International Journal of Colorectal Disease

, Volume 25, Issue 10, pp 1221–1229

Critical analysis of mucin and signet ring cell as prognostic factors in an Asian population of 2,764 sporadic colorectal cancers

Authors

  • Min-Hoe Chew
    • Department of Colorectal SurgerySingapore General Hospital
  • Shen-Ann Eugene Yeo
    • Department of Colorectal SurgerySingapore General Hospital
  • Zhi-Peng Ng
    • Yong Loo Lin School of MedicineNational University of Singapore
  • Kiat-Hon Lim
    • Department of PathologySingapore General Hospital
  • Poh-Koon Koh
    • Department of Colorectal SurgerySingapore General Hospital
  • Kheng-Hong Ng
    • Department of Colorectal SurgerySingapore General Hospital
    • Department of Colorectal SurgerySingapore General Hospital
Original Article

DOI: 10.1007/s00384-010-1033-3

Cite this article as:
Chew, M., Yeo, S.E., Ng, Z. et al. Int J Colorectal Dis (2010) 25: 1221. doi:10.1007/s00384-010-1033-3

Abstract

Introduction

Conflicting data on the clinicopathological characteristics as well as prognosis and survival of signet ring cell (SRC) and mucinous adenocarcinomas (MA) of the colorectum persist.

Methods

Consecutive patients (2,764) with sporadic colorectal cancer from 1999 to 2005 were evaluated. The clinicopathological characteristics of these patients were reviewed. Univariate analysis was performed, and survival curves were constructed using the Kaplan–Meier method. Multivariate analysis assessed independent prognostic factors.

Results

The incidence of MA and SRC is 6% and 1.1%, respectively. MA and SRC tend to occur in patients aged ≤50 years (SRC 33%, MA 22%, ordinary adenocarcinomas (OA) 14%, p = 0.001) and are more commonly right-sided (MA 30%, SRC 27%, OA 19%, p = 0.001) than OA. SRC tend to be poorly differentiated (SRC 77%, MA 26%, OA 6%, p < 0.0001) and have a higher risk of recurrence (SRC 40%, MA 26%, OA 6%, p < 0.0001). SRC and MA are more likely to have locally advanced lesions (T3/T4; SRC 100%, MA 90%, OA 83%, p = 0.002) and lymph node metastases (SRC 89%, MA 61%, OA 52%, p < 0.0001) and present with an advanced stage at diagnosis (stage III/IV SRC 94%, MA 67%, OA 56%, p < 0.0001). SRC has poorer 5-year cancer-specific survival (CSS; 11.1%, 95% confidence interval (CI) 0–22.9%) compared with MA (46.8%, 95% CI 38.6–55.0%) and OA (58.7%, 95% CI 56.5–60.9%, p < 0.001). In a multivariate analysis, SRC is an independent poor prognostic factor (HR 1.9, 95% CI 1.1–3.0) but MA is not.

Conclusion

SRC and MA demonstrate clinicopathologic characteristics suggestive of a different biology compared with OA. In our dataset, SRC has a significantly poorer CSS whereas survival rates for MA are similar to OA. These characteristics are similar in both Asian and Western studies reported. Asian reports however suggest a lower incidence of MA.

Keywords

Colorectal mucinous adenocarcinomaSignet ring cellSurvival

Introduction

In Singapore, the incidence of colorectal cancer (CRC) has risen steadily and is now the most common cancer in our country [1]. The presence of mucin and signet ring cells are recognized as subtypes of CRC by the World Health Organization (WHO) [2], and reviews have suggested that these subtypes may have different biologic behavior, thus conferring variable prognostic outcomes. Mucinous adenocarcinomas (MA) are characterized by abundant extracellular mucin with more than 50% of the tumor cell being composed of mucin. Signet ring cell adenocarcinomas (SRC), on the other hand, is another variant subtype that contains abundant intracytoplasmic mucin (>50% signet ring cells) displacing their nuclei to the periphery, thereby giving the characteristic appearance of a signet ring cell.

