Firm conclusions about colon cancer rates are limited by the scope of this study being laboratory based. More so, the hospital in which this study was conducted is an apex hospital with the inclination for selecting only patients who can afford treatment at that level. Again, even though the number of cases used in this study is above the calculated sample size, the cases with incomplete data, missing and inadequate blocks had to be excluded and so reducing the statistical power of the study.
The lymph node yield was low, circumferential margins and apical nodes were not mentioned. For this reason, large proportion of the cases reviewed did not meet the requirements for reporting as stipulated in the CAP protocol. This limited the pathological characterization of the disease or objective assessment of the quality of surgery. Future studies will employ strict adherence to a widely accepted synoptic scheme for characterizing colorectal tumours.
Preoperative chemo-radiation of rectal cancer may have complicated IHC interpretation and/or decreased tumour mass in patients who had received some treatment. It also made MSI testing difficult. Ideally, evaluation of pretreatment biopsies would have been the preferred option.
From the way colorectal cancers are screened for and reported presently, it is difficult to determine if de novo adenocarcinomas without a benign histopathological precursor lesion ever occur in the large bowel. More so, when it is known that adenocarcinoma can overgrow the precursor lesion.
The prolonged time interval usually required for precursor lesions to become invasive carcinomas provides us with the opportunities to interfere with the process and reduce mortality. However, inadequate follow-up is a serious pitfall to any study or intervention.
75 APPENDICES
APPENDIX 1: Table 2.4. TNM and Modified Dukes classifications for colorectal cancers and survival rates
Key to Tumour-Node-Metastasis (TNM) Staging System T- Primary tumour
Tx Primary tumour cannot be assessed To No evidence of primary tumour
Tis Carcinoma in-situ: intraepithelial or invasion of lamina propria T1 Tumour invasion of the submucosa
T2 Tumour invasion of the muscularis propria
T3 Tumour invasion through the muscularis propria into the subserosa or into non-peritonealised pericolic/perirectal tissues
T4 Direct tumour invasion of other organs or structures and/or perforation of visceral peritoneum N- Regional Lymph Nodes
Nx Regional lymph nodes cannot be assessed No No regional lymph nodes metastasis N1 1 to 3 regional lymph nodes metastasis N2 4 or more regional lymph nodes metastasis M- Distant Metastasis
Mx Distant metastasis cannot be assessed Mo No distant metastasis
M1 Distant metastasis
Table 2.4. TNM and Modified Dukes classifications for colorectal cancers and survival rates Stage T N M Modified Astler-Coller
classification
Modified Dukes’
classification
Overall 5 year survival rate (%)
Stage I T1, No Mo A A 80-95
T2 B1
Stage IIA T3 No Mo B2 B 72-75
Stage IIB T4 No Mo B3 65-66
Stage IIIA T1,2 N1 Mo C1 C 55-60
Stage IIIB T3,4 N1 Mo C2/C3 35-42
Stage IIIC Any T N2 Mo C1/C2/C3 25-27
Stage IV Any T Any N M1 D 0-7
76 APPENDIX 2A:
Surgical Pathology Cancer Case Summary Protocol web posting date: October 2013
COLON AND RECTUM: Excisional Biopsy (Polypectomy) Select a single response unless otherwise indicated.
