Clinicopathological factors and survival outcomes of signet-ring cell and mucinous carcinoma versus adenocarcinoma of the colon and rectum: a systematic review and meta-analysis



Histological subtypes of colorectal cancer may be associated with varied prognostic features. This systematic review and meta-analysis aimed to compare clinicopathological characteristics, recurrence and overall survival between colorectal signet-ring cell (SC) and mucinous carcinoma (MC) to conventional adenocarcinoma (AC).


A literature search of MEDLINE, EMBASE, Ovid and Cochrane Library was performed for studies that reported data on clinicopathological and survival outcomes on SC and/or MC versus AC from January 1985 to May 2020. Meta-analysis was performed using random-effect models and between-study heterogeneity was assessed.


Thirty studies of 1,087,055 patients were included: 11,510 (1.06%) with SC, 110,179 (10.13%) with MC and 965,366 (88.81%) with AC. Patients with SC were younger than patients with AC (WMD − 0.47; 95% CI − 0.84 to –0.10; I2 88.6%; p = 0.014) and more likely to have right-sided disease (OR 2.12; 95% CI 1.72–2.60; I2 82.9%; p < 0.001). Locoregional recurrence at 5 years was more frequent in patients with SC (OR 2.81; 95% CI 1.40–5.65; I2 0.0%; p = 0.004) and MC (OR 1.92; 95% CI 1.18–3.15; I2 74.0%; p = 0.009). 5-year overall survival was significantly reduced when comparing SC and MC to AC (HR 2.54; 95% CI 1.98–3.27; I2 99.1%; p < 0.001 and HR 1.38; 95% CI 1.19–1.61; I2 98.6%; p < 0.001, respectively).


SC and MC are associated with right-sided lesions, advanced stage at presentation, higher rates of recurrence and poorer overall survival. This has strong implications towards surgical and oncological management and surveillance of colorectal cancer.


Colorectal cancer is the third most common diagnosed malignancy and the fourth leading cause of cancer death in the world [1,2,3]. There were 1.8 million new cases and approximately 861,000 deaths as a result of colorectal cancer in 2018 [4]. Recent data from the United States Surveillance, Epidemiology, and End Results (SEER) database and other Western cancer registries suggest that colorectal cancer is increasing in adults under the age of 50 years [5,6,7,8]. In the United States, the incidence of colorectal cancer in adults under the age of 50 years steadily increased at a rate of 2% per year from 1995 to 2016 [9]. The cause of this rise in colorectal cancer in younger adults has not yet been established.

The majority of colorectal cancers are adenocarcinomas with three major subtypes: conventional adenocarcinoma (AC), mucinous (MC) and signet-ring cell (SC) adenocarcinomas [10]. MC account for 5–15% of colorectal adenocarcinomas while SC accounts for approximately 1% [11, 12]. MC, also known as colloid adenocarcinomas, were described over 80 years ago and have an abundance of extracytoplamsic mucin that usually comprises > 50% of the total tumour mass [13]. SC carcinoma was first described in the colorectal setting by Laufman and Saphir in 1951 as ‘linitis plastica’ of the colon [14]. It classically consists of cells with peripherally placed nuclei displaced by intracytoplasmic mucin in > 50% of the total tumour mass. Signet-ring cells exist either as single cells or as loose clusters and spread diffusely throughout the bowel wall implying loss of cell–cell adhesion at the molecular level [15].

The histological subtypes of colorectal cancer are believed to have prognostic relevance. It has been suggested that SC and MC tumours are associated with advanced stage at presentation [16] and a poor prognosis [17] compared to AC. However, it is still unclear whether the prognosis of SC and MC is related to the advanced stage of the disease at presentation or whether it is related to the primary tumour characteristics. The purpose of this study, through a systematic review with meta-analyses of the available literature, is to investigate and compare local and systemic recurrence patterns and long-term survival of SC and MC adenocarcinomas compared to AC. Differences in patient and disease-specific variables such as age, gender, tumour location and staging are also analysed. This in turn should help provide further understanding and guidance on how to manage the different subgroups of colorectal cancer.


We conducted this systematic review and meta-analysis according to the Preferred Reporting Items for Systematic reviews and Meta-Analysis group (PRISMA) guidelines [18] and the Cochrane Handbook for Systematic Reviews of Interventions [19]. The work was registered in the PROSPERO database for systematic reviews in August 2020 (CRD42020188060).

Search strategy

A literature search of MEDLINE, EMBASE, Ovid and The Cochrane library was performed. Specific research equations were formulated for each database using the following Medical Subject Headings (MeSH) terms: signet cell-ring adenocarcinoma/cancer, mucinous adenocarcinoma/cancer, mucin, colorectal adenocarcinoma/cancer, comparative study, local/locoregional recurrence, metastasis and survival. We retrieved articles published in English from January 1, 1985, to May 30, 2020, that reported outcomes on SC and MC versus AC. The reference lists from the selected studies were reviewed to identify additional relevant studies.