Literature on mucinous adenocarcinomas in the last 20 years remains non-conclusive, and conflicting results persist in clinicopathologic features such as age, site, and stage of disease at presentation as well as survival compared with ordinary adenocarcinomas (OA). The incidence of these mucinous lesions in Western populations ranges from 9.6% to 25.4% [310], while incidences in Asian populations range from 3.9% to 11.7% [1116]. Signet ring cell lesions were first described by Laufman and Saphir [17] and predominantly occur in the stomach. The overall incidence of SRC in the colon and rectum is thus rare, and their incidence ranges from 0.4% to 1.2% [5, 9, 1113]. The inconsistent differences in outcome and survival may in fact be due to a difference in biology of mucinous and SRC lesions in Asian populations vs Western populations. To examine this possibility, we investigated the outcomes of our own population and compared these together with outcomes previously reported.

Methods

Patient population

This study was approved by the Institutional Review Board of Singapore General Hospital. Clinicopathologic and follow-up data of 2,764 consecutive patients, who had surgical resection for primary colorectal cancer from January 1999 to December 2005, were retrieved from a prospectively recorded computer database. Patients who presented with recurrent cancer, inflammatory bowel disease, familial adenomatous polyposis, and positive family history suggestive of hereditary non-polyposis colorectal cancer by Amsterdam I & II criteria [18] were excluded.

Staging, pathologic analysis, and assessment of recurrence

The location of the index CRC was defined as a right-sided lesion if it arose proximal to the splenic flexure. Lesions at or distal to the splenic flexure were considered left-sided. We defined a synchronous CRC as the one found at the index operation for the CRC or diagnosed within 12 months after resection of the index CRC. In the case of synchronous lesions, the most advanced lesion was used for tumor stage classification comparisons. Stage of disease was evaluated by plain chest radiographs, ultrasound, and/or computed tomography (CT) of the abdomen and pelvis. Pathologic staging of disease was according to the American Joint Committee on Cancer (AJCC) Staging Manual, sixth edition [19], after surgical resection with review of the resected specimen and investigations of distant metastases. Pathologic examination and classification of mucinous carcinoma and signet ring adenocarcinoma were performed in accordance with the WHO criteria [2]. At least two tumor blocks were evaluated per specimen. Local recurrence was defined as the first clinical, radiologic, and/or pathologic evident tumor of the same histological type, within or contiguous to the previously treated tumor bed. Distant recurrence was defined as similar evidence of spread outside the primary tumor site at sites including but not limited to the liver, lungs, bone, brain, and para-aortic region. Mortality data and the cause of death were obtained from the Singapore Cancer Registry.

Statistical analysis

All statistical analyses were performed using SPSS statistical package (version 17.0; SPSS, Chicago, Illinois). For statistical significance analysis, Pearson’s chi-square test and Kruskal–Wallis test were performed as appropriate. In the analysis of disease-free survival (DFS), a patient was considered to have an event if there was local or systemic recurrence after the completion of primary treatment. DFS was calculated from the date of surgery till the date when a recurrence first occurred. Patients with no evidence of disease after treatment were censored at the date of last follow-up. Similarly, the cancer-specific survival (CSS) was computed from the date of surgery to the date when the patient was last known to be alive. The DFS and CSS curves were constructed using the Kaplan–Meier method, and comparisons between groups of clinical interest were made using the log-rank test. Finally, a multivariate Cox regression analysis was done to evaluate the independent prognostic factors, adjusting for possible confounding factors. All statistical tests were assessed at the conventional 0.05 level of significance.

Results

In the 2,764 patients with CRC evaluated, there were 1,512 (54.7%) males and 1,252 (45.3%) females with a median age of 66 years (interquartile range 22–99). Of the cohort evaluated, 90% was Chinese, reflecting the predominantly Chinese population in our country. Subgroup analysis revealed 167 patients (6.0%) with mucinous tumors, 30 (1.1%) with signet ring cell tumors, and 2,567 (92.9%) with ordinary adenocarcinomas. Comparative analysis was performed between the three subgroups (Table 1). Significant differences were noted in median age of presentation between OA, MA, and SRC (OA 66 years, MA 62 years, SRC 63.5 years, p = 0.03). In addition, a higher proportion of patients with SRC were noted to present ≤50 years old compared with MA and OA (SRC 33% vs MA 22% and OA 14%, p = 0.0001). MA and SRC were also noted to have a higher incidence of right-sided lesions (MA 30%, SRC 27% vs OA 19%, p = 0.001) although lesions were still predominantly located on the left side. There was however no difference in patient demographics such as gender or ethnicity, CEA value, or location of the tumor.
Table 1

