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. Author manuscript; available in PMC: 2019 Apr 5.
Published in final edited form as: Histopathology. 2018 Nov 11;74(3):406–414. doi: 10.1111/his.13748

Associations Among Histologic Characteristics and Patient Outcomes in Colorectal Carcinoma with a Mucinous Component

Raul S Gonzalez 1, Justin MM Cates 2, Kay Washington 2
PMCID: PMC6450535  NIHMSID: NIHMS1015764  PMID: 30160323

Abstract

Aims:

Colorectal carcinoma (CRC) often has a mucinous component, with more than 50% mucin by volume defining the mucinous subtype of CRC. The prognostic impact of the mucinous phenotype remains unclear.

Methods and results:

We evaluated 224 CRC with at least 5% mucinous component (herein “mCRC”) for patient sex, age, race, and outcome; tumour size, location, stage, and microsatellite instability (MSI) status; percentage of glands producing mucin; percentage of tumour volume composed of mucin; whether tumoural epithelium floated in mucin pools; tumour budding; signet ring cells (SRCs); and peritumoural inflammation (PI). We related these features to disease-specific survival and compared outcomes to 499 stage-matched, conventional colorectal adenocarcinomas. Factors predicting worse prognosis in mCRC on univariable analysis included non-MSI-high status (P=0.0008), SRC (P=0.0017), and lack of PI (P=0.0034). No parameters were independently associated with outcome after adjusting for tumour stage in multivariate analysis. Percent of glands producing mucin and percent tumour volume composed of mucin did not affect prognosis, including at the recommended 50% cutoff for subtyping mCRC. Disease-specific survival for mCRC and adenocarcinomas were similar after accounting for stage.

Conclusions:

Stage-matched mCRCs and adenocarcinomas have similar outcomes, with no prognostic significance to morphological subtyping. Histologic characteristics of mCRC, including percentage of tumor volume comprised of mucin, were not predictive of outcome.

Keywords: colon cancer, mucinous adenocarcinoma, microsatellite instability, tumour budding

Introduction

Mucinous colorectal carcinoma (mCRC) is one of the most common subtypes of colorectal carcinoma (CRC), accounting for roughly 10–15% percent of cases.1 The malignant epithelium of mCRC either lines or floats within large pools of extracellular mucin. According to World Health Organization (WHO) criteria, CRC is classified as mucinous if “>50% of the lesion is composed of pools of extracellular mucin that contain malignant epithelium.”2 This cutoff, while traditional, is arbitrary and has not been rigorously evaluated.

In some organs, the presence of mucinous features within a carcinoma is associated with differential outcomes; for instance, mucinous mammary carcinoma (also known as “colloid carcinoma”) has an improved prognosis compared to conventional ductal carcinoma.3 In the colon, the impact of a mucinous component is not as clear, as various studied have determined that mucinous phenotype does4–7 or does not8–14 independently predict outcome in stage-matched multivariable analysis. Still, some aspects of mCRC are known to affect prognosis. For instance, a mucinous component within a CRC, especially in the right colon, may indicate that the lesion harbors microsatellite instability (MSI),15 which is associated with a better prognosis.16–18 In contrast, the presence of signet ring cells (SRC), either within mucin pools or invading mural tissue, confers a worse prognosis,18 even though these may be seen in microsatellite-unstable CRC as well.18,20

Since relatively few studies have analysed the clinicopathologic characteristics of mCRC (including percentage of mucinous component) in relation to patient outcome, we evaluated whether any clinical parameters or histologic findings affect prognosis of CRC with a mucinous component.

Materials and methods

With appropriate Institutional Research Board approval, slides from 1,638 CRC resections in the institution-restricted research files of one of the authors (KW) were reviewed for a mucinous component (either malignant glands closely associated with and thereby likely producing mucin, or sizable mucin pools forming part of the tumour volume) constituting at least 5% of the tumour area examined. Cases with predominantly tissue-invasive SRC morphology were excluded, as were cases treated with neoadjuvant therapy, as treatment effect can impart a mucinous appearance to CRC that may not have been mucinous prior to therapy.21 Cases of adenoma-like adenocarcinoma were also excluded; while they often contain a significant mucinous component, they appear to represent a special subset of CRC with a better prognosis than other well-differentiated CRC, meaning their inclusion in this analysis could skew outcome comparisons.22

