Associations between serum carcinoembryonic antigen levels and adenocarcinoma subtypes of the lung

Cancer Treatment Communications 5 (2016) 31–35

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Associations between serum carcinoembryonic antigen levels and adenocarcinoma subtypes of the lung Haruhiko Nakamura a,n, Hisashi Saji a, Hideki Marushima a, Hiroyuki Kimura a, Hirotaka Koizumi b, Masayuki Takagi b a b

Department of Chest Surgery, St. Marianna University School of Medicine, Japan Department of Pathology, St. Marianna University School of Medicine, Japan

art ic l e i nf o

a b s t r a c t

Article history: Received 10 November 2015 Received in revised form 28 December 2015 Accepted 28 December 2015

Background: Increased serum carcinoembryonic antigen (CEA) levels have been associated with a poor outcome in lung cancer. The aim of this study was to further clarify the associations between CEA levels and adenocarcinoma subtypes. Patients and methods: We retrospectively assessed preoperative serum CEA levels and clinicopathological factors in 307 consecutive patients who underwent resection for primary lung adenocarcinoma with curative intent. Results: Subtypes included adenocarcinoma in situ (AIS) in 20 cases, minimally invasive adenocarcinoma (MIA) in 20, invasive mucinous adenocarcinoma (IMA) in three, lepidic predominant adenocarcinoma (LPA) in 41, papillary predominant adenocarcinoma (PPA) in 106, acinar predominant adenocarcinoma (APA) in 90, solid predominant adenocarcinoma (SPA) in 23, and micropapillary predominant adenocarcinoma (MPA) in four. Serum CEA levels varied according to gender, age, smoking status, clinical stage, lymph node metastasis, pathological stage, and adenocarcinoma subtype. Serum CEA levels were higher in the APA, MPA, IMA, and SA subtypes than in the AIS, MIA, PPA, and LPA subtypes. Multiple regression analysis revealed that the clinical stage and adenocarcinoma subtype were significantly associated with serum CEA levels. Univariate analysis demonstrated that preoperative CEA levels were significantly associated with both the postoperative disease-free survival (DFS) and overall survival. Cox regression analysis revealed that the clinical stage and adenocarcinoma subtype were significantly associated with the postoperative DFS. Conclusion: The serum CEA level was elevated in advanced disease stages and certain adenocarcinoma subtypes, suggesting the usefulness of CEA as a marker reflecting the malignant behavior of lung adenocarcinomas. & 2016 Elsevier Ltd. All rights reserved.

Keywords: Acinar adenocarcinoma Micropapillary predominant adenocarcinoma Solid predominant adenocarcinoma Invasive mucinous adenocarcinoma CEA Prognosis

1. Introduction Carcinoembryonic antigen (CEA) was first identified as an oncofetal protein of colon cancer in 1965 [1]. More recent studies have revealed that the human CEA family comprises 35 genes tandemly arranged within the same chromosomal region (19q13.2–13.4) [2]. Importantly, CEA, also known as CEA-related cell adhesion molecule 5, is frequently associated with a poor clinical outcome in malignant tumors through a variety of mechanisms, including the promotion of invasion, dissemination, metastasis, and immune suppression via the interactions between cell surface receptors and the suppression of dendritic cells and n Correspondence to: Department of Chest Surgery, St. Marianna University School of Medicine 2-16-1 Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8511, Japan. E-mail address: [email protected] (H. Nakamura).

http://dx.doi.org/10.1016/j.ctrc.2015.12.005 2213-0896/& 2016 Elsevier Ltd. All rights reserved.