Tumor Site (Note A) ___ Cecum
___ Right (ascending) colon ___ Hepatic flexure
___ Transverse colon ___ Splenic flexure
___ Left (descending) colon ___ Sigmoid colon
___ Rectum
___ Other (specify): ________________________
___ Not specified + Specimen Integrity + ___ Intact
+ ___ Fragmented + Polyp Size
+ Greatest dimension: ___ cm
+ Additional dimensions: ___ x ___ cm + ___ Cannot be determined (see Comment) + Polyp Configuration
+ ___ Pedunculated with stalk + Stalk length: ___ cm + ___ Sessile
Size of Invasive Carcinoma Greatest dimension: ___ cm
+ Additional dimensions: ___x ___ cm ___ Cannot be determined (see Comment) Histologic Type (Note B)
___ Adenocarcinoma
___ Mucinous adenocarcinoma ___ Signet-ring cell carcinoma
___ High-grade neuroendocrine carcinoma ___ Large cell neuroendocrine carcinoma ___ Small cell neuroendocrine carcinoma ___ Squamous cell carcinoma
___ Adenosquamous carcinoma ___ Medullary carcinoma ___ Undifferentiated carcinoma
___ Other (specify): __________________________
___ Carcinoma, type cannot be determined
77 Histologic Grade (Note C)
___ Not applicable
___ Cannot be determined
___ Low-grade (well-differentiated to moderately differentiated) ___ High-grade (poorly differentiated to undifferentiated) Microscopic Tumor Extension (Note D)
___ Cannot be determined Invasion (deepest):
___ Lamina propria ___ Muscularis mucosae ___ Submucosa
___ Muscularis propria Margins (select all that apply) Deep Margin (Stalk Margin) ___ Cannot be assessed
___ Uninvolved by invasive carcinoma
Distance of invasive carcinoma from margin: ___ mm or ___ cm ___ Involved by invasive carcinoma
Mucosal Margin (required only if applicable) ___ Cannot be assessed
___ Uninvolved by invasive carcinoma ___ Involved by invasive carcinoma ___ Involved by adenoma
Lymph-Vascular Invasion (Notes D and E) ___ Not identified
___ Present ___ Indeterminate
+ Type of Polyp in Which Invasive Carcinoma Arose (Note F) + ___ Tubular adenoma
+ ___ Villous adenoma + ___ Tubulovillous adenoma + ___ Traditional serrated adenoma + ___ Sessile serrated adenoma + ___ Hamartomatous polyp + ___ Indeterminate
+ Additional Pathologic Findings (select all that apply) + ___ None identified
+ ___ Inflammatory bowel disease + ___ Active
+ ___ Quiescent
+ ___ Other (specify): ___________________________
+ Ancillary Studies
Note: For reporting molecular testing and immunohistochemistry for mismatch repair proteins, and for other cancer biomarker testing results, the CAP Colorectal Biomarker
78
Template should be used. Pending biomarker studies should be listed in the Comments section of this report.
+ Comment(s)
APPENDIX 2B:
Surgical Pathology Cancer Case Summary() Protocol web posting date: October 2013
COLON AND RECTUM: Resection, Including Transanal Disk Excision of Rectal Neoplasms
Select a single response unless otherwise indicated.
Specimen (select all that apply) (Note A) ___ Terminal ileum
___ Cecum ___ Appendix ___ Ascending colon ___ Transverse colon ___ Descending colon ___ Sigmoid colon ___ Rectum ___ Anus
___ Other (specify): __________________________________
___ Not specified Procedure
___ Right hemicolectomy ___ Transverse colectomy ___ Left hemicolectomy ___ Sigmoidectomy
___ Rectal/rectosigmoid colon (low anterior resection) ___ Total abdominal colectomy
___ Abdominoperineal resection
___ Transanal disk excision (local excision)
___ Other (specify): ____________________________
___ Not specified
+ Specimen Length (if applicable) + Specify: ___ cm
Tumor Site (select all that apply) (Note A) ___ Cecum
___ Right (ascending) colon ___ Hepatic flexure
___ Transverse colon ___ Splenic flexure
___ Left (descending) colon ___ Sigmoid colon
___ Rectosigmoid ___ Rectum
79 ___ Ileocecal valve
___ Colon, not otherwise specified
___ Cannot be determined (see Comment) + Tumor Location
+ ___ Tumor is located above peritoneal reflection + ___ Tumor is located below the peritoneal reflection + ___ Not specified
Tumor Size
Greatest dimension: ___ cm
+ Additional dimensions: ___ x ___ cm ___ Cannot be determined (see Comment) Macroscopic Tumor Perforation (Note G) ___ Present
___ Not identified
___ Cannot be determined
+ Macroscopic Intactness of Mesorectum (Note H) + ___ Not applicable
+ ___ Complete + ___ Near complete + ___ Incomplete
+ ___ Cannot be determined Histologic Type (Note B) ___ Adenocarcinoma
