Dr. Malcolm Hayes BC Cancer Agency Vancouver, Canada Update in Surgical Oncology 2014 The pathological basis of Breast Carcinoma – a primer for surgeons Dr. Malcolm Hayes BC Cancer Agency Vancouver, Canada

Conflict of Interest Nothing to declare

SUMMARY – General Pinciples

How does Breast Carcinoma develop? Study of Carcinomas from all organs in the body, including the breast, has shown that in the early stages of their inception, they develop from transformed neoplastic cells within the normal epithelial surface or glands. In most cases the cell of origin is a stem cell that differentiates in different lineages. Later, some of these neoplastic cells may break out of the boundaries of the glands and invade the surrounding tissues to form an INVASIVE CARCINOMA.

SUMMARY

BUT it’s not so simple! There are many different types of in-situ breast neoplasia, although all are potentially curable or controllable. Some early lesions traditionally thought of and labeled as “hyperplasia” or “atypical hyperplasia” are now know to be neoplastic. Different types of in-situ breast neoplasia carry different risks for progression to invasion. The invasive cancers arising from those different in-situ lesions have different degrees of malignancy

Terminology Issues Because the neoplastic cells within the ducts in evolving breast cancer look like the malignant cells in invasive breast cancer they have been termed “Carcinoma in-situ”. However, since only some of these cells have the potential to invade out of the ducts within the lifespan of the patient and because, when confined within the ducts, they have no ability to spread and kill the patient the term “In-situ Neoplasia” is now preferred by many.

Mammary Intraepithelial Neoplasia (MIN) Terminology Ductal intraepithelial neoplasia (DIN) Lobular intraepithelial neoplasia (LIN) Why not BIN? Garbage can Benign intradermal nevus

Mammary Intraepithelial Neoplasia Proliferations Intraductal Usual Duct Hyperplasia Hyperplasia Radial scar Papilloma Atypical ductal hyperplasia Traditional DCIS (DIN) Neoplasia (MIN) Flat epithelial atypia Traditional LIN

Simple translation of MIN DCIS (Ductal carcinoma in-situ) = DIN (Ductal in-situ Neoplasia) Also includes FEA and ADH LCIS (Lobular carcinoma in-situ) = LIN (Lobular in-situ neoplasia) Also includes ALH

New understanding of in-situ Breast Neoplasia – “MIN for the Pro’s” Low Grade MIN Family Ductal Family = DIN1 Flat epithelial atypia (FEA) – many synonyms = DIN1a Atypical ductal hyperplasia (ADH) = DIN1b Traditional Low-grade DCIS = DIN1c Lobular family Atypical lobular hyperplasia = LIN1 Classical Lobular carcinoma in-situ = LIN2 Pleomorphic LCIS = LIN3 Intermediate Grade – various types DIN2 High Grade – various types DIN3

New understanding of Breast Carcinoma

Genetics of Breast cancer pathways LOW grade Intermediate Grade High grade NBN Nijmegen BS ATM Ataxia Tel CHEK2 Li Fraumeni P-TEN Cowden’s 16q LOH 8p loss PI3 kinase Pathway* STK11 PJ syndrome CDH-1 E-cadherin BRACA 2 BRACA1 Her2-neu P53 Li Fraumeni ER+ PR+ Luminal B ER+ PR- Her2 +/- Proliferation genes Inflammatory genes M-tor abnormalities Wnt-pathway abnormalities DNA repair abnormalities Luminal A

Postulated differentiation pathways in Breast Carcinoma Mucinous Type B Endocrine papillary DCIS Solid papillary Ca MANEC Metaplastic Luminal CK7+,CK5/6- ER+ Myosecretory Ca Myoepithelial CK5/6+, Actin +, ER- Neuroendocrine Syn+, Chromo+ Basal type CK5/6+, Actin -, ER- Carcinoid-like Merkel-cell like Pulmonary-like Ductal Ca Lobular Ca Her-2 positive Intermediate basal CK5/6+, CK7+ Intermediate luminal CK7+, CK5/6+ Mixed luminal-basal Ca Stem cell CD44+, CK18+

Low-grade Family Low-grade MIN 16q loss 1q gains Diploid PIK3Ca & ESR1mutations DIN1c DIN1b DIN1a LIN2 LIN1 E-cadherin intact E-cadherin deletion/inactivation Rosen’s Triad: Tubular ca, ADH, LCIS

Evolution or progression of DIN1

How do we know that precursor lesions are related to invasive breast cancer? They are seen associated with one another on the slides. The morphology of the cells is similar in the in-situ and invasive components. Chromosomal abnormalities detected by LOH and CGH are similar 16q deletion Gene expression profiles are similar PIK3Kinase mutations in both. Some mutations also shared with the myoepithelial cells in the involved ducts.

