ADONIS 0j077772910003YF

Clin. Omlurwqol. 1991. 16, 182-186

Carcinoembryonic antigen and head and neck cancer D . A . W . L A A R M A N , * G . J . V A N K A M P , t A.J.M.BALM,* B.J.M.BRAAKHUIS* & G.B.SNOW* Department of 'Otolaryngology and ?Clinical Chemistry. Free University Hospital, A m s t e r h . The Netherlands Accepted for publication 19 January 1990



V A N K A M P G . J . . B A L M A.J.M., B R A A K H U I S

B.J.M. & SNOW G . B .

(1991) Clin. Otoluryngol. 16, 182-186

Carcinoembryonic antigen and head and neck cancer Carcinoembryonic antigen (CEA)concentrations were determined in the sera of 45 patients with a head and neck squamoqs cell carcinoma and of 13 controls. In 13 patients serial CEA measurements were made during the follow-up period. In 38% of the patients the serum CEA level was slightly elevated ( 2 2.5 ng/ml). Only 13% of the patients had clearly elevated CEA levels ( > 5 ngjml). CEA levels were significantly higher in patients with advanced, e.g. stage IV, disease but a correlation between serum CEA concentration and prognosis was not found. Patients who smoked had significantly higher serum CEA levels than non-smoking patients. In the serial determinations slight CEA elevations could be found in only 50% of patients with tumour recurrence. Combined with the data from the literature we conclude that serum CEA determination is not useful in predicting the outcome in patients with a head and neck squamous carcinoma. Keywords carcinoembryonic antigen head and neck cancer squamous cell carcinoma

Introduction In 1965, Gold and Freeman discovered carcinoembryonic antigen (CEA),a glycoprotein with a molecular weight of about 180 kDa.' Since then, the clinical value of CEA in establishing prognosis and monitoring therapy has been demonstrated for carcinoma of the colon" as well as other malignancies. such as breast'-' and However, about 15-20'70 of these patients with proved cancers have normal serum CEA levels. Furthermore, raised CEA levels have also been found in the serum of cigarette smokers, of patients with benign neoplasms, and of patients with inflammatory disorders such as ulcerative colitis. Crohn's disease and pancreatitis.' This apparent lack of specificity limits the role of CEA in cancer diagnosis and screening. However, its importance in monitoring treatment, especially of cancer of the colon, is generally recognized.' In 1976 Silverman ei al.' investigated CEA levels in patients with a head and neck squamous cell carcinoma. They reported that CEA levels could be correlated to tumour stage. In their series, elevated CEA levels fell to normal after tumour resection or irradiation therapy so that serial deterCorrespondence: D.A.W.Laarman. Free University Hospital, D e Boelelaan I 117, 1007 MB Amsterdam, The Netherlands.


minations seemed to be of value in monitoring the treatment response. There seems to be a consensus of opinion in the literature that there is a positive correlation between serum CEA levels and tumour size,e".'' but not on the hypothesis that CEA is useful for monitoring treatment response. Some investigators have reported that elevated CEA concentrations returned to normal after successfuI treatment,"'0.'c16 but others have failed to find a correlation between the success of treatment and serum CEA concentration." It has become clear that CEA is elevated in a varying proportion of patients with a head and neck squamous cancer. This is partly due to the fact that different assays are used with different upper normal levels. More important is the fact that most patients with a head and neck cancer are heavy smokers, and thus may have elevated CEA serum levels due to smoking alone. Only a few investigators have chosen a higher upper norme! CEA concentration in order to prevent a high rate of false positive CEA concentrations due to ~ m o k i n g . ~ ~ " This study was undertaken to determine the role of serum CEA measurements in the management of head and neck squamous cell carcinoma. For this purpose, we investigated the prognostic value of CEA determination compared to clinical staging and the predictive value of serial CEA determinations during follow-up for detection of early tumour

Carcinoemhryonic. antigen and head and neck cancer


recurrence. Further, correlations were made between CEA concentrations. tumour stage and smoking history.