Comparison of pathologic and prognostic data

Factor

Ordinary adenocarcinoma (%; n = 2,567)

Mucinous adenocarcinoma (%; n = 167)

Signet ring cell (%; n = 30)

P value

Gender

Male

1,166 (45)

78 (47)

8 (27)

0.113 (NS)

Female

1,401 (55)

89 (53)

22 (73)

Ethnic group

Chinese

2,341 (91)

149 (89)

26 (87)

0.685 (NS)

Non-Chinese

226 (9)

18 (11)

4 (13)

Age (years)

Median (range)

66.0 (18–99)

62.0 (25–94)

63.5 (28–90)

0.03

≤50

346 (14)

34 (20)

10 (33)

0.001

>51

2,221 (86)

133 (80)

20 (67)

CEA (ng/ml)

Mediana

4.4

5.7

3.7

0.725 (NS)

≤5

1,334 (55)

72 (47)

16 (55)

0.230 (NS)

>5

1,114 (45)

80 (53)

13 (45)

Site of lesion

Left

2,084 (81)

116 (70)

22 (73)

0.001

Right

483 (19)

51 (30)

8 (27)

Colon

1,678 (65)

114 (68)

22 (73)

0.501 (NS)

Rectum

889 (35)

53 (32)

8 (27)

Tumor differentiation

Well

269 (11)

7 (4)

0

<0.001

Moderate

2,127 (83)

94 (56)

2 (7)

Poor

165 (6)

42 (26)

23 (77)

Not stated

6 (<1)

24 (14)

5 (16)

Perineural invasion

 

463 (18)

32 (19)

10 (33)

0.172 (NS)

Vascular emboli

 

587 (23)

33 (20)

18 (60)

<0.001

T stageb

T1/T2

446 (17)

16 (10)

0

0.002

T3/T4

2,113 (83)

150 (90)

28 (100)

N stagec

Node positive (N1/N2)

1,320 (52)

101 (61)

25 (89)

<0.001

Node negative

1,239 (48)

65 (39)

3 (11)

M stage

0

2,047 (80)

122 (73)

17 (57)

0.009

1

520 (20)

45 (27)

13 (43)

AJCC stage

I

346 (13)

8 (5)

0

<0.001

II

795 (31)

47 (28)

2 (6)

III

911 (36)

68 (41)

14 (47)

IV

515 (20)

44 (26)

14 (47)

Values in parentheses are in percentages unless otherwise stated

aMissing data 135

b11 cases, no resection performed

c11 cases, no resection performed

Histological variables reviewed (Table 1) suggest that SRC were more likely to have poorly differentiated lesions (77%) compared with MA (26%) and OA (6%, p < 0.001). Moreover, SRC were more likely to have vascular emboli (SRC 60%, MA 20%, OA 23%, p < 0.001) and locally advanced lesions (T3/T4; SRC 100%, MA 90%, OA 83%, p = 0.002), have lymph node metastasis (SRC 89%, MA 61%, OA 52%, p < 0.001), have metastases on presentation (SRC 43%, MA 27%, OA 20%, p = 0.009), and be diagnosed with later stage lesions (stage III/IV 94% vs MA 67% and OA 56%, p < 0.001).

