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BMC Cancer

, 19:1071 | Cite as

Adenocarcinoma with mixed subtypes is a rare but aggressive histologic subtype in colorectal cancer

  • Hui Sheng
  • Xiaoli Wei
  • Minjie Mao
  • Jincan He
  • Tianqi Luo
  • Shilin Lu
  • Liye Zhou
  • Zhixin HuangEmail author
  • Anli YangEmail author
Open Access
Research article
  • 138 Downloads
Part of the following topical collections:
  1. Survivorship, cancer burden and supportive therapy

Abstract

Background

Although numerous studies have investigated the clinicopathologic and prognostic relevance of mucinous adenocarcinoma (MAC) and signet-ring cell carcinoma (SRCC) compared with classic adenocarcinoma (CA), little is known about the prognosis of adenocarcinoma with mixed subtypes (AM) and the differences among these four subtypes.

Methods

The statistics of colorectal cancer registered in the Surveillance, Epidemiology and End Results (SEER) database were retrieved and analyzed. We also compared the clinicopathologic and prognostic relevance between CA, SRCC, MAC, and AM.

Results

The frequencies of these four subtypes were 69.9% (CA, n = 15,812), 25.1% (MAC, n = 5689), 3.6% (SRCC, n = 814) and 1.4% (AM, n = 321), respectively. All of MAC, SRCC, and AM were significantly related with aggressive features. Only SRCC and AM were identified as independent poor prognostic markers for overall survival by multivariate analysis. The aggressiveness of AM was between MAC and SRCC according to the clinicopathologic associations. The prognosis of AM was significantly worse than MAC but comparable with SRCC.

Conclusions

We confirmed the clinicopathologic relevance with aggressive features of MAC and SRCC, as well as poor prognostic relevance of SRCC by analyzing a large study population data set. Furthermore, we identified AM as a rare but aggressive histologic subtype in colorectal cancer, to which particular attention should be given in clinical practice.

Keywords

Colorectal cancer Histologic subtypes Prognosis 

Abbreviations

AJCC

American Joint Committee on Cancer

ALK

Anaplastic lymphoma kinase

AM

Adenocarcinoma with mixed subtypes

CA

Classic adenocarcinoma

CEA

Carcinoembryonic antigen

CRC

Colorectal cancer

CRM

Circumferential resection margin

EGFR

Epidermal growth factor receptor

ICD-O-3

3rd edition of the International Classification of Diseases for Oncology

MAC

Mucinous adenocarcinoma

MSI-H

High microsatellite instability

NCCN

National Comprehensive Cancer Network

SEER

Surveillance, Epidemiology and End Results

SRCC

Signet-ring cell carcinoma

TNM

Tumor-node-metastasis

Background

Colorectal cancer (CRC) is the third most common malignancy in the US and the fifth in China [1, 2]. Early-stage CRC is curable by radical surgery. However, cancer recurrence and distant metastasis occur frequently after curative treatment, especially for more advanced stage CRC patients, which leads to poor outcomes [3, 4, 5, 6, 7, 8]. Thus, the identification of prognostic markers is of great importance in patient management and decision making.

American Joint Committee on Cancer / Tumor-node-metastasis (AJCC/TNM) staging system is well accepted as the most efficient prognostic factor in CRC [9] However, heterogeneity of prognosis exists even among patients at the same TNM stage. Thus, it underlines the importance of incorporating multiple prognostic markers, such as tumor differentiation degree [10, 11, 12, 13], some genetic markers [14, 15], and several postoperative pathologic features [16, 17, 18].

The histologic subtypes of CRC have also been demonstrated with prognostic relevance. Most CRCs are adenocarcinomas, including three well-studied major subtypes: classical adenocarcinoma (CA), mucinous adenocarcinoma (MAC), and signet-ring cell carcinoma (SRCC) [19]. MAC was primarily identified as a negative prognostic factor [20]. However, subsequent studies have proved that the prognostic difference between SRCC and MAC is not independently significant [19, 21, 22, 23]. Furthermore, in stage II CRC, MAC is associated with high microsatellite instability (MSI-H) [24, 25], a marker of superior prognosis and no benefit from adjuvant 5-Fu chemotherapy. Thus in the 3rd version of 2012 National Comprehensive Cancer Network (NCCN) guidelines for colorectal cancer, a poor differentiation with MSI-H was removed from the list of high-risk factors for stage II CRC. SRCC has been widely recognized as a marker of aggressive tumors with inferior prognosis [26, 27]. While there may still be other histologic subtypes with distinct clinicopathologic and prognosis relevance apart from CA that need special concern in clinical management.