DIN1A Follow-up screening DIN1B Excision biopsy DIN1C Excision biopsy If DIN1A (FEA), DIN1B (ADH) and DIN1C (DCIS-low grade) have similar genetic changes why do we manage them differently? Increasing architectural complexity and size of the lesion seem to correlate with increased probability of associated invasive carcinoma. DIN1A Follow-up screening DIN1B Excision biopsy DIN1C Excision biopsy

Common features of the Low-grade Family Common lesions in breasts of elderly Often co-exist as the spectrum of ductal and lobular morphologies Multifocal Bilateral Slowly evolving Occasionally evolve to invasive low grade carcinomas Carcinoma often away from site of original in-situ lesion Rarely de-differentiate to high-grade lesions May be controllable by hormone modifying agents Cannot reasonably “cut it all out” short of bilateral Mx

DIN1a = Flat Epithelial Atypia

DIN1a = Flat Epithelial Atypia

Luminal DIN 1a

DIN1a = Flat Epithelial Atypia

Core biopsy – Din 1a and Tubular carcinoma Normal lobule Normal lobule

Core biopsy – Din 1a and Tubular carcinoma

Core biopsy – Din 1a and Tubular carcinoma

Core biopsy – Din 1a and Tubular carcinoma

Core biopsy – Din 1a and Tubular carcinoma Invasive Carcinoma

Core biopsy – Din 1a and Tubular carcinoma Normal - p63 Normal - ER

Core biopsy – Din 1a and Tubular carcinoma Din 1a – p63 DIN1a-ER

Core biopsy – Din 1a and Tubular carcinoma Tubular carcinoma – p63 Tubular carcinoma - ER

DIN1a and DIN1b

DIN1a and DIN1b

DIN1a and DIN1b

DIN1 - E-cadherin

Luminal DIN 1b Focal micropapillary structures

DIN1b = Atypical Ductal Hyperplasia (ADH)

DIN1c = DCIS Grade 1

DIN1c = DCIS - Grade 1

Evolution and Progression of LIN

LIN 2 = Lobular Carcinoma in-situ

LIN2 (LCIS) of Breast IPOX for E-Cadherin

LCIS (LN3) - pleomorphic apocrine large cell type

LCIS (LN3) - large cell type with comedonecrosis

59F Breast Mass – The low-grade family in one patient

59F Breast Mass – Normal duct and lobule

59F Breast Mass – DIN 1a (FEA)

59F Breast Mass – DIN1a (FEA)

59F Breast Mass – DIN1b (ADH)

59F Breast Mass – DIN1c (DCIS)

59F Breast Mass – Invasive ductal carcinoma – grade 1

59F Breast Mass – Invasive carcinoma with adjacent DIN1a

59F Breast Mass – LIN1 (ALH)

59F Breast Mass – LIN2 (LCIS)

59F Breast Mass – LIN2 (LCIS)

59F Breast Mass – Distant DIN1a and LIN1

59F Breast Mass – Distant LIN1 (ALH)

Tabar Theory of MIN In-situ carcinoma Breast and prostate Acinar Type Origin in TDLU Clustered calcifications No duct neogenesis Low grade family Ductal Type Origin in major ducts Casting calcifications Duct neogenesis DCIS-like invasive pattern Good prognosis Low fatality Bad prognosis High fatality

The magic of 3-D, subgross, thick section histology of the breast

The grapes represent the TDLUs (terminal ductal lobular units). The controllable/non-killing cancer develop from the TDLUs.

Breast cancer of acinar origin: AAB (acinar adenocarcinoma of the breast)

Breast cancer of acinar origin: AAB

Women with 1-9 mm invasive breast cancer originating from the TDLU had excellent 24-year survival, except those with associated casting type calcifications – regardless of: node status histologic malignancy grade mode of treatment

Cumulative survival of 40-69 year old women with breast cancer associated with crushed stone-like calcifications on the mammogram 98/99/100% 90/93/100% Invasive“ductal” carcinoma “DCIS”

Cumulative survival of cicular/oval and stellate breast cancer cases with no associated calcifications on the mammogram. Women 40-69 yrs old, diagnosed in Dalarna county, Sweden between 1977-2006 95% 93% 91% 87%

The largest subgroup which also has extremely good outcome is the stellate tumors without calcifications or associated with powdery calcifications.

Frequency of stellate tumors among 1-9 mm invasive breast cancers. 99.0% 49.2% --

Conclusion All 1-9 mm tumors, except for the small group associated with casting type calcifications, have excellent 24-yr survival without extensive surgery or any adjuvant treatment.

Morphologic demonstration of neoductgenesis Disorganized architecture 69

We propose that the formation of duct-like structures be called: neoductgenesis.

Diffuse (duct forming) breast cancer

Cumulative survival of breast cancer cases with casting type calcifications on the mammogram. Women 40-69 yrs old, diagnosed in Dalarna county, Sweden between 1977-2006 71%

Cumulative survival of women aged 40-69 years with 1-14 mm invasive breast cancers by mammographic tumor features. Dalarna county, Sweden. 100% 94% 93% 88% 65%

Concluding remarks The pathobiology of in-situ breast neoplasia is diverse and determines clinical behaviour. The old theory of a stepwise progression of neoplastic transformation through UDH is defunct. A modern approach to the treatment of different types of in-situ breast neoplasia must take into account new the understanding of their pathobiology.

Concluding remarks The different types of MIN give rise to invasive carcinomas with parallel differences in their biology and clinical behaviour. Invasive breast cancers may become progressively more genetically complex and show clonal evolution. Understanding the latter will require knowledge of their underlying genetic and proteomic uniqueness to enable rational targeted therapy to be used for individual patients.