Aspects on the Role of the Pathologist in CRC

1
Aspects on the Role of the Pathologist in CRC

• Najib Haboubi FRCS FRCP FRCPath D Path
• Professor of Health Sciences, Liver and
  Gastrointestinal Pathology.
• University Hospital of South Manchester
• UK

2
Selected Topics

• Multi Disciplinary Meeting(MDT).
• Resection Margins (Long and Circumferential).
• Assessment after CRT for Rectal Cancer

3
Background

• In UK (60m) there are 35,000 new
  cases and 16,000 deaths per
  annum.
• New patterns in some parts of the world.
• In India 6th commonest among female and 9th
  amongst male.

4
Accurate Pathological Reporting

• Confirm diagnosis.
• Inform prognosis.
• Plan treatment of individual patients.
• Audit pathology services.
• Evaluate and audit the quality of other services
  like radiology, surgery and oncology.
• Collect accurate data for cancer registration and
  epidemiology.
• Facilitate high quality research.
• Plan service delivery.

5
Multi Disciplinary Team (MDT)

• Colorectal Surgeons
• Radiologists.
• Pathologists.
• Oncologists.
• Specialist Nurse.

• Hepatobiliary(Thoracic) Surgeon
• Stoma Nurse.
• Clinical geneticist / counsellor.
• Social worker.
• Clinical trials coordinator or research nurse.
• GP
• Dietician.
• Gastroenterlogist

6
(No Transcript)
7
Video Conferencing
8
MDT

• Takes place at regular intervals
• Encourages a more efficient and team working
  atmosphere .
• Have a consensus approach to treatment according
  to agreed protocols.
• Quick and appropriate referral pattern.
• Audit surgical treatment.
• Audit pathology reports.

9
(No Transcript)
10
(No Transcript)
11
Evidence Based
12
Second Edition

• 2007
• Few important additions.
• www.rcpath.org

13
(No Transcript)
14
(No Transcript)
15
Assessment of RM

• Longitudinal
• Circumferential / lateral /Radial / non
  peritonealised resection margin.

16
Minimum safe Longitudinal Margin

• 5
• 3
• 2
• 1
• lt 1cm

17
Reappraisal of 5 cm rule of distal excision for
carcinoma of rectum

• Williams , Dixon and Johnston.
  Br.J.Surgery 1983

18
Conclusion

• The application of the 5 cm rule of distal
  excision may cause patients with low rectal
  cancer to lose their anal sphincter unnecessarily.

19
Kirwan , Drumm, Hogan, Keohane

• Determining safe margin of resection in low
  anterior resection for rectal cancer. Br.J.Surg
  1988
• 1cm

20
Declining indication for APR resection in favour
of AR

• Kirwan , ORiordain and Waldron..
• Br.J.Surg 1989

21
Karanjia, Schache, North and Heald

• Close shave in anterior resection.
• Br.J.Surg. 1990
• lt1cm V gt1cm

22
Conclusion

• Reduction of resection margins (provided TME and
  washout is properly performed) does not increase
  local recurrence or compromise survival.

23
DCR 2011
24
Conclusion

• Does not influence Oncological outcome

25
Additions in the 2nd edition(1)

• Documentation type of procedure .
• For rectal cancer, it is expected to have more AP
  than APR .

26
National Audit

• AR 1670
• APR 746
• Hartmans 299
• There is a trend of increase the AR over APR due
  to
• Better preoperative treatment
• Better imaging modalities and
• Better surgery . Good surgeons should be able to
  undertake AR for tumours above 5cm from anal
  verge.

27
Currently

• Increasingly there are surgeons who practice
  restorative surgery for ultra low rectal
  cancer 3 cm

28
Circumferential (CRM) / Lateral / Radial / Non
Peritonealised Resection Margin (NPRM)
29
(No Transcript)
30
Circumferential resection margin Involvement
(CRMI) 1mm or less

• High Local Recurrence.
• Low Survival.
• Poor Standard of Surgery.
• Aggressive Disease.
• Tumour Location.
• Male gender.

31
(No Transcript)
32
(No Transcript)
33
(No Transcript)
34
(No Transcript)
35
Addition to the 2nd edition(2)

• Grading of surgical plane of resection in rectal
  cancer.
• The continuous feedback to surgeons may lead to
  improve quality of surgery.

