Thin FV stalks (Goldblum). Atypia everywhere in lesion (Schnitt)
§ Invasive: stromal invasion BEYOND cyst wall (Goldblum). Careful with pseudoinvasion (tumor nests within fibrous capsule) (Goldblum)
§ Reporting: “although recent studies have suggested that these may represent circumscribed nodules of low-grade invasive carcinoma rather than in situ lesions, they should be managed in a manner similar to DCIS” (Schnitt)
IHC
§ SMMS NOT useful to assess invasion because negative in encystic papillary carcinoma and invasive papilllary carcinoma (SenGupta)
DDX
§ Intraductal papilloma (SenGupta): benign cytology
§ Invasive papillary carcinoma (SenGupta): examine fibrous capsule for invasion
§ Papillary DCIS (Schnitt): peripheral MEC present in papillary DCIS but absent in encapsulated papillary carcinoma
INVASIVE IDPC
Report size of ONLY invasive component, clearly BEYOND capsule, better prognosis,
§ Demo: 1% of all breast carcinomas (Robbins).
§ Outcome: better than other forms of breast carcinomas (Robbins).
§ Ssx: similar to IDC (Robbins)
Micro
§ Stromal invasion must be CLEARLY BEYOND cyst wall (Steinberg, Goldblum). Careful with tumor within cyst wall because it can just be entrapped glands (Goldblum).
§ Caveat: report size of ONLY invasive tumor to avoid overtreatment (Schnitt, Goldblum)
IHC
§ ER and PR+ but HER2-. SMMS-
SOLID IDPC
NE features, more spindly, solid growth around FV cores, no MEC, more MUCIN and often associated with mucinous carcinoma, older women,
§ Associations: mucinous carcinoma (Goldblum)
§ Demo: typically older with mean 72 (Goldblum)
§ Spread: 1/10 with positive LN (Goldblum)
Micro
§ Solid growth of ovoid to SPINDLY cells arranged around FV cores (Goldblum). Low nuclear grade (Goldblum). More mucin (intra/extracellular) common (Goldblum). NE features with chromogranin+ (Goldblum). No MEC iwthin cellular proliferation +/- MEC in periphery (Goldblum).
§
NIPPLE LESIONS
Types (WHO)
§ Nipple adenoma
§ Syringomatous adenoma
§ Paget’s disease
1. NIPPLE ADENOMA
Micro (Steinberg, Goldblum, Rosai)
§ WC, not encapsulated
§ Below nipple[222]
§ Dilated glands harboring intraluminal papillary growth
§ Extends to surface with abrupt transition into squamous
§ Fibrotic stroma
§ +/-all secondary changes of papillomas possble (UDH[223], any metaplastic change, necrosis, inflammation)
Perimenopausal, benign nipple proliferation, variant of central papilloma, mimicking Paget’s clinically, well-circumscribed papillary growth with connection to epidermis, RR?, focal NECROSIS permitted,
§ Aka nipple duct adenoma (not same as ductal adenoma), erosive adenomatosis, papillary adenoma of nipple, florid papillomatosis (Steinberg, Rapini)
§ Def: benign proliferative lesion in area of nipple (Goldblum)
§ Demo: all age but mostly perimenopausal (Goldblum)
§ Caveat: variant of central papilloma; in fact, florid papillomatosis of nipple (Goldblum, WHO)
§ Ssx: nipple discharge +/- erosion and ulceration, mimicking Paget’s[224] (Steinberg, Goldblum)
Gross
§ Crusted papule or plaque on nipple (Rapini).
DDX
§ Syringomatous adenoma (Steinberg): comma-shaped glands
§ Tubular carcinoma (Steinberg)
2. SYRINGOMATOUS ADENOMA
§ Ill defined subareolar mass
§ Comma-shaped glands
§ 2 cell layers
§ Scant pink cytoplasm
§ Squamous differentiation common
§ Perineural and fat infiltration
IHC
§ Luminal cells: CEA+; basal cells actin+
DDX
§ Tubular ca, nipple adenoma, low grade adenosquamous ca
§
3. PAGET’S DISEASE
Clinical
§ Red crusted, eczematous nipple
§ Nests above the basement membrane
§ Milk filled cavity ↑cytoplasm with prominent nucleoli
§ Usually associated with IDC+/-DCIS
§ IHC: her2/neu, lmk, cea, ck7, ema, er/pr, mucin
2/3 with in situ or invasive carcinoma, HER2+,
§ Associations: 2/3 with underlying in situ or invasive carcinoma (Steinberg). Crum says nearly 100% (Robbins)
§ Caveat: malignant cells (Paget cells) extends from DCIS (not LCIS) to nipple epidermis without crossing BM (Robbins).
§ Caveat: underlying cancer usually PD and HER2+ (Robbins)
§ Def: intraepithelial spread of underlying breast carcinoma to nipple epidermis (Steinberg).
§ Outcome: extent of underlying carcinoma (Steinberg)
§ Incidence: rare (1%, Robbins).
§ Ssx: 1/2 have palpable mass (almost all patients with palpable masses have underlying IDC vs <50% without palpable masses have IDC) (Robbins). Rash around nipple and areola (Steinberg). NOT peau d’orange (inflammatory carcinoma) (me)
Micro
§ Ugly cells[225]
§ Singly in all layers but more nested at base
§ Abundant pink cytoplasm
IHC
§ Use BER, CEA, low molecular weight keratin (CAM 5.2, AE1), CK7 to prove it. CK20 can be either (Marosh). S100- (to R/O melanoma), HMK- (good to R/O SCC) (Marosh)
§ HER2+ (usually, Robbins; remember it’s aggressive, me). Rather unusual for Paget’s disease cells to be Her2- (Marosh, Rowlands)
§ EMA+, LMK+, HER2/neu+, S100-, HMB45- (Steinberg)
DDX
§ Melanoma:
§ Toker clear cells: normal cells in nipple epidermis. CK7+
§ Bowen disease (pagetoid):
§ SCC in situ
Ø Multinuc. Gc, keratinization of individual cells
Ø IHC: hmk, p63
§ Melanoma
Ø Cells touch the basement membrane
Ø IHC: s100, hmb45, mart1
FIBROEPITHELIAL
Types (WHO)
§ FA
§ Phyllodes
Ø Benign, borderline, malignant
§ Periductal stromal sarcoma, LG
§ Mammary hamartoma
1. FIBROADENOMA
ADULT
Clinical
§ No1 benign breast tumour
§ Often multiple and bilateral
§ Before 30yo
§ Young women present with palpable mass, older women present with mammographic lesion
§ Association with cyclosporine A
§ Origin: intralobular stroma
§ Completely benign
§ Sometimes in vulva
Treatment
§ Nothing on biopsy and nothing on excision
Gross
§ Well circ. Mass with slits
§ Circumscribed bulging, whorled or slit-like spaces (Rosai)
Micro
§ Intracanalicular[226] or pericanalicular[227] pattern
§ Compressed epithelial lumina
§ Balanced epithelial/stromal growth
§ Loose stromal proliferation[228][229] with no atypia
§ +/-UDH but ADH/DCIS/LCIS rare
§ Complex FA[230] if
Ø Sclerosing adenosis
Ø Papillary apocrine change
Ø Epithelial calcifications
Ø Cysts >3mm
§ Fibrous capsule (Robbins)
§ Mitoses permitted up to 1/10 (?)
§ No: leaf-like structures, stromal atypia (Goldblum).
§ Permitted: focal stromal hypercellularity, occasional bizarre giant stromal cells, heterologous elements, apocrine metaplasia
§ Fibroadenomatoid lesion/mastopathy: small FA involving multiple TDLU, not WC
How to tell a FA from a PT
stromal hypercellularity most helpful
§ Also look for infiltrating mac, over!
§ Also recall the different clinical features
IHC*
§ both are CD34+
DDX
§ Phyllodes: atypia, stromal cellularity, leaf-life (expansile stroma attached to rest of lesion by a thin STALK), mitoses (<5/10 in phyllodes but none in FA)
| Cellular FA | Benign phyllodes |
| 30 | 50 |
| Moderate cellularity | Higher |
| No | Mild stromal atypia[231] |
| Rare | Mitoses <5/10 |
| Slit-like[232] spaces | True cleft-like spaces |
| -No stromal overgrowth
-WC[233] |
|
§ Tubular adenoma[234]: WC, small tubules within fibrovascular spindled stroma
§ Hamartoma
JUVENILE
Clinical
§ Young women
Micro
§ Gynecomastoid HP[235] and stroma is more cellular than FA but not as cellular as a PT
§ Essentially same microscopy for FA except more cellular stroma (Goldblum). More pericanalicular type (therefore round ducts, not slit-like) (Goldblum).