Study selection and data extraction

Studies were included if they met the following criteria: (1) studies were comparative between SC and/or MC with AC, (2) at least one outcome of recurrence and survival pattern was reported, (3) studies reported outcomes at least at yearly intervals throughout the duration of follow-up to enable hazard ratio (HR) calculations, (4) the site of the cancer had to be specified as ‘colon’ or ‘rectum’, (5) definitions of SC and MC had to be reported according to the World Health Organisation criteria or equivalent [20]. Exclusion criteria were the following: (1) studies reporting on appendiceal tumours, benign/premalignant tumours or adenomas or non-colonic primary adenocarcinomas, (2) articles published in a non-English language or in a book, (3) letters to the editor or case reports, (4) non-comparative studies to AC, (5) no reported outcomes on recurrence rates or survival.

Two authors conducted the search and identification independently, and a third author confirmed that the final selected manuscripts met the inclusion criteria. The two authors independently extracted the following information from the included studies: first author, year of publication, country, patient number, study design, age, gender, tumour location, stage (as defined by the American Joint Committee of Cancer, AJCC) [21] and tumour size (cm). The following outcomes were also recorded: locoregional recurrence rate and systemic recurrence rate according to stage, and 5-year overall survival from the time of diagnosis.

Statistical analysis

The weighted mean difference (WMD) was used to analyse continuous variables, such as patient age and tumour size, accounting for sample size and event rate. Standard deviation (SD) was calculated using statistical algorithms. The odds ratio (OR) was used as the statistical measure for all other dichotomous outcomes. The OR represents the odds of an adverse event (e.g. recurrence) occurring in the experimental group (SC and MC) versus the control group (AC) and approximates the relative risk. An OR of greater than one indicated greater risk of an adverse event happening in the SC or MC groups.

The logarithm of the HR with 95% confidence intervals (CI) was used as the primary summary statistic as described by Parmar et al. [22]. The estimate of HR and its variance was either extracted directly from the study or required additional calculation depending on the method of data presented: annual mortality rates, survival curves, number of deaths or percentage freedom from death. Calculation of the logarithm of the HRs and their 95% CI was also performed yearly for the first three years after treatment. Meta-analysis of data was conducted using a random-effects model. Publication bias was explored graphically with funnel plots to detect asymmetry and any outliers. Inter-study heterogeneity was assessed using the Chi2-statistic and the I2 value to measure the degree of variation not attributable to chance alone. This was graded as low (I2 < 25%), moderate (I 2 = 25–75%) or high (I2 > 75%). This study was performed in line with Cochrane recommendations and following PRISMA guidelines and using the statistical software STATA V 12.

Quality assessment of studies

The quality of all observational studies was assessed using the Newcastle–Ottawa Scale (NOS) [23]. This was calculated by examining three factors: method of patient selection, comparability of the study groups and number of outcomes reported. The full score was nine stars, and studies that had a score of seven stars or more were considered to be of higher quality. Two reviewers independently assessed the quality of the study and any disagreement was resolved by re-examining the relevant paper until consensus was achieved.


A total of 799 published articles were identified from the initial search, of which 700 were excluded based on title and abstract review. The remaining 99 articles underwent full-text evaluation and 69 studies were further excluded. The remaining 30 comparative studies, comprising a total of 1,087,055 patients, were eligible and were included in the qualitative and quantitative analyses [10, 14, 16, 17, 24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49]. The PRISMA diagram of the literature search is shown in Fig. 1.

Fig. 1

The flowchart shows the literature search and study selection process according to the PRISMA guidelines

Fifteen studies evaluated outcomes for all three types of cancer [10, 14, 25,26,27, 31, 32, 34, 37, 39, 42,43,44,45, 47]. Six studies compared SC to AC only [16, 24, 35, 40, 41, 49] and nine studies compared MC to AC only [17, 28,29,30, 33, 36, 38, 46, 48]. The final analysis included 11,510 (1.06%) patients with SC, 110,179 (10.13%) with MC and 965,366 (88.81%) patients with AC. Nine studies were prospective non-randomised controlled studies [17, 24, 25, 27, 31, 37, 39, 40, 44] with the remaining being retrospective. Fifteen studies were considered to be of higher quality [10, 16, 17, 25, 28, 30,31,32, 36,37,38, 40, 42, 44, 47] and 20 studies were published during or after the year 2000 [10, 14, 17, 24, 25,26,27, 31,32,33,34,35,36,37, 39, 42, 444547, 49]. The demographic information, tumour location, staging for patients at presentation with SC, MC or AC and the quality scoring for the 30 individual studies included in the analysis is summarised in Additional file 1: Table S1.