In total, 224 malignancies (14% of cases) meeting these criteria were identified; they are hereafter identified as mCRC for study purposes. For each case, patient medical records and gross descriptions were reviewed for patient sex, age, race, and outcome; and tumour size, location, number of sections reviewed, and American Joint Committee on Cancer (AJCC) combined tumour stage. Original haematoxylin and eosin (H&E)-stained slides were reviewed to determine tumour edge (pushing vs. infiltrative), presence of SRC or non-SRC single cells floating within mucin, presence of lymphovascular or perineural invasion, presence and type of precursor adenoma, presence of tumour deposits, and number of positive lymph nodes. (As the WHO states that grading does not apply to CRC subtypes, histologic grade was not included in analysis.2) For large mucin pools, the associated epithelium was recorded as either floating within mucin or attached to the adjacent stromal wall, and epithelium associated with these pools was subcategorized as forming thin strips (architecturally), large glandular aggregates (easily observed at low magnification), or small clusters (10 or fewer cells, not always visible at low magnification). Tumour budding was quantified according to International Tumor Budding Consensus Conference criteria and scored as low, intermediate, or high.23 Peritumoural inflammation immediately adjacent to the tumour was marked as absent, acute, or chronic. Cases where peritumoural inflammation manifested as large lymphoid aggregates in the general periphery, rather than scattered inflammatory cells immediately adjacent, were denoted as having a peripheral Crohn’s-like reaction.

Two additional variables recorded for each mCRC were percentage of malignant glands producing mucin (Figure 1A) and percent of tumour volume composed of mucin (Figure 1B). Both were determined by eyeball estimation of the two parameters on each section of tumor; the percentages of each were then summed and divided by the number of tissue sections per case. Roughly one tissue section was submitted for microscopy per gross cm of tumor among the mCRC cases (mean number of sections per cm of tumor, 1.08; median, 1; range: 0.81–3.33).

Figure 1.

Figure 1.

Figure 1.

Figure 1.

Figure 1.

Figure 1.

Figure 1.

Figure 1.

Figure 1.

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A, In this mucinous colorectal carcinoma, most of the malignant glands produce visible mucin, but the mucin itself constitutes a low overall percentage of the tumour volume.

B, In contrast, while only 30% of the malignant glands in this carcinoma produce mucin, the mucin itself constitutes 60% of the tumor volume. C, The epithelium in this carcinoma floats within mucin, forming small clusters of malignant cells. D, The epithelium in this carcinoma forms strips lining the mucin-filled pools. E, The epithelium in this carcinoma forms large complex aggregates rather than thin strips, F, Peripheral chronic inflammation closely associated with mucinous colorectal carcinoma. G, Abundant signet ring cells floating within mucin pools. H, Tumour budding at the leading edge of a mucinous colorectal carcinoma, which was not significantly linked to outcome in these tumours.

Microsatellite instability (determined either by immunohistochemical methods and/or a sendout PCR-based assay test tumor DNA for hypermethylation of the MLH1 promoter, performed at the Mayo Clinic [Rochester, MN]24) had been assessed as part of patient care for 129 cases; this information was recorded as well, with cases dichotomized as MSI-negative (microsatellite stable or low instability by PCR) or MSI-high (high instability by PCR or mismatch repair protein-deficient by immunohistochemistry). KRAS and BRAF mutational analysis had been assessed by PCR as part of patient care for 54 cases (24%); given the relatively small subset of cases with this information, KRAS and BRAF status were excluded from subsequent analysis.

Of the remaining non-mucinous adenocarcinomas from the set of 1,638 CRC, there were 499 conventional colorectal adenocarcinomas with previously compiled outcome data and clinicopathologic findings, aside from those related to mucinous component (e.g., whether tumor cells floated in mucin) or SRC component. These 499 cases formed a comparison group. MSI status was available for 125 of these cases (25%).