§ Caveat: characteristic tufted or gynecomastoid pattern in tubular component (Steinberg)
Juvenile=cellular, fast growing often mistaken for malignancy, adolescents, can be very large, round ducts (not slit-like), LARGE,
§ Aka juvenile FA (Goldblum)
§ Def: triad including adolescent, LARGE and stromal HYPERCELLULARITY +/- epithelial hyperplasia (Steinberg)
§ Demo: adolescents, especially in BLACKS (Steinberg, Goldblum)
§ Ssx: rapidly growing well-defined mass (up to 20cm), mistaken for malignancy (Goldblum).
§ Treatment: curative with excision (Goldblum).
DDX
§ Phyllodes (Steinberg): older women, hypercellularity, mitoses in stroma
CELLULAR
§ Features of a FA but stromal is cellular
2. PHYLLODES
Clinical
§ Usually occur 50’s (1020 yrs later than fibroadenomas)
§ Low grade tumours, rare mets
§ Local recurrence
Gross
§ Well circ. Mass with clefts
§ Round well-circumscribed firm (Rosai). NEVER attached to skin (Rosai). Gray-white cut surface with clefts (Rosai). Secondary changes possible and sometimes extensive (Rosai). Size alone can not rule in or rule out phyllodes; FA can be very large too (Rosai)
Micro
§ Leaf like structures lined by eptihelial and myoepithelial layer
§ Hypercellular stroma
§ Periepithelial stromal condensatoin
§ Mitoses (>=1/HPF is phyllodes), stromal cell atypia, infiltrative border, stromal overgrowth (see only stroma at lower power or 4x objective; nuclei touching eath other) (Lit, Rosai). Hypercellularity (Steinberg, Farmer).
§ Caveat: glands may be proliferative but still no clinical significance because non neoplastic (Rosai). Notice this can also occur in FA (Rosai)
§ Caveat: it’s the stroma (appearance and amount) which determines whether FA or phyllodes (Rosai). Remember it’s not a sharp distinction (Rosai)
§ Caveat: stroma can be monomorphic (firbomasarcomatous) or pleomorphic (MFH) or even heterologous (liposarcomatous, metaplastic bone or cartilage) (Rosai)
§ Mitoses: benign (<5/10, must be STROMAL mitoses) vs borderline (5-10/10) vs malignant (>10/10).
§ Patterns: Leaf-life structures (expansile stroma attached to rest of lesion by a thin STALK) quite characteristic (Rosai)
Variants
§ Lipophyllodes: when there is prominent mature fat in stroma (Rosai)
Infiltrating mac, over
§ Infiltrating border
§ Mitoses
§ Atypia
§ Cellularity (more than 2x that of the intralobular stroma)
§ Overgrowth of stroma (no gl. Visible at 4x/LPF)
>=2/HPF, stromal overgrowth at 4x, same age as cancer but at least 10 older than FA, leaflike growth, clefted cut surface, size no matter, stromal overgrowth strongest, THOROUGH sampling, do NOT need LN dissection
§ Aka cystosarcoma phyllodes (Rosai).
§ Demo: 45 (same as breast carcinoma) but much OLDER than FA (20-35) (Rosai, Steinberg). More in Hispanics (Rosai)
§ EM: fibroblasts with focal myoid differentiation (Rosai)
§ http://www.breastpathology.info/phyllodes.html
§ Origin: intralobular stroma (Steinberg)
§ Prognosis: tumor necrosis bad, stroma other than fibromyxoid bad, anaplasia bad (Rosai, Steinberg).
§ Outcome: recurs and occasionally mets (Steinberg). Metastatic potential in relation to degree of anaplasia including stromal cellularity, atypia and mitoses (Steinberg)
§ Caveat: THOUROUGH sampling to look for malignant areas because high heterogenity (Steinberg)
§ Treatment: NO need for LN dissection (Osler, Exam)
IHC
§ BCL2+ (Rosai)
§ Caveat: ER and PR expression similar to FA (Rosai)
§ CD34+ (Rosai)
Ø CD34+ and BCL2+ can be used to DDxx from sarcomatoid carcinoma (Rosai)
§ ER+ (1/3, Rosai)
§ PR+ (all, Rosai)
Treatment
§ Wide excision because does not spread to LN (rather to lungs and brain)
DDX
§ Cellular FA: slit-like glands (not leaf-like with thickened stroma), <5/10, well-circumscribed, NO stromal overgrowth, no atypia, CD34-
§ Metaplastic carcinoma
§ Primary sarcomas
3. MAMMARY HAMARTOMA
§
MESENCHYMAL
1. HEMANGIOMA
2. ANGIOMATOSIS
3. HPC
4. PASH
5. MYOFIBROBLASTOMA
6. FIBROMATOSIS (AGGRESSIVE)
7. INFLAMMATORY MYOFIBROBLASTIC TUMOR
8. LIPOMA
9. ANGIOLIPOMA
10. NEUROFIBROMA
11. SCHWANNOMA
12. ANGIOSARCOMA
13. RMS
14. OS
15. LM
16. LMS
17. LIPOMA
18. LPS
19. GRANULAR CELL TUMOR
20. BENIGN MIXED TUMOR
4. PSEUDOANGIOMATOUS STROMAL HP PASH
Define
§ Non-neoplastic but reactive (hormonal influences; Steinberg).
§ Named this way due to its unique immunoprofile (Steinberg).
Clinical
§ Can present as mass
Micro
§ Anastomozing slit-like spaces, lined by MFB
§ Densely collagenous stroma
§ Empty spaces[236]
§ No: atypia[237], mitoses
DDX
§ Misdiagnosed as angiosarcoma (Steinberg)
Treatment
§ Wide local excision!!!
IHC***
§ CD34+
§ CD31-
§ F8-
§ VIM+
§ SMA+[238]
5. MYOFIBROBLASTOMA
Micro
§ WC
§ Short fascicles of spindle cells
§ Bland
§ Intervening thick hyalinized collagen[239] with some fat and mast cells
§ No: necrosis
§ Mitoses ≤1/10
DDX
§ Nodular fasciitis
§ Fibromatosis
§ Spindle cell lipoma
§ Spindle cell metaplastic carcinoma
§ LG FS
6. FIBROMATOSIS
Micro
§ Long fasiclces[240] of spindle cells
§ Mixed collagenous and myxoid stroma[241]
§ Bland[242]
§ Infiltrative border
§ No: atypia
§ Mitoses ≤2/10
DDX
§ Metaplastic carcinoma with sarcomatoid features (Goldblum)
§ Phyllodes
§ Sarcomas
§ Spindle cell melanoma (Goldblum)
IHC
§ Sometimes SM markers+ but not S100, CK or desmin
7. INFLAMMATORY MYOFIBROBLASTIC TUMOR
12. ANGIOSARCOMA
19. GRANULAR CELL TUMOR
Micro
§ Infiltrative
§ Large polygonal cells with abundant cytoplasm forming nests or in sheets
§ DPAS+ granules
§ Small nuclei, prominent nucleoli
§ Permitted: moderate atypia
§ No: mitoses
FOCAL STROMAL FIBROSIS (FIBROUS NODULE)
§ Dense fibrosis occupying more than 90% of the interlobular stroma.
§ Perilobular fibrosis (within the lobular unit).
§ Septal fibrosis (in stroma between lobular units)
Haphazard fibrosis (also involves the interlobular stroma, thick collagen fibers are a matted haphazard array or radiate in thick bands from a central focus
PERILOBULAR HEMANGIOMA
§ Perilobular arrangement without atypia or mitoses, DDxx angiosarcoma,
§ Incidence: most common vascular neoplasm (Steinberg)
§ Thin-walled capillaries (Steinberg). No invasion of breast lobular units (Steinberg). No atypia or mitoses (Steinberg)
§ Patterns: characteristic perilobular arrangement (Steinberg)
DDX
§ Angiosarcoma (Steinberg): anastomosing channels, atypia
SARCOMA
§ Extremely rare in breast (SenGupta). Nodal dissection not needed (SenGupta). Mostly angiosarcoma and leiomyosarcoma. MFH, rhabdomyosarcoma rare.