We conducted this study with Surveillance, Epidemiology, and End Results Program (SEER) database for CRC registered during 2010–2012 to investigate the frequency distribution of histologic subtypes in CRC, and explore other possible histologic subtypes with distinct clinical significance compared with CA. Additionally, we sought to describe the impact of histological subtypes on prognosis.

Methods

The SEER database and cases selection

As the largest publicly available cancer dataset worldwide, the SEER database collects cancer information including morbidity, mortality, and disease status of patients with malignancies across the US. Unified and standardized tumor information in the database is updated regularly. Here we focused on colorectal adenocarcinomas, coded by the 3rd edition of the International Classification of Diseases for Oncology (ICD-O-3) as C18.0, C18.2 - C18.7, C19.9 and C20.9 for topography and 8140–8147, 8210–8211, 8220–8221, 8255, 8260–8263, 8480–8481, 8490 and 8574 for histology. In addition, the present study only covered patients with records of histologic codes (ICD-O-3), the 7thAJCC/TNM classification and follow-up information. Patients with other tumors as primary tumor were excluded.

Histologic subtypes

The ICD-O-3 (updated in 2000) was used in tumor or cancer registries for coding the topography and histology. We summarized the histologic codes and the relevant corresponding descriptions in Additional file 1: Table S1. A further categorization was conducted to categorize patients into four histologic subtypes, including CA (Code 8141–8147, 8210–8211, 8220–8221, 8260–8263), MAC (Code 8480–8481), SRCC (Code 8490), and AM (Code 8255). Adenocarcinoma with neuroendocrine differentiation (Code 8574) was not included in the final analysis because of the difficulty in categorization and limited sample size.

Statistical analysis

All the analyses were conducted with SPSS for Windows V.13.0. (SPSS Inc., Chicago, IL, USA). The frequency distribution of histologic subtypes was calculated with descriptive method. The comparisons of clinicopathologic characteristics between CA and the other histologic subtypes including MAC, SRCC, and AM were performed with chi-square test or Kruskal-Wallis H test. CRC-specific overall survival (OS) was the interval from the date of CRC diagnosis to the date of last follow-up or cause-specific death. Patients alive at the last follow-up or died of other causes were classified as censored cases. Univariate and multivariate analyses were performed for prognostic differences between histologic subtypes. Survival curves were plotted and compared using the Kaplan-Meier method and the log-rank test. A two-tailed P value < 0.05 was considered statistically significant. Variables with a P value < 0.05 in univariate analyses were included in multivariate analyses. We adopted “forward: conditional” method for multivariate analyses. With this method, only variables with a significant P value would be included for the estimation of hazard ratio (HR) 95% confidence interval (95% CI) in the Cox proportional hazards model.

Results

The frequency distribution of histologic subtypes in CRC

71,810 CRC patients were included in this study from SEER registers during 2010–2012. According to the ICD-O-3 codes and description, 49,131 (68.4%) cases were classified as adenocarcinoma NOS, not otherwise specified. The rest 22,679 (31.6%) patients were analyzed for the frequency distribution of histologic subtypes in CRC (Additional file 1: Table S1). Except for adenocarcinoma with neuroendocrine differentiation (Code 8574), which is a distinct subtype but accounts for a very small population, all the others (n = 22,636, 99.8%) were included and categorized into four histologic subtypes: CA, MAC, SRCC, and AM. The most common subtype was CA, with 15,812 cases accounting for 69.9%. The numbers and frequencies of MAC, SRCC, and AM were 5689 (25.1%), 814 (3.6%), and 321 (1.4%), respectively (Table 1). Both SRCC and AM are relatively rare with their frequencies lower than 5%.
Table 1

The frequency distribution of classical adenocarcinoma, mucinous adenocarcinoma, signet-ring cell carcinoma and adenocarcinoma with mixed subtypes in colorectal cancer

Histologic subtype

Number (%)

Classical adenocarcinoma

15,812 (69.9)