CEA was determined in 89 serum samples. In 17 of the 45 pretherapeutic samples (38%) CEA was 2 2.5 ng/ml. If an upper limit of 5 ng/ml was used 6 (13%) of the 45 patients had elevated levels. These 6 patients all had advanced disease, including the two patients with synchronous tumours. One patient had stage 111 and 5 patients had stage IV disease. The relationship between CEA levels is shown in Figure I . I t was found that CEA was elevated with advanced (i.e. stage IV) disease, namely in 5 of the I2 patients (41 YO)serum CEA exceeded 5 ng/ml. In the other stages only I of 20 patients (So/.) had a high serum CEA concentration. This difference was significant ( P< 0.05). We found no differences in survival between the patients with elevated and those with normal serum CEA levels in the stage IV disease group. Of these 12 patients 10 patients had positive neck nodes. Only 2 of these 12 patients are still alive; both patients had a normal pretreatment CEA. but, more importantly, these two patients were the only stage IV disease patients with a No neck status. These figures stress the importance of neck node status in the prognosis; at the same time they show that serum CEA estimation has no prognostic value. In 42 patients the smoking habits were known. Twenty-eight patients were smokers, 14 (500/.) of them had serum CEA levels higher than 2.5 ng/ml. Fourteen patients did not smoke: only three (21 %) of them had elevated serum CEA (Figure 2) ( P < 0.05, one-sided P-value Chi-squared test). As can be seen in Figure 2, there was little difference in tumour stage between the smokers with an elevated serum

Materials and methods Forty-five patients with a head and neck squamous cell carcinoma (39 men; 6 women; mean age 63 years (41-90 years)) were investigated in this study together with 13 control patients ( I 1 men; 2 women; mean age 57 years (3576 years)), with no clinical evidence of tumour or with a benign head and neck disease. Tumour sites were as follows: oral cavity 15; oropharynx 7; hypopharynx 4; larynx 14; nasal vestibule 3, and external ear 2. Of the 45 patients 35 had a previously untreated head and neck cancer and 32 of these could !x staged according to the TNM system." Two patients had synchronous tumours: one patient had a T,N2 laryngeal carcinoma and a T,N, bronchial carcinoma; the other patient had a T,N, hypopharyngeal carcinoma and a T,N, oropharyngeal carcinoma. Ten patients had a tumour recurrence at the beginning of this study. The mean follow-up time was 10.5 months (1-20 months). Venous blood samples were taken, allowed to clot, centrifuged, and stored a t -70°C until analysis. CEA was measured by using a solid-phase, double antibody immunoenzymatic assay (Abbott CEA EIA, North Chicago, 111.. USA). The upper normal limit, as established in our laboratory, was chosen to be 2.5 ng/ml. Pretreatment levels were determined from all 45 patients. In addition, from 13 of these patients serial determinations were made during the followup period. The data were analysed either by a Chi-squared test or by the Fisher-.Invin exact test.




+ +




i + + + +















n = 12

Tumour stage




n = 13

Figure I. Carrelation of CEA serum concentration with

tumour stage. - +, Patients: ...., 2.5 ng/ml; ---,5 ng/ml.


D . A . W.Laarman et al.


Smoker CEA>2-5

42 tumour patients Smoker Stage

Figure 2. Correlation of smoking habit with CEA concentration and tumour stage.




4 Stage




EC 0

3 0

28 tumour patients

CEA and the smokers with a normal CEA serum level. These figures strongly suggest that CEA elevation in patients with head and neck cancer is mainly caused by smoking. Of the control group, 7 patients smoked: 2 (28%) of them had serum CEA levels higher than 2.5 ng/ml, whereas one (16%) non-smoking control patient had a serum CEA 2 2.5 ng/ml. These differences were not significant. Of the 13 patients who were serially monitored 6 had tumour recurrence. Only 3 of these had slightly elevated CEA levels a t the time of recurrence. These 3 patients also had pretherapeutic elevated Serum CEA levels; the 3 other patients with normal serum CEA levels at the time of recurrence also had normal pretherapeutic CEA levels. In 3 of 4 cases the elevated pretherapeutic CEA returned to normal after successful therapy. Two patients who were free of tumour after successful therapy maintained elevated CEA values in the follow-up period.