___ Mucinous adenocarcinoma ___ Signet-ring cell carcinoma
___ High-grade neuroendocrine carcinoma ___ Large cell neuroendocrine carcinoma ___ Small cell neuroendocrine carcinoma ___ Squamous cell carcinoma
___ Adenosquamous carcinoma ___ Medullary carcinoma ___ Undifferentiated carcinoma
___ Other (specify): __________________________
___ Carcinoma, type cannot be determined Histologic Grade (Note C)
___ Not applicable ___ Cannot be assessed
___ Low-grade (well-differentiated to moderately differentiated) ___ High-grade (poorly differentiated to undifferentiated) ___ Other (specify): ____________________________
+ Histologic Features Suggestive of Microsatellite Instability (Note I)
80
+ Intratumoral Lymphocytic Response (tumor-infiltrating lymphocytes) + ___ None
+ ___ Mild to moderate (0-2 per high-power [X400] field) + ___ Marked (3 or more per high-power field)
+ Peritumor Lymphocytic Response (Crohn-like response) + ___ None
+ ___ Mild to moderate + ___ Marked
+ Tumor Subtype and Differentiation (select all that apply) + ___ Mucinous tumor component (specify percentage: ____) + ___ Medullary tumor component
+ ___ High histologic grade (poorly differentiated) Microscopic Tumor Extension
___ Cannot be assessed
___ No evidence of primary tumor ___ No invasion of lamina propria
___ Intramucosal carcinoma, invasion of lamina propria/muscularis mucosae ___ Tumor invades submucosa
___ Tumor invades muscularis propria
___ Tumor invades through the muscularis propria into the subserosal adipose tissue or the nonperitonealized pericolic or perirectal soft tissues but does not extend to the serosal surface
___ Tumor penetrates to the surface of the visceral peritoneum (serosa)
___ Tumor is adherent to other organs or structures (specify: _________________) ___ Tumor directly invades adjacent structures (specify: __________________)
___ Tumor penetrates to the surface of the visceral peritoneum (serosa) and directly invades adjacent structures (specify: _____________________)
Margins (select all that apply) (Note J)
If all margins uninvolved by invasive carcinoma:
Distance of invasive carcinoma from closest margin: ___ mm or ___ cm Specify margin: __________________________
Proximal Margin ___ Cannot be assessed
___ Uninvolved by invasive carcinoma
___ No adenoma or intraepithelial neoplasia / dysplasia identified ___ Adenoma (low-grade intraepithelial neoplasia / dysplasia) present
___ High-grade intraepithelial neoplasia / dysplasia or intramucosal carcinoma present
(specify): ___________________________________
___ Involved by invasive carcinoma Distal Margin
___ Cannot be assessed
___ Uninvolved by invasive carcinoma
___ No adenoma or intraepithelial neoplasia / dysplasia identified ___ Adenoma (low grade intraepithelial neoplasia / dysplasia) present
81
___ High-grade intraepithelial neoplasia / dysplasia or intramucosal carcinoma present
(specify): ___________________________________
___ Involved by invasive carcinoma
Circumferential (Radial) or Mesenteric Margin ___ Not applicable
___ Cannot be assessed
___ Uninvolved by invasive carcinoma
___ Involved by invasive carcinoma (tumor present 0-1 mm from margin) Deep Margin (endoscopic mucosal resections) (required only if applicable) ___ Cannot be assessed
___ Uninvolved by invasive carcinoma ___ Involved by invasive carcinoma
Mucosal Margin (noncircumferential transanal disk excision) (required only if applicable)
___ Cannot be assessed
___ Uninvolved by invasive carcinoma
Distance of invasive carcinoma from closest mucosal margin: ___ mm or ___ cm + Specify location (eg, o’clock position), if possible: ___________________
___ Involved by invasive carcinoma
+ Specify location (eg, o’clock position), if possible: ___________________
___ Uninvolved by adenoma ___ Involved by adenoma
Other Margin(s) (required only if applicable) Specify margin(s): __________________________
___ Cannot be assessed
___ Uninvolved by Invasive carcinoma ___ Involved by invasive carcinoma
Treatment Effect (applicable to carcinomas treated with neoadjuvant therapy) (Note K) ___ No prior treatment
___ Present
+ ____ No residual tumor (complete response, grade 0) + ____ Moderate response (grade 1, minimal residual cancer)
+ ____ Minimal response (grade 2) ___ No definite response identified (grade 3, poor response) ___ Not known
Lymph-Vascular Invasion (Note E) ___ Not identified
___ Present ___ Indeterminate
Perineural Invasion (Note E) ___ Not identified
___ Present ___ Indeterminate
82
Tumor Deposits (discontinuous extramural extension) (Note L) ___ Not identified
___ Present (specify number of deposits: ____) ___ Indeterminate
+ Type of Polyp in Which Invasive Carcinoma Arose (Note F) + ___ None identified