Associations between clinicopathologic factors and disease-specific survival in mCRC cases were initially assessed by univariable Cox proportional hazard regression. Potential confounding variables (sex, race, age, AJCC stage, tumour size, anatomic site, and presence of Crohn’s-like reaction, tumour budding, mesenteric tumor deposits, lymphovascular invasion, or perineural invasion) were evaluated by multivariate Cox proportional hazard regression. Variables were dropped from the multivariate model in order of increasing absolute value of z-score until all variables were statistically significant. As only AJCC stage remained significant after this process, subsequent analysis of variables of interest was performed using Cox proportional hazard regression adjusted for AJCC stage. Similar methods, as well as Fisher’s exact test and the unpaired t test, were used to compare clinicopathologic variables and stage-matched mCRC outcomes to the comparison group. Finally, a second multivariable analysis looking at both cohorts combined was performed. Statistical analysis was performed using Stata v13 (Stata Corp, College Station, TX). All hypothesis tests were two-sided, with α=0.05.

Results

The cohort of patients with mCRC (n=224) and colonic adenocarcinoma (n=499) were similar overall. Mean age was 64 years both (P=0.50), males made up 51% of the former group and 53% of the latter group (P=0.57), and 88% of the former group and 85% of the latter group were Caucasian (P=0.42). While mean tumor size was larger (5.1 cm) for mCRC than for adenocarcinoma (4.0 cm; P<0.0001), a similar proportion of mCRC and adenocarcinoma cases cases were AJCC stage IV (16% vs. 20%, P=0.25), and, a similar proportion of mCRC and adenocarcinoma patients died from disease based on available follow-up data (25% vs. 31%, P=0.11).

Clinicopathologic details of the 224 mCRC cases, along with the results of statistical analyses, are summarized in Tables 1 and 2. On univariable analysis, factors influencing prognosis included size (hazard ratio [HR] 1.12 for every 1.0 cm increase in size, 95% confidence interval [CI] 1.06–1.17, P<0.001) and number of positive lymph nodes (HR 1.11 for every incremental positive node, 95% CI 1.09–1.13, P<0.001). Additionally, by log-rank test, more adverse events occurred than would otherwise be expected for patients whose mCRC was MSI-negative (P=0.0008), formed small epithelial clusters (Figure 1C) rather than strips (Figure 1D) or large aggregates (Figure 1E) (P=0.022), lacked peripheral inflammation (P=0.0034) (Figure 1F), lacked a peripheral Crohn’s-like reaction (P=0.026), had tumour deposits (P<0.0001), had SRC or single non-SRC cells floating in mucin (P=0.0017) (Figure 1G), showed lymphovascular invasion (P<0.0001), or was stage IV by AJCC criteria (P<0.0001). The other factors, including tumour budding (Figure 1H), did not significantly impact prognosis. Micropapillary features were only seen in nine mCRC and were therefore excluded from analysis.

Table 1 –

Cox Regression of Continuous Variables in Mucinous Colorectal Carcinoma

Findings in mCRC (n=224) Hazard Ratio 95% CI P-value
Age Median: 66 years 1.0 0.99–1.01 0.98
Range: 10–93 years
Size Median: 5.0 cm 1.12 1.06–1.17 <0.001
Range: 0.4–18.5 cm
Percent mucin-producing glands Median: 50% 1.00 0.99–1.01 0.60
Range: 5–100%
Percent mucin by tumour volume Median: 60% 1.00 1.00–1.01 0.27
Range: 5–100%
Positive node count Median: 0 1.11 1.09–1.13 <0.001
Range: 0–41
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Table 2 –

Log-rank Test for Equality of Survivor Functions in Categorical Variables in Mucinous Colorectal Carcinoma