Mucinous adenocarcinoma

5689 (25.1)

Signet-ring cell carcinoma

814 (3.6)

Adenocarcinoma with mixed subtypes

321 (1.4)

Comparisons of clinicopathologic differences between histologic subtypes

MAC was more common in female (P <  0.001) and older patients (P <  0.001) compared with CA. There was no significant difference in the distribution of gender and sex between CA and SRCC or AM. Compared with CA, all the other three subtypes were found less common in rectal cancer (all P <  0.001). In addition, MAC, SRCC, and AM, were significantly associated with some features of aggressiveness, including poor tumor differentiation, large size of primary tumors, high level of carcinoembryonic antigen (CEA), advanced T stage and N stage, distant metastasis, high positive rates of circumferential resection margin (CRM) involvement, and perineural invasion, as well as frequent presence of tumor deposits (all P <  0.001, Table 2, P1 using “CA” as the reference).
Table 2

Comparisons of the clinicopathologic features between classical adenocarcinoma and other histologic types, including mucinous adenocarcinoma, signet-ring cell carcinoma and adenocarcinoma with mixed subtypes

Characteristics (N)

Classical adenocarcinoma N (%)

Mucinous adenocarcinoma N (%)

P1a

P2a

Signet-ring cell carcinoma N (%)

P1a

P2a

Adenocarcinoma with mixed subtypes N (%)

P1a

Gender

  

<  0.001

0.05

 

0.11

0.33

 

0.89

Male

8511 (53.8)

2759 (48.5)

  

415 (51.0)

  

175 (54.2)

 

Female

7301 (46.2)

2930 (51.5)

  

399 (49.0)

  

147 (45.8)

 

Age (yrs, median: 66)

  

<  0.001

0.59

 

0.53

0.06

 

0.07

≤ 66

8894 (56.2)

2818 (49.5)

  

467 (57.4)

  

164 (54.5)

 

>  66

6918 (43.8)

2871 (50.5)

  

347 (42.6)

  

157 (45.5)

 

Tumor location

  

<  0.001

0.29

 

<  0.001

0.76

 

<  0.001

Colon

12,198 (77.1)

5055 (88.9)

  

713 (87.6)

  

279 (86.9)

 

Rectum

3614 (22.9)

634 (11.1)

  

101 (12.4)

  

42 (13.1)

 

Grade

  

<  0.001

<  0.001

 

<  0.001

<  0.001

 

<  0.001

Well differentiated

2308 (17.6)

705 (13.4)

  

8 (1.1)

  

4 (1.4)

 

Moderately differentiated

9491 (72.6)

3344 (63.7)

  

58 (8.0)

  

53 (18.0)

 

Poorly differentiated or undifferentiated

1278 (9.8)

1199 (22.8)

  

656 (90.9

  

237 (80.6)

 

Primary tumor size (cm)

  

<  0.001

0.76

 

<  0.001

0.48

 

<  0.001

≤ 4

7754 (71.7)

1628 (31.3)

  

223 (32.8)

  

89 (30.5)

 

>  4

3148 (28.9)

3568 (68.7)

  

457 (67.2)

  

203 (69.5)

 

CEA

  

<  0.001

0.06

 

<  0.001

0.52

 

<  0.001

Normal

4804 (69.9)

1558 (46.4)

  

217 (42.4)

  

76 (39.2)

 

Borderline

25 (0.4)

29 (0.9)

  

3 (0.6)

  

3 (1.5)

 

Elevated

2043 (29.7)

1770 (52.7)

  

292 (57.0)

  

115 (59.3)

 

T category

  

<  0.001

<  0.001

 

<  0.001

0.29

 

<  0.001

Tis

1988 (12.6)

21 (0.4)

  

4 (0.5)

  

0 (0.0)

 

T1

7516 (47.5)

309 (5.4)

  

45 (5.5)

  

11 (3.4)

 

T2

2168 (13.7)

547 (9.6)

  

34 (4.2)

  

21 (6.5)

 

T3

3316 (21.0)

3120 (55.0)

  

341 (42.0)

  

150 (46.7)

 

T4

822 (5.2)

1680 (29.6)

  

388 (47.8)

  

139 (43.3)

 

N category

  

<  0.001

<  0.001

 