natural killer (NK) cells, which function in tumor immunity [3]. In lung cancer, CEA is expressed in both non-small cell lung cancer (NSCLC) and SCLC and is thought to be associated with an adverse prognosis in NSCLC [4]. Most studies have reported higher serum CEA levels in lung adenocarcinoma than in other histological types of NSCLC [5,6], with some conflicting results indicating higher levels in squamous cell carcinoma [7,8], presumably due to the influence of a smoking history. In 2011, new histopathological classification criteria of lung adenocarcinoma were proposed by the International Association for the Study of Lung Cancer (IASLC), the American Thoracic Society (ATS), and the European Respiratory Society (ERS) [9]. In these new criteria, invasive adenocarcinomas are classified according to the predominant pattern. The 2015 classification of lung cancer published by the World Health Organization employs the proposed subtypes of the IASLC/ATS/ERS criteria [10], which include adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA),

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lepidic predominant adenocarcinoma (LPA), acinar predominant adenocarcinoma (APA), papillary predominant adenocarcinoma (PPA), micropapillary predominant adenocarcinoma (MPA), solid predominant adenocarcinoma (SPA), and rare variants of invasive adenocarcinomas, consisting of invasive mucinous adenocarcinoma (IMA), colloid adenocarcinoma (CA), fetal adenocarcinoma (FA), and enteric adenocarcinoma (EA). Because the relationship between serum CEA levels and lung adenocarcinoma subtypes was unknown, we retrospectively analyzed patients who underwent surgery for primary lung adenocarcinoma to clarify the clinicopathological significance of serum CEA levels, as defined by the proposed subtypes. To the best of our knowledge, this is the first report to clarify the associations between serum CEA levels and the newly defined lung adenocarcinoma subtypes.

5. Statistical analysis Values between two groups were compared using the nonparametric Mann–Whitney U test. Values between multiple groups were compared by the Kruskal–Wallis test. Multiple regression analysis was used to identify significant predictive factors for serum CEA levels. Disease-free survival (DFS) and overall survival (OS) after surgery were calculated using the Kaplan–Meier method, and differences in survival between the patient groups were identified using the log-rank test. Cox regression analysis was used to identify significant risk factors for postoperative DFS. A p value of o0.05 was considered statistically significant for all statistical tests.

6. Results 2. Patients and methods 2.1. Patients The study protocol was approved by the Institutional Review Board of our institution. We retrospectively reviewed the medical records of 307consecutive patients who underwent resection for lung adenocarcinoma with curative intent, with available data for preoperative serum CEA levels from April 2008 to December 2013. Patients who received preoperative induction therapy or those with synchronous multiple lung cancers were excluded. Final adenocarcinoma subtyping was obtained from resected lung specimens. Staging was assessed according to the most recent criteria provided by the American Joint Committee on Cancer, the Union for International Cancer Control, and the IASLC [11], using 18 F-fluorodeoxyglucose-positron emission tomography combined with computed tomography (18F-FDG-PET/CT) or abdomen CT/ chest CT/bone scintigraphy and brain CT or brain magnetic resonance imaging. Clinical mediastinal and hilar lymph node statuses were considered positive if the shorter axis was 410 mm. The mean postoperative follow-up period for the surviving patients was 277 18 months.

Characteristics of the included patients were shown in Table 1. The patients included 153 men and 154 women [age range, 22–88 years; mean 7standard deviation (SD), 69 79 years]. Clinical (c-) stages were IA in 186 cases, IB in 93, IIA in 10, IIB in 10, IIIA in six, and IV in two. The two c-stage IV cases were patients with solitary brain metastasis who were simultaneously treated with lung resection. Because of the omission of lymph node dissection, mainly due to limited lung resection, information regarding the pathological (p-) N-stage could not be obtained in 67 cases. Sixty-six cases were excluded from the analyses of pathological staging because of the above stated reasons, with the exception of one case that was determined as p-stage IV due to pleural dissemination (pM1a) found intraoperatively in spite of the lack of pathological information regarding regional lymph node status. The postoperative pathological stage was p-IA in 155 patients, p-IB in 41, p-IIA in 10, p-IIB in nine, p-IIIA in 23, and p-IV in three. Surgical methods were lobectomy in 203 cases, sublobar resection Table 1 Characteristics of the included patients who underwent surgery for lung adenocarcinoma. Factor Gender

