Expression of CD10 and CD15 in colorectal mucinous and signet ring adenocarcinomas and its relation to clinicopathological features and prognosis

Abstract

BACKGROUND:

CD10 and CD15 expression has been reported in several tumors. Whether CD10 and CD15 have a role in colorectal mucinous and signet ring adenocarcinoma (MSA) tumorigenesis is not yet known.

OBJECTIVE:

We aimed to investigate the role of CD10 and CD15 expression in mucinous colorectal adenoma-carcinoma sequence (ACS) and determine if there is any clinical and prognostic significance associated with their expression.

METHODS:

Seventy-five cases of colorectal MSA, and 9 cases of adenoma samples were collected. Manual TMA blocks were constructed and immunohistochemistry for CD10 and CD15 was done.

RESULTS:

Compared to adenomas, CD15 expression was significantly higher in MSA ( $p=$ 0.002), in contrast to CD10 expression. CD15 positivity was significantly associated with microsatellite stable (MSS) tumors ( $p=$ 0.018). The association between CD10 positivity and fungating tumor growth showed marginal significance. Unlike CD10, CD15 positivity showed significant association with overall survival of colorectal MSA patients.

CONCLUSIONS:

CD15 expression seems to have a role in mucinous colorectal ACS, with significant impact on the survival of MSA patients. Further studies are suggested to identify any genetic alterations that may underlie a potential association with disease progression.

Keywords

CD10 CD15 mucinous colorectal carcinoma

1. Introduction

Colorectal carcinoma (CRC) is the third most common cancer and the third most deadly malignancy worldwide based on data from GLOBOCAN 2018 [1]. CRC arises from adenomatous polyps in 80% of cases [2]. Histologically, 90% of CRC are adenocarcinoma not otherwise specified (ANOS). Less common are certain subtypes with mucinous activity, namely mucinous and signet ring adenocarcinomas (MSA) [3]. MSA distinctively show more than 50% mucinous component, either extracellularly (mucinous carcinoma), or intracellularly (signet ring adenocarcinoma) [4]. Although MSA is uncommon accounting for only 5% to 15% of CRC cases, it is usually associated with larger primary lesions, deeper tumor invasion, and higher chances of both lymph node and distant sites involvement. Regarding prognosis, patients with MSA are almost similar to those with ANOS in stages I and II. However, in stages III and IV, MSA patients show significantly worse disease outcome [5].

Matrix metalloproteases (MMPs) play an important role in the interaction between normal epithelial cells and stromal cells, thus defining the potential for tumor invasiveness and metastatic spread. CD10 is a zinc-dependent metalloprotease of 100 kDa that is expressed on the surface of many normal cells such as precursor B and T cells, epithelial cells of the breast, kidney, intestine, and salivary glands myoepithelial cells [6]. It is not expressed by the epithelial cells of the normal colorectal mucosa [7]. CD15 is a cell adhesion molecule which is normally expressed on the surface of human leukocytes and responsible for embryogenesis, neural stem and progenitor cells development [8]. CD10 and CD15 are both known to be expressed in many different types of tumors as melanomas, esophageal, gastric, lung, breast, prostate, and colorectal carcinomas [9, 10, 11]. Melanoma and breast carcinoma expressing dysregulated CD10 were shown to have more aggressiveness and worse prognosis [9]. In contrast, CD10 expression in primary bladder tumors was correlated with good prognosis [12]. On the other hand, higher expression of CD15 in primary liver and bile duct tumors was correlated with invasiveness [13]. Moreover, CD15 mediates leukocyte extravasation at inflammatory sites, which can also lead to easier metastasis of tumor cells [14].

In CRC, few studies linked CD10 and CD15 expression to both clinical and prognostic aspects of the disease. The correlation between both markers was suggested to be an indication of poor prognosis and associated with disease progression [15]. Furthermore, they were associated with increased invasion and metastasis especially liver metastases [16]. However, previous studies were concerned with CD10 and CD15 expression in ANOS with exclusion of MSA cases [15, 17]. In this study, we aimed to examine the expression of CD10 and CD15 in colorectal adenomas and MSA using immunohistochemical (IHC) staining, and to investigate any association of CD10 and CD15 with clinicopathological features or prognosis in this group of patients.