Findings in mCRC (n=224) Events Observed Events Expected P-value
Sex Male: 114 25 28 0.49
Female: 110 31 28
Race White: 196 47 48 0.38
Black: 19 5 6
Other: 9 4 2
AJCC Stage 1: 39/221 2 10 <0.0001
2: 80/221 6 23
3: 67/221 17 16
4: 35/221 28 5
MSI Status Negative: 69/129 21 13 0.0008
MSI-high: 60/129 3 11
Epithelium lining mucin pools Detached: 45 14 10 0.21
Attached: 134 31 37
Mixed: 45 11 10
Architectural pattern of epithelium Strips: 130 29 35 0.022
Aggregates: 63 15 16
Clusters: 31 12 6
Grade Low: 37 7 10 0.015
Intermediate: 134 29 34
High: 53 20 11
Signet ring cells Absent: 177 39 47 0.0017
Single non-SRC cells: 14 5 3
Focal: 14 3 3
Abundant: 19 9 3
Peripheral inflammation Absent: 155 47 34 0.0034
Acute: 32 6 10
Chronic: 37 3 12
Peripheral Crohn’s-like reaction Absent: 145 36 28 0.026
Present: 62 20 28
Tumour budding Low: 82/222 15 17 0.79
Intermediate: 92/222 27 25
High: 48/222 13 13
Site Cecum: 48/220 10 11 0.62
Ascending: 78/220 17 20
Transverse: 18/220 10 7
Descending: 19/220 4 3
Sigmoid: 34/220 9 8
Rectum: 23/220 4 6
Edge Pushing: 104/217 24 24 0.91
Infiltrative: 113/217 30 30
Precursor adenoma No residual: 128/220 33 33 0.084
Tubular adenoma: 19/220 5 3
Tubulovillous/villous adenoma: 63/220 15 17
Sessile serrated adenoma/polyp: 6/220 0 2
Traditional serrated adenoma: 4/220 3 1
Tumour deposits Absent: 172/219 27 47 <0.0001
Present: 47/219 29 9
Lymphovascular invasion Absent: 141/223 22 38 <0.0001
Present: 82/223 33 17
Perineural invasion Absent: 210 50 52 0.17
Present: 14 6 4
Molecular findings KRAS mutant: 20/54 9 6 0.26
BRAF mutant: 22/54 3 4
Neither: 12/54 3 5
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None of the analyzed attributes, however, remained statistically significant on AJCC stage-matched multivariable analysis. Furthermore, survival within the mCRC group was not impacted by percent of mucin-producing glands or percent volume of tumour composed of mucin (HR 1.00 for both [10% intervals], 95% CI 0.99–1.01 for volume and 1.00–1.01 for glands, P=0.60 for volume and P=0.27 for glands). After stratifying the cases as having ≤50% or >50% tumour volume composed of mucin (i.e., the definitional criteria advocated by the WHO), there remained no prognostic difference (P=0.23). This was also the case for stratifying cases as having ≤50% or >50% mucin-producing glands (P=0.38).

A multivariable analysis including the cases from both cohorts (mCRC and adenocarcinoma) is shown in Table 3. Factors that had a significant negative effect on prognosis in this larger analysis included increased age, increased tumor size, female sex, black race, mesenteric tumor deposits, large-vessel invasion, lack of Crohn’s-like reaction, and AJCC stage III or IV disease.

Table 3 –

Comparison of Clinicopathologic Features for Molecular Subtypes of Mucinous Colorectal Carcinoma