3. Histological diagnosis Two pathologists (H.K. and M.T.) independently assessed hematoxylin and eosin-stained glass slides prepared from the resected lung cancer specimens to determine the adenocarcinoma subtype according to the IASLC/ATS/ERS criteria [12]. Disagreements on the individual pathological diagnosis of a case were resolved by the consensus achieved after a discussion between the two pathologists while viewing specimens under a double-headed microscope, as previously reported [13].

Age (years) Tumor size (mm) Clinical stage

Surgery

Subtypes

4. CEA measurement The serum CEA level was measured using a “sandwich-type” immunoassay [14] with an acridinium ester-conjugated anti-CEA rabbit polyclonal antibody and a magnetic particle-bound antiCEA murine monoclonal antibody on an automated chemiluminescence detection system (ADVIA Centaur CP Immunoassay System; Siemens Healthcare, Munich, Germany), according to the manufacturer's instructions. In this system, the range of detectable serum CEA was 0.5–100 ng/mL. Serum samples were collected from all patients within 1 month prior to lung surgery.

Total

N (%) Male Female Mean 7 SD Range Mean 7 SD Range IA IB IIA IIB IIIA IIIB IV Lobectomy Sublobar resection Pneumonectomy AIS MIA LPA PPA APA IMA SPA MPA

153 (50) 154 (50) 697 9 22–88 297 13 8–93 186 (61) 93 (30) 10 (3) 10 (3) 6 (2) 0 2 (1) 203 (66) 102 (33) 2 (1) 20 (7) 20 (7) 41 (13) 106 (35) 90 (29) 3 (1) 23 (7) 4 (1) 307 (100)

Abbreviations; SD ¼standard deviation, AIS¼ adenocarcinoma in situ, MIA ¼minimally invasive adenocarcinoma, LPA ¼lepidic predominant adenocarcinoma, PPA ¼ papillary predominant adenocarcinoma, APA ¼acinar predominant adenocarcinoma, IMA¼ invasive mucinous adenocarcinoma, SPA ¼solid predominant adenocarcinoma, MPA ¼micropapillary predominant adenocarcinoma.

H. Nakamura et al. / Cancer Treatment Communications 5 (2016) 31–35

Table 2 Clinicopathological factors and serum CEA levels in patients who underwent resection for lung adenocarcinoma. Factor

Gender Age Smoking Clinical stage Pathological N-factorn Pathological stage† Subtypes

Subtype groups All patients

CEA levels (mean 7SD)

Male Female Z 69 o 69 Smoker Non-smoker IA–IB IIA–IV p-N0

154 153 164 143 170 137 279 28 209

(50) (50) (53) (47) (55) (45) (91) (9) (87)

3.4 7 5.3 6.17 26.4 4.3 7 11.3 5.4 7 25.3 6.5 7 25.3 2.7 7 4.4 4.17 18.2 11.3 7 26.2 2.8 7 3.9

p-N1–2 IA–IB

31 (13) 196 (81)

17.8 7 53.1 2.5 7 2.3

o 0.0001‡

15.2 7 44.7 1.8 7 1.0 2.0 7 1.6 2.6 7 2.1 2.5 7 2.0 8.8 7 33.9 4.3 7 1.9 7.2 7 15.5 15.0 7 17.4 2.4 7 1.9

‡

IIA–IV AIS MIA LPA PPA APA IMA SPA MPA AISþ MIAþ LPA þ PPA

45 20 20 41 106 90 3 23 4 187

(19) (7) (7) (13) (35) (29) (1) (7) (1) (61)

APA þ IMA þSPA þMPA 120 (39) 307 (100)

8.6 7 30.2 4.8 7 19.1

p

0.0481‡ 0.0009

CEA ng/mL 1000

N (%)