Demographic analysis

Age, gender, location, stage and tumour size differences between SC and MC with AC were suitable for analysis as shown in Table 1. Patients with SC and MC were found to be significantly younger than patients with AC (WMD − 0.47; 95% CI − 0.84 to − 0.10, p = 0.014 and WMD − 0.22; 95% CI − 0.44 to − 0.00; p = 0.047, respectively) (Additional file 1: Fig. S1a). No gender difference was found between SC and AC patients (OR 1.00; 95% CI 0.94–1.07; p = 0.972). There was a gender difference found between MC and AC (OR 1.14; 95% CI 1.09–1.19; p < 0.001) (Additional file 1: Fig. S1b). Both SC and MC were most commonly found in the right colon (OR 2.12; 95% CI 1.72–2.60, p < 0.001 and OR 2.28; 95% CI 2.07–2.52; p < 0.001, respectively) when compared to AC and less frequently in the left colon (OR 0.53; 95% CI 0.44–0.64; p < 0.001 and OR 0.60; 95% CI 0.57–0.64; p < 0.001, respectively) and rectum (OR 0.71; 95% CI 0.62–0.81; p < 0.001 and OR 0.57; 95% CI 0.53–0.62; p < 0.001, respectively) (Fig. 2a–c).

Table 1 Comparison of clinicopathological factors, recurrence and survival outcomes of signet-ring cell cancer and mucinous cancer versus conventional adenocarcinoma
Fig. 2

Meta-analysis and forest plot comparing a Right-sided lesion, b Left-sided lesion, c Rectal lesion, d Delayed presentation (stage III/IV) of signet-ring cell cancer and mucinous cancer to conventional adenocarcinoma. SC: signet-ring cell cancer; MC: mucinous cancer; AC: conventional adenocarcinoma; OR: odds ratio; CI: confidence interval

Stage at presentation was significantly more advanced in SC (OR 4.95; 95% CI 3.83–6.39; p < 0.001) and MC (OR 1.68; 95% CI 1.36–2.08; p < 0.001) than AC (Fig. 2d). Similarly, tumour size at presentation was significantly greater for SC and MC (WMD 0.60; 95% CI 0.24–0.96; p = 0.001 and WMD 0.53, 95% CI 0.41–0.65; p < 0.001, respectively) when compared to AC (Additional file 1: Fig. S1c).

Local and systemic recurrence analysis

Risk of 5-year local recurrence for stage I-III disease was higher for both SC and MC versus AC (OR 2.81; 95% CI 1.40–5.65; p = 0.004 and OR 1.92; 95% CI 1.18–3.15; p = 0.009, respectively) (Fig. 3a). Only one study included local recurrence for only stage III disease, and therefore this was not assessed in the meta-analysis. The 5-year systemic recurrence rate for stage I–III disease for SC and MC was also significantly higher when compared to AC (OR 4.25; 95% CI 1.98–3.27; p < 0.001 and OR 1.81; 95% CI; p < 0.001, respectively) (Fig. 3b).

Fig. 3

Meta-analysis and forest plot comparing a 5-year local recurrence for stage I–III, b 5-year all recurrences (local and systemic) for stage I–III, c 5-year overall survival of signet-ring cell cancer and mucinous cancer to conventional adenocarcinoma. SC: signet-ring cell cancer; MC: mucinous cancer; AC: conventional adenocarcinoma; OS: overall survival; OR: odds ratio; CI: confidence interval

Survival analysis

Five-year overall survival was significantly poorer for both SC and MC when compared to AC (HR 2.54; 95% CI 1.98–3.27, p < 0.001 and HR 1.38; 95% CI 1.19–1.61; p < 0.001, respectively) (Fig. 3c). In particular, significant heterogeneity was observed when comparing the staging at presentation of SC and MC to AC (I2 92.4% and 99.4%, respectively). Survival analysis was also subject to great between-study heterogeneity in the case of both SC and MC (I2 99.1% and 98.6%, respectively). Begg’s and Egger’s tests were performed for all outcomes with significant heterogeneity and funnel plots were inspected without significant evidence of publication bias.


To our knowledge this study provides the first systematic review and meta-analysis of the clinicopathological characteristics and survival outcomes for SC and MC compared to AC. Thirty studies with a combined population of 1,087,055 patients met the inclusion criteria and were included in the final meta-analysis. The results highlight the important clinical implications associated with the different histological subgroups of colorectal cancer. We have identified the behaviour of SC and MC and their prognostic significance which should provide guidance on how to further manage SC and MC of the colon and the rectum. Key factors to improve survival include closer follow-up, earlier detection of recurrent disease, efficacy of systemic therapies, resection of metastases and implementation of a ‘continuum of care’ [50, 51].

Our meta-analysis has shown that SC and MC present at an earlier age, by 0.47 and 0.22 years respectively, compared to AC. The histological subtypes of SC and MC may be contributing to the increase in incidence seen in colorectal cancer in younger adults. There is also significantly more chance of SC and MC developing in the right colon, presenting at an advanced stage. Local recurrence at five years for SC and MC were more likely than AC, with a poorer overall survival at five years.

