Prognostic features of Colon Cancer

SEAP -Aproximación Práctica a la Patología GastrointestinalMadrid, 26 de mayo, 2006
Datos Prognósticos del Cáncer Colorectal
Gregory Y. Lauwers, M.D.
Director, GI Pathology Service
Massachusetts General Hospital
Harvard Medical School
[email protected]
GI Pathology
th Edition
TNM Stage Groupings: 6th
TNM Stage Groupings
Stage 0
Tis
Stage I
T1
T2
Stage II A
T3
Stage II B
T4
Stage IIIA
T1-T2
Stage IIIB
T3-T4
Stage IIIC
Any T
Stage IV
Any T
N0
N0
N0
N0
N0
N1
N1
N2
Any N
M0
M0
M0
M0
M0
M0
M0
M0
M1
(AJCC
(AJCC-2002)
(AJCC-2002)
Astler-Coller
Dukes
N/A
N/A
Stage A
A
Stage B1
A
Stage B2
B
Stage B3
B
Stage C1
C
Stage C2; C3
C
Stage C1;C2;C3
C
Stage D
N/A
GI Pathology
TNM Stage Groupings:6th Edition
Cummulative Survival Rate
TNM Stage
-Stratified 55-Yr
-Yr Survival Rates: 116,847 CRCs
Stage-Stratified
Diagnosed 1994
-1995
1994-1995
100
90
80
70
60
50
40
30
20
10
0
0
I
II
III
IV
Dx
1 Year
2 Years
3 Years
4 Years
5 Years
Years From Diagnosis
GI Pathology
National Cancer Data Base, Am Coll Surg
Pathologic Evaluation of resected CRcs
• Prognostic factors
• Data relevant to post-operative management
• Information regarding genetics of tumor
GI Pathology
• Pathologic stage (pTNM Staging)
– T= Local extent of primary tumor
– N= Regional lymph node metastasis
– M= Distant metastasis
– Prognostic power:
• Does not apply to residual tumor following
neoadjuvant therapy (ypTNM)
• modified by residual tumor (incomplete
resection) (R classification)
GI Pathology
Validated prognostic factors
• Tumor Grade
Well Differentiated
Moderately Differentiated
Poorly Differentiated
GI Pathology
Validated prognostic factors
vein
EVG (elastic stain)
• Vascular Invasion
– Small vessel (lymphovascular invasion)
(L1)
– Large vessel (extramural invasion) (V1)
GI Pathology
Risk of Metastases for Stage I/II CRCs
GI Pathology
Prall F. Histopathology 2005
Not
-yet-validated prognostic factors
Not-yet-validated
•
High-grade histologic types
•
Perineural invasion
•
Tumor border configuration
•
Host lymphoid response to
tumor
•
Microsatellite stability
(DNA repair gene) status
•
LOH at 18q
budding
GI Pathology
Risk of Metastases for Stage I/II CRCs
budding
GI Pathology
Prall F. Histopathology 2005
th Edition
TNM Stage Groupings: 6th
TNM Stage Groupings
Stage 0
Tis
Stage I
T1
T2
Stage II A
T3
Stage II B
T4
Stage IIIA
T1-T2
Stage IIIB
T3-T4
Stage IIIC
Any T
Stage IV
Any T
N0
N0
N0
N0
N0
N1
N1
N2
Any N
M0
M0
M0
M0
M0
M0
M0
M0
M1
(AJCC
(AJCC-2002)
(AJCC-2002)
Astler-Coller
Dukes
N/A
N/A
Stage A
A
Stage B1
A
Stage B2
B
Stage B3
B
Stage C1
C
Stage C2; C3
C
Stage C1;C2;C3
C
Stage D
N/A
GI Pathology
TNM Stage Groupings:6th Edition
Survival-stage III patients based on T subcategories
100
90
Cummulative Survival Rate
80
70
60
IIIA
pT1/T2 N1
50
IIIB
pT3/T4 N1
40
IIIC
Any T/N2
30
20
p <0.0001
10
0
Dx
1 Year
2 Years
3 Years
4 Years
5 Years
Years From Diagnosis
GI Pathology
Greene FL. Ann Surg 2002
CRCs evaluation: how do we do?
• Pathologic stage can not be coded in:
– 8% of colon CAs and 24% of rectal CAs:
• Non-valid recording of a data element
• pT or pN unknown or indeterminate
• No LN evaluation in 4% colon / 15% rectum CAs
• Number of LN evaluated not specified:8% of cases
• <40% of patients receive adequate LN evaluation
GI Pathology
Pathologic Staging ((pTNM):
pTNM ): Issues
T = Primary Tumor
Tis Carcinoma in situ (intraepithelial or intramucosal)
T1
Invades submucosa
T2
Invades muscularis propria
T3
Invades through muscularis propria into subserosa
or nonperitonealized extramural tissues
T4
Directly invades other organs or structures (T4a)
or “perforates” visceral peritoneum (T4b)
GI Pathology
Serosal Involvement
Underestimated: 26% of cancers judged as T3 by histopathology have tumor
cells on serosal cytologic touch preps
(Zeng et al, Cancer 1992)
Serosal surface
•
tumor close to, but not at, the serosal surface with mesothelial inflammatory
and/or hyperplastic reaction
•
tumor at the serosal surface with inflammatory reaction, mesothelial
hyperplasia, and/or erosion
•
free tumor cells on the serosal surface with underlying ulceration
Shepherd et al, Gastroenterol ‘97
GI Pathology
Circumferential (radial) margin (CRM)
Serosa w/ “perforation”:T4
Resection considered
complete
Non-serosal surface: + CRM
Tumor classified as T3
Resection considered
incomplete (R1/R2)
reported in only 21% of cases in ‘79-’92 NCCTG rectal cancer treatment trial
(Stocchi et al, 2001)
GI Pathology
Transverse Margins: Sample or not to sample?