The site of recurrences after a curative–intent resection as well as type of metastasis on presentation is listed in Table 2. SRC was noted to have a significantly higher risk of recurrence (40%) compared with MA (28%) and OA (23%, p = 0.012). There was however no differences in the type of recurrence (locoregional vs systemic, p = 0.22). The most common pattern of metastasis in SRC was the peritoneum/ovaries (50%) followed by lung (22%). MA lesions also favored peritoneal/ovarian dissemination (46%) but were followed by liver metastasis (25%). OA lesions however were more likely to involve the liver (50%) and less likely to involve the peritoneum/ovaries (12%). The predilection for different sites of metastasis was noted to be statistically significant (p < 0.001).
Table 2

Comparison of recurrence and metastatic data

Factor

Ordinary adenocarcinoma (%; n = 2,567)

Mucinous adenocarcinoma (%; n = 167)

Signet ring cell (%; n = 30)

P value

Recurrence (n = 613)

Yes

555 (22)

46 (28)

12 (40)

0.012

No

2,012 (78)

121 (73)

18 (60)

Locoregional

85 (15)

11 (24)

3 (25)

0.220

Distant

470 (85)

35 (76)

9 (75)

Site of metastasis (n = 579)

Total

n = 521

n = 44

n = 14

<0.001

Liver

265 (50)

11 (25)

1 (7)

Lungs

39 (8)

4 (9)

3 (22)

Peritoneum, including ovary

60 (12)

20 (46)

7 (50)

Others

17 (3)

1 (2)

1 (7)

Diffused metastasis

140 (27)

8 (18)

2 (14)

Values in parentheses are in percentages unless otherwise stated

On follow-up, 7% of the patients (n = 205) died from non-cancer related causes and were excluded from survival analysis. Of the cases, 3% (n = 80) were lost to follow-up and were also excluded from analysis. With a median follow-up of 48 months (range 1–129 months), the median 5-year CSS is 57.4% (95% confidence interval (CI) 55.4–59.4%). In our cohort, SRC had significantly poorer CSS 11.1% (95% CI 0–22.9%) compared with both OA and MA (p < 0.001, Fig. 1). MA patients had shorter median 5-year CSS of 46.8% (95% CI 38.6–55.0%) compared to OA CSS of 58.7% (95% CI 56.5–60.9%, p = 0.012). There were no statistical differences found in comparisons of DFS (Fig. 2). When we analyzed the survival of MA stage for stage, there was no difference in stage-specific survival between MA and OA (p = 0.609). To adjust the curves for any other factors that might have influenced overall survival of the cohort, we used the Cox proportional hazards model in a forward-stepwise manner to analyze covariates of age, gender, ethnicity, tumor location, tumor grade, histological subtype, T-stage, N-stage, perineural invasion, vascular emboli, and stage of disease. From our analysis, a higher age group of >51 years, poorly differentiated tumor grade, high tumor stage (T3/T4), nodal disease, advanced stage of disease, and presence of vascular emboli were all significant factors that worsened survival (Table 3). In addition, signet ring cell lesions were found to significantly affect survival (hazard ratio 1.9, 95% CI 1.1–3.0, p = 0.015), but MA was noted not to influence survival (p = 0.89).
https://static-content.springer.com/image/art%3A10.1007%2Fs00384-010-1033-3/MediaObjects/384_2010_1033_Fig1_HTML.gif
Fig. 1

Cancer-specific survival according to histological subtype comparing ordinary, mucinous, and signet ring cell carcinomas. P < 0.0001

https://static-content.springer.com/image/art%3A10.1007%2Fs00384-010-1033-3/MediaObjects/384_2010_1033_Fig2_HTML.gif
Fig. 2

Disease-free survival according to histological subtype comparing ordinary adenocarcinoma vs mucinous adenocarcinoma. P = 0.356

Table 3

Multivariate analysis of patient and tumor factors influencing cancer-specific survival

Variable

Cancer-specific survival

Hazard ratio (95% confidence interval)

P value

Age

≤ 50

1.0

0.03

>51

1.2 (1.0–1.5)

Tumor grade

Well

1.0

 

Moderate

1.2 (0.3–0.9)

0.31

Poor

2.2 (0.2–1.1)

<0.0001

Histological subtype

Adenocarcinoma

1.0

 

Mucinous

1.0 (0.7–1.3)

0.89

Signet ring cell

1.9 (1.1–3.0)

0.015

Vascular emboli

No

1.0

<0.001

Yes

1.6 (1.4–1.9)

