In this study, MAC and SC were shown to be uncommon, respectively, rare histological colorectal cancer subtypes with differences in clinical and histopathological findings. Compared with patients with AC, patients with MAC had more advanced tumor stages and reduced survival. SC were rare; however, these tumors implicated a clearly different behavior and reduced survival even after correction for tumor stage.
To our knowledge, we report on the largest European cohort investigating patients with AC, MAC, and SC and confirm previous nationwide epidemiologic data from the United States and Asia.9,10,19 The number of patients we studied is considerably smaller than in population-based reports; nevertheless, our thoroughly documented clinicopathological and long-term follow-up data are a strength of the cohort we describe.
The prevalence of 11% for MAC and 0.9% for SC in our cohort is in line with population-based data sets.9,10,19 Patients suffering from these tumor subtypes may be candidates for individually tailored treatment regimens, such as intensified systemic therapy and more frequent follow-up. Nevertheless, no prospective study has yet been performed to investigate different management of these entities, and specific therapeutic regimens are not recommended in current guidelines.7
In accordance with the majority of published series including cohorts from the United States and Asia, MAC and SC were largely located within the right hemicolon,4,9,10,20,21 had higher stages of the primary tumor4,5,13,20 and lymph node involvement,5,13,14,20,21 and more advanced UICC stages4,10,13,21 and poorer differentiation.4,9,10,14 Differences in these variables were more pronounced between SC and AC than between MAC and AC. AC of the right hemicolon were not associated with higher tumor stages than those of the left hemicolon. Thus, a putative delayed diagnosis for right-sided colon cancer in general does not explain the advanced tumor stages of MAC and SC. The more aggressive tumor biology of MAC and particularly SC is more likely.
Against our expectations, patients with MAC had low rates of angioinvasion but more local recurrences, whereas patients with SC had high rates of lymphatic invasion and more metachronous distant metastases. However, these results should be interpreted carefully because angioinvasion and lymphatic invasion were reported on the basis of routinely performed hematoxylin and eosin staining. A reduced sensitivity compared with detailed immunohistochemical staining methods cannot be excluded. More complete tumor resections (R0) were performed for MAC than for SC. However, the higher number of local recurrences for MAC could be due to higher rates of multivisceral resections in this group. The 3 large population-based studies from the United States9,10 and Asia19 did not investigate angioinvasion or lymphatic invasion, and there is no study that confirms or contradicts our findings. Thus, generalizability may be restricted because of the relatively small number of patients in our cohort. Overall, only a few studies have reported on angioinvasion and lymphatic invasion of AC, MAC, and SC so far.4,6,20,21 Lee et al21 and Sung et al6 found higher rates of angioinvasion in SC than in MAC; however, they did not evaluate AC. The same observation was made in our cohort when comparing SC with MAC (data not shown).
There was a significant shorter cause-specific survival for MAC than that for AC and for SC than that for AC and MAC. However, multivariable analysis including TNM stage confirmed SC to be an independent prognostic factor but not MAC. Survival curves confirmed no significant differences between MAC and AC when analyzed by tumor stage (Table 4 and Fig. 3). These findings are reflected in the current literature.4,5,8–10,14,20,21 However, small reports6,13 and 2 meta-analyses3,12 identified MAC as an independent prognostic factor for poor outcome. Study heterogeneity of the prognostic impact of MAC was high between the studies included in the meta-analyses, and the pooled HR did not exceed 1.05 (95% CI = 1.02–1.08, P < 0.001)3 and 1.06 (95% CI = 1.04–1.08, P < 0.001),12 respectively. Therefore, a significant prognostic effect of MAC is possible but might not be clinically relevant. In our multivariable analysis, the HR for MAC compared with AC was 1.001 (95% CI = 0.83–1.21, P = 0.991).
Regarding tumor biology, AC, MAC, and SC do not seem to represent consecutive steps of de-differentiation during the development of mucus-producing colorectal carcinoma but rather constitute different genetic pathways.5,11 Our study revealed distinct histopathological features and recurrence patterns for MAC and SC (Table 2), which were discussed previously. These results are supported by described genetic profiles specific for MAC and SC, including microsatellite instability and mutations of the genes BRAF, p53, and p16.4,5 In addition, downregulation of the adhesion molecules E-cadherin and β-catenin may lead to reduced cell adhesion in areas of high mucus content and promote scattering of tumor cells, further leading to advanced tumor stages and poorer prognosis.5,6 In our cohort, high rates of local recurrences including localized peritoneal carcinomatosis for patients with MAC and distant recurrences for patients with SC might reflect the aggressive phenotype of MAC and SC. In particular, local invasiveness may be increased in areas of high extracellular mucus content, as it is found in MAC.