36
Macroscopic Evaluation of Rectal cancer Resection
Specimens

• Clinical Significance of the Pathologist in
  Quality Control.
• 2 years follow up.
• Iris Nagtegaal et al
• J Clin Oncol 2002, 20 1729-1734

37
Macroscopic Grading of TME

• A (3) ( Good). Complete. Smooth, no coning,
  defect gt5 mm and regular CRM
• C (1) ( Poor). Defects down to the Muscularis
  ,conning, no bulk and irregular CRM
• B(2) .Nearly complete. Defect present but
  Muscularis is not apparent(except at the
  insertion of LA) and irregular CRM.

38
(No Transcript)
39
Results
40
Addition to the 2nd edition(3)

• Measurement of tumour beyond the muscularis
  propria recorded in mm.
• This is to
• a/ facilitate audit of preoperative imaging
  of extramural spread as it is of importance in
  selecting patients of rectal cancer to choose a
  therapy arm .
• b/ It has a prognostic implication for rectal
  cancer.
• 5mm or more is associated with adverse
  prognosis.

41
(No Transcript)
42
Addition to the 2nd edition(4)

• Recording tumour involvement of the NPRM in
  colonic tumours (in addition to rectum) like the
  caecum. These patients may be selected for post
  operative adjuvant therapy.
• Bateman et al J Clin Path 2005 and Quirke et al
  2006 J Path

43
Addition to the 2nd edition(5)

• Recording serosal ( peritoneal surface)
  involvement.
• Tumour cells visible either on the peritoneal
  surface or free in the peritoneal cavity carry
  bad prognosis

44
Influence of local peritoneal involvement on
pelvic recurrence and prognosis in rectal cancer.

• Shepherd, Baxter and Love
• J. Clin. Path 1995

45
Local Peritoneal Involvement

• Detected in 25.8 (54/209) of cases.
• Showed considerable prognostic disadvantage in
  curative and non curative cases.
• May be an important factor in local recurrence of
  upper rectal cancers.

46
The Prognostic Importance of Peritoneal
Involvement in Colonic Cancer a Prospective
Evaluation

• Shepherd et al Gastroenterology 1997
• Strong predictive value for local recurrence /
  persistent disease specially when there is
  mucinous differentiation.

47
Additions in the 2nd edition(6)

• Recording of marked or complete tumour regression
  in patients with rectal cancer that have received
  adjuvant chemo / radiotherapy (CRT)

48

• Rectal cancer that have received adjuvant R/CRT.
• Tumour regression is associated with improved
  prognosis.

49
Pathologist should record marked or CTR

• Rectal cancer that have received adjuvant R/CRT.
• Tumour regression is associated with improved
  prognosis.

50
1895

• XRT 1st used

51
BMJ 1897
52
Rationale for combined CRT for Rectal Cancer

• Chemotherapy increases tissue sensitivity towards
  radiation.
• Radiation stops proliferation.
• Both tumourus and non tumourus tissue are
  affected.

53
Changes afflicting Tumour
54
Short course preoperative radiotherapy interferes
with the determination of pathological parameters
in rectal cancer Iris Nagtegaal et al. J Path
2002,19720-27. 1306 patients(706 TME alone,
598 TMERT)

• No change in stage (No change in depth and
  although there is decrease in no. of LN retrieval
  but not in ve lymph nodes)!!
• Three folds decrease in local recurrence.

55
Long course CRT

• Improves staging (depth and LN status).
• Associated with cpCTR

56
Classifications of Regression

• Mandard Cancer 1994,732680. (1-5)
• Dworak Int CRD 1997,1219. (0-4)
  
• Wheeler DCR 2002,451051. (1-3)
  
• Ryan Histopathol 2005,47141.(1-3)
  
• PRINCIPLE
• Tumour Volume V Fibrosis.

57
Discrepancy in Staging
58
Ryans modification of Mandards 5 point system

• G1 No viable cancer cells (pCTR)
• Single cells or small groups of cancer
  cells.
• G2 Residual cancer cells outgrown by fibrosis.
• G3 Significant fibrosis outgrown by cancer
  cells.
• No fibrosis with extensive residual cancer.

59
Pathological response following long-course
neoadjuvant CRT for locally advanced rectal cancer

• Rayan et al Histopathology2005,47141-146.
• 60 patients
• G1, G2,G3.
• none of the G12 (excellent and good) had local
  recurrence after mean 22 months.

60
(No Transcript)
61
(No Transcript)
62
(No Transcript)
63
(No Transcript)
64
(No Transcript)
65
(No Transcript)
66
CTR we must be clear either pathologic (pCR) or
clinical (cCR)

• 15-30 achieve pCR
• 25-50 of cCR are confirmed as pCR at subsequent
  surgery.