IHC
§ Easily ruled out by neg vimentin (SenGupta: vimentin- sarcoma is extremely rare).
DDX
§ Metaplastic carcinoma with sarcomatoid feature (SenGupta): easily nailed by HMK+ and p63+
§ Phyllodes (SenGupta)
§ Fibromatosis (SenGupta)
MYOEPITHELIAL LESIONS
1. MYOEPITHELIOSIS
2. ADENOMYOEPITHELIAL ADENOSIS
3. ADENOMYOEPITHELIOMA
Micro
§ Proliferation of myoepithelial cells
§ Can look like Pagetoid spread
§ Epithelial cells are not increased but may have apocrine change
§ Looks like the myoepithelial cells are pushing the epithelial component up
§ Clear cells admixed with tubules
§ Cuboidal cells with CLEAR cytoplasm admixed with tubules (Steinberg). Clear cells positive for MEC markers (Steinberg)
§ Malignant: aka myoepithelial carcinoma, obvious atypia (Steinberg)
Clinical
§ Incidence: rare (Steinberg)
§ Origin: MEC, therefore S100+, actin+,… (Steinberg)
§ Outcome: may recur but rarely mets (Steinberg)
§ Ssx: freely movable nodule (Steinberg)
4. MALIGNANT ADENOMYOEPITHELIOMA
OTHERS
COLLAGENOUS SPHERULOSIS
Micro
§ Round amorphous hyaline deposits next to epithelial cells
§ Spherules eosinophilic material between epithelial and ME cells. Eosinophilic cuticle at periphery, mucinous spherulosis (flocculent basophilic material). Focus of FB/MFB hyperplasia surrounding round spherules containing basement membrane-like material (therefore collagen4+; Steinberg). Focus of epithelial/MEC hyperplasia surrounding characteristic round spherules containing BM-like material (thus stains for collage IV) (Steinberg)
DDX
§ Looks like adenoid cystic ca. Or cribriform carcinoma
§ AdCC (Steinberg): more atypia
§ Cribriform DCIS: no MEC around cribriform spaces
§ Collagenous spherulosis vs DCIS (cribriform) vs adenooid cystic k vs lobular neoplasia with signet ring cells
§
IHC
§ Collagen IV +ve
§ Spheres: collagen4+ (not collagen1)
§ MEC: S100+, SMA+
Clinical
§ Locations: also in salivary glands.
§ Associations: sometimes sclerosing adenosis (Steinberg)
§ Nature: variant of UDH. Benign.
§ Caveat: part of proliferative FFC
§ RR: ? (same as UDH???)
GALACTOCOELE
Gross
§ Milk filled cavity
Micro
§ Lined by dilated epitheliumlined channels
LACTATIONAL CHANGE
§ Caveat: foci of necrosis permitted, vacuolization, adenosis, dilated lobules
Aka
§ Lactional metaplasia
Etio
§ Estrogens, progesterone, prolactin, GH (Steinberg)
Micro
§ Marked enlargement and dilation of lobules with increased number of acini and cytoplasmic vacuolization (Steinberg). Cells vary from columnar to cuboidal (Rosai). Misdiagnosed as malignancy (Steinberg).
§ Caveat: foci of necrosis permitted (Steinberg)
§ Compare resting vs lactional change
Ø Resting: 2 layers (epithelial and myoepithelial, myxoid stroma, plasma cells and intraepithelial lymphocytes)
Ø Lactional: glandular acini/stroma ratio increases, lipid vacuoles with HOBNAILING
PREGNANCY CHANGE
Micro
§ Hobnailing of the epithelial cells, clear cell change
AMYLOIDOSIS
§ Associated with RA or amyloidosis
§ Amorphous EOSINOPHILIC material with GIANT cell reaction
DDX
§ ELASTOSIS
HYPERSECRETORY CHANGE
§ Can occur in postmenopausal or non-pregnant women (Farmer)
CYSTIC HYPERSECRETORY HYPERPLASIA
Etio
§ Pregnancy
Micro
§ Cystic dilation, lined by simple columnar epithelium WITHOUT apical snout, secretion
MONDOR’S DISEASE
§ Weird thrombophlebitis of breast and thoracic wall (Rosai). Self-limited. Clinically resembling malignancy (Rosai)
JUVENILE HYPERTROPHY
§
MALE BREAST
GYNECOMASTIA
Clinical
§ Hypertrophy and hyperplasia of glands and stroma
§ Often reversible
Etio (hint: estrogen excess)
§ Idiopathic
§ Puberty
§ Medications: digitalis, Dilantin, methotrexatem spironolactone, anabolic CTSD
§ Drugs: heroin, marijuana
§ Cirrhosis
§ Functioning testicular tumors (Leydig, Sertoli)
§ Klinefelter
§ Alcohol
Micro
§ Proliferation of ducts without lobules
§ Dense, periductal stromal fibrosis or edema
§ Micropapillary hyperplasia
§ Mild lymphocytic infiltrate
§ Epithelium may be surrounded by prominent swollen stroma giving “halo” effect
§ Focal squamous metaplasia
§ Over time, less hyperplasia and more stromal fibrosis
§ May have PASH
§ Gynecomastoid HP means longer tapered papillae
Variants
§ Florid (no1): hyperplastic epithelium, PASH
§ Fibrous:
MALE BREAST CANCER
RF
§ Klinefelter RR=50!!!
§ BRCA2
§ Not gynecomastia
Outcome
§ Same stage to stage to female breast cancers
Micro
§ IDC (no1)
§ Papillary carcinoma (no2)
§ Lobular carcinoma rare
IHC
§ ER+ (even in male patients!)
HEREDITARY
What are the familial and hereditary breast diseases? (Coward attacks and lick “p”)
§ BRCA1
§ BRCA2
§ Li-Fraumeni syndrome
§ Ataxia telangiectasia
§ Cowden syndrome
§ Peutz-Jeghers syndrome
BRCA1[243] (17, AD)
§ Young + mult. Breast primary tumours
§ High grade + ↑ inflammation response + pushing margins
“MO”
Medullary ca
§ Ovarian ca
Genetics (17). Locations (breast, ovary, endometrium, cervix, FT).
§ Genetics: 17q21 BRCA1 germline mutations (Lester).
§ Locations: breast (85%), ovary (63%) (mainly serous), endometirum, cervix, liver, colon, FT, peritoneum (WHO)
Micro
§ Breast cancer often “medullary” type and triple negative and have p53 mutations (Lester). Ovarian carcinomas generally serous type (90%), high-grade and bilateral (Lester)
BRCA2 (13, AD)
Genetics (13). Locations (breast, ovary, prostate).
§ Locations: MALE and female breast (85%), ovary (27%) (mainly serous), prostate, pancreas, gallblaDDxer, stomach, melanoma (WHO)
§ Genetics: 13q12.3 BRCA2 germline mutations (Lester)
Micro
§ Tumors from BRCA2 are less specific histologically (Lester). High grade ductal ca (no special type) but atypia with pushing margins
Clinical
§ Young + mult. Breast primary tumours
“OPP”
§ Ovarian ca
§ Pancreas
§ Prostate
LI-FRAUMENI SYNDROME
§ Mutations to p53
“Sosa”
§ Sarcomas
§ Osteosarcomas
§ Adrenocortical
Genetics (p53 on 17). Locations (BREAST, sarcoma, brain).
§ Locations: breast, sarcoma, brain, adrenal, leukemia (WHO)
§ Outcome: risk for invasive cancer is 50% by age 30 and 90% by age 70 (Cheng)
- SSx: Soft tissue sarcoma, early onset breast cancer, adrenocrotical and brain tumors, leukemia
§
Diagnosis
§ Sarcoma before age 45, first degree relative under 45 with any cancer and a third affected first or second degree relative with either sarcoma at any age or cancer under age 45 (Cheng)
Genetics
§ 50% have germline mutation of TP53 (Robbins). Nonsense mutations, splice site mutations generate truncated protein products (Cheng)
Treatment
§ Annual mammogram (Cheng)… many other stuffs
§
ATAXIATELANGECTASIA SYNDROME
§ Mutation at ATM
§ Progressive cerebellar ataxia
§ Ocular telangiectasias
§ immunodeficiency
§ Breast ca.