<  0.001

0.27

 

<  0.001

N0

12,776 (80.8)

3130 (55.0)

  

251 (30.8)

  

110 (34.3)

 

N1

2244 (14.2)

1405 (24.7)

  

176 (21.6)

  

68 (21.2)

 

N2

792 (5.0)

1154 (20.3)

  

387 (47.5)

  

143 (44.5)

 

M category

  

<  0.001

0.002

 

<  0.001

0.01

 

<  0.001

M0

14,931 (94.4)

4505 (79.2)

  

519 (63.8)

  

231 (72.0)

 

M1

881 (5.6)

1184 (20.8)

  

295 (36.2)

  

90 (28.0)

 

CRM

  

<  0.001

<  0.001

 

<  0.001

0.60

 

<  0.001

Negative

5685 (85.7)

2163 (73.7)

  

220 (62.1)

  

101 (59.8)

 

Positive

950 (14.3)

770 (26.3)

  

134 (37.9)

  

68 (40.2)

 

Perineural invasion

  

<  0.001

<  0.001

 

<  0.001

0.003

 

<  0.001

Negative

12,234 (95.6)

3957 (89.7)

  

383 (70.8)

  

201 (80.7)

 

Positive

569 (4.4)

454 (10.3)

  

158 (29.2)

  

48 (19.3)

 

Tumor deposits

  

<  0.001

<  0.001

 

<  0.001

0.21

 

<  0.001

Absent

12,369 (95.2)

4161 (84.1)

  

421 (67.5)

  

197 (71.6)

 

Present

622 (4.8)

786 (15.9)

  

203 (32.5)

  

78 (28.4)

 

Abbreviation: CEA carcinoembryonic antigen, CRM circumferential resection margin

a P1, comparisons using “classical adenocarcinoma” as the reference. P2, comparisons using “adenocarcinoma with mixed subtypes” as the reference

We further compared the clinicopathologic differences between AM and the other two relatively more aggressive histologic subtypes: MAC and SRCC. Compared with MAC, AM was found more frequently in males (P = 0.05). AM was also associated with aggressive tumor characteristics including poor differentiation (P <  0.001), more advanced T and N stage (P <  0.001), distant metastasis (P = 0.002), higher positive rates of CRM (P <  0.001), perineural invasion (P <  0.001), and frequent presence of tumor deposits (P <  0.001). As for the comparison between AM and SRCC, AM was associated with better differentiation (P <  0.001), distant metastasis (P <  0.001), and perineural invasion (P = 0.003). No differences were found in other clinicopathologic characteristics between AM and SRCC. Detailed information was shown in Table 2 (P2, using “MA” as the reference).

The prognostic value of histologic subtypes for CRC specific OS

We compared the 3-year CRC specific OS rates between histologic subtypes (Table 3) in the general population and subgroups stratified by TNM stage (0 + I/II/III/IV), tumor location (Colon / Rectum), sex (Male / Female) and age(≤ 66 / > 66). The 3-year OS rates was 90.3 ± 0.004%, 71.6 ± 0.01%, 38.0 ± 0.06% and 49.8 ± 0.06% for CA, MAC, SRCC, and AM, respectively. MAC, SRCC, and AM showed significantly poor survival rates compared with CA. And this difference sustained in most of the subgroups, except for certain TNM stage subgroups. For instance, in stage IV patients, MAC did not show a significant difference in the 3-year OS rate compared with CA. Additionally, there was no obvious difference in the 3-year OS rate when comparing SRCC and CA in stage 0 + I patients. So was when comparing AM and CA in stage II patients. Compared with AM, MAC showed significantly better 3-year OS in the general population as well as in most subgroups, while no prognostic differences were found between AM and SRCC (Table 3, P1 using “CA” as the reference, P2 using “MA” as the reference). The CRC-specific OS of the four subtypes estimated using the Kaplan-Meier method were shown in Fig. 1. When stratified by TNM stage, AM remained presenting significantly worse CRC-specific OS compared with CA in stage 0 + I, stage III, and stage IV groups (Additional file 2: Figure S1, P = 0.04, P <  0.001, P = 0,001), but not in stage II (Additional file 2: Figure S1, P = 0.43).
Table 3

Comparisons of the 3-year colorectal cancer specific overall survival rates between classical adenocarcinoma and other histologic types

