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Ann Thorac Surg 2003;76:203-207
© 2003 The Society of Thoracic Surgeons

Original article: general thoracic

Immunohistochemical analysis of resectedclinical Stage I pulmonary adenocarcinomas withhigh preoperative levels of serumcarcinoembryonic antigen

Noriyoshi Sawabata, MDa,c*, Hiroshi Hirano, MDb, Masayoshi Inoue, MDa,c, Yoshitomo Okumura, MDa, Hiroki Asada, MDa,c, Shin-ichi Takeda, MDa,c, Hajime Maeda, MDa,c

a Division of Surgery, Osaka, Japan
b Division of Clinical Pathology, Toneyama National Hospital, Osaka, Japan
c Division of General Thoracic Surgery, Department of Surgery (E-1), Osaka University Graduate School of Medicine, Osaka, Japan

Accepted for publication January 22, 2003.

* Address reprint requests to Dr Sawabata, Division of Surgery, Toneyama National Hospital, 5-1-1 Toneyama, Toyonaka, Osaka, 560-8552, Japan.
e-mail: nori{at}toneyama.hosp.go.jp


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Comment
 References
 
BACKGROUND: Clinical stage I pulmonary adenocarcinoma (AD) patients with persistently high serum carcinoembryonic antigen (CEA) levels after surgery have a poor prognosis. Although CEA staining pattern is reported to be a prognostic indicator for patients with colorectal cancer, the relationship with lung cancer is unclear.

METHODS: One hundred eighteen patients with clinical stage I AD underwent surgery from 1993 to 1997. Of them, 19 (16%) patients with a high preoperative serum level of CEA and 19 randomly selected control patients with preoperatively normal CEA were studied. CEA staining of tumor specimens from each of the 38 patients was performed, and the staining patterns were then classified into two types: apical and diffuse.

RESULTS: Patients with normal postoperative serum CEA levels (group HN, n = 13) had a 5-year survival rate higher than those with persistently high postoperative serum CEA (group HH, n = 6). In a comparison between the two groups, apical patterns (n = 10) were only seen in group HN, and those who demonstrated an apical CEA staining pattern had a 5-year survival rate (5-YSR) of 80% as compared with 13% for those HN patients with only a diffuse pattern (p = 0.01). In the control group, 16 (84%) patients had an apical staining pattern and the other 3 patients showed no staining.

CONCLUSIONS: Patients with normalized serum CEA levels had a high chance of showing an apical staining pattern, which may be a very good prognosis predictor for patients with high preoperative levels of CEA.


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Comment
 References
 
Serum carcinoembryonic antigen (CEA) levels are abnormally high in 40% to 60% of patients with advanced non–small cell lung cancer (NSCLC) [1–3], and an elevated serum CEA level is a poor prognostic factor, even in patients with clinical stage I NSCLC [1, 4–11]. Furthermore, clinical stage I NSCLC patients with persistently high serum CEA levels after surgery have worse prognoses than those with postoperatively normalized serum CEA levels [12–14].

Few studies have assessed the relationship between clinical features of lung cancer patients with high serum CEA levels and the immunohistochemical staining patterns of primary lesions; however, CEA staining patterns have been reported to be a predictor of prognosis for patients with colorectal cancer [15–20].

We conducted a retrospective study of consecutive patients with clinical stage I pulmonary adenocarcinoma who had preoperatively high serum CEA levels, in order to investigate the relationship between the change in serum CEA level after surgery and histopathological features of the primary lesion.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Comment
 References
 
Patient characteristics
One hundred eighteen patients with clinical stage I pulmonary adenocarcinoma underwent surgery from 1993 to 1997 at Toneyama National Hospital. Among them, 19 (16%) with preoperatively high serum CEA levels were studied, and each was followed up for more than 5 years. These 19 patients were divided into two groups according to their postoperative serum CEA levels: those with persistently high serum CEA levels (group HH, n = 6) and those with normalized serum CEA levels following surgery (group HN, n = 13).