T stage

T1/T2

1.0

0.001

T3/T4

2.1 (1.4–3.2)

N stage

N0

1

0.001

N1/N2

1.6 (1.2–2.1)

AJCC stage

I

1

 

II

1.3 (0.7–2.4)

0.426

III

1.7 (0.8-3.2)

0.128

IV

8.8 (4.6–16.9)

<0.001

Discussion

Both MA and SRC are well-defined histopathologic entities. SRC of both the colon and rectum, although rare, appear to have adverse prognostic significance [5, 913, 2025]. Conflicting results however are found in the published literature regarding the relationship between mucinous colorectal cancers and survival. The difficulty in the interpretation and lack of consensus may be a result of the variety of published data ranging from matched control studies, cohort studies, or epidemiological reviews. In addition, there could be a distinct biological behavior between Asian and Western populations. This current study reviewed data of patients treated in a single Asian institution, and comparison was performed against published reports. Only reviews which adopted similar methodologies to this current study were used for comparison. Matched control studies which did not include the entire cohort of CRC patients managed in the time frame were thus excluded from comparison as this did not give a true indication of proportions. In addition, only reviews within the last 20 years were used to allow for uniformity in disease staging as well as pathological analysis of MA and SRC.

In our study, SRC accounted for 1.1% of our total of 2,764 cases, a finding compatible with the incidence of 0.4–1.2% described in the literature [5, 9, 1113]. For MA, however, our reported 6% proportion is similar to Asian data of 3.9–11.7% [1116] but lower compared to the reported Western data of 9.6–25.4% [310] (Table 4). We noted no statistical differences related to gender comparing SRC, MA, and OA in our study, and this was similar to the literature reported [316]. Interpretation of age at presentation, however, was difficult due to the different methods of description in the various studies. Patient with MA and SRC in our study were younger compared with OA, and a higher proportion of those with MA and SRC were ≤50 years old which is similar to the clinical demographics reported (Table 5) [3, 58, 1016]. We noted a higher propensity for MA and SRC located in the right side compared with OA. This was also noted in the majority of the literature in both Asian [12, 15, 16] and Western reports [68, 21, 23] (Table 6). There were few reports which noted a higher incidence of MA lesions in the rectum [5, 11], but the majority similar to ours did not identify this relationship [6, 8, 10, 13]. SRC lesions similarly did not have a higher predisposition for being located in the rectum [5, 11, 2023].
Table 4

Proportions of SRC vs MA vs OA

Source

Year

Region

Country

No. of patients

Proportion (%)

SRC

MA

OA

Song et al. [11]

2009

Asia

China

2,006

1.2

5.4

93.4

Lee et al. [12]

2006

Korea

5,022

0.7

5.8

93.5

Du et al. [13]

2004

Singapore

15,762

0.4

3.9

95.6

Kanemitsu et al. [14]

2003

Japan

2,294

NR

4.2

95.0

Nozoe et al. [15]

2000

Japan

283

NR

6.3

93.6

Wu et al. [16]

1996

Taiwan

454

NR

11.7

88.3

Xie et al. [3]

2009

USA/Europe

Canada

1,460

NR

12.0

88.0

Maksimović [4]

2007

Bosnia

406

NR

9.6

90.6

Kang et al. [5]

2005

USA

164,628

0.9

10.3

88.8

Papadopoulos et al. [6]

2004

Greece

1,160

NR

25.4

74.6

Adell et al. [7]

2002

Spain

205

NR

17.6

82.0

Consorti et al. [8]

2000

Italy

248

NR

11.7

88.3

Secco et al. [9]

1994

Italy

352

1.1

11.1

87.8

Green et al. [10]

1993

USA

395

NR

13.2

86.8

NR not reported

Table 5

Comparison of age between SRC vs MA vs OA

Source

Year

Region

Age (years)

SRC

MA

OA

P value

Song et al. [11]

2009

Asia

40.4 ± 12.8

52.2 ± 16.3

58.73 ± 13.6

<0.001

Lee et al. [12]

