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Extramural venous invasion in rectal cancer

Dr Gina BrownRoyal Marsden Hospital

UKgina.brown@rmh.nhs.uk

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Vascular Invasion historic data• Brown and Warren Surg Obstet Gynaecol1938• 170 rectal cancer post mortem examinations majority

palliative colostomy/ no surgery/ immediate postoperative death.

• histological evidence of tumour invasion of veins in 61% of 165 rectal adenocarcinomas

• 67 of the 100 patients with vascular invasion were found to have visceral metastases, mostly liver.

• Only one case of metastasis in the absence of any vascular invasion was found

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Detection of venous invasion

• The search for vessel invasion as recommended by Brown and Warren.

• At least three sections of the tumor were taken in each case and stained with Masson's aniline blue trichromestain to emphasize the smooth muscle wall of the small veins.

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Venous invasion important

“as far as the prediction of visceral metastases in rectal carcinoma from the local growth and nodes is concerned, the presence of intravascular tumour means as much from the prognostic standpoint as neoplastic nodes, and their absence means much more”

Brown and Warren 1938

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Do you think this is a venous deposit or a Lymph node?

Tumour along the

course of a vessel- Classifed as N1c

disease – ie extranodal disease

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Lymph node or venous deposit?

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• Poor interobserver agreement for EMVI

• Large variations in reporting rates 10% -50% - underreporting widespread

• Lack of agreement of definitions

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EMVI detection by MRI

Upper rectal tumour (red arrow) + separate ‘nodule’ in superior

rectal vein

Histology of ‘nodule’ shows some microscopic EMVI (black arrows) and tumour filling lumen of larger vessel

EMVI is Present in 30%-40% of rectal cancer patientsMRI enables pre-operative detection of EMVI.

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Characteristic features of EMVI• Expansion of

extramural vessels by tumour

• Serpiginous / tubular extension of tumour signal

MRI for detection of extramural vascular invasion in rectal cancer.

AJR Am J Roentgenol 191(5): 1517-1522.

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Grinnell – mapping of nodes along lymphovascular channels

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Gross tubular extension along

the course of lateral rectal vein

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Gross lateral vein invasion

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Venous invasion is associated with pelvic sidewall nodal spread

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Histological EMVI status & Outcome

0

20

40

60

80

100

0 1 2 3 4 5 6Time since operation (Years)

% R

elap

se-fr

ee

Histological EMVI-Histological EMVI+

p < 0·00001

n=135. Median follow-up=3·12 (0·9-5·7) years.

73%

28%

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MRI-EMVI score & Outcome

0

20

40

60

80

100

0 1 2 3 4 5 6

Time since operation (Years)

% R

elap

se-fr

ee

MRI-EMVI score= 0-2MRI-EMVI score= 3-4

p = 0·0015

71%

32%

n=135. Median follow-up=3·12 (0·9-5·7) years.

Smith et al. “Prognostic significance of MRI-detected Extramural Vascular Invasion." BJS. 2008

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MRI detected more persistent EMVI post CRT than pathology

Chand M, Evans J, Swift RI, et al. Prognostic Significance of Postchemoradiotherapy High-Resolution MRI and Histopathology Detected Extramural Venous Invasion in Rectal Cancer. Ann Surg. 2014.

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Survival curves – 3-year DFS

mrVein invasion negmrVein converted pos to negmrVein remains pos after Rx

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Which came first the spread into the vessels or spread into the lymph nodes?

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Irresectable liver metastases developed after 1 year

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Odds ratio 4.6 (95% CI 1.3-

16.2)P=0.01

Odds Ratio 4.6(95% CI 2.9-

14.4)P=0.001

94 low risk 136 high risk

Whole group:33/230 (14.3%) distant

mets on PET/CT

230 patients with all imaging available

6 patients (2.5%) imaging unavailable for review236 patients enrolled

5/94 (5.3%) distant mets on PET/CT

28/136 (20.6%)distant mets on PET/CT

Same mets

PET/CT and CT

2/94(2.1%)

Same mets

PET/CT and CT10/136 (7.4%)

CT mets & more mets on PET/CT

2/94(2.1%)

CT Mets & more mets on PET/CT8/136 (5.9%)

Mets only on PET/CT

1/94(1.1%)

Mets only on PET/CT10/136 (7.4%)

Any mets on PET/CT not CT

3/94 (3.2%)

Any mets on PET/CT not CT

18/136 (13.2%)

T Vuong, A Garant, G Artho

R Lisbona

McGill University Health Centre

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Serenade trial

• Phase II study : in patients with high metastatic risk colorectal cancer (vein invasion visible on MRI,T3>5mm)

• primary objective : find early liver spread diagnosed by Liver diffusion weighted MRI when CT scan is negative for metastatic disease.

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Endpoint phase II

The primary endpoint will be to show a >5% increase in the detection of unsuspected spread to liver detected in patients at high risk by DW-MRI when standard CT is negative or not able to confirm the presence of metastatic disease.

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What do we hope to achieve with the Serenade trial?

• Improve survival by treating patients with very early spread to liver earlier and when spread is more susceptible to chemotherapy/surgery

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MARVEL

• NCRN Study• Examining clinical behaviour in EMVI+ positive tumours

following CRT• Radiological and molecular change• Multi-centre

• Tissue banking of rectal cancers• Microarray analysis of tumour profile• Predict behaviour

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Hypothesis• mrEMVI positive rectal cancer has worse relapse rates than EMVI negative

rectal cancer following CRT CLINICAL endpoint

• Where mrEMVI positive rectal cancer changes to mrEMVI negative following CRT, it is associated with an improvement in time to relapse. IMAGING PREDICTIVE BIOMARKER

• mrEMVI positive rectal cancer is associated with worse response rates following CRT. IMAGING PREDICTIVE BIOMARKER

• EMVI positive rectal cancer exhibits a distinct molecular/genetic profile compared to EMVI negative rectal cancer. MECHANISM AND THERAPEUTIC PATHWAYS

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Grade 3 EMVI

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Grade 3 EMVI

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EMVI grade 4

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Identification of high risk, predicted margin safe patients

• MRI Tumour spread >5mm or

• Extramural venous invasion Look for metastases at diagnosis and

surveillance (SERENADE trial)

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The future of MR EMVI• A poor prognostic group 30-40% of patients with significantly

worse DFS than EMVI negative Node positive patients• EMVI strongly associated with nodal spread and is

underreported by pathologists – deeper sections and elastin stains for MRI histopathology discordance

• Current and future trials will be able to assess impact of neoadjuvant chemotherapy in improving DFS for imaging identified high risk

• Training and support for radiologists to seek and document EMVI – close assessment and surveillance metastatic disease: the MARVEL trial