+ ___ Tubular adenoma + ___ Villous adenoma + ___ Tubulovillous adenoma + ___ Traditional serrated adenoma + ___ Sessile serrated adenoma + ___ Hamartomatous polyp + ___ Indeterminate
Pathologic Staging (pTNM) (Note M)
TNM Descriptors (required only if applicable) (select all that apply) ___ m (multiple primary tumors)
___ r (recurrent) ___ y (posttreatment) Primary Tumor (pT)
___ pTX: Cannot be assessed
___ pT0: No evidence of primary tumor
___ pTis: Carcinoma in situ, intraepithelial (no invasion of lamina propria) ___ pTis: Carcinoma in situ, invasion of lamina propria/muscularis mucosae ___ pT1: Tumor invades submucosa
___ pT2: Tumor invades muscularis propria
___ pT3: Tumor invades through the muscularis propria into pericolorectal tissues ___ pT4a: Tumor penetrates the visceral peritoneum
___ pT4b: Tumor directly invades or is adherent to other organs or structures Regional Lymph Nodes (pN)
___ pNX: Cannot be assessed
___ pN0: No regional lymph node metastasis ___ pN1a: Metastasis in 1 regional lymph node ___ pN1b: Metastasis in 2 to 3 regional lymph nodes
___ pN1c: Tumor deposit(s) in the subserosa, or non-peritonealized pericolic or perirectal tissues without regional lymph node metastasis
___ pN2a: Metastasis in 4 to 6 regional lymph nodes ___ pN2b: Metastasis in 7 or more regional lymph nodes ___ No nodes submitted or found
Number of Lymph Nodes Examined Specify: ____
___ Number cannot be determined (explain): ______________________
Number of Lymph Nodes Involved Specify: ____
___ Number cannot be determined (explain): ______________________
83 Distant Metastasis (pM)
___ Not applicable
___ pM1: Distant metastasis
+ Specify site(s): ______________________________
___ pM1a: Metastasis to single organ or site (eg, liver, lung, ovary, nonregional lymph node) ___ pM1b: Metastasis to more than 1 organ/site or to the peritoneum
+ Additional Pathologic Findings (select all that apply) + ___ None identified
+ ___ Adenoma(s)
+ ___ Chronic ulcerative proctocolitis + ___ Crohn disease
+ ___ Dysplasia arising in inflammatory bowel disease
+ ___ Other polyps (type[s]): ___________________________
+ ___ Other (specify): ___________________________
+ Ancillary Studies
Note: For reporting molecular testing and immunohistochemistry for mismatch repair proteins, and for other cancer biomarker testing results, the CAP Colorectal Biomarker Template should be used. Pending biomarker studies should be listed in the Comments section of this report.
+ Comment(s)
84
Emory University Hospital/ Winship Cancer Centre Core Laboratories Atlanta Immunohistochemistry Protocol
1. From the tissue specimens 1.5 mm cylinders were punched out and collected in tissue microarray (TMA) paraffin blocks each containing about 80 samples each.
2. TMA blocks are kept overnight in the oven to improve adherence of the tissue cores to the well. Tissue from normal colonic mucosa, ovaries were included in the tissue arrays serving as reading frame and controls.
3. Sections of formalin-fix, paraffin-embedded tissue were tested for the presence of primary antibodies using Bond Polymer Refine Detection kit (DAB chromogen), (Leica Microsystems, Bannockburn, ILL). The detection system avoids the use of streptavidin and biotin, and therefore eliminates nonspecific staining as a result of endogenous biotin.
All steps were performed on the Leica Bond Maxx III automated system.
4. Specimens were deparaffinised and antigen retrieved on the instrument.
5. All slides were incubated with the primary (monoclonal) antibodies for 15 minutes, with post primary polymer for 8 minutes, blocked with 3% hydrogen peroxide for 5 minutes, 3,3-diaminobenzidine (DAB, brown chromogen) for 10, minutes and haematoxylin was used as counterstain for 5 minutes.
These incubations were performed at room temperature; between incubations, sections were washed with Tris-buffered saline (Bond wash solution).
6. Coverslipping was done using the Tissue Tek SCA (Sakura Finetek USA, Inc. Torrance, CA) coverslipper.
7. Positive controls of known positive tissue (colonic mucosa and endometrial, and lymphoid tissue) and negative control (section of ovarian tissue) with primary antibody replaced with Tris buffer were run with the study slides.
The Bond Polymer Refine Detection is a biotine-free, polymeric horseradish peroxidase (HRP)-linker antibody conjugate system for the detection of tissue-bound mouse and rabbit IgG and some mouse IgM primary antibodies.
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