As a control group, 19 of the 99 remaining patients with preoperatively normal serum CEA levels were chosen randomly using Stat View 5.0 (Abacus Concept Inc, Berkley, CA). CEA staining of tumor specimens from each of the 38 patients studied was performed, and the staining patterns were then classified into two types: apical and diffuse.

Serum CEA measurement
Serum CEA levels were examined as a part of the routine preoperative and postoperative evaluations, and calculated using an enzyme-linked immunosorbent assay kit (IM-CEA assay system; Dynabotto, Tokyo, Japan). The level defined as normal in our hospital is 7.0 ng/mL, which is based on a 95% specificity level for benign lung disease. Postoperatively, serum CEA levels were reevaluated once, 3 months after the operation.

Patient survival
Survival data were obtained by reviewing hospital records and contacting the patients or their families. All surviving patients were contacted by March 2002; thus the observation periods ranged from 64 to 112 months, with a median of 88 months. Because clinical symptoms and radiographic studies are not sensitive enough to accurately diagnose early recurrence, a disease-free interval is difficult to calculate; therefore, survival was the major endpoint of the present study. Survival duration was measured from the operation date to the date of follow-up or death.

Histopathological analysis
A pathologist (H.H), one of the coauthors, observed tumor specimens from each of the 38 patients, which had previously been fixed in formalin solution and embedded in paraffin, without any clinical information. Immunohistochemical staining was carried out using an avidin-biotin-peroxidase complex method with the antibody for CEA (1:80; Lipshow, Philadelphia, PA). Detailed observations were made of the tumor histologic type and vessel invasion, as well as the staining pattern and intensity of CEA. The CEA staining pattern was classified as either apical or diffuse. Those tumors containing CEA immunoreactivity along the cytoplasmic membrane regardless of steric distribution were classified as apical (Fig 1), and those with only homogenous staining in the cytoplasm, including the cytoplasmic membrane, were classified as diffuse.



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  		Fig 1. Apical carcinoembryonic antigen (CEA) staining pattern. An apical pattern was defined as CEA immunoreactivity along the cytoplasmic membrane (arrows) regardless of steric distribution. (Hematoxylin & eosin, x200.)

 
Statistical analysis
A t test, {chi}-square test, and the Fischer’s exact test were used as appropriate. Survival curves were obtained using the Kaplan-Meier method. Comparisons of survival curves were carried out using a log-rank test. Statistical calculations were conducted using StatView 5.0 (Abacus Concept Inc), and values of p less than 0.05 were regarded as significant.


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Comment
 References
 
Patient characteristics
Patient characteristics are shown in Table 1. There were no statistically significant differences in demographics, clinical stage, or pathologic stage between the HH and HN groups, although the average serum CEA level was higher in group HH.


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  		Table 1. Characteristics of Patients With High Serum Carcinoembryonic Antigen Levels Before Surgery

 
Patient survival
Patients in group HH had a median survival time of 22 months and a 5-year survival rate (5-YSR) of 14%, whereas those in group HN had a 5-YSR of 74% (p = 0.006). There were nine deaths, of which, one was due to local relapse and eight to distant metastases (three brain metastases, two bone metastases, two lung metastases, and one in multiple regions). The 19 randomly selected control patients with preoperatively normal CEA had a 5-YSR of 89%.

Histologic characteristics of tumors
There were no statistically significant differences in prevalence of tumor differentiation, blood vessel invasion, or lymph duct invasion between group HH and group HN (Table 2).


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  		Table 2. Histological Characteristics of Tumors in the Present Study

 
Characteristics of CEA staining patterns
The preoperatively high CEA group had a positive CEA staining rate of 95% (18/19). After surgery, apical patterns were only found in group HN. However, there was no statistically significant difference in the ratio of CEA-positive cells and the intensity of CEA staining (Table 3). Furthermore, 84% (16/19) of the specimens from lung cancer patients with preoperatively normal serum CEA levels showed positive CEA staining with an apical pattern.


