doniach lecture 2017 fields of carcinogenesis 1 doniach lecture 2017 fields of carcinogenesis in...
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Doniach Lecture 2017Fields of carcinogenesisin breast and oesophagus
James J. GoingQueen Elizabeth Hospital &
University of Glasgow
Israel Doniach1911-2001
Sebastian Doniach1934-Sonny and Deborah
Doniach in 1954
ודורלדורL'Dor V'Dor
Breast physiologyAutoradiography using 3H TdR
Breast physiology and anatomyN=347 women 14-48, open breast biopsy, benign final
diagnosis Lobules dissected, incubated in 5 μCi/ml 3H thymidine -
> autoradiography -> thymidine labelling indexMenarche, LMP, next menses, OC use ascertainedData normalised (log transformation), analysed in GLIM
Going JJ, Anderson TJ, Battersby S, Macintyre CCA. Proliferative and secretory activity in human breast during natural and artificial menstrual cycles. American Journal of Pathology 1988;130:193-204. Anderson TJ, Battersby S, King RJB, McPherson K, Going JJ. Oral contraceptive use influences resting breast proliferation. Human Pathology 1989;20: 1139-1144.
N = 25 89 90 67 371-5 6-10 11-15 16-20 >20
¢
¢ ¢ ¢
¢
Thymidine labelling index adjusted for day of menstrual cycle 1.0%
2.0%w
w
w w w wwYears since menarche −>
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1-5 6-13 14-20 21-28Day of menstrual cycle
3w
1w
2w
TLI%
17
31
40
49
Follicular phase Luteal phase
44
43
43
38
< No OC
< OC
Cell proliferation in normal breast
Proliferative responses to sex steroids completely different in breast and endometrium
Cell proliferation in human breast strongly influenced by age / years since menarche, OC use in nulliparous women
Current view - some increase in BC risk with current OC use, no excess by 10 years post-OC use
Going JJ. Efficiently estimated histological cell counts. Human Pathology 1994;25:333-336.
Going JJ. Counting cells made easier. Histopathology 2006;49: 309-311
Unbiased, only need count 10% of cells
Estimate 161299Actual 160490
Estimated number of cells
All cells counted
20 breast, 20 cervical cancers10 hpf counted in each tumour
'Field cancerization'
The propensity of multiple neoplasia to arise in an anatomically connected field (head and neck epithelia, Danely R. Slaughter (1940s/50s), colon, urinary tract, Barrett's oesophagus)
Multiple in time and spacePossible mechanisms - shared carcinogen exposureClonal expansion within the fieldDefinition of the field
Where does breast cancer come from?
'Ductal' and 'lobular' breast cancers said to arise from terminal duct lobular unit
(TDLU) ->Cancers 'monoclonal' ie can
be tracked back to one founder cell
But that doesn't mean one cell establishes a cancer
Propidium iodide
By expansion of clones and sub-clones –
eventually a cancer maydevelop
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Cancer breasts usually contain many abnormal TDLU
∴ no reason to think this process 'begins' in a TDLU
What then is the important unit of organisation in the human breast?
THE LOBE – ie one central duct + all its branches and associated glandular tissue
The Lobe is the field of breast cancerisation (Tibor Tot, Laszlo Tabar)
Lobes immensely variable in their development Excess risk of breast cancer per Sievert of radiation
exposure 6th and 9th August 1945, by age at exposure 0-4y 4-14y 15-19y 20-30yx 3.9 x 2.8 x 2.7 x 1.3
The hypothesis of Lobar Insulation (JG): barriers to inter-lobe cell traffic (relatively if not absolutely)
Ducts in the papillaare separated by epidermis
3DR in Reconstruct Journal of Microscopy 2005; 218:52-61)
Duct injection studies by Sir Astley Cooper: no inter-lobar anastamoses
Lobar anatomy of normal human breast
Little studied since Cooper
Many questions, few answers
Important for understanding breast in health and disease
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A common view of what the breast is like on the inside: the ‘grapefruit' model
A more realistic view of what the breast is like inside
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Time to pick up the challenge from Cooper
We have advantages AstleyCooper did not have. We should be able to take his work further!
Duct bundle in nipple: DCIS usually monoductal
One duct ⇔ One lobe 11 - [ 21 - 27 - 30 ] - 48Central duct N in 72 breasts
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George Lenthal C
heatle KC
B
1865 -1951 (Bassano / N
PG)
Sir George Lenthal Cheatle 1920s studies entire breasts in giant histological sections: sees lobar changes leading to breast cancer
HS Gallagher 1960s studies entire breasts in giant sections, with radiological correlation: sees lobar changes leading to breast cancer
Tibor Tot 2000s studies entire breasts in giant sections, with radiological correlation: sees lobar changes leading to breast cancer
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Questions about lobes
Is breast cancer a lobar disease?Why is lobe development so diverse?Do lobes compete to build the breast?Do these differences influence cancer risk?Do early mutations determine lobe growth?Do ‘supercompetitor’ cells colonise lobes?Is the 'lobar insulation'* hypothesis correct?