Characteristics

Classical adenocarcinoma (mean ± SD)

Mucinous adenocarcinoma (mean ± SD)

P1a

P2a

Signet-ring cell carcinoma (mean ± SD)

P1a

P2a

Adenocarcinoma with mixed subtypes (mean ± SD)

P1a

All

90.3 ± 0.4%

71.6 ± 1.3%

<  0.001

<  0.001

38.0 ± 5.8%

<  0.001

0.29

49.8 ± 5.2%

<  0.001

TNM stage

 0 + I

96.3 ± 0.3%

91.0 ± 2.4%

<  0.001

0.32

94.3 ± 4.0%

0.21

0.53

85.9 ± 9.5%

0.03

 II

90.2 ± 1.1%

85.5 ± 2.3%

0.04

0.83

71.6 ± 6.1%

<  0.001

0.15

88.7 ± 5.5%

0.43

 III

84.1 ± 1.5%

72.0 ± 1.7%

<  0.001

<  0.001

41.4 ± 12.3%

<  0.001

0.51

41.7 ± 10.5%

<  0.001

 IV

35.2 ± 2.9%

36.1 ± 2.5%

0.99

<  0.001

9.4 ± 4.8%

<  0.001

0.78

19.5 ± 7.2%

0.001

Tumor location

 Colon

90.2 ± 0.5%

71.8 ± 1.4%

<  0.001

<  0.001

38.4 ± 6.6%

<  0.001

0.54

48.3 ± 5.8%

<  0.001

 Rectum

90.4 ± 0.8%

70.4 ± 3.1%

<  0.001

0.10

26.6 ± 12.5%

<  0.001

0.19

56.4 ± 11.9%

<  0.001

Sex

 Male

90.7 ± 0.5%

70.9 ± 2.2%

<  0.001

<  0.001

26.7 ± 11.5%

<  0.001

0.38

51.4 ± 5.2%

<  0.001

 Female

89.8 ± 0.6%

72.3 ± 1.3%

<  0.001

<  0.001

45.9 ± 3.8%

<  0.001

0.50

48.8 ± 8.8%

<  0.001

Age (yrs)

  ≤ 66

92.9 ± 0.5%

74.7 ± 1.5%

<  0.001

<  0.001

39.8 ± 4.5%

<  0.001

0.12

53.4 ± 6.3%

<  0.001

  > 66

86.9 ± 0.7%

68.6 ± 2.0%

<  0.001

<  0.001

39.1 ± 9.4%

<  0.001

0.99

47.8 ± 7.0%

<  0.001

Abbreviation: TNM tumor-node-metastasis

a P1, comparisons using “classical adenocarcinoma” as the reference. P2, comparisons using “adenocarcinoma with mixed subtypes” as the reference

Fig. 1

Comparisons of prognosis in histological subtypes plotted with the Kaplan-Meier method

We then conducted univariate and multivariate analysis to test the prognostic differences in CRC specific OS between histologic subtypes. By univariate analysis, besides histologic subtypes (P <  0.001), other significant prognostic factors including age (≤ 66 / > 66, P <  0.001), tumor location (Colon / Rectum, P <  0.001), grade (Well differentiated / Moderately differentiated / Poorly differentiated or undifferentiated, P <  0.001), TNM stage (0 + I/II/III/IV, P <  0.001), race (American Indian/Alaska Native / Asian or Pacific Islander / Black / White, P <  0.001), insurance status (Insured / Others, P <  0.001), marital status (Married / Widowed / Others, P <  0.001), CEA level (Normal / Borderline / Elevated, P <  0.001), CRM (Negative / Positive, P <  0.001), perineural invasion (Negative / Positive, P <  0.001) and tumor deposits (Absent / Present, P <  0.001) were identified. All the significant prognostic factors identified by univariate analysis were included for multivariate Cox regression analysis. Factors remained as independent prognostic factors included age (P <  0.001), grade (P = 0.001), TNM stage (P <  0.001), marital status (0.003), CEA (P <  0.001), CRM (P <  0.001), tumor deposits (P <  0.001), and histologic subtype (P <  0.001). After adjusting for confounding factors, MAC didn’t have a significantly different prognosis (P = 0.20, hazard ratio (HR) and 95% confidence interval (95% CI): 1.14 (0.93–1.39)), while the inferior prognosis of SRCC and AM remained significant (P <  0.001 and P = 0.003, HR and 95% CI: 1.88 (1.37–2.58) and 1.89 (1.25–2.85), respectively) compared with CA (Table 4). In addition, compared with AM, MAC had a significantly better prognosis (P = 0.01, HR and 95% CI: 0.60 (0.40–0.90)), while no survival difference was found between AM and SRCC (P = 0.98, HR and 95% CI: 0.99 (0.65–1.53)) (Table 4).
Table 4

