MEDULLARY CARCINOMA “ sheets of malignant cells with vesicular nuclei, prominent nucleoli and abundant eosinophilic cytoplasm exhibiting prominent infiltration by intra-epithelial lymphocytes” ? component of glandular ( mucinous / signet ring cell ) differentiation allowed : 20 – 30% of tumour area. ( Jessurun et al 1999 ; Lanza et al 1999 )
lower incidence of EMVI, lymph node and distant metastasis than poorly differentiated adenocarcinoma better prognosis than other poorly differentiated tumours 60 – 90 % MSI ( 79% loss of hMLH1 )
MEDULLARY CARCINOMA MEDULLARY CARCINOMA
POORLY DIFFERENTIATED ADENOCARCINOMA
EMVI
22 %
50 %
Lymph node metastasis
38 %
85 %
Distant metastasis ( at diagnosis )
2.2 %
44 %
P53 positive
12 %
61 %
DNA diploid
84 %
13.8 %
MSI
90 %
16 % ( Lanza et al 1999 )
MEDULLARY CARCINOMA • Immunohistochemistry : CK 20 may be reduced or absent CK 7 positive in 13 % CDX2 may be reduced or absent ( > 80 %) • neuroendocrine markers negative • Calretinin positive in 73 % • hMLH1 expression lost in 79 % ( Hinoi et al 2001; Winn et al 2009 )
pT4a versus pT4b definition of pT4 in the lower rectum: infraperitoneal/retroperitoneal perforation invasion of the external sphincter/levator muscle
N1a : 1 node involved N1b : 2-3 nodes involved N1c : satellite tumour deposit in pericolic or perirectal fat without lymph node metastasis
• N2 : metastasis in 4 or more regional nodes
N2a : 4-6 nodes involved N2b : 7 or more nodes involved
T & N status : 5 year survival in the SEER database : Rectal Cancer N0
N1a ( 1 positive node )
N1b ( 2-3 positive nodes )
N2a ( 4-6 positive nodes )
N2b ( 7 or more positive nodes )
T1-2
93.6 %
86.5 %
83.1 %
70.7 %
49.5 %
T3
78.7 %
66.9 %
59.7 %
49.9 %
37.5 %
T4
61.6 %
48.6 %
41.6 %
39.5 %
22.8 %
Gunderson et al 2010
Lymph node staging • How many lymph nodes are needed for accurate staging ? • Satellite tumour deposits / PTDs
Variability in Lymph Node Retrieval from CRC Specimens : The ACGBI National Audit • prospective audit of CRC patients treated in 79 centres between 2000 – 2002 • 5164 patients undergoing surgery identified • No. of lymph nodes found in the specimen recorded in 48 % - 100 % of cases ( > 90 % complete in 75.9 % of centres ) • Average no. of nodes found = 11.7 ( 95 % CI : 11.4 – 11.9 ) • Average no. varied between centres from 5.5 to 21.3 !!!! Tekkis et al 2006
Factors which affect Lymph Node Yield in Colorectal Cancer Specimens • patient factors : Age • treatment factors : operation : AR versus APR neoadjuvant therapy pathologist
Lymph Node Recovery & Incidence of Lymph Node Metastasis No. of nodes found
Total no. of specimens
% of specimens with lymph node metastasis
1–5
462
6.49 %
6 – 10
596
8.89 %
11 – 15
334
41.62 %
16 – 20
138
31.16 %
more than 20
112
80.36 %
Goldstein 2002
LYMPH NODE HARVEST & PROGNOSIS IN STAGE II RECTAL CANCER. • 527 stage II & 1,137 stage III rectal cancer patients undergoing radical surgery with post-operative chemo-radiotherapy 5 year relapse rate
NB No difference in survival for stage III disease. Tepper et al 2001
LYMPH NODE HARVEST & PROGNOSIS IN STAGE II COLON CANCER • 35,787 colon cancers from the National Cancer Data Base ( 1985 – 1991 ) • 7 % received post-operative adjuvant chemotherapy • 5 year survival
all T3N0
T3N0 1 – 7 nodes T3N0 8 – 12 nodes T3N0 13 or more nodes
T3N1 T2N0
77 % 69.3 % 77.5 % 84.5 %
57 % 87.1 % Swanson et al 2003
Lymph Node Retrieval & Survival in Colorectal Cancer
Morris et al 2007
Lymph Node Recovery & Prognosis • Understaging : inadequate lymph node examination leads to some Dukes C cancers being understaged as Dukes A or B
• Larger numbers of lymph nodes found indicate a host immune response to the tumour which improves survival • Another unidentified factor is associated both with the number of nodes found and survival ???