COWDEN SYNDROME
§ Mutations to PTEN
§ Multiple hamartomas
“Cow but”
§ Breast
§ Uterine
§ Thryoid ca (nonmedullary)
Genetics (PTEN on 10). Multiple colorectal hamartomatous polyps. Locations (GI hamartomas, BREAST, THYROID, endometrium, skin such as trichilemmomas, cerebellum)
§ Aka multiple hamartoma syndrome, Cowden’s disease (Bronner, Cheng)
§ Complications: skin, breat and thyroid cancers (Osler)
§ Incidence: rare (Jass)
§ Lab: mutational analysis (Cheng)
§ Locations (GI, BREAST, thyroid, skin, cerebellum) (WHO)
§ Nature: one of the hereditary GI HAMARTOMATOUS polyposis (Bronner)
§ Outcome: 25-50% of females develop breast cancer (Cheng, Robbins). Also at risk for thyroid and endometrial cancers (Cheng)
§ Ssx: one of the colorectal polyposis syndromes (Osler). GI, oral and cutaneous hamartomas, breast and thyroid tumors, autoimmune thyroiditis, macrocephaly, mental impairment (Jass). GI polyps NO risk for malignancy (Jass)
§ Multiple hamartomas from all three germinal layers: cobblestone-like hyperkeratotic papules of gingiva adnd buccal mucosa, breast FA, GI HAMARTOMATOUS POLYPS (stomach, SB, LB), cerebellar gangliocytomatosis, facial trichilemmomas, acral keratoses (Osler, Robbins, Cheng).
§ In kids, mucocutaneous lesions, lipomas, fibromas, hemangioma, progressive macrocephaly (Cheng)
Genetics
§ PTEN on 10q (remember Cowd”EN”=PT”EN”) (Jass, Cheng, Bronner).
Treatment
§ Surveillance for thyroid and breast masses from age 20 (Cheng)
§ Consider prophylactic mastectomy for women (Cheng)
PEUTZJEGHERS SYNDROME
§ Mutations to STK11 gene
§ ”GI, pancreas and gyne stuff”
§ GI hamatomas, pancreas, breast, ovaries, uterus, cervix
STEWART-TREVES SYNDROME
§ LYMPHangiosarcoma arising in the upper extremities following radical mastectomy with axillay LN dissection (Rapini).
HER2 TESTING***
Elements
§ Pre-analytic
Ø Fixation
§ Sliced at 0.5-1cm intervals
§ 10% neutral buffered formalin
§ 24-48h ideally[244]
§ <6h fixation precludes HER2 testing (reject specimen)[245]
§ Analytic
Ø Assay validation
§ 25-100 samples should be tested when validating a new ABà need to reach 95% concordance rate for both positive and negative categories
§ Must be documented
Ø Antigen retrieval
§ Stringent compliance to validated procedures
§ QC documentation must be done
Ø Controls
§ Both positive and negative must be run[246]
Ø Automated methods
§ Acceptable but must be validated
§ Maintain a log
§ Post-analytic
Ø Digital image scoring
§ Acceptable but must be supervised by pathologists
Ø Mandatory reporting for IHC
§ ID (patient, physician)
§ Date
§ Specimen ID (case, tissue block)
§ Specimen type and site
§ Fixative type
§ AB used
§ Method used
§ Adequate controls
§ Sample adequacy
§ Results
- % of complete membranous positivity
- Uniformity of staining
§ Interpretation
Ø Mandatory reporting for FISH
§ Same
§ Probe used
§ Imaging analysis
§ Controls
§ Sample adequacy (number of invasive tumor cells)
§ Results
- Number of invasive cells counted
- Average number of HER2 signals per nucleus
- Average number of chromosome 17 signals per nucleus
- Ratio HER2/17
§ Interpretation
Proficiency of lab for HER2 testing
§ Must do ≥20/months (meaning about 250 cases yearly)
Ø Pathologists and technologists must be properly trained
QA
§ Internal QA
Ø Equipment maintenance
Ø QC comprising ongoing competency assessment and education of personal (technologists and pathologists)
Ø Revalidation for any modification in procedures
§ External QA
Ø At least 2 testing annually is mandatoryà must reach ≥90% concordance
§ Lab accreditation
Ø Onsite inspection every other year with annual self-inspection
§ Statistical requirement for assay validation
Ø Sensitivity: % positive results/truly positive specimens
Ø Specificity: % negative results/truly negative specimens
HER2+ on IHC
§ 0: no stain
§ 1+: incomplete in any %
§ 2+: from ≥10% weak-moderate complete to ≤30% strong complete
§ 3+: >30% strong complete
§ Positive: >2.2 or >6 average gene copies
§ Equivocal: 1.8-2.2 or 4-6 average gene copies
§ Negative: <1.8 or <4 gene copies
Algorithm
§
§
§
§
§ HR RECEPTOR
Grading
§ Negative: <1%
§ Weakly+: 1-10%
§ Positive: ≥10%
H-SCORE (Allred)
§ % positive cells
§ Intensity score
REPORTING
RISK FACTORS
§ Sexual/reproductive history
Ø Age at menarche (if <11 then increased)
Ø Age at first birth (increased age = increased risk)
Ø Late menopause
§ Family history (mother, daughter, sister); higher if premenopausal
§ Familial syndromes (see above)
§ Exogenous estrogens, radiation
§ Proliferative FCC
PROGNOSIS
What are the major and minor prognostic factors?
Major
§ Invasive vs. In situ
§ Size
§ Local spread
§ Distant spread
§ Lymph node spread
§ Inflammatory carcinoma
Minor “details”
§ Histologic type
§ SBR grade
§ ER/PR
§ Her2/neu
§ DNA content
§ Lymphovascular invasion
§ Proliferative rate (Sphase, Ki67)
CLINICAL ENDPOINTS:
§ Core biopsy:
§ ADH or DCIS → do excisional bx
ALH or LCIS→ ↑risk, so follow closely
SENTINEL NODES
What is a sentinel node?
§ The first node receiving drainage from a specified anatomic site.
Why is it performed in breast carcinoma?
§ For prognostication. May have less morbidity than full axillary node dissection (ie. Lymphedema, ↓range of arm motion)
Has ↑ the rate of the detection of micromets, although the significance remains unclear
How is it performed?
§ Intraoperative injection of blue or radiolabeled dye → Visualization or detection of gamma particles then determine the sentinel node(s) site.
How are sentinel lymph nodes processed?
(include handling, IHC)
§ Sentinel lymph nodes should be submitted individually
§ Sentinel nodes are cut at 2mm thickness and submitted in toto.
§ Cut levels at 500microns for ideal sampling and representation.
§ Note: false negative rate for frozen section analysis is up to 30%
SYNOPTIC REPORT
Ps hhttll mnc
§ Side, distribution: (mulitfocal/multilocal)
§ Histologic grade: (Tubules, Nuclear grade,Mitoses)
§ Tumour extent: (skin, nipple)
§ Lymph nodes (Sentinel and nonsentinel)
§ Margins (peripheral and deep for invasive and DCIS components)
Extras:
§ Necrosis
§ Microcalcifications
IHC/fish:
Ø Er
Ø Pr
Ø Her2/neu***
DCIS
Ø Architectural pattern
Ø Nuclear grade
Ø Necrosis
Ø Microcalcifications
Ø Extent
Tumours most likely to met. To breast?