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Going JJ. Lobar anatomy of human breast and its importance for breast cancer. In: Breast cancer - A Lobar Disease. Tot, Tibor (Ed.), Springer, 2011 pp 19-37.
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Pacific barrel-eye Macropinna microstoma
Tissues can be made transparent:'Subgross' technique
Janet HarrietLane-Claypon Chick
Lister Institute 1907
Serial 2mm sections
Stained alum carmine or haematoxylin
Cleared in methyl salicylate
Subgross sections show mesoscale features
Breast tissue – thick sections
Breast tissue - thick sections -stacked and aligned Going JJ, Moffat
DF. Escaping from Flatland: clinical and biological aspects of human mammary duct anatomy in three dimensions. Journal of Pathology2004;203: 538-544
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All twenty lobes in one breast
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Nick Wright et al tracked a p53 mutation retrogradely from rectum to terminal ileum over 3 years in IBD1m/1000 days = 40μm/hourCrypt fission implausible...Motile 'spercompetitor' cells ?
A candidate breast supercompetitor cell ? Cyril Toker,James Paget
Toker cells,Paget cells
Resemble small and large light cells (mammary precursor cells ?)Concentrate around duct ostiaNumbers highly variablePersist after menopauseResist apoptosis ?Appear motile
Toker cells
Breast
Lobule
Lobe
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Our ignorance of breast lobar anatomy is scandalous
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Risk stratification in Barrett’s oesophagus:
Dysplasia and oesophageal adenocarcinoma
Edgren G, Adami H-O et al A global assessment of the oesophagealadenocarcinoma epidemic Gut 2013:62:1406-14
There is an OA epidemic
Derakhshan MH, Arnold M, Brewster DH, Going JJ, Mitchell DR, Forman D, McColl KEL. Worldwide inverse association between gastric cancer and esophageal adenocarcinoma suggesting a common environmental factor exerting opposing effects Am J Gastroenterol 2016;111:228-239.
Barrett's cancer risk
Sikkema M et al Risk of oesophageal adenocarcinoma and mortality in patients with Barrett’s oesophagus: a systematic review and meta-analysis. Clin Gast Hepatol 2010:8:235-44
51 studies, 64% males, OA risk 0.63 [0.5-0.8] % p.a.
‘low risk of malignant progression… predominantly die of other causes… undermines cost effectiveness of BE surveillance… supports search for risk stratification tools to identify patients likely to benefit from surveillance’
Sikkema et al 2010 OA risk estimate +/- 95% CI
NL
NI
DK
Comparison with UK breast cancer risk at different ages
Can advanced adenocarcinoma be prevented in people with Barrett's oesophagus ?
Guidelines recommend endoscopic and biopsy surveillance
What is the biological rationale for surveillance ?
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The dysplasia spectrum
None LGD
HGDCan Pathologists be trusted to diagnose Barrett's dysplasia ?
Literature shows moderate agreement at best.
None v LGD v HGD v imACa v ...
'The Silence of the Pathologists'Wilfred Weinstein
We need to talk about this...
SURF Trial
N = 136 patients with Barrett's oesophagus and validated low grade dysplasia (LGD), randomised 1:1 between radiofrequency ablation and surveillance
Endpoint - progression to HGD or ACa
Endoscopy and biopsy at 6, 12, 24, 36 mo
SURF Trial
RFA treatment arm
Surveillance only arm
SURF Trial
Safety board recommended early stoppage and treatment of control group
Strikingly high progression rate compared to other published series – probably because cohort purged of spurious 'dysplasia' cases
Moyes LH, Oien KA, Foulis AK, Fullarton GM, Going JJ.Prevalent low-grade dysplasia: the strongest predictor of malignant progression in Barrett's columnar-lined oesophagus. Gut. 2016;65:360-1
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Progression to HGD or OA in 722Glasgow Barrett's cases
Identical progression of LGDto HGD / OA in Glasgow (red) and Amsterdam (orange)
Barr
et’s
muc
osa
–no
dys
plas
ia. G
oble
t cel
ls im
ply
inte
stin
al d
iffer
entia
tion
Conclusions Glasgow pathology as originally reported (not after expert review, as in NL)
With all its imperfections, dysplasia still the best available predictor of cancer risk in Barrett's oesophagus.
Pathologist interest, peer review essential
SURF trial raises stakes. Systematic biopsy (Seattle protocol) finds more prevalent dysplasia
Abela, JE, Going JJ et al. Systematic four-quadrant biopsy detects Barrett's dysplasia in more patients than non-systematic biopsy Am J Gastro 2008:103:850-5
Early History
Beiträge zur experimentellen Pathologie und Chemotherapie 1909, 117-164.
Paul Ehrlich
'After half a century of almost exclusively anatomical research, which revealed at the hand of leading masters the finest details of histological structure, there came a time of obvious stagnation.'
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Proofs and Refutations: The Logic of Mathematical Discovery 1976.
When a powerful new method emerges the study of those problems which can be dealt with by the new method advances rapidly and attracts the limelight, while the rest tends to be ignored or even forgotten, its study despised.
Imre Lakatos
Michel de Montaigne1533-1592Que sçay-je?