Accumulation of mutations in various oncogenes and tumour suppressor genes drives the development of colorectal cancer [52]. Results from the present study may be explained to a certain extent by considering the molecular genetics of SC and MC and the differences from AC. E-cadherin is a calcium-dependent cell-to-cell adhesion molecule that has been implicated in the biological behaviour of SC. It has been suggested that e-cadherin together with catenin can act as an ‘intercellular glue’ with a suppressor role in tumour invasion in colorectal cancer [53]. Downregulation of e-cadherin in association with locally infiltrative behaviour and peritoneal metastases has been shown in gastric SC and was associated with poorer prognosis [54, 55]. In a study by Kim et al. [56] in 2002, 100% of colorectal SC was shown to have markedly reduced or absent expression of e-cadherin when compared to only 23.5% of AC (p < 0.05). Peritoneal metastases and a locally aggressive behaviour in colorectal cancer was found in association with e-cadherin proteolysis [57]. Another molecular complex known as ‘trefoil factor’ has a major role to play in mucosal healing by disturbing the complexes among e-cadherin and β-catenin and allowing epithelial proliferation [58]. ‘Trefoil factor’ and mucin are often co-expressed leading to the theory that overexpression of mucin in SC and MC leads to a secondary overexpression of ‘trefoil factor’ and disruption of the E-cadherin/β-catenin complexes [59]. It has also been suggested that due to the mucin content of SC and MC, local immune host recognition as tumour cells is evaded allowing easier locoregional spread [60]. Loss of e-cadherin may be key in disruption of cell-to-cell cohesion, allowing a more locally invasive and infiltrating behaviour involving the surrounding structures, peritoneum and lymph nodes. This may in turn explain the more advanced stage at presentation of these cancers as well as the metastatic pattern and aggressive behaviour.

Other studies have also made similar observations regarding tumour location of MC and SC. Benedix et al. [61] in a study of 17,641 patients found that right-sided cancers were more often poorly differentiated or of SC/MC morphology and presented more commonly with peritoneal metastases compared to left-sided tumours that presented with liver metastatic disease. This observation was enhanced in a review by the same author reaching similar conclusions [62] and indeed suggesting that tumours at different colonic locations may be different entities. However, the study from Lee et al. [14] that included poorly differentiated AC showed equal preponderance of AC to MC in the right colon.

Our study seems to indirectly suggest a continuum of poorer prognosis that may not only depend on tumour type but on tumour location as well. Analysis of survival based on tumour type as well as location was not possible from the included studies although other authors have suggested location to be an independent predictor or survival [63,64,65,66,67,68,69]. Chew et al. [25] on the other hand using a multivariate Cox proportional hazards model showed independent association of histological subtype but not tumour location to survival. These findings are consistent with the results of the present meta-analysis where histological subtype is the direct determinant of the colonic region involved with tumour type dictating survival and locoregional recurrence patterns. SC seems to have an inherently more aggressive biological behaviour even to poorly differentiated AC, and results in poorer survival outcomes. Local recurrence appears to be frequent in both SC and MC. This may be directly related to the above-mentioned hypothesis of e-cadherin loss that can occur at the onset of carcinogenesis resulting in a more aggressive locoregional behaviour [55].


This study is subject to some limitations that must be addressed. Between-study heterogeneity was evident particularly in staging at presentation and survival outcomes. Attempts were made by the authors to statistically account for this with a random-effects model analysis to allow for differences between studies and treatment centres. There was no significant publication bias found within the statistical powers of the Begg’s and Egger tests. Heterogeneity has been reduced by employing these techniques but not abolished as there are factors inherent to the studies that cannot be controlled by meta-analytical techniques. A different mix of populations from the included studies may account for the heterogeneity observed in the demographic characteristics.

Multimodal treatments, surgical approaches and techniques as well as imaging tools and histopathological classifications have changed significantly over the last few decades which makes the comparison of the results more difficult. Tumour grade was another important factor that could not be accounted for as only one study was matched for tumour grade [41], one study included only poorly differentiated AC [14] while another included only well and moderately differentiated AC [39]. Studies were non-randomised as is frequently the case in surgical research but meta-analysis of non-randomised studies has been shown to be a useful tool in its own remit. Moreover, the overall level of evidence emerging from the literature were judged as high in the majority of cases.


Based on the available evidence, SC and MC present and behave in a pattern distinct from AC. SC seems to be an aggressive type of colorectal cancer presenting in younger patients, in the right colon and at a more advanced stage. This in turn leads to a poorer stage-by-stage survival and a higher probability of local recurrence rates when compared to AC. MC seems to behave in a similar fashion to SC in terms of local recurrence and overall survival. These factors need to be taken into consideration when planning surgical and oncological management of such cancers. Follow-up may be needed more regularly for SC and MC compared to AC due to the higher recurrence rates. Local control would also be important in the case of SC and MC with implications on the need for careful lymphadenectomy and/or peritonectomy with or without neoadjuvant therapy. Post-resection surveillance protocols may need to be adjusted to detect local and peritoneal spread early and this could form the basis of future trials.