KRAS (n=20) BRAF (n=22) Neither (n=12) P-value
Age (years) 0.77
  Mean 64 70 62
  Range 37–83 49–88 41–78
Sex 0.24
  Male 11 (55%) 9 (41%) 3 (25%)
  Female 9 (45%) 13 (59%) 9 (75%)
Race 0.51
  White 16 (80%) 21 (95%) 11 (92%)
  Black 2 (10%) 0 0
  Other 2 (10%) 1 (5%) 1 (8%)
Size (cm) 0.015
  Mean 5.98 6.74 5.16
  Range 2.5–10.0 1.9–14.2 2.0–8.0
AJCC Stage 0.12
  I 0 3 (14%) 0
  II 6 (30%) 10 (45%) 8 (67%)
  III 7 (35%) 7 (32%) 2 (17%)
  IV 7 (35%) 2 (9%) 2 (17%)
MSI Status 0.004
  Negative 12/16 (75%) 5/21 (24%) 8 (67%)
  MSI-high 4/16 (25%) 16/21 (76%) 4 (33%)
Percent mucin-producing glands 0.93
  Mean 56% 60% 46%
  Range 5–100% 5–100% 5–100%
Percent mucin by tumour volume 0.64
  Mean 56% 64% 50%
  Range 5–100% 5–100% 5–95%
Epithelium lining mucin pools 0.26
  Detached 2 (10%) 7 (32%) 1 (8%)
  Attached 15 (75%) 11 (50%) 10 (83%)
  Mixed 3 (15%) 4 (18%) 1 (8%)
Architectural pattern of epithelium 0.64
  Strips 14 (70%) 13 (59%) 10 (83%)
  Aggregates 4 (20%) 5 (23%) 2 (17%)
  Clusters 2 (10%) 4 (18%) 0
Grade 0.33
  Low 4 (20%) 3 (14%) 3 (25%)
  Intermediate 14 (70%) 11 (50%) 7 (58%)
  High 2 (10%) 8 (36%) 2 (17%)
Signet ring cells 0.11
  Absent 18 (90%) 13 (59%) 11 (92%)
  Single non-SRC cells 0 3 (14%) 1 (8%)
  Focal 0 1 (5%) 0
  Abundant 2 (10%) 5 (23%) 0
Peripheral inflammation 0.65
  Absent 16 (80%) 19 (86%) 8 (67%)
  Acute 3 (15%) 2 (9%) 2 (17%)
  Chronic 1 (5%) 1 (5%) 2 (17%)
Crohn’s-like reaction 0.49
  Absent 14 (70%) 13 (59%) 6 (50%)
  Present 6 (30%) 9 (41%) 6 (50%)
Tumour budding 0.043
  Low 3 (15%) 11 (50%) 5 (42%)
  Intermediate 14 (70%) 8 (36%) 3 (25%)
  High 3 (15%) 3 (14%) 4 (33%)
Site 0.38
  Cecum 9 (45%) 10 (45%) 2 (17%)
  Ascending 5 (25%) 6 (27%) 7 (58%)
  Transverse 2 (10%) 4 (18%) 1 (8%)
  Descending 0 1 (5%) 0
  Sigmoid 3 (15%) 1 (5%) 1 (8%)
  Rectum 1 (5%) 0 1 (8%)
Edge 0.68
  Pushing 10 (50%) 12/21 (57%) 8 (67%)
  Infiltrative 10 (50%) 9/21 (43%) 4 (33%)
Precursor adenoma 0.67
  No residual 9 (45%) 13/21 (62%) 7 (58%)
  Tubular adenoma 3 (15%) 2/21 (10%) 0
  Tubulovillous/villous adenoma 6 (30%) 4/21 (19%) 5 (42%)
  Sessile serrated adenoma/polyp 0 1/21 (5%) 0
  Traditional serrated adenoma 2 (10%) 1/21 (5%) 0
Tumour deposits 0.030
  Absent 11 (55%) 19/21 (90%) 9/11 (82%)
  Present 9 (45%) 2/21 (10%) 2/11 (18%)
Lymphovascular invasion 0.76
  Absent 10/19 (53%) 13 (59%) 9 (75%)
  Present 9/19 (47%) 9 (41%) 3 (25%)
Perineural invasion 0.32
  Absent 18 (90%) 22 (100%) 11 (92%)
  Present 2 (10%) 0 1 (8%)
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Stage-matched disease-specific survival was similar for the two patient cohorts, namely mCRC (median follow-up, 35 months) and adenocarcinoma (median follow-up, 50 months) (Figure 2A; P=0.95). This finding held after paring down the mCRC comparison group to only include cases with >50% mucin by volume (Figure 2B; P=0.15).

Figure 2.

Figure 2.

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A, Kaplan–Meier plot comparing disease-specific survival for colorectal carcinoma with any mucinous component and conventional colorectal adenocarcinoma, stage by stage (P=0.95). B, Kaplan–Meier plot comparing disease-specific survival for mucinous colorectal carcinoma meeting WHO criteria (>50% mucinous tumor volume) and colorectal adenocarcinoma, stage by stage (P=0.15).

Discussion

When evaluating a colorectal carcinoma specimen, pathologists must determine whether the carcinoma meets criteria for a particular subtype and whether certain histologic features or findings are relevant to patient treatment and prognosis. Historically, CRC has been termed mCRC when more than 50% of the tumour volume is composed of extracellular mucin. This has been adopted by the WHO,2 and most studies comparing CRC to mCRC use this criterion (if any is mentioned). The prognostic impact of this criterion remains unclear. Our study suggests that, in concurrence with most other studies that account for tumour stage,8–14 the mucinous component of CRC has no significant impact on patient prognosis. The lack of prognostic significance was not only observed using a dichotomized 50% cutoff, but also when evaluating percent mucin as a continuous variable.