SC have been described as being positive for intestinal trefoil factor and MUC2, 2 peptides that are usually produced only by goblet cells.5 Thus, SC could arise from different cells of origin than AC.5,23 Although they can be localized in the colorectum, SC may be genetically more related to signet-ring cell cancers of other organs (eg, gastric cancer) than to AC or MAC of the colorectum.5,11 The absence of E-cadherin/β-catenin and amplification of Bcl-2 are features typically shared with signet-ring cell cancer of the stomach but not with classical colorectal adenocarcinomas.5
In the past, all MAC and SC were classified as “poorly differentiated/high grade.”16 However, since 2010, the World Health Organization classification2 noted that grade of epithelial differentiation indeed formally determines the pathological grading (G1–G4, also described for the patients reported here). Microsatellite instability is an important molecular marker that occurs more frequently in MAC and SC than in classical AC and allows for risk stratification.2,7,16 Because of the association with right-sided tumors, the increased rate of microsatellite instability in MAC and SC may be caused by its embryologic origin. Although the distal part of the colon derives from the hindgut, the proximal part derives from the midgut and exhibits specific cellular genetic characteristics.24 Microsatellite instable tumors are associated with better prognosis and are currently classified as “low-grade.” If MAC or SC are microsatellite stable, they are associated with more aggressive biological behavior and are classified as “high-grade.”2,16,25 In current practice, microsatellite testing should be performed for all patients with MAC and SC.16 Because of lack of tissue samples from early patients of this cohort, we do not report on microsatellite data in detail here. In accordance with other reports,6 higher rates of microsatellite instability were detected in MAC and SC than in AC in a subgroup analysis (P = 0.006). Patients with microsatellite instable tumors had a better survival25; however, these findings were not statistically significant, most likely due to the small size of the individual groups (data not shown).
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adenocarcinoma: analysis from the National Cancer
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E. Rullier (Bordeaux, France):
I want to congratulate you for this very impressive cohort of more than 3000 patients extracted from a prospective database of colorectal cancers operated on at a single institution.
My first question concerns the period of evaluation that is very long, 30 years, and you know that during this period the TNM classification has been changed many times. So, how did you manage the pathologic classification of your database? Did you reclassify the tumors; did you review all the cases asking a single pathologist to do that?
The second question is about the resection that is very impressive, 96% of complete microscopic resection. I suspect that multivisceral resection is the explanation for that but I also suspect that maybe you have some incomplete or missing data, because the concept of R0 resection came after the beginning of your study. So, my question is about the definition of R0 resection. Could you specify what was the definition, was it only longitudinal or also circumferential resection margin?
Again, a question about the pathology methodology; you know that assessment of irradiated specimens, especially rectal resections, is very difficult because irradiation produces mucin pools. Did you have any difficulty in distinguishing between natural and irradiated mucin pools because you determined that 10% of your specimens were mucinous tumors?
During your presentation, you did not present the local recurrence data, but I read your article and you used local recurrence to demonstrate the potential difference in terms of biology and prognoses in your subgroup of mucinous tumors. In your article, you conclude that local recurrence is higher in the group of mucinous tumors. I am not sure I agree with you on that because you demonstrate clearly that the groups are not the same. You showed that there is higher stage in the mucinous group than in the conventional one.
So finally, when you analyzed survival, the worse prognoses of mucinous tumors disappeared after multivariate analysis. Did you use multivariate analysis also for local recurrence, which is not described in your article and not presented here? I suspect that the main conclusion of the article would be that signet-ring cell but not mucinous tumors may have a different biology and prognoses as compared with conventional colorectal cancer.
Response From U. Nitsche (Munich, Germany):
Thank you for these encouraging comments and questions. Regarding your first question, the long review period, you are correct. During these last 30 years, there were 5 different TNM classification systems, but, indeed, we did reclassify all the patients regarding the latest, seventh TNM classification system, which was possible by reviewing the pathological reports and our data.
You also asked whether all the specimens were reviewed by a single pathologist; this was not the case. What we did was to review all the pathological reports and we included or defined only those tumors as mucinous or signet-ring carcinomas in which we clearly had the definition according to the pathological report or at least the statement of the amount of mucin pools. But you raise a good point because nearly every tumor is described as having some mucus component, but that does not qualify every tumor as a mucinous carcinoma.