2. Methods

2.1 Samples

We reviewed slides and archived paraffin blocks of colorectal adenomas and adenocarcinomas for patients attending Gastroenterology Center, Mansoura University, Egypt during the period from January 2007 till January 2011. Clinicopathological data and follow-up data were retrieved from the patients’ electronic records and by contacting patients through telephone calls. Cases with incomplete clinical data or tissues with few epithelial cells containing mucous were excluded from the study. Seventy-five cases of colorectal MSA, and nine cases of adenomas were included in this study.

The slides were examined for tumor type, grade, depth of invasion (T), tumor margins (infiltrating or pushing), lymphatic, vascular, and perineural invasion. The slides were also examined for associated schistosomiasis, and development of the tumor in an underlying adenoma. The TNM classification and staging were reviewed for each case. The demographic data of patients including gender, age, along with the size, shape, location, and multiplicity of the tumor were also retrieved.

2.2 Tissue microarray construction

Modified mechanical pencil tip method was utilized to prepare three manual tissue microarrays (TMA) [18]. From each block, 0.8 mm diameter core of tissue was taken for section preparation, minding the representativeness of the tissue. Both normal and charged slides were coated with 4 $\mu$ m thickness section for standard hematoxylin and eosin (H&E) stains and immunohistochemistry (IHC) studies, respectively.

2.3 Immunohistochemistry (IHC) procedure

Sections of 4 $\mu$ m thickness were deparaffinized and incubated with 0.3% hydrogen peroxide in methanol for 30 minutes and then microwaved for 30 minutes in EDTA buffer solution with pH 8.0. Staining of the sections was done by indirect immunoperoxidase technique, using antibodies against monoclonal rabbit anti-human CD10 Ab (Clone SP67, Cat. # 790-4506, ready-to-use for IHC, Ventana) and monoclonal mouse anti-human CD15 Ab (Clone MMA, Cat. # 760-2504, ready-to-use for IHC, Ventana). Immunoperoxidase method was done using ImmunoPure Ultra-Sensitive ABC Peroxidase (Catalog no. 32052; Thermo Scientific, UK), using chromogen (diaminobenzidine). Olympus CX31 light microscope and digital camera (Olympus E-620) were used to review and photograph the sections, respectively.

2.4 Evaluation of IHC slides

The slides were reviewed for CD10 and CD15 expression independently by two investigators (Foda AA and Alamer HA). The result was described as negative or positive. Most of the positive cases showed focal staining. Any case with no visible tissue was excluded from the study.

2.5 Statistical analysis

SPSS, version 24.0 (SPSS Inc, IBM, Chicago, Illinois) was utilized for data analysis. The significance of histological and clinical parameters was evaluated using $\chi^{2}$ (Chi-square) and Fischer exact tests. Kaplan-Meier and log-rank tests were used for comparing survival curves. A 2-tailed $P<$ 0.05 was considered significant.

3. Results

The pathology Lab (Gastroenterology Center) at Mansoura University received 75 cases of MSA out of 341 CRC cases (22%) during the period 2007 to 2011. Fifty-six (74.7%) of these cases consisted of mucinous adenocarcinomas, while 19 (25.3%) cases were signet ring adenocarcinomas.

There were 45 (60%) male and 30 (40%) female cases. Most of the cases (70.7%) occurred in patients aged 40 years or older. In 39 cases (52%) the size of the tumor was $\geqslant$ 6 cm. Tumors were located in the recto-sigmoid region in 41 cases (55%), the right colon in 23 cases (31%), the left colon in 6 cases (8%), and the transverse colon in 5 cases (7%). The main tumor morphology was either fungating or ulcerating; 27 cases each (36%), while 21 tumors (28%) were found to be annular. Regarding tumor spread, 69 cases (92%) had tumors that spread into the subserosa or surrounding peritoneum. Only 6 cases (8%) were confined to the muscular layer. In 48 cases (64%), there were regional lymph node metastasis. Other clinicopathological features are summarized in Table 1.

Table 1
Clinicopathological features of 75 MSA cases

Parameter	No. (%)
Age (years)
$<$ 40	22 (29.3%)
$\geqslant$ 40	53 (70.7%)
Gender
Male	45 (60.0%)
Female	30 (40.0%)
Tumor size (cm)
$<$ 6	36 (48.0%)
$\geqslant$ 6	39 (52.0%)
Location
Right	23 (30.7%)
Left	06 (08.0%)
Recto-sigmoid	41 (54.7%)
Transverse	05 (06.7%)
Tumor shape
Fungating	27 (36.0%)
Ulcerating	27 (36.0%)
Annular	21 (28.0%)
Depth of invasion
T1/T2	06 (08.0%)
T3/T4	69 (92.0%)
LN
Negative	27 (36.0%)
Positive	48 (64.0%)
TNM stage
I/II	27 (36.0%)
III/IV	48 (64.0%)
Microsatellite instability
MSI-H	27 (36.0 %)
MSS	47 (64.0)

Figure 1.