67
What do we do when there is cCR?
68
Operative Versus Non Operative Treatment for
Stage 0 Distal Rectal Cancer Following
Chaemoradiation Therapy Long-term Results
Angelita Habr-Gama, et al Ann Surgery 2004
69
Results

• 26.8 of patients who received CRT developed
  complete clinical tumour response (observational
  group).
• Full thickness biopsy?
• The five-year overall and disease-free survival
  rates were 88 and 83 in Resection Group and
  100 and 92 in Observation Group

70
Conclusion

• Stage 0 rectal cancer disease is associated with
  excellent long-term results irrespective of
  treatment strategy.
• Surgical resection may not lead to improved
  outcome in this situation and may be associated
  with high rates of temporary or definitive stoma
  construction and unnecessary morbidity and
  mortality rates.

71
Complete Clinical response After Preoperative CRT
in Rectal cancer

• Is Wait and See Policy Justified?
• Glynne-Jones et al
• DCR 2008
• Narrative Review of 246 studies

72
Results

• The end point of complete clinical response is
  inconsistently defined.
• Insufficiently robust.
• Partial concordance with pathological complete
  response.

73
Conclusion

• The rationale of wait and see policy when
  complete clinical response status is achieved
  relies on retrospective observations which are
  insufficient to support such policy. EXCEPT
• In patients who are recognised as unfit or
  refused surgery

74
What do we do when there is cCR?

• There are at least one trial in UK and an audit
  in the North West Region.
• Registering ALL cases with cCR and cPR.
• Outcome?

75

76
The effective management of CRC requires

• The involvement of the histopathologist at
  various stages of treatment pathway.
• Diagnostic.
• Therapeutic.
• Audit.
• Research.

77
(No Transcript)
78
(No Transcript)
79
(No Transcript)
80
FACTORS INFLUENCING BIOLOGICAL RESPONSE

• Related to host and tissue.
• Related to therapy

81
Factors related to therapy

• Dose . High dose more toxic
• Field. Large field more toxic.
• Concomitant chemotherapy is more toxic
• Post operative RT is more toxic than pre
  operative RT

82
MORPHOLOGY
83
Acute radiation colitis in patients treated with
short term preoperative radiotherapy for rectal
cancer

• Leupin et al (Switzerland)
• Am J Surg. Path.
• 2002

84
Radiation colitis

• Short Course
• Sever mucosal inflammation.
• Prominent eosinophils.
• Crypt disarray
• Crypt epithelial damage.
• Nuclear abnormality
• Apoptosis of crypt epithelium.
• Either clinically silent or quick recovery.

• Long Course
• These features are either absent or rarely
  detected.

85
The Light and Electron Microscopic Features of
Early and Late Radiation-Induced Proctitis

• Haboubi, Rowland, and Schofield
• Am.J.of Gastro.
• 1988

86
(No Transcript)
87
(No Transcript)
88
(No Transcript)
89
(No Transcript)
90
(No Transcript)
91
Conflicts in the literature
92
How SC differs from LC in pathological and
clinical parameters

• 78 patients(SC 65, LC13) Age 38-85 (average 67
  years)
• 54 males and 25 females
• Mean follow up 56 months(4-105)
• AR in 31 cases APR in 47cases.

93
Results 1

• 32 Responders (Ryan grade 1 and 2)
• 10(76) of LC vs. 22(33)SC.

94
Results 2

• 7 patients had local recurrence (6SC,1LC)
• Regression did not correlate with local
  recurrence

95
Result 3

• Regression did not correlate with overall survival

96
Prognostic Significance of Tumour Regression
After Preoperative CRT for RC

• Rodel et al .J Clin Oncol 2005,238688
• G 4 (Good) in 10.4 DFS 86.
• G 23 DFS 75
• G 01(Bad) gt10 DFS 63

97
Result 4

• Overall mortality correlated with lymph node
  positivity (p0.009)
• 29 of responders were LNve versus 48 non
  responders

98
Absence of LN in the resected specimen after
Radical Surgery for Distal Rectal Cancer and
Neoadjuvant CRT What does it mean?Habr-Gama et
al DCR 2008,51277-283

• 32(11) patients had no LN.5YDFS 74
• 171(61) had ypNO. 5YDFS 59
• 78(28) had yp(N). 5YDFS 30