Data availability

The datasets used generated during and/or analysed during the current study are available from the corresponding author on request.


  1. 1.

    Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64(1):9–29.

    PubMed  Article  Google Scholar 

  2. 2.

    Franzè E, Dinallo V, Rizzo A, et al. Interleukin-34 sustains pro-tumorigenic signals in colon cancer tissue. Oncotarget. 2018;9:3432–45.

    PubMed  Article  Google Scholar 

  3. 3.

    Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359–86.

    CAS  Article  Google Scholar 

  4. 4.

    World Health Organisation (WHO) Global Cancer Observatory (GLOBOCAN) database. Cancer Today, Lyon, France; 2020. Accessed October 2020.

  5. 5.

    Brenner DR, Heer E, Sutherland RL, et al. National trends in colorectal cancer incidence among older and younger adults in Canada. JAMA Netw Open. 2019;2:e198090.

    PubMed  PubMed Central  Article  Google Scholar 

  6. 6.

    Abualkhair WH, Zhou M, Ahnen D, et al. Trends in incidence of early-onset colorectal cancer in the United States among those approaching screening age. JAMA Netw Open. 2020;3:e1920407.

    PubMed  PubMed Central  Article  Google Scholar 

  7. 7.

    Davis DM, Marcet JE, Frattini JC, et al. Is it time to lower the recommended screening age for colorectal cancer? J Am Coll Surg. 2011;213:352.

    PubMed  Article  Google Scholar 

  8. 8.

    Meester RGS, Mannalithara A, Lansdorp-Vogelaar I, Ladabaum U. Trends in incidence and stage at diagnosis of colorectal cancer in adults aged 40 through 49 years, 1975–2015. JAMA. 2019;321:1933.

    PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    Siegel RL, Miller KD, Goding Sauer A, et al. Colorectal cancer statistics, 2020. CA Cancer J Clin. 2020;70:145.

    Article  Google Scholar 

  10. 10.

    Sheng H, Wei X, Mao M, et al. Adenocarcinoma with mixed subtypes is a rare but aggressive histologic subtype in colorectal cancer. BMC Cancer. 2019;19(1):1071.

    PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Nozoe T, Anai H, Nasu S, Sugimachi K. Clinicopathological characteristics of mucinous carcinoma of the colon and rectum. J Surg Oncol. 2000;75(2):103–7.

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Du W, Mah JTL, Lee J, Sankila R, Sankaranarayanan R, Chia KS. Incidence and survival of mucinous adenocarcinoma of the colorectum: a population-based study from an Asian country. Dis Colon Rectum. 2004;47(1):78–85.

    PubMed  Article  Google Scholar 

  13. 13.

    Parham D. Colloid carcinoma. Ann Surg. 1923;77(1):90–105.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Lee WS, Chun HK, Lee WY, et al. Treatment outcomes in patients with signet ring cell carcinoma of the colorectum. Am J Surg. 2007;194(3):294–8.

    PubMed  Article  Google Scholar 

  15. 15.

    Bӧrger ME, Gosens MJEM, Jeuken JWM, et al. Signet ring cell differentiation in mucinous colorectal carcinoma. J Pathol. 2007;212(3):278–86.

    Article  CAS  Google Scholar 

  16. 16.

    Giacchero A, Aste H, Baracchini P, et al. Primary signet-ring carcinoma of the large bowel. Report of nine cases. Cancer. 1985;56(11):2723–6.

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Consorti F, Lorenzotti A, Midiri G, Di Paola M. Prognostic significance of mucinous carcinoma of colon and rectum: a prospective case-control study. J Surg Oncol. 2000;73(2):70–4.

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Moher D, Liberati A, Tetzlaff J, Altman DG, Group P, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Int J Surg. 2010;8(5):336–41.

    PubMed  Article  Google Scholar 

  19. 19.

    Higgins JPT, Green S, Chandler J. Cochrane Handbook for Systematic Reviews of Interventions, Version 6 (updated July 2019). Cochrane. 2019. Accessed 3 Mar 2020

  20. 20.

    Hamilton S, Aaltonen LA, editors. Pathology and genetics of tumours of the digestive system, in WHO classification of tumours. Lyon: IARC; 2000. p. 104–9.

    Google Scholar 

  21. 21.

    Amin MB, Edge SB, Greene FL, et al. AJCC cancer staging manual. 8th ed. New York: Springer; 2017.

    Google Scholar 

  22. 22.

    Parmar MK, Torri V, Stewart L. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med. 1998;17(24):2815–34.