Representative images of H&E stained slides (a) A case of colorectal adenoma (b) A case of mucinous adenocarcinoma (x200).

Figure 2.

Representative images of IHC staining of studied cases (a) Negative CD10 staining in a case of colorectal adenoma (b) Positive CD10 cytoplasmic staining in a case of mucinous adenocarcinoma (c) Negative CD10 staining in a case of mucinous adenocarcinoma (d) Negative CD15 staining in a case of colorectal adenoma (e) Positive CD15 cytoplasmic staining in a case of signet ring adenocarcinoma (f) Negative CD15 staining in a case of mucinous adenocarcinoma (x200).

While all adenomas were negative for both CD15 and CD10, more than half of MSA cases (53.7%) showed CD15 positivity and only 14.5% of these cases showed CD10 positivity (Figs 1 and 2). This translated into statistically significant ( $p=$ 0.002) expression of CD15 in MSA as compared to adenomas. On the other hand, there was no significant difference between MSA and adenomas for CD10 expression ( $p=$ 0.221).

Studying the association between different clinicopathological features of MSA cases and either CD10 or CD15 expression revealed that CD15 positivity was significantly associated with microsatellite stable (MSS) tumors ( $p=$ 0.018). Additionally, the association between CD10 positivity and fungating tumor shape showed marginal significance ( $p=$ 0.055). No other significant associations were found as shown in Table 2. Moreover, the correlation between CD10 and CD15 expressions in MSA cases was tested. There was no statistical significance ( $p=$ 0.798) found concerning co-expression of both markers in MSA cases as shown in Table 3.

Table 2

Relation of CD10 and CD15 expression to clinicopathological features of MSA cases

	CD10 expression			CD15 expression
Parameter	Negative	Positive	$P$ value	Negative	Positive	$P$ value
	No. (%)	No. (%)		No. (%)	No. (%)
Gross picture
Fungating	18 (30.5%)	07 (70.0%)	0.055 ${}^{1}$	10 (32.3%)	13 (36.1%)	0.814 ${}^{2}$
Ulcerating	25 (42.4%)	02 (20.0%)		12 (38.7%)	15 (41.7%)
Annular	16 (27.1%)	01 (10.0%)		9 (29.0%)	8 (22.2%)
Lymphovascular emboli
Negative	18 (30.5%)	04 (40.0%)	0.551 ${}^{1}$	11 (35.5%)	10 (27.8%)	0.498 ${}^{2}$
Positive	41 (69.5%)	06 (60.0%)		20 (64.5%)	26 (72.2%)
Perineural invasion
Negative	37 (62.7%)	06 (60.0%)	0.870 ${}^{1}$	20 (64.5%)	21 (58.3%)	0.605 ${}^{2}$
Positive	22 (37.3%)	04 (40.0%)		11 (35.5%)	15 (41.7%)
Associated adenoma
Negative	35 (59.3%)	04 (40.0%)	0.254 ${}^{1}$	18 (58.1%)	19 (52.8%)	0.664 ${}^{2}$
Positive	24 (40.7%)	06 (60.0%)		13 (41.9%)	17 (47.2%)
Associated schistosomiasis
Negative	49 (83.1%)	09 (90.0%)	0.579 ${}^{1}$	26 (83.9%)	30 (83.3%)	0.953 ${}^{2}$
Positive	10 (16.9%)	01 (10.0%)		05 (16.1%)	06 (16.7%)
Tumor margins
Budding	55 (93.2%)	09 (90.0%)	0.716 ${}^{1}$	29 (93.5%)	33 (91.7%)	0.770 ${}^{1}$
Pushing	04 (06.8%)	01 (10.0%)		02 (06.5%)	03 (08.3%)
Microscopic abscess formation
Negative	39 (66.1%)	07 (70.0%)	0.809 ${}^{1}$	17 (54.8%)	27 (75.0%)	0.083 ${}^{2}$
Positive	20 (33.9%)	03 (30.0%)		14 (45.2%)	09 (25.0%)
Peri-tumoral lymphocytic response (Crohn-like response)
Negative	46 (78.0%)	10 (100%)	0.099 ${}^{1}$	26 (83.9%)	29 (80.6%)	0.724 ${}^{2}$
Positive	13 (22.0%)	0 (0.0%)		05 (16.1%)	07 (19.4%)
Intra-tumoral lymphocytic response
Negative	57 (96.6%)	10 (100%)	0.555 ${}^{1}$	31 (100%)	35 (97.2%)	0.350 ${}^{1}$
Positive	02 (03.4%)	0 (0.0%)		0 (0.0%)	01 (02.8%)
MSI
MSS	37 (63.8%)	6 (60.0%)	0.818 ${}^{1}$	14 (46.7%)	27 (75.0%)	0.018 ${}^{2*}$
MSI-H	21 (36.2%)	4 (40.0%)		16 (53.3%)	9 (25.0%)