2006

48

52.5

NR

0.03

Du et al. [13], colon

2004

NR

24.6% <50 years

14.8% <50 years

N/A

Du et al. [13], rectum

2004

NR

24.8% <50 years

15.5% <50 years

N/A

Kanemitsu et al. [14]

2003

NR

54.7 ± 13.2

59.1 ± 11.8

0.0003

Nozoe et al. [15]

2000

NR

62.2

66.0

NS

Wu et al. [16]

1996

NR

24.7% <40 years

8% <40 years

<0.05

Xie et al. [3]

2009

USA/Europe

NR

6.1% <50 years

9.6% <50 years

NS

Kang et al. [5]

2005

65.9 ± 16.6

70.3 ± 13.2

70.3 ± 12.7

NR

Papadopoulos et al. [6]

2004

NR

64.6

65.5

NR

Adell et al. [7]

2002

NR

19% <50 years

4% <50 years

0.001

Consorti et al. [8]

2000

NR

61.4 ± 11.1

64.7 ± 10.5

NS

Green et al. [10]

1993

NR

67.1

65.6

NR

NR not reported

Table 6

Comparison of location of tumor between MA vs OA

Source

Year

Region

Location of tumors

MA is more common on R colon (P value)

MA is more common in colon than rectum (P value)

Song et al. [11]

2009

Asia

NR

Yes (<0.001)

Kanemitsu et al. [14]

2003

NR

No (NS)

Nozoe et al. [15]

2000

Yes (<0.05)

NR

Wu et al. [16]

1996

Yes (<0.005)

No (NS)

Kang et al. [5]

2005

USA/Europe

NR

Yes (<0.0001)

Papadopoulos et al. [6]

2004

Yes (0.001)

No (0.6)

Adell et al. [7]

2002

Yes (<0.001)

NR

Consorti et al. [8]

2000

Yes (<0.02)

No (NS)

Green et al. [10]

1993

No (NS)

No (NS)

NR not reported

NS not significant

Furthermore, similar to majority of the reports, we found that both SRC and MA were more likely to be associated with advanced T-stage lesions, lymph node involvement, and thus an advanced stage of disease [47, 911, 1416]. We also demonstrated a higher pattern of peritoneal and/or ovarian metastasis in our population for both SRC and MA. This is significantly different compared to OA which had a higher incidence of liver metastasis which is comparable to findings reported in both Asian and Western data [1115, 20, 23] (Table 7). This higher inclination to peritoneal seeding and infiltration into lymphatics and nodes has been attributed to the mucopolysaccharide nature of the colloid-type carcinoma which prevents discrimination of host immunocytes for tumor cells and thus allowing easier invasion into peri-intestinal tissue and subsequent lymphatics [26].
Table 7

Comparison of advanced nature of lesion and 5-year survival of MA vs OA

Source

Year

Region

MA presents with more advanced lesions (P value)

5 year survival (%)

MA is an independent poor prognostic factor (P value)

MA

OA

P value

Song et al. [11]

2009

Asia

Yes (<0.01)

62

70

<0.01

Yes (<0.01)

Du et al. [13]

2004

Yes

43

50

NR

No (NS)

Kanemitsu et al. [14]

2003

Yes (<0.0001)

41

62.4

<0.0002

Yes (0.0008)

Nozoe et al. [15]

2000

Yes (<0.05)

30.3

60.8

<0.05

NR

Wu et al. [16]

1996

Yes (<0.005)

60

80

<0.005

No (NS)

Xie et al. [3]

2009

USA/Europe

No (NS)

52

53

NS

NR

Maksimović [4]

2007

Yes (0.0001)

39

60.6

0.0002

Yes (NR)

Kang et al. [5]

2005

Yes (<0.0001)

58.1

62.9

<0.0001

No (NS)

Papadopoulos et al. [6]

2004

Yes (0.03)

51.6

65.5

0.05

NR

Adell et al. [7]

2002

Yes (<0.05)

NR

NR

NR

NR

Consorti et al. [8]

2000

No (NS)

NR

NR

NR

No (NS)

Secco et al. [9]