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Wells GA, Shea B, O’Connell D et al. The Newcastle–Ottawa Scale (NOS) for assessing the quality of non randomised studies in meta-analyses. 2019. Accessed October 2020.

  24. 24.

    Bittorf B, Merkel S, Matzel KE, Wein A, Dimmler A, Hohenberger W. Primary signet-ring cell carcinoma of the colorectum. Langenbecks Arch Surg. 2004;389(3):178–83.

    PubMed  Article  Google Scholar 

  25. 25.

    Chew MH, Yeo SAE, Ng ZP, et al. Critical analysis of mucin and signet ring cell as prognostic factors in an Asian population of 2,764 sporadic colorectal cancers. Int J Colorectal Dis. 2010;25(10):1221–9.

    PubMed  Article  Google Scholar 

  26. 26.

    Chen JS, Hsieh PS, Hung SY, et al. Clinical significance of signet ring cell rectal carcinoma. Int J Colorectal Dis. 2004;19(2):102–7.

    PubMed  Article  Google Scholar 

  27. 27.

    Chen JS, Hsieh PS, Chian JM, et al. Clinical outcome of signet ring cell carcinoma and mucinous adenocarcinoma of the colon. Chang Gung Med J. 2010;33(1):51–7.

    PubMed  Google Scholar 

  28. 28.

    Connelly JH, Robey-Cafferty SS, Cleary KR. Mucinous carcinomas of the colon and rectum. An analysis of 62 stage B and C lesions. Arch Pathol Lab Med. 1991;115(10):1022–5.

    CAS  PubMed  Google Scholar 

  29. 29.

    Enriquez JM, Díez M, Tobaruela E, et al. Clinical, histopathological, cytogenetic and prognostic differences between mucinous and nonmucinous colorectal adenocarcinomas. Rev Esp Enferm Dig. 1998;90(8):563–772.

    CAS  PubMed  Google Scholar 

  30. 30.

    Green JB, Timmcke AE, Mitchell WT, Hicks TC, Gathright JB Jr, Ray JE. Mucinous carcinoma–just another colon cancer? Dis Colon Rectum. 1993;36(1):49–54.

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    Hugen N, Verhoeven RH, Lemmens VE, et al. Colorectal signet-ring cell carcinoma: benefit from adjuvant chemotherapy but a poor prognostic factor. Int J Cancer. 2015;136(2):333–9.

    CAS  PubMed  Article  Google Scholar 

  32. 32.

    Hyngstrom JR, Hu CY, Xing Y, et al. Clinicopathology and outcomes for mucinous and signet ring colorectal adenocarcinoma: analysis from the National Cancer Data Base. Ann Surg Oncol. 2012;19(9):2814–21.

    PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    Kanemitsu Y, Kato T, Hirai T, et al. Survival after curative resection for mucinous adenocarcinoma of the colorectum. Dis Colon Rectum. 2003;46(2):160–7.

    PubMed  Article  Google Scholar 

  34. 34.

    Kang H, O’Connell JB, Maggard MA, Sack J, Ko CY. A 10-year outcomes evaluation of mucinous and signet-ring cell carcinoma of the colon and rectum. Dis Colon Rectum. 2005;48(6):1161–8.

    PubMed  Article  Google Scholar 

  35. 35.

    Lee HS, Soh JS, Lee S, et al. Clinical features and prognosis of resectable primary colorectal signet-ring cell carcinoma. Intest Res. 2015;13(4):332–8.

    PubMed  PubMed Central  Article  Google Scholar 

  36. 36.

    Leopoldo S, Lorena B, Cinzia A, et al. Two subtypes of mucinous adenocarcinoma of the colorectum: clinicopathological and genetic features. Ann Surg Oncol. 2008;15(5):1429–39.

    PubMed  Article  Google Scholar 

  37. 37.

    Min BS, Kim NK, Ko YT. Clinicopathological features of signet-ring cell carcinoma of the colon and rectum: a case-matched study. Hepatogastroenterology. 2009;56(93):984–8.

    PubMed  Google Scholar 

  38. 38.

    Minsky BD, Mies C, Rich TA, Recht A, Chaffey JT. Colloid carcinoma of the colon and rectum. Cancer. 1987;60(12):3103–12.

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    Mizushima T, Nomura M, Fujii M. Primary colorectal signet-ring cell carcinoma: clinicopathological features and postoperative survival. Surg Today. 2010;40(3):234–8.

    PubMed  Article  Google Scholar 

  40. 40.

    Nissan A, Guillem JG, Paty PB, Wong WD, Cohen AM. Signet-ring cell carcinoma of the colon and rectum: a matched control study. Dis Colon Rectum. 1999;42(9):1176–80.

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Psathakis D, Schiedeck TH, Krug F, Oovermann E, Kujath P, Bruch HP. Ordinary colorectal adenocarcinoma vs. primary colorectal signet-ring cell carcinoma: study matched for age, gender, grade, and stage. Dis Colon Rectum. 1999;42(12):1618–25.