How many nodes does it take to diagnose stage III colorectal cancer ?
• TNM : 12 nodes • NICE guidance : 12 nodes • RCPath cancer data set : 12 nodes
Fat clearance ( xylene ) Lymph node revealing solutions eg. GEWF Intra-arterial injection of methylene blue Use of a “dedicated pathology assistant” “ fat stretching”
“ there is insufficient evidence to suggest that these techniques increase positive lymph node count or lead to upstaging” Abbassi-Ghadi et al 2012
PTDs : what do we do with them ? Rectal cancer: 4.5 – 31.1 % of cases Colon cancer : 18 – 25.5 % of cases
PTDs & TNM : 1st attempt • 5th Edition ( 1999 ): • “ a tumour nodule greater than 3mm in diameter in perirectal or pericolic adipose tissue without histological evidence of a residual lymph node in the nodule is classified as regional lymph node metastasis. However, a tumour nodule up to 3mm in diameter is classified in the T category as discontinuous extension ie. T3”
PTDs & TNM : 2nd attempt • 6th Edition ( 2002 ) : • “ a tumour nodule in the pericolic/perirectal adipose tissue without histological evidence of residual lymph node in the nodule is classified in the pN category as a regional lymph node metastasis if the nodule has the form and smooth contour of a lymph node. If the nodule has an irregular contour, it should be classified in the T category and also coded as V1 ( microscopic venous invasion ) or V2, if it was grossly evident, because there is a strong likelihood that it represents venous invasion”
PTDs : TNM 6 • No evidence base • Poor reproducibility • Confusion with vascular invasion NOT ADOPTED IN THE UK !!!!
PTDs & TNM : 3rd attempt • 7th Edition ( 2009 ) : • “ tumour deposits ( satellites ) ie. macroscopic or microscopic nests or nodules, in the pericolorectal adipose tissues lymph drainage area of a primary carcinoma without histologic evidence of residual lymph node in the nodule, may represent discontinuous spread, venous invasion with extravascular spread (V1/2) or a totally replaced lymph node (N1/2). If such deposits are observed with lesions that would otherwise be classified as T1 or T2, then the T classification is not changed but the nodule is recorded as N1c. If a nodule is considered by the pathologist to be a totally replaced lymph node ( generally having a smooth contour ) it should be recorded as a positive lymph node and not as a satellite, and each nodule should be counted separately as a lymph node in the final pN determination ”
PTDs, Lymph nodes & TNM staging • 2 independent test populations : 455 CLASICC trial colon & rectal tumours ( images of scanned slides ) 505 colon & rectal tumours from Dalarna County, Sweden ( original glass slides ) 47 cases reviewed by 2 GI pathologists ( PQ & IN ) :
PTDs, Lymph nodes & TNM staging • Doyle & Bateman ( 2012 ) : • 144 consecutive CRCs staged using TNM 5 & 7 pT4a/pT4b category reversed in 28 % No changes to pN1/2 categories Only 3 % classified as pN1c ( all pN1 using TNM 5 as deposits > 3mm )
TNM 5, 6 & 7 : which is better at prognostication ? • Nagtegaal et al ( 2011 ) :
TNM
7>5>6
• Kim et al ( 2011 ) :
TNM
7>6
• Nitsche et al ( 2011 ) :
TNM
7=6
• Hashiguchi et al ( 2011 ) :
TNM
7>6
TOTAL MESORECTAL EXCISION Blunt dissection line
Mesorectal fascia
TME line
A Uniform Residual Tumor ( R ) Classification • TNM : R1 = microscopic residual tumor R2 = macroscopic residual tumor “demonstration of tumor directly at the resection margin ( tumor transected )” • includes continuous and discontinuous tumour spread and distant metastasis !!