1994

Yes

17

34

<0.05

NR

Green et al. [10], colon

1993

No (NS)

60

48

0.004

NR

NR not reported

NS not significant

We have noticed in our study that overall survival of SRC is dismal with significantly poorer 5-year cancer-specific survival of 11.1% compared with MA (48.8%) and OA (58.7%). The poor clinical prognosis for SRC in our series may be due largely to the great proportion of advanced tumor stage (94% stages III and IV) and higher rate of metastasis (47%) as well as a higher recurrence rate (40%). This aggressive tumor behavior has been hypothesized to be due to a higher incidence of lymphovascular invasion [12], which we observed in our series as well, although the small number of patients with SRC and under-representation of stages I and II patients limits the interpretation in our population. Other hypothesis postulated is the decreased expression of cell adhesion molecules (E-cadherin, β-catenin) with a resultant disruption of adhesion complex and thus increased risk of invasion and metastasis [27]. Nonetheless, similar poor survival rates have been reported worldwide [12, 2025] at 9.4–25.5%, and as such, adjuvant chemotherapy has been recommended in this subgroup of patients.

The 5-year survival rates for MA, however, are still conflicting. Our results are similar to an epidemiological study previously performed in our country over the period 1968 to 1997 [13], whereby MA had similar survival to OA in the colon. It was noted, however, that survival was worse in rectal cancers. In our study, while the 5-year survival for MA was significantly lower (48.8%) as compared to OA (58.7%), the prognosis of patients with MA compared with OA patients was similar when multivariate analysis was adjusted for age, site (colon vs rectum and right vs left), grade, and stage differences. Similar observations were noted in both Asian and Western literature [5, 8, 16] but were contradicted in others [4, 11, 14] where poorer prognosis was observed. Kang et al., who have one of the largest studies to date, reviewed 146,115 patients from the Surveillance Epidemiology and End Results (SEER) National Cancer Registry between 1991 and 2000 [5]. They noted that while MA had significantly worse overall 5-year survival, no significant difference was noted when compared stage-for-stage. As such, the worse survival was likely due to mucinous tumors presenting with advanced stage disease and not a negative predictor of mortality which was similar in our analysis.

The current literature thus suggests that MA and SRC are distinct biological entities and are independent from the outcomes of ordinary colorectal adenocarcinomas. Molecular biology analysis has suggested that the expression of p53 proteins in MA is lower (19–49%) as compared with OA (50–75%) [2830], as well as a higher frequency of p16 expression (78%) [30]. Loss of p53 and p16 tumor suppressor genes that regulate cell proliferation has been demonstrated to lead to uncontrolled tissue growth and subsequent more aggressive tumors. These molecular markers may provide future prognostic predictors in patients with MA.

Conclusion

Despite the limitations of a retrospective review as ours, our dataset confirms the higher incidence of MA and SRC in the younger age group as well as predilection for being located in the right side of the colon. Similarly, MA and SRC lesions are more likely to present with advanced disease as well as with peritoneal metastasis. However, in our review of the literature, apart from an observed lower incidence of mucinous lesions reported in Asian countries, there are no geographical differences apparent as these clinicodemographic factors are similarly reported in both Asian and Western data. The survival data of SRC are noted to be markedly inferior compared to OA and MA although the collective data worldwide is small. For MA, the prognosis and impact on survival are less clear and remain controversial, but we have noted that mucin is not a poor prognostic factor. Further reviews are required to provide stronger evidence as to the distinct management of MA lesions.

Acknowledgments

The authors would like to thank the following people in the preparation of the manuscript: (a) Singapore Polyposis Registry coordinator: Ms Loi TT, Carol, RN Msc (Healthcare); (b) Senior Biostatistician, Department of Clinical Research Singapore General Hospital: Ms Fook-Chong MC, Stephanie, BSc MSc(McGill) CStat; (c) Rest of the contributory authors to the manuscript: Dr Ming-Hian Kam, Dr Hak-Mien Quah, Dr Jit-Fong Lim, Dr Kok-Sun Ho, and A/Prof Choong-Leong Tang.

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© Springer-Verlag 2010