Deck 3

Question 1

What is the staging systems used in CRC?

Answer 1

Staging of CRC should be done using the current TNM (tumor, node, metastasis) classification

Other systems (such as Dukes classification) should be regarded as of historical significance only only and must be comprehended solely for the purposes of understanding the studies that were performed.

Question 2

What are the layers of the colon wall from in to out?

Answer 2

1. Mucosa.
2. Muscularis mucosa.
3. Submucosa.
4. Muscularis propria.
5. Subserosa (pericolic/retroperituneal fat).
6. Serosa (visceral peritoneum).

Question 3

What are the Ts in TNM?

Answer 3

• . TIS- includes cancers confined to the glandular basement membrane or lamina propria. The terms high-grade dysplasia and severe dysplasia are synonymous with in situ carcinoma and are also classified as Tis.
• . T1 tumors invade into but not through the submucosa.
• . T2 tumors invade into but not through the muscularis propria.
• . T3 tumors invade through the muscularis propria into the subserosa or into nonperitonealized pericolic or perirectal tissue.
• . T4 tumors perforate the visceral peritoneum (T4a) or invade other named organs or structures (T4b).

Question 4

What “p”, “y” and “r” prefix stands for?

Answer 4

The “p” prefix denotes pathologic (rather than clinical) assessment, and the “y” prefix is attached to those tumors that are being reported after neoadjuvant (presurgical) treatment.
Recurrent tumors are reported with an “r” prefix (rpT3).

Question 5

How many LN sould be examined for propr pathological asessment?

Answer 5

Because of the prognostic significance associated with increased numbers of LNs inspected (see the following discussion), the current TNM classification scheme calls for at least 12 LNs to be analyzed, and both the number of nodes that are positive for tumor and the total number of nodes inspected should be reported.

Question 6

What are the Ns in TNM?

Answer 6

• . Nx is applied if no description of LN involvement is possible because of incomplete information.
• . N0 denotes that all nodes examined are negative.
• . N1a includes tumors with metastasis in one regional LN.
• . N1b refers to involvement of two or three nearby LNs.
• . N1c defines the presence of tumor deposits found in the subserosa, mesentery, or nonperitonealized pericolic or perirectal/ mesorectal tissues, but not in the LNs themselves.
• . N2a indicates metastasis in four to six regional LNs.
• . N2b denotes involvement of greater than seven nodes.

Question 7

How TNM refer to metastatic nodules or foci found in the pericolic, perirectal, or adjacent mesentery without evidence of residual LN tissue.

Answer 7

Regarded as being equivalent to a regional node metastasis and are counted accordingly.

Question 8

What is the definitions of stage I, II? What is Stage III?

Answer 8

Stage I disease is defined as T1 to T2 N0 in a patient without distant metastases (M0).

Stage II disease is defined as T3 to T4 N0 M0. The T-stage carries prognostic significance for stage II, and therefore, T3 N0 is classified as IIA, and T4a to T4b N0 is classified as IIB and IIC, respectively.

Node positivity in the absence of M1 disease defines stage III CRC.

Question 9

what can be said about the prognostic value of T and N?

Answer 9

Within the N1 category, T stage was found to be highly prognostic, with T1 to T2 patients fairing significantly better than T3 to T4.
Within the N2 population, the prognosis was worse than either subgroup of N1 patients, with T stage no longer carrying prognostic significance.
Thus, T stage is prognostic in patients with N0 and N1 but not N2 disease.

Question 10

What are thebasic Ms in TNM (M0/M1)?

Answer 10

Patients are designated M0 if no evidence of distant metastases is present. Identification of distant metastases denotes a classification of M1.

Question 11

What positive LNs are related as M1 and not N+?

Answer 11

external iliac, common iliac, para-aortic, supraclavicular, or other nonregional LNs is classified as distant metastatic (M1) disease.

Question 12

What is the subdivision of M1?

Answer 12

The M1 category is subdivided into M1a, defined as spread of tumor to one distant organ or set of distant LNs, and M1b, where spread has occurred to more than one distant organ or sets of LNs or spread has occurred to the peritoneum, and M1c, where metastasis to the peritoneal surface if identified alone or with other site or organ metastasis.