33

p = 0.0026

100

‡

o 0.0001‡

10

0.0109‡

o 0.0001

1

AIS

MIA LPA APA PPA IMA SPA MPA

Fig. 1. Serum carcinoembryonic antigen (CEA) levels according to adenocarcinoma subtype. The Kruskal–Wallis test revealed significant differences (p¼ 0.0026). Abbreviations; AIS¼adenocarcinoma in situ, MIA¼ minimally invasive adenocarcinoma, LPA¼lepidic predominant adenocarcinoma, PPA¼ papillary predominant adenocarcinoma, APA¼acinar predominant adenocarcinoma, IMA¼ invasive mucinous adenocarcinoma, SPA¼ solid predominant adenocarcinoma, MPA¼micropapillary predominant adenocarcinoma.

0.0026§

CEA ng/mL 0.0002‡

Abbreviations; CEA¼ carcinoembryonic antigen, SD ¼ standard deviation, AIS¼ adenocarcinoma in situ, MIA ¼minimally invasive adenocarcinoma, LPA ¼ lepidic predominant adenocarcinoma, PPA ¼papillary predominant adenocarcinoma, APA ¼ acinar predominant adenocarcinoma, IMA ¼ invasive mucinous adenocarcinoma, SPA ¼solid predominant adenocarcinoma, MPA ¼ micropapillary predominant adenocarcinoma.

1000

p <0.0001

100

‡

Mann–Whitney U test. A total of 67 cases were excluded from the analyses, because of omission of lymph nodes dissection in sublobar resection. † A total of 66 cases were excluded from the same reason above. § Kruskal–Wallis test. n

(segmentectomy or wedge resection) in 102, and pneumonectomy in two. Adenocarcinoma subtypes were AIS in 20 cases, MIA in 20, LPA in 41, APA in 90, PPA in 106, IMA in three, SPA in 23, and MPA in four. The mean serum CEA level of all included patients was 4.8 719.1 ng/mL. The serum CEA levels significantly differed between genders (p ¼0.0481), age groups (Z69 vs. o69 years; p ¼0.0009), smoking status (smoker vs. non-smoker, po 0.0001), clinical stages (c-IA–IB vs. c-IIA–IV; p ¼0.0109), p-N factors (p-N0 vs. p-N1–2; p o0.0001), pathological stages (p-IA–IB vs. p-IIA–IV; p o0.0001), and among adenocarcinoma subtypes (p ¼0.0026; Table 2). Serum CEA levels (ng/mL) according to adenocarcinoma subtype were 1.8 71.0 in AIS, 2.0 7 1.6 in MIA, 2.6 72.1 in LPA, 2.5 72.0 in PPA, 8.8 733.9 in APA, 4.3 7 1.9 in IMA, 7.2 715.5 in SPA, and 15.0 717.4 in MPA. The mean serum CEA level was highest in the MPA subtype followed by the APA, SPA, IMA, LPA, PPA, MIA, and AIS subtypes (Fig. 1). When patients were divided into two subtype groups according to CEA levels, there was a significant difference between the “lower CEA subtype group” (AIS þMIA þLPA þPPA) and “higher CEA subtype group” (APA þIMA þSPA þMPA; 2.4 7 1.9 vs. 8.6 7 30.2 ng/mL, respectively; p ¼0.0002). CEA levels tended to increase with a higher pathological stage (p o0.0001; Fig. 2). Multiple regression analysis revealed that the adenocarcinoma subtype and clinical stage were the best subset to predict serum CEA levels (p ¼0.0078 and 0.0860, respectively; Table 3). When all patients were classified into two groups according to