§ Lung, melanoma
| TUMOURS RISK
What are the relative risks of malignancy with proliferative breast disease? These are also the preneoplastic diseases. |
|
| Histologic changes | Relative risk |
| § Mild ductal HP, adenosis, cystic changes, apocrine metaplasia | § No ↑ risk |
| § Proliferative breast disease w/o atypia
§ Sclerosing adenosis, moderate to florid epithelial HP, papillomas |
§ 2x |
| § Atypical ductal and atypical lobular hyperplasia | § 4x |
| § DCIS and LCIS | § 10x |
PAT’S PRACTICAL PATTERNS
Entities associated with small and distended lobules:
§ Epithelial HP
§ Atypical lobular HP
§ LCIS (discohesive –pap smear like metaplasia)
§ Cancerization of lobule by DCIS (intralobular stroma is fibrotic, cohesive)
DDX of pink and granular cells:
Granular cell tumor
Apocrine carcinoma
Hibernoma
Adrenal cortical carcinoma/adenoma
Pheochromocytoma
Chromophobe RCC
Infectious (MAI, Whipple’s)
Metabolic (Lysosomal storage diseases)
Pathologic features:
§ Ducts seen on end: “Duct profiles”
§ Udh:
§ mild:epithelium > 2 cell layers above normal
§ (myoepi+ normal layer +2 extra layers=4 layers)
§ moderate: epithelium starts to bridge across (5 or more)
§ florid: fills duct
§ Alh: <1/2 of lobule distended and distorted
§ DCIS: should be a focus greater than 2 cm, but on a biospy can call DCIS if you have 2 ducts
§ Myoepithelials may or may not be present
Unfolded lobule: acinii gp together to form a ductsized structre (just much bigger)
Cyst: a really big unfolded lobule cyst, or just by itself
Micropapillary like patterns:
1. smooth®ular with no HP → unfolding lobule
2. well spaced nuclei with cell borders, no nuclear overlapping or streaming, monotonous→DCIS
Apical snouting:
1. seen in columnar cell change
2. seen in normal papilloma
3. tubular ca
Nipple:
§ Smooth muscle bundles in the submucosa
§ Always look for paget disease
Mast cell stains:
§ Alcian blue
§ Giemsa
§ Toluidine blue
§ CD117/ckit
Microinvasion:
§ Focus of ca. No less than 1 mm from the basement membrane from the nearest duct
Sentinel node biopsy
Ø In lieu of ax node dissection for prognostication
CYSTS IN BREAST***
§ Epidermal inclusion cyst[249]
§ Seroma
§ Infectious: abscess
§ Congenital
§ Neoplastic
Ø Mucinous cystadenoma
Ø AdCC
GRANULOMAS
§ Granulomatous mastitis,
§ TB,
§ fungi,
§ ruptured duct,
§ reaction to carcinoma,
§ sarcoidosis,
§ SYPHILIS
FIBROSIS
§ Desmoid tumor,
§ Diabetic mastopathy,
§ host reactive desmoplasia,
§ sclerosing adenosis,
§ radial scar,
§ FA,
§ late stage of duct ectasia
SECRETION FROM NIPPLE***
§ Pregnancy
§ Any causes of increased PRL
§ Infectious: abscess
§ Duct ectasia
§ Papilloma
§ Invasive carcinoma
VASCULITIS
§ Wegener
§ Giant cell vasculitis
§ PAN
SCLEROSING lesions
§ Sclerosing adenosis
§ Radial scar
§ Tubular adenosis
§ Sclerosing papilloma
§ MG adenosis
IPSILATERAL VS BILATERAL RISK
§ Ipsilateral: DCIS
§ Bilateral: ADH, LCIS
GROSSING
MASTECTOMY
Check women fp seps
§ Check req and unique no.
§ Check history
Weight
§ Orient (axillary tail and 4 quads, UO, UI, LO,LI)
Measure
§ Skin, scar, specimen, attached muscle, distance to margins (deep and closest peripheral margins)
Examine
§ skin, nipple, scar
§ Need for special studies
Fix
§ Note
Section and Examine first
Section
§ Ink deep margin and peripheral margins different colors & serial section at 0.5cm intervals
Examine
§ Describe tumour and nontumour tissue
Photograph
Section
§ Done
Examine
§ Tail for lymph nodes
(Photograph)
Submit
§ Skin
§ Scar
§ Nipple
§ Margins (deep and closest peripheral margins)
§ Tumor
§ Representative sections from each quad
§ Lymph nodes
LUMPECTOMY/EXCISIONAL BIOPSY WITH NEEDLE
Check women fp seps
§ Check req and unique no.
§ Check history
§ ADH or DCIS →submit all
§ Check radiograph image for calcifications and tumour with needle
W/ faxitron
§ Ink surface
§ Serial section maintaining orientation
§ Take faxitron image of specimen
§ Submit tumor, suspicious lesions, calcifications, margins, nonneoplastic tissue
W/o faxitron
§ Ink surface
§ Bisect along wire
§ Submit tumor, suspicious lesions, calcifications, margins, nonneoplastic tissue
§ Things to consider
§ Ink with mulitple colors if not oriented
STAGE ”25 SKIN”
§ T0: no evidence of primary tumor
§ Tis: carcinoma in situ (DCIS, LCIS or Paget’s disease)
Ø T1mic: microinvasion <1mm[253]
Ø T1a: 1-5mm
Ø T1b: 5-10mm
Ø T1c: 1-2cm
§ T2: 2-5cm
§ T3: >5cm
§ T4: chest wall or skin
Ø T4a: chest
Ø T4b: edema, ulcer, satellite skin nodules
Ø T4c: both T4a and T4b
Ø T4d: inflammatory carcinoma
Ø N0(i+): ITC[256] by H&E or IHC
Ø NO (m+): ITC by RT-PCR
§ N1[257]: 1-3 nodes
Ø N1mi: micromets≡0.2-2.0mm[258]
Ø N1b: clinically silent intramammary LN
§ N2: 4-9 nodes
§ N3: >10 nodes
SBR GRADING[259][260][261]: how to grade nuclear atypia***
§ Tubules: <10%, 10-75%, >75%
§ Nuclear atypia
Ø 1: small (<1.5x normal epithelial cells) nuclei, uniform chromatin, regular in shape and size (記small uniform regular)
Ø 2: larger (1.5-2x) nuclei, vesicular, visible nucleoli, mild shape variation
Ø 3: large (>2x) nuclei, vesicular, prominent nucleoli, marked shape variation, +/-large bizarre forms
§ Mitoses[262]
Ø 1-7/10
Ø 8-14/10
Ø ≥15/10
REPORT OF DCIS[263][264] (WHO)[265]***
§ Margins (including distance)
§ Grade
Ø Necrosis
Ø Architectural patterns
§ Size
Ø Extensive DCIS≥25% of tumor area
§ Microcalcification (whether within or outside DCIS)
§ Microinvasion
GRADING FOR DCIS (WHO)[266]***
§ Nuclear atypia
§ Necrosis
§ Mitoses
§ Calcification
§ Polarization
§ Architecture is not endorsed by WHO as criterion
| LG[267] | HG |
| Small[268] | Large[269] |
| Monomorphic[270] | Pleomorphic[271] |
| Diffuse fine chromatin | Coarse DNA |
| No nucleoli | Macronucleoli[272] |
| Nuclear polarization[273] | No |
| No mitoses | Mitoses[274] |
| Never necrosis[275] | Necrosis[276] |
| -Arcades
-Cribriform (no1)[277] -Micropapillae[278] -Papillae -Solid (least common) |
-Comedo[279] (no1)
-Clinging/flat[280] -Any form of LG |
| Psammoma-type microcal | Amorphous microcal |
VARIANTS OF PHYLLODES
| FA | LG[281] | IG | HG |
| WC[282] | WC | WC | Infiltrative |
| Stromal cellularity forms a spectrum from paucicellular to markedly cellular[283] | |||
| Atypia forms a spectrum from minimal to marked | |||
| 0-rare | <5/10 | 5-10/10 | ≥11/10 |
| No | No | No | Stromal overgrowth[284] |
| +/-benign lipomatous or osseous metaplasia | +/-heterologous elements[285] | ||
| CD34- | CD34+ | CD34+ | CD34+ |
| Slit-like | ? | ? | Leaf-like |
GRANULOMAS IN BREAST
§ Granulomatous mastitis
§ Breast implant: clear spaces of varying sizes
§ Perilobular mastitis: granulomatous inflammation around a lobuleà is this duct rupture?