You mentioned the multivisceral resection and the high R0 rate. Indeed, we had a 96% R0 rate for stages 1 to 3 and this was possible by a 19% rate of multivisceral resection. However, for the stage 4 disease, we obtained R0 in 19%.
With regard to the earlier pathological reports, I'm not quite sure when resection was first included in the TNM classification but, of course, whenever it was stated, we included it for our analysis. In the earlier cases when R0 may have not been stated, at least our pathologist routinely reported for every tumor if there were microscopic or macroscopic tumor cells at the resection margin, which obviously is one of the most important findings for the surgeon. This was done for all specimens as well for the longitudinal and also for the circumferential resection margin.
Your next question was a very interesting one, the rate of mucinous adenocarcinomas or of cancers with mucinous differentiation, which obviously according to the literature is higher after neoadjuvant radiation. Unfortunately, we were not able to investigate whether there was a higher rate of mucinous adenocarcinomas after radiation as we did not have the preoperative findings, but we did investigate if there was a higher rate of mucinous adenocarcinomas for patients with rectal cancer if they were radiated in comparison to if they did not undergo preoperative radiation. And this was the case, it was 7% compared with 9%, which was not significant.
I think we also agree with your final comment. The mucinous adenocarcinomas were diagnosed at higher tumor stages and this may have contributed to the higher rates of local recurrence. We did a multivariable analysis on these data and found similar results to the other multivariable analysis; the mucinous adenocarcinoma was not an independent predictor of local recurrence. We concluded that mucinous adenocarcinomas do represent some specific characteristics that clearly differ from the classical adenocarcinomas. However, the signet-ring cell carcinomas seem really to represent another different histological or biological type.
N. Senninger (Munster, Germany):
These findings are shown in a large series and you should be congratulated because we all know how difficult it is to bring back the files of previous surgical generations. The second point is not completely new because in pathology, in the 1970s we have been told about the difficult biological properties of tumors.
My question is, we saw the advent of neoadjuvant regimens, new drugs, and so forth in the last 30 years, and how could you make Kaplan-Meier curves with patients who had been treated so differently inside the last 30 years? If you did not do that, I would strongly recommend that you compare the decades, first decade, second, and third, because there the patients would be rather homogenous.
Response From U. Nitsche (Munich, Germany):
I think one of the strengths of our series, even if not all the findings were new, is that we had very complete documentation of lymphatic and vascular invasion; however, you are correct, we did not compare the Kaplan-Meier curves regarding decades. Perhaps that is a good idea. However, to our mind the treatment may have shifted during recent years. This should be the same effect for all cancers in regard to the histological subtypes. Therefore, we do not assume that a bias may be raised because of this factor.
J. Izbicki (Hamburg, Germany):
I enjoyed your presentation very much. Following on Professor Senninger's comment, it is not a new finding that a signet-ring cell carcinoma had a different biological behavior, worse prognosis than a normal adenocarcinoma. So, my at least a little bit provocative question is what is exactly new in your presentation?
The second comment is with regard to the pathological workup. Did I understand this correctly that you just adhered to the pathological written reports and reviewed them or did a specific pathologist rereview the slides of the specimen?
Response From U. Nitsche (Munich, Germany):
We adhered to the pathological reports and we did not review every single slide of all the more than 3000 patients. And to your first question, indeed, there have been many reports that signet-ring cell cancers are different in terms of behavior. However, our study still remains a large analysis that compares the 3 most frequent cancer types; mucinous, classical adenocarcinoma, and signet-ring cell carcinomas. We report on comprehensive markers such as lymphatic invasion, lymph node invasion, local recurrence rate, or overall survival that has not been done in this extensive method so far.
P. Gertsch (Zurich, Switzerland):
This is a very nice study and I congratulate you. Those treating peritoneal carcinomatosis often see the dismal prognoses of appendix tumors with signet-ring histology. In your presentation, you mentioned that most signet-ring cell carcinomas were on the right side of the colon. Have you been able to differentiate the appendix from the right colon tumor?
Response From U. Nitsche (Munich, Germany):
We included appendix tumors with the right-sided cancers but you make a good point, the appendix tumors can be different and include neuroendocrine tumors. If that was the case, they were excluded from this analysis as we investigated only the classical, the mucinous, and the signet-ring cell carcinomas.