1. 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

2. Conflict of Interest
Nothing to declare

3. SUMMARY – General Pinciples

4. 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.

5. SUMMARY

6. 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

7. 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.

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

9. 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

10. 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

11. 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

12. New understanding of Breast Carcinoma

13. 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

14. 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+

15. 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

16. Evolution or progression of DIN1

17. 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.

18. 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

19. 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

20. DIN1a = Flat Epithelial Atypia

21. DIN1a = Flat Epithelial Atypia

22. Luminal DIN 1a

23. DIN1a = Flat Epithelial Atypia

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

25. Core biopsy – Din 1a and Tubular carcinoma

26. Core biopsy – Din 1a and Tubular carcinoma

27. Core biopsy – Din 1a and Tubular carcinoma

28. Core biopsy – Din 1a and Tubular carcinoma
Invasive Carcinoma

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

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

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

32. DIN1a and DIN1b

33. DIN1a and DIN1b

34. DIN1a and DIN1b

35. DIN1 - E-cadherin

36. Luminal DIN 1b
Focal
micropapillary
structures

37. DIN1b = Atypical Ductal Hyperplasia (ADH)

38. DIN1c = DCIS Grade 1

39. DIN1c = DCIS - Grade 1

40. Evolution and Progression of LIN

41. LIN 2 = Lobular Carcinoma in-situ

42. LIN2 (LCIS) of Breast IPOX for E-Cadherin

43. LCIS (LN3) - pleomorphic apocrine large cell type

44. LCIS (LN3) - large cell type with comedonecrosis

45. 59F Breast Mass – The low-grade family in one patient

46. 59F Breast Mass – Normal duct and lobule

47. 59F Breast Mass – DIN 1a (FEA)

48. 59F Breast Mass – DIN1a (FEA)

49. 59F Breast Mass – DIN1b (ADH)

50. 59F Breast Mass – DIN1c (DCIS)

51. 59F Breast Mass – Invasive ductal carcinoma – grade 1

52. 59F Breast Mass – Invasive carcinoma with adjacent DIN1a

53. 59F Breast Mass – LIN1 (ALH)

54. 59F Breast Mass – LIN2 (LCIS)

55. 59F Breast Mass – LIN2 (LCIS)

56. 59F Breast Mass – Distant DIN1a and LIN1

57. 59F Breast Mass – Distant LIN1 (ALH)

58. 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

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

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

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

62. Breast cancer of
acinar origin: AAB

63. 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

64. 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”

65. 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
95%
93%
91%
87%

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

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

68. 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.

69. Morphologic demonstration of neoductgenesis
Disorganized architecture 69

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

71. Diffuse (duct forming) breast cancer

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

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

74. 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.

75. 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.