• Anastomotic recurrence rare if
? 5 cm
• RCPath (UK) guidelines:
– No histology required for
margins >3 cm
• Distal margin of 2 cm proven
adequate for LAR:
– 1cm often adequate for T1-T2
tumors
GI Pathology
Pathologic Staging ((pTNM):
pTNM ): Issues
N = Regional Lymph Nodes
N0 No regional lymph node metastasis
N1 Metastasis in 1 to 3 lymph nodes
N2 Metastasis in 4 or more lymph nodes
M= Distant Metastasis
M0 No distant metastasis
M1 Distant metastasis
GI Pathology
LN
•
How to classified: extramural nodules w/o evidence of residual nodal tissue?
Round nodules: replaced LN
Irregular nodules: discontinuous
extension of tumor (T category)
GI Pathology
Lymph Nodes: How Many?
• There is no minimum number of LN
Stage II CRC
• pN0 not accurately predicted by <12-18 LNs
GI Pathology
Jestin P. Eur J Cancer 2005
pT3 N0 CRC
GI Pathology
Swanson RS Ann Surg Oncol 20035
Lymph Nodes: How Many?
• There is no minimum number of LN
• pN0 not accurately predicted by <12-18 LNs
• Low efficacy of gross identification of LN
– Average number found on diligent search: 21
– Average number found after fat clearing: 69
– 82% of additional nodes were = 2.0 mm
– 75% of all positive nodes were < 2.0 mm in size
Brown HG, et al. Modern Pathology 2004; 17: 402-6
• Number of LNs harvested is a stage-independent prognostic factor
Le Voyer TE, et al. J Clin Oncol 2003; 2: 2912-9
GI Pathology
Stage III CRC
GI Pathology
Jestin P. Eur J Cancer 2005
Number
Number of
of LNs
LNs directly
directly influences
influences the
the accuracy
accuracy of
of nodal
nodal staging
staging and
and
prognosis
prognosis
((1,664
node
-positive rectal
1,664 T3,
T3, T4,
T4, or
or nodenode-positive
rectal cancers)
cancers)
• No significant differences were found (by quartiles) among
patients determined to be node-positive.
• Number of LNs examined correlated w/ 5 yr relapse-free &
overall survival in node-negative patients:
=14 LNs:
9-13 LNs:
5-8 LNs:
<5 LNs:
Relapse-free: 81%
Relapse-free 74%
Relapse-free: 66%
Relapse-free: 63%
- overall survival: 82%
- overall survival: 72%
- overall survival: 73%
- overall survival: 68%
GI Pathology
Tepper, JE. J Clin Oncol 2001
Number of lymph nodes harvested is determined by:
•
Diligence of pathologic examination
•
Surgical technique
– Mesentery trimmed too close to wall
– Incomplete mesorectal excision
•
Patient anatomic variation and/or age
• (Pre-operative treatment)
GI Pathology
What Counts as a Metastasis?
• Isolated Tumor Cells (ITC)
– Single tumor cells or minute clusters of tumor cells
– Seen on H&E or IHC: = 0.2 mm
– Classified as pN0(i+) or (mol+) / pM0 (i+) or (mol+)
• Micrometastasis (greater than 0.2mm but < 2.0mm)
– Classified as pN1(mi) or pM1(mi)
GI Pathology
Not-yet-validated prognostic factors
•
High-grade histologic types
•
Perineural invasion
•
Tumor border configuration
•
Host lymphoid response to
tumor
•
Microsatellite stability
(DNA repair gene) status
•
LOH at 18q
budding
GI Pathology
CRCs in the U.S.
Colorectal cancers
- 135,000/year
MSI-H
- 15% of total
- 20,000/year
HNPCC
< 3% of total
< 6,500/year
MSI-L/MSS
- 85% of total
- 115,000/year
Sporadic
> 12% of total
> 13,500/year
80% : hMLH1 - / hMSH2 +
10% : hMLH1 + / hMSH2 10% : hMLH1 + / hMSH2 +
GI Pathology
Survival of MSI-H CRC
Hazard Ratio
0.45 (0.30-0.68)
P<0.001
Disease specific survival of 215 pts according to MSI status
GI Pathology
Gryfe et al, NEJM 342:69-77;2000
Crohn’s like reaction
Medullary Carcinoma
MSI-H
MSI-H CRC
CRC
Mucinous Carcinoma
hMLH1
GI Pathology
Datos Prognósticos del Cáncer Colorectal
• Staging of resected CRCs:
– Simple rules (pTNM)
– Frequent suboptimal evaluation
– Collaboration of all physicians
• Pathologic features
– can suggest a specific molecular pathway
– increasing importance with targeted
therapies
GI Pathology