1. Fischer exact test. 2. Chi-square test. ${}^{*}$ Significant.

Table 3

Correlation between CD10 and CD15 expression in MSA cases

Marker expression		CD 15 expression		$P$ value
		Negative	Positive
CD10 expression	Negative	26 (83.9%)	31 (86.1%)	0.798 ${}^{1}$
	Positive	05 (16.1%)	05 (13.9%)

1. Chi-square test.

Regarding disease outcome, after median follow-up duration of 25.6 months (interquartile range $=$ 53.2), CD10 expression did not show a significant association with either disease-free survival (DFS) or overall survival (OS) in the studied MSA patients; however, CD15 expression was associated with better overall survival ( $p=$ 0.018; Table 4 and Fig. 3).

Table 4

Relation of CD10 and CD15 expression to disease-free and overall survival in MSA cases

Marker expression		Mean DFS (SEM) months	Median DFS (SEM) months	$P$ value	Mean OS (SEM) months	Median OS (SEM) months	$P$ value
CD10	Negative expression, 59 patients (86%)	71.8 (6.3)	97.4 (26.3)	0.576 ${}^{1}$	80.3 (5.7)	100.6 (36.3)	0.935 ${}^{1}$
	Aberrant expression, 10 patients (14%)	82.9 (14.2)	Not reached		81.0 (15.1)	Not reached
CD15	Negative expression, 31 patients (46%)	63.3 (9.9)	100.6 (0.0)	0.093 ${}^{1}$	66.8 (9.3)	100.6 (0)	0.018 ${}^{1\ast}$
	Aberrant expression, 36 patients (54%)	81.9 (7.6)	97.4 (10.5)		95.1 (6.2)	Not reached

1. Log rank test. ${}^{*}$ significant.

Figure 3.

Relation of CD10 (a&b) and CD15 (c&d) expression to disease-free (DFS) and overall survival (OS) in MSA patients.

4. Discussion

Adenoma-carcinoma sequence (ACS) is a predominant pathogenic pathway of colorectal carcinogenesis. It follows a step-up pattern in which transformation of normal colorectal epithelium to adenoma occurs initially, followed by development of invasive carcinoma. Genetic instability starts in the adenoma phase followed by changes occurring within the tumor histologically [19]. Previous studies have suggested that CD10 expression may be associated with the development or progression of CRC [15, 17]. CD10 enzymatically cleaves polypeptides leading to the accumulation or loss of peptides which alters cellular proliferation and differentiation. It also functions by interfering with intracellular signaling pathways [6].

In our study, although CD10 expression was higher in MSA compared to adenomas (14.5% vs. 0%), the difference was not statistically significant ( $p=$ 0.221). Jang et al. [15] found that the expression level of CD10 progressively increased from non-neoplastic colon to CRC; being 14% in low grade adenoma in comparison to 40% in intramucosal CRC and 44% in invasive CRC. Based on their findings, they suggested that CRC development and progression was associated with CD10 expression. However, in their study they excluded patients with MSA which may explain the differing results. In another interesting study, Koga et al. [20] found that de novo colorectal carcinoma had more significant CD10 expression than colorectal adenoma-carcinoma (32% vs. 5%, respectively). Hirano et al. [7] also found non-polypoid carcinomas to have more expression of CD10 as compared to polypoid carcinomas (70.8% vs. 51.0%, $p=$ 0.01). Thus, it seems that CD10 expression might potentially estimate the malignant phenotype of early colorectal carcinomas. Of course, this needs to be more elucidated in further studies with respect to different histological subtypes of CRC.

Regarding the correlation between CD10 expression and clinicopathological features of MSA cases, we found no significant relation with a variety of tested parameters. Noteworthy that CD10 expression was more in fungating tumors with marginal significance. This goes in line with findings of Oliveira et al. [21] who reported higher CD10 expression in exophytic CRC lesions ( $p=$ 0.04). In the same context, other studies reported a correlation between CD10 and lymph node metastasis, but none reported CD10 to increase lymphovascular invasion or to predict lymphatic metastasis [22, 23].

