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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)

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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?