10

1

pIA

pIB

pIIA

pIIB

pIIIA

pIV

Fig. 2. Serum carcinoembryonic antigen (CEA) levels according to pathological (p-) stages. The CEA levels were 2.2 7 2.0 [mean 7 standard deviation (SD), ng/mL] in p-stage IA (n ¼155), 3.4 7 3.1 in p-stage IB (n¼ 41), 13.2 7 22.9 in p-stage IIA (n ¼10), 3.1 72.4 in p-stage IIB (n ¼9), 19.17 60.2 in p-stage IIIA (n ¼23), and 28.2 7 23.0 in p-stage IV (n¼ 3). The three p-stage IV cases included two cases with solitary brain metastasis and one with pleural dissemination. The Kruskal–Wallis test revealed significant differences (p o 0.0001).

the median CEA value (r 2.2 vs. 42.2 ng/mL), both DFS and OS were significantly shortened in the patient groups with higher CEA levels (p¼ 0.0140 and 0.0165, respectively; Fig. 3a). When p-stage I patients were classified into two groups according to the median CEA value ( r 1.9 vs. 41.9 ng/mL), there was a marginal difference in DFS and no difference in OS (p ¼0.0559 and 0.2574, respectively; Fig. 3b). Cox regression analysis revealed that the patient age and CEA level were significant predictive factors of postsurgical DFS in all included patients (p ¼0.0335 and 0.0016, respectively; Table 4). When limited to p-stage I patients, CEA alone was identified as a marginally significant factor (p ¼0.0526).

7. Discussion Although there are no previous data regarding the relationships between serum CEA levels and adenocarcinoma subtypes, a

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Table 3 Multiple regression analysis to predict serum CEA levels.

Table 4 Cox regression analysis for postoperative disease-free survival.

Variable

β

t

p

Patients

Variable

HR

95% CI

p

Intercept Gender Age Smoking indexn Clinical stage† Adenocarcinoma subtype‡

4.306  4.250  0.020 0.003 6.199 5.884

0.510  1.689  0.169 1.192 1.649 2.648

0.6105 0.0923 0.8656 0.2344 0.1002 0.0085

All

Best subset Intercept Clinical stage† Adenocarcinoma subtype‡

1.889 6.453 5.923

1.343 1.722 2.679

0.1804 0.0860 0.0078

Gender Age Clinical stagen Smoking index† CEA Gender Age Pathological stage‡ Smoking index† CEA

1.838 1.043 2.102 1.000 1.012 1.796 1.039 2.306 1.000 1.145

0.904–3.737 1.003–1.085 0.918–0.815 0.999–1.000 1.005–1.020 0.596–3.737 0.977–1.105 0.906–5.869 0.999–1.001 0.998–1.314

0.0926 0.0335 0.0790 0.4547 0.0016 0.2979 0.2251 0.0797 0.8157 0.0526

Pathological stage IAþ IB

n

†

Abbreviations; CEA¼ carcinoembryonic antigen, β¼ regression coefficient, t ¼tstatistic. n

† ‡

number of tobacco/day  years. c-IAþ IB vs. c-IIA þIIB þIIIA þ IIIBþ IV. APA þ SPA þ IMA þMPA vs. AISþ MIA þLPA þ PPA.

Disease-free survival 1

CEA < 2.2 ng/mL (n = 158)

.8 .6

CEA ≥ 2.2 ng/mL (n =149)

.4

All patients (n = 307)

.2

p = 0.0140

0 0

6

12 1

18

24 2

30

36 3

42

48 4

54

60 5

Years Disease-free survival 1

CEA ≤ 1.9 ng/mL (n = 95)

.8 CEA > 1.9 ng/mL (n =101)

.6

p-stage IA + IB (N = 196)

.4 .2

p = 0.0559

0

0

1

2

3

4

5

Years Fig. 3. Kaplan–Meier analysis of disease-free survival (DFS). a. There were significant differences in survival when all included patients were classified according to the median preoperative serum CEA level ( r 2.2 vs. 42.2 ng/mL, p ¼ 0.0140). b. There was a marginal difference in the survival of patients with pathological stage I disease when classified by the median preoperative serum CEA level ( r 1.9 vs. 41.9 ng/mL, p ¼ 0.0559).