§ Usual
Ø Sarcoidosis
Ø Infectious (TB, fungal, bacteria (schisto, leprosy)
Ø FB
Ø Neoplastic (HD)
Ø Vasculitis (Wegener’s, Churg, RA)
GRADING FOR UDH
§ 3-4 layersà mild
§ Bridgingà moderate
§ Solid with peripheral irregular fenestrations[286]à florid
UDH VS ADH/DCIS
| UDH | ADH/DCIS |
| Nuclear overlap | No |
| Irregular nuclei | Round unless HG |
| Uneven spacing | Even |
| No or tiny nucleoli | |
| Slit peripheral lumens | Rounded random lumens |
| Polymorphic population | One cell population |
| Streaming | Perpendicular |
| Indistinct borders | |
| No | Mitoses, necrosis |
| Apocrine metaplasia | No |
| CK5/6+ | CK5/6-[287] |
| No | Periductal fibrosis |
| Microcalcifications | Microcalcifications |
VARIANTS OF FA***
§ Apocrine metaplasia
§ Cellular: juvenile
§ Fibrocellular: cellular and fibroblastic
§ Hyalinized, sclerosed, calcified, ossified: more in elderly (Rosai)
§ Involuted: hypocellular, hyalinized stroma
§ Lactational change:
§ Mature fat, skeletal muscle, cartilage (Rosai)
§ Prominent myxoid: Carney’s complex (Rosai)
§ Squamous metaplasia
§ Stromal reactive multinucleated giants: same mechanism as in mucosal polyps (Rosai)
MG ADENOSIS VS TUBULAR CARCINOMA
| MG adenosis | Tubular carcinoma |
| Round glands | Angulated |
| DPAS+ secretions | |
| Apical snouts | |
| Hyalinized[288] | May be elastotic or cellular |
| BM present[289] | No BM |
| -No MEC
-In fat -Haphazard gland distribution |
|
RADIAL SCAR VS TUBULAR CARCINOMA
| Radial scar | Tubular carcinoma |
| Stellate with radiating ducts, larger at periphery | Haphazard |
| Fibroelastotic stroma | No |
| Distorted glands | Angulated, open lumen |
| MEC | No |
| No | Apical snouts, polarized glands[290] |
COLLAGENOUS SPHERULOSIS VS AdCC
| Spherulosis | AdCC |
UDH VS ADH VS DCIS
| UDH | ADH | DCIS |
| -Lobulocentric
-Rarely extensive |
-Usually focal
-≤2mm or 2 gland spaces |
-May be extensive |
| Polymorphous cell population | Uniform in involved areas | Uniform |
| -Streaming
|
-Same as DCIS except necrosis | -Micropapillary
-Cribriform -Solid |
| Irregular slit-like spaces, more in periphery | -Focal well-formed rounded lumens | -Cribriform with punched out |
| -Overlapping
-Irregular nuclear shape and size -Indistinct borders |
-No overlapping
-Dark -Larger -Monotonous |
|
LCIS VS SOLID DCIS
| LCIS | Solid DCIS |
| No | Perpendicular tumor cells at nodule periphery |
| Discohesion | |
| Intracellular vacuoles | |
| Pagetoid into ducts | No |
| -Neg
-34βE12+ |
-E-cad+
-Neg |
LCIS VS CANCERIZATION OF LOBULES
| LCIS | Cancerization of lobules |
| Discohesion | No |
| Mild-moderate pleomorphism | Higher |
| Solid only | Cribriforming or micropapillae but sometimes solid |
| Neg | E-cad+ |
| Rare | Necrosis |
| Rare | Mitoses |
| No | Surrounding inflammation |
| No | Surrounding fibrosis |
| E-Cad- but HMK+ | HMK+ but E-cad+ |
BENIGN VS MALIGNANT MICROCALCIFICATION ON IMAGING
| Benign | Malignant |
| -Finer
-Closely clustered -Rodlike or branched |
-Coarse calcification
-Widely spaced -Rounded and smooth |
PAPILLOMA VS PAPILLARY CARCINOMA
| Papilloma | Papillary carcinoma |
| Well-formed papillae | Delicate or absent |
| Similar to UDH | Can be thick with perpendicular oval nuclei |
| MEC+ | No on papillae but controversial on periphery |
| Apocrine metaplasia | No |
| Nipple discharge | Less common |
MEDULLARY CARCINOMA VS ATYPICAL VARIANT
| Medullary carcinoma | AMC |
| Syncytial >75% | Syncytial >75% |
| All of following
-Pushing -Stromal lymphoplasmacytic infiltrate -HG nuclei with mitoses -No gland |
≤2 of following
-Pushing -Stromal lymphoplasmacytic infiltrate -HG nuclei with mitoses -No gland |
| Never | DCIS |
HEMANGIOMA VS ANGIOSARCOMA
| Hemangioma | Angiosarcoma |
| Small size | Large |
| Regular | Irregular channels |
| Fibrous septa | No |
| Unconnected | Anastomosing |
| No | Atypia, mitoses |
| Feeder BV | No |
NIPPLE ADENOMA VS TUBULAR CARCINOMA
| Nipple adenoma | Tubular carcinoma |
| Subareolar | Peripheral |
| WC | Haphazard, infiltrative |
| Variable gland shape | Angulated |
| MEC | No |
| No | Luminal bridging |
| BM | No |
| +/-Squamous metaplasia | No |
| Normal | Cellular stroma |
MUCOCELE VS MUCINOUS CARCINOMA
| Mucocele | Mucinous carcinoma |
| MEC on floating cells | No |
TUBULAR CARCINOMA VS MG ADENOSIS VS SCLEROSING ADENOSIS
| Sclerosing adenosis | Radial scar | Tubular carcinoma | MG adenosis | |
| Distribution | Lobulocentric | ? | Haphazard | Haphazard |
| Glands | More compressed tubules | Central small, peripheral dilated | Angulated, always open | Regular, rounded |
| Secretion | No | No | No | Pink secretion |
| MEC | Yes | Yes | No | No |
| Apical snouts | No | No | Yes | No |
| Stroma | Fibrous or hyaline | Fibroelastosis | Desmoplastic (cellular) | Fibrous or in fat |
| Luminal bridging | No | No | Common | No |
| IHC | -HR+[291]
-GCDFP15+ -EMA+ -Collagen IV- -Laminin- -S100- |
-HR-
-GCDFP15- -EMA- -Collagen IV+ -Laminin+[292] -S100+
|
[1] Lobules which contain a cluster of ductules/acini
[2] Including CAM5.2
[3] Mature cells lose those lineage markers
[4] Negative for EMA, desmin, ER, PR.
[5] Less specific because also in MFB. SMA+ because both muscular and epithelial phenotypes
[6] Acquired if after surgery
[7] Abundant pink cytoplasm, central small nuclei
[8] More common in ductal (both DCIS and IDC) than ILC because often comedonecrosis. More in HG than LG DCIS
[9] This implies that malignancies with microcalcification more chance to be HG because of necrosis
[10] Same biochemical as in urine stones (therefore not watersoluble but radiopaque for both types)
[11] Tea cup-shaped are usually benign
[12] Aka lumpectomy: requires 10mm free margin for DCIS excision (Lit)
[13] Mastectomy always with skin
[14] Is this same as total mastectomy (removal of entire breast but no LN, no muscle)?
[15] Aka partial mastectomy
[16] Aka acute purulent mastitis, periareolar/subareolar abscess
[17] Nearly exclusively in lactating breast
[18] Aka periductal mastitis, plasma cell mastitis
[19] Due to periductal fibrosis
[20] Numerous plasma cells (formerly called plasma cell mastitis
[21] May show atypia
[22] Ancient: fibrotic stroma with microcalcification and granulomatous inflammation
[23] Chronic granulomatous mastitis, perilobular mastitis
[24] Similar to granulomatous thyroiditis or orchitis (Rosai)
[25] Granulomas in lobular epithelium
[26] If indicated, culture should be performed
[27] Aka diabetic mastopathy, lymphocytic mastopathy, sclerosing lymphocytic mastitis, fibrous mastopathy, lymphocytic lobulitis (Steinberg)
[28] Steinberg says young women
[29] Name of lesion says all
[30] Can mimic signet-ring cell carcinoma or LPS!