Question 13

What is one problem with TNM classification?

Answer 13

survival of stage IIIA patients continues to be superior to stage IIB.

Question 14

What is R staging? What is its value?

Answer 14

Residual Tumor (R Stage) at Margins of Resection.
R0 - Tumors that are completely resected with histologically negative margins
R1- positive margin indicating that at least microscopic tumor remains in the patient.
R2 - Patients who have incomplete resections with grossly positive margins are classified as having had an R2 resection.

The R0, R1, and R2 designations carry strong prognostic implications.

Question 15

What is the definition of CRM?

Answer 15

The CRM (circumferential radial margin) is, by definition, a surgically dissected surface. It is defined as the cut retroperitoneal or perineal soft tissue margin closest to the deepest penetration of tumor. It is considered positive if tumor is present microscopically (R1) or macroscopically (R2) on a cut radial or lateral aspect of the surgical specimen.

Question 16

What are the histological grading system? What is the problem?

Answer 16

The majority of staging systems divide tumors into grade 1 (well differentiated), grade 2 (moderately differentiated), grade 3 (poorly differentiated), and grade 4 (undifferentiated). Many studies collapse this into low grade (well to moderately differentiated) and high grade (poorly differentiated or undifferentiated).

Although histologic grade has been shown to have prognostic significance, there is significant subjectivity involved in scoring of this variable, and no one set of criteria for determination of grade are universally accepted.

Question 17

What is the College of American Pathologists (CAP) categories for prognostic factors?

Answer 17

Category I was defined as those factors proven to be of prognostic import based on evidence from multiple, statistically robust, published trials and generally used in patient management.
Category IIA included factors intensively studied biologically or clinically and repeatedly shown to have prognostic value for outcome or predictive value for therapy that is of sufficient importance to be included in the pathology report but that remains to be validated in statistically robust studies.
Category IIB included factors shown to be promising in multiple studies but lacking sufficient data for inclusion in category I or IIA.
Category III included factors felt to be not yet sufficiently studied to determine their prognostic value.
Category IV included those factors that are adequately studied to have convincingly shown no prognostic significance.

Question 18

What prognostic factors are classified as category I?

Answer 18

1. The TNM staging.
2. Blood or lymphatic vessel invasion.
3. Residual tumor following surgery with curative intent (the R category).
4. Elevation of the preoperative CEA level.

Question 19

What prognostic factors are classified as category IIA?

Answer 19

1. Tumor grade.
2. Radial margin status (for resection of specimens with nonperitonealized surfaces).
3. Residual tumor in the resection specimen following neoadjuvant therapy.

Question 20

What prognostic factors are classified as category IIB?

Answer 20

1. Histologic type.
2. Histologic features associated with MSI (i.e., host lymphoid response to tumor and medullary or mucinous histologic type).
3. High degree of MSI (MSI-H).
4. Loss of heterozygosity (LOH) of 18q (DCC [deleted in colon cancer] gene loss).
5. Tumor border configuration (infiltrating versus pushing border).

Question 21

What pathological factor is included in category IV?

Answer 21

Tumor size.

Question 22

Is there association between MSI phenotype and LN yield? What is the meaning?

Answer 22

Belt et al. found a significant association between MSI phenotype and high LN yield in both stage II and III colon cancers, with the strongest effect in the latter group.
The authors postulate that this may be due to a more prominent lymphocytic antitumor response known to be exhibited by MSI-H cancers.

Question 23

Factors besides MSI that are related to high LN yield?

Answer 23

Low body mass index, proximal tumor location, well or moderately differentiated histology, and stage IIIC cancer.

Question 24

What is the CAP consensus for munber of LN to be dissected? Is there relation to OS?- describe related study.

Answer 24

The CAP consensus statement suggests that a minimum of 12 to 15 LNs should be examined in order to determine node negativity.