‡

c-IA þ IB vs. c-IIA þIIB þIIIA þ IIIBþ IV. number of tobacco/day  years. p-IA vs. p-IB.

recent study reported that higher serum CEA levels were observed in lung adenocarcinomas with a lower ground-glass opacity ratio, presence of notch, and coexistence with bullae or honeycomb cysts, as observed on chest CT [15]. These results seem to be concordant with our present findings, as these features are common in the non-lepidic type adenocarcinomas, namely APA, MPA, SPA, and IMA. Multiple studies have reported that a high serum CEA level is associated with poor OS of patients with NSCLC [16]. Limited to adenocarcinoma p-stage I, CEA levels are reportedly associated with DFS and/or OS [17–19]. When classified by the median CEA value, the results of this study revealed only a marginal difference in DFS and no difference in OS of patients with p-stage I disease. We propose three plausible reasons to explain these conflicting results. First, there may have been different proportions of adenocarcinoma subtypes among the individual studies. If the proportions of MPA, SPA, and IMA cases having poor prognoses with elevated serum CEA levels increased among p-stage I populations, the differences in survival, as defined by CEA levels, are expected to become significant. Second, recent advancements in chemotherapy and molecularly targeted therapies after recurrence have resulted in prolonged OS and smaller differences in survival. Third, it was difficult to detect statistical differences in OS because of the small number of events (deaths) in patients with p-stage I disease and possibly the relatively short postoperative follow-up period in our study. Multiple recent studies validating the new IASLC/ATS/ERS criteria indicated that the MPP, SPA, and IMA subtypes were associated with a poor prognosis, compared with other subtypes [20– 27]. In colon cancer, local tumor invasion has been associated with increased serum CEA levels [28,29]. Similarly, in p-stage I NSCLC, higher serum CEA levels are associated with microscopic pleural and vascular invasion [7]. Thus, an aberrant overexpression of CEA seems to play a critical role in the implantation of metastatic tumor cells[3,30]. Moreover, CEA inhibits NK cell killing via interaction with CEA cell adhesion molecule 1, resulting in the suppression of tumor immunity and subsequent progression of lung cancer [3,31]. Therefore, these functions of CEA, which are related to invasion, cell adhesion, and tumor immunity, appear to worsen the prognosis of lung adenocarcinomas secreting higher amounts of CEA. Several studies on advanced lung cancer have identified associations between higher serum CEA levels and hilar and/or mediastinal lymph node metastases, as well as brain metastases [6,32]. In accordance, our findings demonstrated significantly increased CEA levels in p-N-positive cases, as opposed to p-Nnegative cases. Two p-stage IV cases in our study had brain metastasis, which was previously reported as a status associated with high CEA levels [32].

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The present study has several limitations that should be addressed. First, the number of patients was insufficient for the analyses of rare subtypes, such as IMA (n¼ 3) and MA (n ¼4). Second, the observational period was relatively short for appropriate survival analyses, particularly OS. Third, CEA production in each case was not confirmed in cells or tissues. To further address these issues, we are now conducting quantitative measurements of CEA mRNA levels in the tissues of each subtype.

[12]

[13]

[14]

[15]

8. Conclusion The results of the present study confirmed differences in serum CEA levels among lung adenocarcinoma subtypes, with higher values in APA, MPA, SPA, and IMA as well as lower values in AIS, MIA, PPA, and LPA. Because CEA promotes cancer progression through local invasion, metastasis, and immune suppression, [3,30,31] the poorer prognoses of MPA, SPA, and IMA, as reported by multiple institutions, [13,20–27] might be partly predictable by CEA overexpression. Further studies including larger numbers of patients are warranted to confirm this hypothesis.

[16] [17]

[18]

[19]

[20]

Conflicts of interest None.

[21]

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