[31] Silicon can be found in LN (silicon migration)
[32] Lined by macrophages
[33] Because involutes after menopause
[34] OCP decreases FCC
[35] No fibrosis unlike ductal ectasia
[36] Cholesterol cleft if ruptured, flattened epithelium (2 layers)
[37] Apocrine metaplasia benign because never in carcinoma. Change may be incomplete, prominent nucleoli
[38] Periductal (not perilobular) because it’s due to duct/cyst rupture
[39] ≤2 layers is called CC change. ≥3 layers is called CC HP
[40] Not same as hyperplasia (cell layers ≥2) (Farmer)
[41] Physiologic, often misdiagnosed as cancer (Steinberg)
[42] Combined with stromal fibrosis causing gland distortion (Steinberg)
[43] Same treatment as florid UDH
[44] Difference in treatment with radial scar because latter often associated with cancer (me)
[45] Usually no mass unless florid or large lesion (Steinberg)
[46] Often bilateral but small (Steinberg)
[47] Resembling DCIS at low power but tubular carcinoma in low power
[48] Lower power shows multiple nodules of retained lobular units, usually WC and rounded (Steinberg)
[49] Adenosis means increased number of glands
[50] Dilated ducts in periphery but compressed (sometimes obliterated) in center (Steinberg, Goldblum). Not as prominent as radial scar (me)
[51] Each ducts surrounded by thickened BM
[52] Often no luminal content (Steinberg)
[53] Sometimes hyalinized, required for diagnosis (Steinberg)à name says all again
[54] May be ugly looking (Steinberg)
[55] Pseudovascular invasion can also occur
[56] Very common, luminal (Steinberg)
[57] Indistinguishable from cancer
[58] Mimics cancer both radiologically and macroscopically (Steinberg)
[59] Steinberg says usually nonpalpable
[60] Generalized risk, higher with multiple or larger lesion
[61] Radial scar is the only adenosis with increased risk (not for MG adenosis or sclerosing adenosis or simple adenosis) (me)
[62] Because high association with DCIS and IDC, especially when large (“complex sclerosing lesion”) (Steinberg)
[63] “Flower head” lesion at low power (Steinberg)
[64] Not just fibrosis but also elastosis
[65] Not specific because invasive cancer can have fibroelastosis too (Goldblum)
[66] FCC including UDH and adenosis common at periphery (Steinberg)
[67] Similar to sclerosing adenosis
[68] Especially LCIS
[69] Exactly same as tubular adenoma with secretory change
[70] Aka microglandular HP (Rosai)
[71] Despite absent MEC, thick BM present and can be demonstrated using IHC or EM (Rosai)
[72] Most often in fibrous tissue but sometimes in fat (Rosai, Steinberg)
[73] For time being, only ADH and DCIS are classified as precurors to cancers
[74] WHO use DIN to comprise UDH, FEA, ADH and DCIS
[75] Except HG DCIS with extensive comedonecrosis
[76] Often slit-like vs more punch-out in DCIS
[77] Vs thick rigid bridges in DCIS
[78] Vs micropapillary DCIS (no FV core)
[79] Can form a central core composed of spindle cells
[80] Some can spindle
[81] Or very small
[82] No fibrosis, no elastosis or chronic inflammation (Steinberg)
[83] If HG atypia, it’s clinging DCIS
[84] Bulbous pedunculated polyp appearance attached to luminal wall
[85] Rigid
[86] DCIS is a premalignant lesion (precursor)
[87] DCIS treated with biopsy alone have 2575% of invasive cancer (Steinberg)
[88] Majority non-palpableà most picked up on imaging due to microcalcifications
[89] Majority detected due to microcalcifications
[90] Benign microcalcifications are tea cup-shaped
[91] Due to lobular arrangement
[92] Because they follow ductal course
[93] Aka “casting-type”
[94] So quite close together
[95] Always make multiple levels to R/O invasion
[96] Mixed DCIS and LCIS possible
[97] 3mm cutoff in papillary lesions (Steinberg, Goldblum)
[98] Even <1mm ductule can be diagnostic!!!
[99] More in HG DCIS (Steinberg)
[100] Good hint for HG DCIS (Steinberg)
[101] Nuclei in DCIS either ┴ to bridge or randomly oriented (Steinberg)
[102] Round, rigid spaces throughout lesion (Steinberg)
[103] True cribriform and micropapillary require cell polarization (perpendicular nuclei) (Steinberg).
[104] 34βE12 and E-cad expression are opposite for LCIS***
[105] Adjuvant radiation aDDxed if small and distant foci from margins (SenGupta)
[106] Either IDC or ILC
[107] Careful that we are not talking about ILC but precursor lesions
[108] Just remember similar to DCIS vs ADH, LCIS vs ALH has also a numeric measure
[109] Significantly smaller compared to ADH or DCIS tumor cells
[110] Similarly to DCIS, mitoses and necrosis mean HG (pleomorphic LCIS)
[111] ≡DCIS extending from ducts into lobular acini (retrograde migration)
[112] If clinically palpable, 1/2 have nodal spread (Robbins). In contrast, only 1/5 of mammography-detected tumors are node+
[113] Benign breast masses includes FA, cyst, lipoma, LN
[114] Coward (Cowden) person (PJ) lick (Li-Fraumeni) and attacks (Ataxia-Telangiectasia) breast (BRCA)
[115] Sclerosing adenosis, atypical ductal hyperplasia, columnar cell lesion with atypia, radial scar
[116] Inner quadrantà lymphatics along internal mamary arteriesà infraclavicular or supraclavicular (Robbins)
[117] Bone, lung, liver
[118] US can DDxx cyst vs solid, tell accurately benign or malignant BUT limited sensibility for in situ carcinoma. Used mostly AFTER mammo confirming a lesion and before a biopsy. Anechoic (cyst), hypoechoic (solid), heterogeneous echoegenicity (suspicious)
[119] Radiologist must report mass vs density as calcification
[120] Stellate appearance produced by desmoplasiaà therefore more in LG tumors (HG does not have much desmoplasia (WHO)
[121] Most important size cutoffs are 1 and 2cm (SenGupta)
[122] Clnical staging done prior to definitive treatment by gathering physical, imaging, biopsy, surgical exploration. Pathologic staging after definitive treatment
[123] PR predicts more accurately treatment response than ER (Lester)
[124] No value for doing it on DCIS or LCIS
[125] Indian filing, targetoid can be seen but no morphologic features of ILC
[126] Rare signet-ring cells can be seen
[127] Sometimes focal elastosis
[128] Lymphoplasmacytic
[129] IDC/ILC or IDC/special type
[130] No influence on prognosis. Very pink cytoplasm
[131] Lymphocytes, monocytes
[132] Extravasated RBC, hemosiderin
[133] Considered special type (WHO)
[134] Current thought is that it’s probably similar to IDC in terms of bilaterality
[135] Still larger than normal epithelial cells
[136] Often harboring mucoid inclusion
[137] So very minimal host response
[138] Vs nearly always present in IDC. Therefore, E-cad+ ILC much more common than E-cad- IDC
[139] Only 10%+ in pleomorphic variant
[140] Rarely+ unless pleomorphic variant
[141] E-cad locus
[142] Which is mucin droplet; aka magenta body
[143] No solid, no single cells
[144] LN mets rare (1/10). Even LN+, it has little effect on prognosis!
[145] Some centers don’t even use adjuvant radiation!
[146] Whereas BM is negative in all invasive breast cancers
[147] So WC as to being confused with benign tumors on imaging
[148] Must meet all five (not four) criteria because atypical medullary carcinomas are as bad as IDC
[149] Diagnosis requires strict adherence to criteria
[150] If infiltrates into fat, then it’s not medullary carcinoma
[151] Mostly T cells
[152] Not intratumoral! Can have granulomas, lymphoid follicles
[153] Must be completely absent
[154] Not 90% like other tumors. Can have focal (not diffuse) hemonecrosis and squamous differentiation
[155] Tumors with syncytial growth with 2-3 other criteria are called atypical medullary carcinomaà this is probably basal-like carcinoma (SenGupta)
[156] Large vesicular nuclei, single or multiple macronucleoli, sometimes atypical giants
[157] Reason why it’s soft (Robbins)
[158] Must be pure mucinous carcinoma. Mixed type has slightly worse prognosis
[159] Must be >90% (otherwise, called IDC with mucinous differentiation)
[160] HG atypia not permitted because incompatible with its good prognosis (Goldblum)
[161] Implying NE differentiation
[162] No prognostic significance
[163] So both ILC and IDC can have signet-ring cells…
[164] Often with tiny or obliterated central lumens. No endothelial lining
[165] No independent prognostic value (WHO)
[166] Strict criteria
[167] Spindle cells or squamous cells may be pure without any visible adenocarcinomatous component (WHO)
[168] Must be more than adenocarcinoma. Adenocarcinomatous component may be absent in pure metaplastic carcinoma!