Univariate and multivariate analysis for the colorectal-specific overall survival of histologic subtypes in colorectal cancer

Characteristics

Univariate analysis

Multivariate analysis

  
 

P value

HR

95% CI

P value

Sex

0.06

   

 Male

    

 Female

    

Age (yrs)

<  0.001

2.26

1.87–2.73

<  0.001

  ≤ 66

    

  > 66

    

Tumor location

<  0.001

   

 Colon

    

 Rectum

    

Grade

<  0.001

  

0.001

 Well differentiated

 

1

Reference

 

 Moderately differentiated

 

1.50

0.96–2.34

0.08

 Poorly differentiated or undifferentiated

 

2.06

1.30–3.28

0.002

TNM stage

<  0.001

  

<  0.001

 0 + I

 

1

Reference

 

 II

 

2.04

1.24–3.35

0.01

 III

 

5.12

3.23–8.09

<  0.001

 IV

 

15.39

9.55–24.79

<  0.001

Race

<  0.001

   

 American Indian/Alaska Native

    

 Asian or Pacific Islander

    

 Black

    

 White

    

Insurance status

<  0.001

   

 Insured

    

 Others

    

Marital status

<  0.001

  

0.003

 Married

 

1

Reference

 

 Widowed

 

1.40

1.10–1.78

0.01

 Others

 

1.33

1.08–1.63

0.01

CEA

<  0.001

  

<  0.001

 Normal

 

1

Reference

 

 Borderline

 

1.43

0.45–4.51

0.54

 Elevated

 

1.76

1.44–2.15

<  0.001

CRM

<  0.001

1.47

1.22–1.77

<  0.001

 Negative

    

 Positive

    

Perineural invasion

<  0.001

   

 Negative

    

 Positive

    

Tumor deposits

<  0.001

1.70

1.39–2.08

<  0.001

 Absent

    

 Present

    

Histologic subtype (classical adenocarcinoma as reference)

<  0.001

  

<  0.001

 Classical adenocarcinoma

 

1

Reference

 

 Mucinous adenocarcinoma

 

1.14

0.93–1.39

0.20

 Signet-ring cell carcinoma

 

1.88

1.37–2.58

<  0.001

 Adenocarcinoma with mixed subtypes

 

1.89

1.25–2.85

0.003

Histologic subtype (adenocarcinoma with mixed subtypes as reference)

<  0.001

  

<  0.001

 Adenocarcinoma with mixed subtypes

 

1

Reference

 

 Classical adenocarcinoma

 

0.53

0.35–0.81

0.003

 Mucinous adenocarcinoma

 

0.60

0.40–0.90

0.01

 Signet-ring cell carcinoma

 

0.99

0.65–1.53

0.98

Abbreviation: TNM tumor-node-metastasis, CEA carcinoembryonic antigen, CRM circumferential resection margin

Discussion

In this study, we compared the clinicopathologic and survival differences of CA with two previously widely investigated histologic subtypes, MAC and SRCC. Both subtypes were significantly associated with more aggressive features compared with CA, while only SRCC showed significantly poorer survival. Furthermore, we also focused on another rare histologic subtype, AM, whose frequency is about 2/5 of SRCC. We identified AM as a subgroup significantly associated with more advanced tumor grade and stage, as well as worse survival compared with CA. In addition, the aggressiveness of AM was between MAC and SRCC according to the clinicopathologic associations. The prognosis of AM was found comparable with SRCC and worse than MAC.