CD15 expression in cancer is involved in adhesion between tumor cells and endothelial cells and is linked to metastatic potential [24, 25]. Very few studies addressed CD15 expression in CRC. Of these, Jang et al. [15] reported an increasing CD15 expression during CRC development; 23% in low grade adenoma compared to 50% in intramucosal CRC and 44% in invasive CRC. Whether CD15 expression is related to progression of mucinous CRC or not is not yet fully investigated. Expression of CD15 was also investigated in various epithelial cancers other than CRC with contradicting evidence about its relation to disease behavior. Its expression appears to signify aggressive behavior in some tumors and benign behavior in others. For instance, it highly predicts poor survival when expressed in patients with hepatocellular carcinoma [26]. Similarly, in breast carcinoma, it showed association with invasiveness and metastatic potential [11]. In contrast, clear cell renal carcinoma was associated with poor prognosis in absence of CD15 expression [27].

To the best of our knowledge, this is the first study to examine CD15 expression in colorectal MSA. Unlike CD10, the expression of CD15 in MSA was significantly more frequent compared to adenomas (53.7% vs. 0%, $p=$ 0.002). This supports the conclusion of Jang et al. [15] that the expression of CD15 is associated with the development and progression of CRC, including the mucinous subtype. Interestingly, we found that CD15 expressing tumors were more likely to be MSS compared to CD15 negative tumors (75% vs. 46.7%, $p=$ 0.018). The association between either CD10 or CD15 expression and microsatellite instability (MSI) in CRC is not well studied. A study by Kumagai et al. found no association between CD10 positivity and MSI status in small intestinal adenocarcinomas [28]. No significant correlation was detected between CD15 expression and other clinicopathological parameters of MSA cases.

Several studies have identified CD10 as a prognostic marker for worse survival in different tumor types such as breast cancer, prostate cancer, and melanoma [9]. Data on prognostic value of either CD10 or CD15 expression in CRC are scarce. One study by Khanh and colleagues [29] found that CD10 expression in infiltrating immune cells, but not tumor cells, was a useful predicting marker for high recurrence risk and mortality in stage II CRC. Concerning the impact of CD10 and CD15 expression on our patients’ prognosis, only CD15 positivity was associated with better OS ( $p=$ 0.018) in studied MSA patients. CD10 expression did not show a significant association with either DFS or OS.

We recognize an important aspect in studying metastatic tumors which is assessment for molecular markers such as RAS expression. We are still working on RAS expression in metastatic/recurrent tumors, although a small number of these tumors were included in this study. Once we are ready with these data, they can be published in the future.

5. Conclusion

We conclude that CD15 expression seems to have a role in mucinous colorectal ACS. Although CD10 expression was linked to CRC progression in other studies, its role in mucinous and signet ring carcinomas is unclear. Unlike CD10, CD15 positivity has a significant impact on the survival of colorectal MSA patients. Further research with more patient numbers of this rare entity is suggested to confirm the role of CD10 and CD15 in mucinous colorectal ACS and to identify any genetic alterations that may underlie a potential association with disease progression.

Footnotes

Acknowledgments

None.

Author contributions

Conception: Abd AlRahman Foda

Interpretation or analysis of data: Abd AlRahman Foda, Hadi Abdulhadi Helali, Fayza Sami Fayad, Sara Waleed Hussian

Preparation of the manuscript: Abd AlRahman Foda, Ziad Emarah, Ahmed M. Ramez

Revision for important intellectual content: Khaled Abdelwahab, Tamer Akl

Supervision: Haitham Abdulkarem Alamer, Nadeem Ikram

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Expression of CD10 and CD15 in colorectal mucinous and signet ring adenocarcinomas and its relation to clinicopathological features and prognosis

Abstract

BACKGROUND:

OBJECTIVE:

METHODS:

RESULTS:

CONCLUSIONS:

Keywords

1. Introduction

2. Methods

2.1 Samples

2.2 Tissue microarray construction

2.3 Immunohistochemistry (IHC) procedure

2.4 Evaluation of IHC slides

2.5 Statistical analysis

3. Results

Table 1 Clinicopathological features of 75 MSA cases

5. Conclusion

Footnotes

Acknowledgments

Author contributions

References

Table 1
Clinicopathological features of 75 MSA cases