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    Razenberg LGEM, van Gestel YRBM, Lemmens VEPP, de Wilt JHW, Creemers GJ, Hingh IHJT. The prognostic relevance of histological subtype in patients with peritoneal metastases from colorectal cancer: a nationwide population-based study. Clinic Colorectal Cancer. 2015;14(4):e13–9.

    Article  Google Scholar 

  43. 43.

    Secco GB, Fardelli R, Campora E, et al. Primary mucinous adenocarcinomas and signet-ring cell carcinomas of colon and rectum. Oncology. 1994;51(1):30–4.

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Song W, Wu S, He Y, et al. Clinicopathologic features and survival of patients with colorectal mucinous, signet-ring cell or non-mucinous adenocarcinoma: experience at an institution in southern China. Chin Med J. 2009;122(13):1486–91.

    PubMed  Google Scholar 

  45. 45.

    Song BR, Xiao CC, Wu ZK. Predictors of lymph node metastasis and prognosis in pT1 colorectal cancer patients with signet-ring cell and mucinous adenocarcinomas. Cell Physiol Biochem. 2017;41(5):1753–65.

    CAS  PubMed  Article  Google Scholar 

  46. 46.

    Umpleby HC, Ranson DL, Williamson RC. Peculiarities of mucinous colorectal carcinoma. Br J Surg. 1985;72(9):715–8.

    CAS  PubMed  Article  Google Scholar 

  47. 47.

    Wu X, Lin H, Shaotang L. Prognoses of different pathological subtypes of colorectal cancer at different stages: a population-based retrospective cohort study. BMC Gastroenterol. 2019;19(1):164.

    PubMed  PubMed Central  Article  Google Scholar 

  48. 48.

    Yamamoto S, Mochizuki H, Hase K, et al. Assessment of clinicopathologic features of colorectal mucinous adenocarcinoma. Am J Surg. 1993;166(3):257–61.

    CAS  PubMed  Article  Google Scholar 

  49. 49.

    Yun SO, Cho YB, Lee WY, et al. Clinical significance of signet-ring-cell colorectal cancer as a prognostic factor. Ann Coloproctol. 2017;33(6):232–8.

    PubMed  PubMed Central  Article  Google Scholar 

  50. 50.

    Luzietti E, Pellino G, Nikolaou S, et al. Comparison of guidelines for the management of rectal cancer. BJS Open. 2018;2(6):433–51.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. 51.

    Pellino G, Warren O, Mills S, Rasheed S, Tekkis PP, Kontovounisios C. Comparison of western and Asian guidelines concerning the management of colon cancer. Dis Colon Rectum. 2018;61(2):250–9.

    PubMed  Article  Google Scholar 

  52. 52.

    De Simone V, Ronchetti G, Franzè E, et al. Interleukin-21 sustains inflammatory signals that contribute to sporadic colon tumorigenesis. Oncotarget. 2015;6(12):9908–23.

    PubMed  PubMed Central  Article  Google Scholar 

  53. 53.

    Nigam AK, Savage FJ, Boulos PB, Stamp GW, Liu D, Pignatelli M. Loss of cell-cell and cell-matrix adhesion molecules in colorectal cancer. Br J Cancer. 1993;68(3):507–14.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. 54.

    Becker KF, Atkinson MJ, Reich U, et al. E-cadherin gene mutations provide clues to diffuse type gastric carcinomas. Cancer Res. 1994;54(14):3845–52.

    CAS  PubMed  Google Scholar 

  55. 55.

    Shino Y, Watanabe A, Yamada Y, et al. Clinicopathologic evaluation of immunohistochemical E-cadherin expression in human gastric carcinomas. Cancer. 1995;76(11):2193–201.

    CAS  PubMed  Article  Google Scholar 

  56. 56.

    Kim HC, Kim HJ, Kim JC. Reduced E-cadherin expression as a cause of distinctive signet-ring cell variant in colorectal carcinoma. J Korean Med Sci. 2002;17(1):23–8.

    PubMed  PubMed Central  Article  Google Scholar 

  57. 57.

    Céspedes MV, Larriba MJ, Pavón MA, et al. Site-dependent E-cadherin cleavage and nuclear translocation in a metastatic colorectal cancer model. Am J Pathol. 2010;177(4):2067–79.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  58. 58.

    Efstathiou JA, Liu D, Wheeler JM, et al. Mutated epithelial cadherin is associated with increased tumorigenicity and loss of adhesion and of responsiveness to the motogenic trefoil factor 2 in colon carcinoma cells. Proc Natl Acad Sci USA. 1999;96(5):2316.

    CAS  PubMed  Article  Google Scholar 

  59. 59.