Our conclusions about the clinicopathologic relevance of MAC and SRCC were mainly in consistency with previous reports. They were associated with poorer tumor grade [19, 28, 29, 30], deeper primary tumor invasion [19, 22, 28], regional lymph nodes metastasis [19, 28], more advanced TNM stage [29, 30], and higher level of CEA [22]. Both MAC and SRCC have been repeatedly reported to be less common in the rectum [19, 22, 29, 30]. MAC was found more frequently in females [30]. We also demonstrated the relevance of MAC and SRCC with several postoperative features, including CRM, perineural invasion and tumor deposits. These factors had been found to be associated with poor survival [16, 17, 31]. From the above, the prognostic value of histologic subtypes might be confounded by these prognostic factors. Interestingly, although MAC was significantly associated with aggressive tumor features and advanced tumor stage, its survival difference from CA was not independently significant according to multivariate analysis. The prognostic value of MAC has been controversial. Several studies reported MAC to be an independent negative prognostic factor [32, 33]. However, most of the other reports were in accordance with our conclusions [19, 22, 23]. MSI-H, more frequently found in MAC, was identified as a positive prognostic marker in CRC [24, 25]. This might partially explain the discordance between the clinicopathologic and prognostic relevance of MAC.

The consistency of clinicopathologic and prognostic relevance of SRCC highlighted a potential distinct aggressive tumor biology mechanism. Previous studies speculated that SRCC might arise from different cell origins compared with CA [34]. This distinct aggressive histologic subtype might benefit from intensified systemic therapy [26] and closer follow-up. Most importantly, our study identified that AM had a poor prognosis relative to SRCC. This subtype has not been well documented in the literature of CRC. In lung cancer, AM exhibited a greater genetic heterogeneity of EGFR mutation and ALK rearrangement. Thus, both intrinsic vicious biology and high heterogeneity might contribute to the aggressiveness and refractory of AM. Immunohistochemistry might be helpful for identification of tumor components [35], which should be considered when selecting systemic chemotherapy regimens.

The main limitation of our study is that this is a retrospective analysis of patients using the SEER database. The majority of patients in the SEER database were defined as adenocarcinoma NOS and were not included in the analysis. This could possibly cause some biases. Thus the results need to be validated in a more precise database.

Conclusions

Our study not only confirmed the clinicopathologic and survival differences of CA with MAC and SRCC with a large-sized sample, but also identified another histologic subgroup with aggressive tumor features and poor prognosis. The relatively large study population and the data source of the SEER database made the conclusions quite credible. However, there was no available information on DFS and genetic alterations, lack of such information is a limitation of our study.

Notes

Acknowledgments

The authors acknowledge the staff members of the National Cancer Institute and their colleagues across the United States and at Information Management Services, Inc. who have been involved with the SEER Program.

Authors’ contributions

AY and HS contributed to the conception and design of the study and drafted the manuscript; XW, MM, and ZH contributed to data analysis and interpretation; JH, TL, SL, and LZ participated in data collection and literature research. All authors read and approved the final manuscript.

Funding

Not applicable.

Ethics approval and consent to participate

This study was deemed exempt from institutional review board approval by Sun Yat-sen University Cancer Center and the informed consent was waived. This study was conducted in accordance with the ethical standards of the World Medical Association Declaration of Helsinki.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Supplementary material

12885_2019_6245_MOESM1_ESM.docx (15 kb)
Additional file 1 : Table S1. The frequency distribution of ICD-O-3 codes and histologic types in colorectal adenocarcinoma.
12885_2019_6245_MOESM2_ESM.tif (851 kb)
Additional file 2: Figure S1. Comparisons of prognosis in histological subtypes stratified by TNM stage.

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Copyright information

© The Author(s). 2019

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors and Affiliations

  1. 1.Department of Experimental ResearchSun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineGuangzhouChina
  2. 2.Department of Medical OncologySun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineGuangzhouChina
  3. 3.Department of Clinical LaboratorySun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineGuangzhouChina
  4. 4.Zhongshan School of Medicine, Sun Yat-sen UniversityGuangzhouChina
  5. 5.Department of Gastric SurgerySun Yat-sen university Cancer center, State key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineGuangzhouChina
  6. 6.Department of Medical OncologyDana-Farber Cancer InstituteBostonUSA
  7. 7.Department of EmergencyFoshan Traditional Chinese Medicine Chancheng High-tech Zone HospitalFoshanChina
  8. 8.Department of Breast OncologySun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineGuangzhouChina

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