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  		Table 3. Characteristics of CEA Staining

 
Cea staining pattern characteristics
To determine characteristics of the CEA staining pattern for each patient, we carried out further analyses after dividing the patients into two groups, which consisted of those with an apical CEA staining pattern (Table 4) and those with only a diffuse CEA staining pattern (Table 5). Only patients in group HN (10/19) showed an apical CEA staining pattern. Furthermore, those with an apical CEA straining pattern had a 5-YSR of 80% as compared with 13% for those with only a diffuse CEA staining pattern (p = 0.01) (Fig 2).


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  		Table 4. Proportion of Patients With Preoperatively High Serum CEA Levels and Apical Staining Patterns

 

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  		Table 5. Proportion of Patients With Preoperatively High Serum CEA Levels and Diffuse Staining Patterns

 


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  		Fig 2. Survival curve for patients with preoperatively high serum carcinoembryonic antigen (CEA) levels based on staining pattern. Patients with pulmonary adenocarcinoma containing an apical CEA staining pattern had a 5-YSR of 80%, whereas those with only a diffuse staining pattern had a 5-YSR of 13% (p = 0.01). (YSR = year survival rate.)

 

   Comment
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Comment
References
 
Several studies have found that the prognosis for patients with preoperatively high serum CEA levels was poor [1, 4, 7, 9, 10], which has also been seen in c-stage I cases [7, 9, 11, 12]. Further, there have been many reports of the relationship between postoperative serum CEA levels and prognosis. Dent and colleagues [21] were the first to find that patients with high postoperative serum CEA levels had poor survival rates as compared with those with postoperatively normal levels. Further, Yoshimatsu and associates [22] reported that CEA half-time after surgery was closely related to disease-free survival. In addition, several studies involving only patients with c-stage I NSCLC [11, 13, 14] have revealed that patients with persistently high serum CEA levels had a worse survival rate than those with normalized levels.

Patients with early-stage NSCLC do not usually undergo induction therapy before surgery, though there are ongoing studies in this regard, including the BLOT study (phase II) [23] and the S9900: Intergroup Lung Cancer Trial (phase III), in which patients with early-stage NSCLC have been administered preoperative chemotherapy. Induction therapy is undertaken with the idea to improve the survival of patients with NSCLC. Thus, if patients with stage I NSCLC and a preoperatively high serum CEA level demonstrate a poor prognosis, it may be reasonable to perform induction therapy for them as well. However, only postoperatively persistently high serum CEA levels and pathologic stage, and not preoperative serum CEA levels, have been shown to be independent predictors of prognosis in a multivariate analysis [12]. Therefore, induction therapy for patients with persistently high serum CEA levels may be warranted, even though the prediction of postoperative serum CEA is impossible at this time. As a result, it is important to elucidate the characteristics that can distinguish patients with persistently high serum CEA levels from those who will attain normalized levels.

Several reports on the patterns of CEA immunoreactivity have revealed that a diffuse staining pattern is more indicative of tumor invasive capability than an apical pattern [15–20]. This clinical disadvantage may be due to the inhibitive effects of those molecules that contribute to the diffuse staining pattern, as with anoikis, which serves as a surveillance mechanism that preserves the normal architecture of human colonic crypts [24].

As for colorectal cancer patients, immunohistochemical localization of CEA has been shown to be a predictor of lymph node status [15–17], rate of recurrence [17, 18], and survival [16, 19, 20], and may also be effective for cases of lung cancer. In our present study, 100% of the apical staining pattern cases belonged to group HN patients, who had a 5-YSR of 80%. Thus, an apical CEA staining pattern may be an indicator of good survival, and a diffuse CEA staining pattern may be an indicator of poor survival in the case of pulmonary adenocarcinoma as well.

If a CEA staining pattern could be obtained for a specimen acquired using a biopsy technique such as trans-bronchial biopsy (TBB) before surgery, it may be helpful to reveal clinical features of the original lesion. Furthermore, c-stage I NSCLC patients with a preoperatively high serum CEA level might have a good chance of survival if the CEA staining pattern in the specimen obtained by TBB was apical. However, further study using specimens obtained by TBB are required.

In conclusion, a large number of patients with preoperatively high serum CEA levels followed by normalized serum CEA levels after surgery had tumors that demonstrated an apical CEA staining pattern, which might be a good predictor of long-term survival.


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Comment
 References
 

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