[169] Ranging from low to high grade (Goldblum)
[170] Chondroid matrix, osteoclast-like giant cells
[171] Purely SCCà HMK+, LMK- (SenGupta)
[172] Purely spindle cells without glands
[173] Including mucoepidermoid carcinoma
[174] Remember secretory for small kids and secretions. No1 breast malignancy in kids
[175] Looks like milk…
[176] Seems PAS+
[177] Important for grading
[178] Cylinders of BM
[179] Glassy eosinophilicà so blue cells surround pink material and vice versa
[180] Basaloid cells more in center whereas larger pink cells more at periphery
[181] Means serous cells of acinus in parotid
[182] Not same as apocrine or secretory
[183] Similar to lipid-rich clear cell carcinoma
[184] Small lymphatic emboli may not be found on small biopsies
[185] Multiple, more peripheral, higher risk for ADH/DCIS
[186] Solitary, larger, proximal
[187] DDX includes nodular adenosis (not encapsulated)
[188] Can ulcerate and mimick Paget’s disease
[189] Bloody discharge if infarcted
[190] Less common, only if >3cm
[191] Look for BV!
[192] careful not confuse MEC with globoid cells (use SMMS to confirm ME cells)
[193] UDH (solid area with nuclear overlapping and streaming) or ADH/DCIS/carcinoma (monomorphic cells with punchedout spaces or rigid growth)
[194] SMMS lost in areas of ADH or DCIS but present on periphery. DCIS usually LG
[195] Often with infarction
[196] Pseudoinvasion can also be caused by needle biopsy. Looks like entrapped tumor nests in capsule (Goldblum)à use IHC for MEC
[197] Infarct often with torsion, sometimes very atypical (Goldblum)
[198] All these 3 often misdiagnosed as malignant (Steinberg, Goldblum)
[199] Same as florid UDH and radial scar
[200] RR=3 if multiple papilloma, 5-7.5 if with ADH/ALH, 7 if multiple and with ADH/ALH
[201] Especially when papillomas are sclerosed
[202] Small papilloma may be entirely removed by needle core biopsy, then no need for excision
[203] “Atypical papillomas” designate papillomas with ADH/DCIS (Schnitt)
[204] Often LG atypia (Steinberg, Goldblum)
[205] Tavassoli’s definition (not reliable approach): >1/3 but <90% of lesion (Steinberg)
[206] Often LG atypia
[207] Page and O’Malley’s definition
[208] Means areas of preexisting benign papilloma present. Diagnose as papillary DCIS if papilloma completely replaced by DCIS
[209] Usually LG nuclei (Steinberg)
[210] Aka intracystic papillary carcinoma (Steinberg)
[211] Loss of MEC at periphery debatable (Goldblum)
[212] Better term would be encapsulated (Schnitt)
[213] Whether this is DCIS (focal presence of peripheral MEC) or expansile cancer but not yet invasive (complete loss of peripheral MEC) is debatable. WHO favors first whereas Schnitt favors second. Bottom line is that it has good prognosis (me). The problem is that if it is allowed to have focal MEC, then it’s identical to papillary DICS…
[214] By definition, non-invasive and devoid of MEC on papillae
[215] Can be in males
[216] WHO permits focal presence whereas Steinberg favors total absence.
[217] Papillae often more slender than benign papillomas (Goldblum). At least foci of papillae must be seen, otherwise it’s not a “papillary” carcinoma!
[218] Mostly LG although IG and HG may be present
[219] Debatable. WHO permits presence of MEC at periphery whereas Schnitt wants complete absence. O’Malley in between
[220] Pseudoinvasion (entrapment of malignant cells in cyst wall) from needle biopsy common.
[221] SMMS not useful to assess invasion because negative in encystic papillary carcinoma and invasive papilllary carcinoma
[222] Look for SM bands (good hint)
[223] Thickened epithelium
[224] Red crusty nipple is typical (Steinberg)à significance of this lesion is more clinical because it mimics Paget’s (me)
[225] Irregular nuclei, macronucleoli
[226] Slit-like spaces
[227] Stromal proliferation around round tubules
[228] Myxoid in young but hyalinized or with microcalcifications in elderly (Goldblum)
[229] Balanced epithelial and stromal growth (Farmer)
[230] Increased malignant behavior (Goldblum)
[231] Plumper rather than spindled (Goldblum)
[232] Minimal visible spaces vs more true cleft-like spaces in phyllodes
[233] WC in benign and borderline PT but infiltrative in malignant PT
[234] Most authorities consider this to be variant of FA
[235] Slender tapered micropapillae
[236] Sometimes RBC
[237] Sometimes dark
[238] Because they are MFB
[239] Looks like a sac of red worms in blue sea
[240] +/-focal storiform or herringbone
[241] Sometimes very collagenized
[242] Regular spindle to oval nuclei
[243] Both BRCA1 and 2 have increased risk for BOTH ovarian and tubal cancers (17%) (Crum). Also primary peritoneal carcinoma (40%) (Crum).
[244] Minimal fixation of ≥6h sufficient for biopsies
[245] True for both IHC and FISH
[246] Must be fixed and processed in same manner as patient samples
[247] FISH is gold standard
[248] Must count at least 20 cells
[249] Granular layer, lamellar keratin
[250] Bilateral synchronous tumors (within 2 months) must be staged separately
[251] Poor correlation between gross and microscopic measurements. When in doubt, use microscopic measure
[252] Gross measurement recommended (either fresh or fixed); however if significant in situ disease is present or invasive tumor extends microscopically beyond the grossly measured mass, then microscopic measurements may be more accurate; using microscopic measurements only is discouraged, because processing artifact may cause significant tissue expansion or shrinkage.
[253] If multiple foci, use largest focus, don’t aDDx sizes of individual foci but aDDx a comment)
[254] Intramammary lymph nodes are coded as axillary lymph nodes for staging purposes
[255] Supraclavicular lymph nodes are coded as regional lymph nodes for staging purposes
[256] ITC≡<0.2mm (about 20 cells side by side). Still classified as N0
[257] Osler says wants to have at least 12
[258] “i” stands for isolated tumor cells; “i+” means either tumor cells detected by IHC only (regardless of size) or tumor cell clusters detected by H&E or IHC that are 0.2 mm or less); isolated tumor cells are not counted as a positive node below
[259] All tumors should be graded regardless of histologic type
[260] 3-5=low, 6-7=moderate, 8-9=high
[261] Tubular carcinoma WD, medullary PD by definition
[262] Count at tumor periphery. at least 10 areas (not necessarily contiguous), count most active areas, fields should be filled with tumor as much as possible, avoid areas of poor preservation
[263] Size and margin extremely important (Steinberg)
[264] “NAG”=necrosis, architecture, grade
[265] 3 most important prognosticators for DCIS are margin status (no1), grade and size
[266] Nuclear atypia and necrosis are major criteria (WHO)
[267] IG exhibits both features of LG and HG
[268] All rounded, 1.5-2x normal nuclear size or RBC
[269] Irregular contour, >2.5x normal nuclear size or RBC
[270] Round
[271] Vesicular and angulated
[272] Often multiple
[273] Means ┴ to lumina
[274] Not obligatory
[275] Never accepted in LG
[276] Not obligatory
[277] Punched out with cell polarization
[278] Clublike
[279] More HER2 overexpression (Osler)
[280] Single layer of nasty cells around duct
[281] Better call benign phyllodes “LG phyllodes” because still can metastasize
[282] Fibroadenomatoid change may be ill-defined
[283] 2x cellular of intralobular stroma
[284] Only stroma visible at 4x power (Rosai)à true only for malignant PT, not borderline!
[285] Malignant
[286] Sometimes compact HP in center (cell darker and more crowding in center of lumen but no overlapping)
[287] Because no CK5/6+ MEC (?) admixed with epithelial cells. Remember it’s still primarily a morphologic diagnosis
[288] Not elastotic or cellular (Rosai)
[289] Demonstrable by IHC or EM
[290] ???
[291] Nearly always+
[292] EMA, collagen IV and lamin simply due to preserved BM