    Efstathiou JA, Noda M, Rowan A, et al. Intestinal trefoil factor controls the expression of the adenomatous polyposis coli-catenin and the E-cadherin-catenin complexes in human colon carcinoma cells. Proc Natl Acad Sci USA. 1998;95(6):3122–317.

    CAS  PubMed  Article  Google Scholar 

  60. 60.

    Sugarbaker PH. Mucinous colorectal carcinoma. J Surg Oncol. 2001;77(4):282–3.

    CAS  PubMed  Article  Google Scholar 

  61. 61.

    Benedix F, Kube R, Meyer F, et al. Comparison of 17,641 patients with right- and left-sided colon cancer: differences in epidemiology, perioperative course, histology, and survival. Dis Colon Rectum. 2010;53(1):57–64.

    PubMed  Article  Google Scholar 

  62. 62.

    Benedix F, Meyer F, Kube Gastinger I, Lippert H. Right- and left-sided colonic cancer - different tumour entities. Zentralbl Chir. 2010;135(4):312–7.

    CAS  PubMed  Article  Google Scholar 

  63. 63.

    Meguid RA, Slidell MB, Wolfgang CL, Chang DC, Ahuja N. Is there a difference in survival between right- versus left-sided colon cancers? Ann Surg Oncol. 2008;15(9):2388–94.

    PubMed  PubMed Central  Article  Google Scholar 

  64. 64.

    Wray CM, Ziogas A, Hinojoas W, Le H, Stamos MJ, Zell JA. Tumor subsite location within the colon is prognostic for survival after colon cancer diagnosis. Dis Colon Rectum. 2009;52(8):1359–66.

    PubMed  Article  Google Scholar 

  65. 65.

    Collaborative EuroSurg. EuroSurg: a new European student-driven researchnetwork in surgery. Colorectal Dis. 2016;18(2):214–5.

    Article  Google Scholar 

  66. 66.

    Sica GS, Fiorani C, Stolfi C, Monteleone G, Candi E, Amelio I, Catani V, Sibio S, Divizia A, Tema G, Iaculli E, Gaspari AL. Peritoneal expression of Matrilysin helps identify early post-operative recurrence of colorectal cancer. Oncotarget. 2015;6(15):13402–15.

    Article  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Sibio S, Di Giorgio A, D’Ugo S, Palmieri G, Cinelli L, Formica V, Sensi B, Bagaglini G, Di Carlo S, Bellato V, Sica GS. Histotype influences emergency presentation and prognosis in colon cancer surgery. Langenbecks Arch Surg. 2019;404(7):841–51.

    Article  PubMed  Google Scholar 

  68. 68.

    Sica GS, Iaculli E, Biancone L, di Carlo S, Scaramuzzo R, Fiorani C, Gentileschi P, Gaspari AL. Comparative study of laparoscopic vs open cancer management. World J Gastroenterol. 2011;17(41):4602–6.

    Article  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Di Prete M, Baciorri F, Franceschilli M, Bagaglini G, Sica G, Doldo E, Palmieri G, Orlandi A. Adenosquamous carcinoma of the right colon with diffuse signet-ring mucinous component. Clin J Gastroenterol. 2020.

    Article  PubMed  Google Scholar 

Download references



Author information




MGF and GM: performed the collection, analysis and interpretation of the data and wrote the manuscript. VC and GP: contributed to the analysis of the data and critical revision of the manuscript. PT and CK: supervised the study and approved the final manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Michael G. Fadel.

Ethics declarations

Competing interests

The authors declare that they have no conflicts of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Table S1.

Additional file 1: Demographic details, tumour location and staging and quality scoring for the thirty studies included in the analysis. SC = signet-ring cell cancer, MC = mucinous cancer, AC = conventional adenocarcinoma; - = not available/not extractable, ‡ = includes mucinous adenocarcinoma, ⁞ = includes poorly differentiated conventional adenocarcinoma, ▲ = proximal colon/distal colon, • = colon/rectum; R = retrospective, PNR = prospective non-randomised; RC = right colon; TC = transverse colon; LC = left colon; R = rectum; AJCC = American Joint Committee on Cancer; NOS = Newcastle–Ottawa score (maximum score of nine). Figure S1. Meta-analysis and forest plot comparing (a) Age, (b) Gender, (c) Tumour diameter (cm) of signet-ring cell cancer and mucinous cancer to conventional adenocarcinoma. SC = signet-ring cell cancer, MC = mucinous cancer, AC = conventional adenocarcinoma, OR = odds ratio, CI = confidence interval.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Fadel, M.G., Malietzis, G., Constantinides, V. et al. Clinicopathological factors and survival outcomes of signet-ring cell and mucinous carcinoma versus adenocarcinoma of the colon and rectum: a systematic review and meta-analysis. Discov Onc 12, 5 (2021).

Download citation


  • Colorectal cancer
  • Signet-ring cell cancer
  • Mucinous cancer
  • Survival
  • Recurrence