• Quirke : CRM positive = tumor 1mm or less from the radial margin of the rectal cancer excision R1/2 & CRM positive rectal cancers are NOT synonymous or directly comparable R1/2 status may be due either to local disease at a surgical margin OR distant metastasis Wittekind et al 2009
Proposed Expanded Residual Tumor ( R ) Classification. • RX : presence of residual tumor cannot be assessed • R0 > 1mm : no residual tumor, minimal distance between tumor and resection margin ; margin > 1mm • R1 < 1mm : no residual tumor, minimal distance between tumor and resection margin; margin 1mm or less • R1-dir : microscopic residual tumor, tumor directly at the resection margin ( tumor transected ) • R2a : local macroscopic residual tumor
• R2b : distant macroscopic residual tumor • R2c : macroscopic residual tumor at both sites Wittekind et al 2009
LOCAL RECURRENCE AFTER CURATIVE RESECTION author
n.
CRM-
CRM+ total Follow-up ( median ) 60 % 20 % 26.6
Ng et al (1993)
80
17 %
Adam et al (1994)
190 8 %
66 %
23 % 63
HaasKock et al(1996)
253 8 %
29 %
11 % 29
MRC – CRO7 TRIAL : CRMI and LOCAL RECURRENCE 3 year LR
3 year DFS
CRM positive
17 %
50 %
CRM negative
6 %*
79 %**
* p = 0.0011 ** p < 0.0001
Quirke et al. 2009
CRMI versus R0 classification for Rectal Cancer
Wittekind et al 2009
Mode of Circumferential Margin Involvement number Direct spread 46 Discontinuous spread 110 Lymph node 19 Blood vessel 23 Lymphatic vessel 14 Perineural 11 No CRMI
421
% LR 52.2% 40.9% 10.5% 30.4% 71.4% 54.6% 10% Birbeck et al 2002.
MRC CRO-7 TRIAL : RISK FACTORS FOR CRM INVOLVEMENT • SCRT versus Selective Post-Operative chemoradiotherapy : 10% v. 12 % • APR versus AR : 16% v. 7 % ( p 20% of cases 57.6 % reported using special stains if VI suspected Higher rates of VI associated with :
practice in a university affiliated laboratory sub-specialist interest in GI pathology acceptance of the “orphan arteriole” sign as an indication of EMVI ( 75 % of pathologists )
( Messenger et al 2011 )
DIAGNOSING EMVI : INTEROBSERVER VARIATION • 51 consecutive cases of pT3 & pT4 colon cancer ( 2001 ) • 131 H&E stained slides showing invasion of tumour through the muscularis propria • NO special stains used • 4 specialist GI pathologists ( EMVI – yes or no ) Littleford et al 2009
LYMPHO-VASCULAR INVASION IN CRC : AN INTEROBSERVER STUDY • 50 cases of stage II CRC • stained with H&E, CD31 & D2-40 • scored for small and large vessel invasion by 6 specialist GI pathologists • overall kappa statistic: 0.24 = “fair” • while rate of detection of LVI increased with immunohistochemistry the level of agreement between pathologists DID NOT !!! ( Harris et al 2008 )
EMVI IN COLORECTAL CANCER • low & variable rates of EMVI reporting • poor inter-observer agreement
Is it time to start using an elastic stain as a matter of routine ?