In addition to investigating the prognostic significance of tumour volume composed of extracellular mucin, we also evaluated the percentage of tumour glands producing mucin. These two percentages can be quite different, as a few markedly dilated glands producing copious mucin in an otherwise unremarkable CRC would lead to a high percentage of mucin comprising tumour volume, but a low percentage of malignant glands producing mucin. Regardless, this characteristic similarly had no prognostic significance.

Although properly identifying the mucinous subtype of CRC may not have prognostic significance, it may connote potentially important biologic and therapeutic information. Mucinous CRC have higher rates of MSI25 and lower rates of TP53 mutation than adenocarcinoma,26 and they also demonstrate higher expression of HATH127 and MUC2.28 KRAS mutation may29 or may not26 be related to mucinous differentiation in CRC. Some of these associations are important from a prognostic and therapeutic perspective, as MSI-high status confers improved survival in mCRC25 and may qualify a patient for anti-PD-1 therapy,30 and tumours with a KRAS mutation are not eligible for treatment with EGFR inhibitors.31 Mucinous CRC may also respond differently to chemotherapy than adenocarcinoma, as the mucin may act as a barrier to drug delivery.1 To our knowledge, no specific targetable mutations have been identified in mCRC not also seen in adenocarcinomas, although loss of HES1 (which is associated with worse prognosis) occurs more commonly in mCRC.32 As therapeutically relevant molecular properties can be tested on individual cases, there appears to be little intrinsic relevance to mucinous phenotype in CRC. While mucinous features should still be mentioned in a signout report (if for no other reason than to guide histologic interpretation of potential future metastatic lesions), utilizing criteria such as a 50% cutoff is not supported by currently available data.

While univariable analysis did identify a few clinicopathologic variables as potentially prognostic, none remained so on multivariate analysis. These included abundant SRC (which others have linked to poor prognosis20) and chronic inflammation surrounding a tumour (which others have linked to improved outcome33,34). Tumour budding, which has undergone much scrutiny recently in CRC,23 did not emerge as a prognostic factor in our mCRC cohort. The majority of cases showed low or intermediate tumour budding, potentially in keeping with reports that tumour budding is uncommon in MSI-high CRC.35,36

Our study admittedly has at least two notable limitations. The first is that percentage of malignant glands producing mucin and percent of tumour volume composed of mucin for mCRC were both estimated by eyeballing. Eyeballing is generally considered to be less accurate than more precise methods of quantification, such as software analysis. However, in our experience, eyeballing remains the most common method of quantification in daily practice and therefore the most translatable to routine pathologic evaluation. Additionally, determining the “true” percentages of the above parameters would be nearly impossible, even with specialized software, as most carcinomas in the study were not entirely submitted for microscopy, and mucin volume and mucin production sometimes varied widely from section to section within a tumor. For these reasons, we considered eyeballing an acceptable modality to utilize in this study, despite its disadvantages.

The second notable limitation is the relative lack of molecular data. MSI status was available for 58% of our mCRC cases, as the others predated routine evaluation of mismatch repair immunohistochemistry on colon carcinomas. Far fewer mCRC cases – only 24% – had undergone molecular analysis for KRAS and BRAF mutational status. Recent studies have reported intriguing results regarding molecular findings in mCRC; most notably, Liddell et al37 suggested that mCRC can be split into four distinct subtypes depending on clinical and molecular factors. Our lack of molecular data in most cases precluded us from evaluating our cases in a similar, statistically sound manner.

In conclusion, colorectal carcinoma with a mucinous component, matched stage for stage, shows no prognostic difference compared to conventional colorectal carcinoma. This holds true when dichotomizing cases at any cutoff of mucinous volume, including the 50% value typically required for a diagnosis of mCRC.

Acknowledgements

This project was funded by NIH/NCI 6P50 CA095103–15.

RSG co-conceived the study, reviewed cases, and wrote the manuscript. JMMC provided statistical analysis and expert advice. KW co-conceived the study, collected cases, and gathered clinical and molecular data.

* The work for this project was performed while Dr. Gonzalez was at the University of Rochester. Dr. Gonzalez is currently at Beth Israel Deaconess Medical Center.

Footnotes

Conflicts of interest

None to declare.

Ethics statement

A waiver of consent was obtained for this project. The study was performed according to the Declaration of Helsinki. The Institutional Research Board at Vanderbilt University approved the study (IRB #130726, originally approved 13/05/2013).

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