Danish cohort study that indicates that the advantage of larger LN harvest extends beyond more accurate staging. In addition to improved outcomes for node-negative patients, the authors found a significant increase in OS for stage III patients with > 12 LNs removed as well (58.6% versus 45.2% for < 12 LNs), despite a higher prevalence of N2 disease in this group. This may be related to better surgical technique or an underlying benefit of wider lymphadenectomy in general.

Question 25

What is the meaning of micrometastasis in LN versus microscopic positive LN?

Answer 25

Although the actual TNM staging is not altered by the presence of micrometastases, many clinicians choose to regard the presence of such a finding as a poor prognostic variable in their consideration of adjuvant treatment.
The prognostic value of these positive LNs, which otherwise would not be detected, remains controversial.
If micrometastases are reported, the methodology by which they are detected should be specified, as it is likely that differences in reliability and reproducibility of different techniques will emerge.

Question 26

What is the role of sentinal LN analysis in CRC?

Answer 26

Unlike sentinel node approaches for melanoma and breast, where the goal is to potentially limit the extent of an unnecessary formal dissection of a node basin, the goal of the sentinel node in colon cancer is to focus the pathologic analysis on fewer nodes, so a more extensive study can be performed. The same extent of node dissection is performed regardless of the sentinel node procedure.

Question 27

What studies show about Sentinal LN dissection? What is the bottom line?

Answer 27

The initial studies of sentinel node biopsy demonstrated it was technically feasible, with accuracy rates > 80% and upstaging in 15.4% of patients.
Saha et al. suggest that sentinel LN mapping may not just improve staging accuracy but influence the extent of nodal dissection as well. In this study, sentinel LN mapping detected aberrant lymphatic drainage in 22%, which in turn led to a change in operation (i.e., more extensive resection).

However, alse-negative rates as high as 60% have been reported, and some studies have failed to demonstrate any change in the stage determination of the lesion.

The utility of this technique has not yet been established, and further large-scale trials are required to establish its role in the staging of patients with CRC.

Question 28

Give examples of histological types and there specific independent prognostic significance.
.

Answer 28

Signet ring carcinomas are characterized by > 50% of cells demonstrating the “signet ring” morphology in which intracellular mucin accumulation displaces the nuclei and cytoplasm toward the cellular periphery.
This histology carries an adverse prognosis.

Mucinous (> 50% mucinous) carcinoma, the prognostic significance remains controversial.

Small-cell (extrapulmonary) tumors are high-grade neuroendocrine tumors with clearly adverse prognostic features. Most data indicate that extensive neuroendocrine differentiation is associated with a poorer prognosis.

Medullary carcinoma is a subtype characterized by an absence of glands and distinctive growth pattern that previously would have been classified as undifferentiated. It is typically infiltrated with lymphocytes. This histologic subtype is tightly associated with MSI-H and carries a more favorable prognosis.

Question 29

What are the two distinct mutational pathways that give rise to CRC? What is its prevelance in CRC?

Answer 29

The MSI pathway(15% of CRC) and the chromosomal instability pathway(85%).

Question 30

What are Microsatellites? What is MSI?

Answer 30

Microsatellites are sections of DNA in which a short sequence of nucleotides (most commonly a dinucleotide) is repeated multiple times. MSI is a situation in which a microsatellite has gained or lost repeat units and has undergone a change in length, resulting in frame shift mutations or base-pair substitutions.

Question 31

What cause MSI?

Answer 31

This form of genetic destabilization is typically associated with defective DNA mismatch repair function. Studies of HNPCC tumor specimens demonstrated mutations in mismatch repair genes such as MLH1 and MSH2.

Question 32

What are the types of MSI phenotypes?

Answer 32

MSI-High, MSI-Stable, MSI-Low (MSI-L and MSS tumors tend to behave and present similarly).

Question 33

What are hte characteristics of disease with MSI-H versus MSI-S/L?

Answer 33

MSI-H tumors are more frequently right sided, high grade, and mucinous type, associated with increased peritumoral lymphocytic infiltration, are more likely to have a larger primary at the time of diagnosis but are more likely to be node negative.
have better long-term prognosis than stage-matched patients with cancers exhibiting MSS.

Question 34

What is the doubt about MSI-H prognostic value?

Answer 34

MSI was found to carry a favorable prognosis for right-sided colon lesions but was a negative prognostic factor in left-sided colon lesions.

Question 35

What is the prevelance of BRAF mut in CRC? What is the link to MSI?

Answer 35

BRAF mutation, present in 8% to 10% of CRCs, is linked to a subset of MSI-H tumors that are sporadic.

Question 36

What is BRAF prognostic value? give studies related?

Answer 36

Generally have poorer prognosis.
Ogino et al. confirmed this relationship in comparative analysis of 506 stage III patients enrolled in the Cancer and Leukemia Group B (CALGB) 89803 trial. BRAF-mutated patients had significantly worse OS (HR, 1.66) compared to wild-type, a finding that was most pronounced in the setting of MSS.

In a follow-up study, Lochhead et al. also identified combined BRAF/ MSI status as a powerful prognosticator and recommends stratification of all patients into poor (MSS/ BRAF mutant), intermediate (MSS/ BRAF wild-type), and favorable (MSI-H/ BRAF wild-type) groups in order better inform treatment strategies.

Question 37

What is CpG island methylator phenotype (CIMP)?

Answer 37

Approximately 15% to 20% of CRCs are characterized by widespread promoter DNA hypermethylation, known as CpG island methylator phenotype (CIMP), which is associated with aberrant silencing of tumor suppressor genes.
m/p Related to poor prognosis.

Question 38

What is the prevelance of Allelic loss of 18q? What are the consequences?

Answer 38

Allelic LOH that involves chromosome 18q occurs in half or more of all CRCs. Allelic loss of 18q typically involves the DCC gene however, other genes in this region, such as SMAD2 and SMAD4, may also be relevant to CRC development.
Loss of DCC is associated with metastasis and an adverse prognosis. Loss of DCC as a result of allelic loss in 18q could also be anticipated to impair apoptosis, thereby resulting in greater resistance to chemotherapy.

Question 39

What is lymphoid response prognostic value? To what its related to? Give studies about its prognostic value.

Answer 39

Lymphocytic infiltration has been identified as a favorable prognostic indicator.
Whether this is a truly independent predictor of outcome is not clear, however, as this finding is tightly associated with MSI-H, a favorable prognostic factor.

Chiang et al. found that elevated preoperative neutrophil-to-lymphocyte ratio (> 3) was associated with significantly worse DFS in stage I to III colon but not rectal cancers on multivariate analysis. In another study, neutrophil-to-lymphocyte ratio > 5 was also found to be an independent risk factor for recurrence.

Question 40

What is the value of CEA as prognostics factors in CRC?

Answer 40

An elevated preoperative CEA is a poor prognostic factor for cancer recurrence. Although there is variability in the available data regarding the level that denotes a prognostic cutoff, a preoperative CEA level > 5 ng/ mL is considered a category I poor prognostic indicator.
in addition, patients in whom the elevated CEA fails to normalize after a potentially curative operation are at particularly high risk.

Question 41

What is the role of CA19-9 in CRC?

Answer 41

No other serum markers have been demonstrated to be reliably prognostic or predictive in CRC. Cancer antigen (CA) 19-9, a factor that has become widely used for pancreas cancer, has no role at this time in the routine management of CRC.

Question 42

Clinical situations that are poor prognostics?

Answer 42

Carcinoma of the colon that is complicated by obstruction or perforation has been recognized as having a poorer prognosis.

Question 43

In what anatomical position obstruction has worse prognosis and why?

Answer 43

The effect of bowel obstruction was more pronounced when the obstruction was located in the right colon. The larger sized tumor needed to block the ascending colon completely might allow a longer time for these tumors to grow and spread when compared with tumors located in the descending colon.

Question 44

What showed study about 5-year survival rate seen in patients who presented with obstruction?

Answer 44

A review of the Massachusetts General Hospital records compared patients who presented with obstruction or perforation with a control group who underwent curative resection. The actuarial 5-year survival rate seen in patients who presented with obstruction was 31%, in contrast to 59% in historical controls.