Discussion CEA determination is useful in establishing prognosis and monitoring therapy in carcinoma of the colon.' In this disease, a pretherapeutic level of serum CEA > 10 ng/ml is correlated with a poorer prognosis.' A sustained and progressive rise after surgical resection of colorectal cancer is

,. . I I

Stage III 0







L "





Stage XI I

14 turnour patients

strong evidence of recurrence in which case further surgery is advocated." A general correlation between CEA and clinical response to chemotherapy has been reported. For patients with metastatic tumour. CEA may offer the only index to measure changes in tumour burden.' For head and neck cancer elevated pretherapeutic levels are reported in 28-58% of the patients if a 'cut-off concentration of 2.5 n d m l is chosen (Table I). In our series this figure was 38% and thus rather low and this may be due to the fact that a more specific assay with monoclonal antibodies was used. In the past. CEA estimations were performed using polyclonal immunoassays or even extraction procedures, less sensitive and specific than today's monoclonal technique. It is a well known fact that CEA is elevated in smokers. As most patients with head and neck cancer are heavy smokers. many authors advocate an upper limit of Serum CEA of 5 ng/ml and Silvermany even suggests 7 ndml. If we choose 5 n d m l as an upper limit we find the serum CEA levels elevated in only 13% of our patients. These patients all had advanced disease and therefore a poor prognosis. A direct correlation between serum CEA levels and prognosis of head and neck cancer has not been demonstrated by any study so far, nor in the present study (Table 2). This is in contrast to

Carcinoemhryonic antigen and head and neck cancer

Table 1. Percentage of elevated serum CEA values in head and neck cancer

Author Meeker)? Silveman9 Amiel'' Grossenbacherl' Bolla" Dcmard" SchrMerlI Y anagawal' Tothi& Gustafsson" Shiveleyl" This study

Upper limit of CEA (nglml) 2.5 5.0 5.0 10.0 2.5 10.0 10.0 5.0 2.5 5.0 10.0 5.0 20.0 2.5 5.0

Percentage of elevated values 58

Table 2. Correlations of elevated CEA values with tumour stage. prognosis and recurrence in head and neck cancer

Author No of cases 53

30 36 21 29 39 31

I76 57 65 72 238



28 7 61 19 19 38 I3


73 70 42


Meeker': Silverman' Amiel" Grossenbacher" Bolls I'

hardIJ Schr6derlI Yanagawa'" Toth14 Gustafsson" Shiveley" This study ~~

n.d. Not done.

Tumour stage









n.d. n.d.


+ -





n.d. n.d. n.d. n.d.





+ n.d. -





c n.d. n.d. -


+ Positive correlation; - no correlation.


the findings in colonic cancer. namely, that CEA has discriminating prognostic valuc for patients with the same tumour stage.> Thus. serum CEA is elevated only in advanced head and neck cancer. In these cases. serum CEA determination does not provide additional prognostic information. In our patients the smoking habits were known in 42. We found little difference in turnour stage between the smokers with an elevated serum CEA and the smokers with a normal CEA serum level (Figure 2). Furthermore, we found significantly greater elevation of serum CEA levels in the smoking patients compared to the non-smoking patients. Our results strongly suggest that serum CEA elevation in this group of patients is caused by smoking and only in a few cases by tumour burden. In patients with breast cancer the pretherapeutic levels are usually normal, but CEA levels are frequently elevated in early turnour recurrence: We found slightly elevated or normal CEA serum levels in patients with recurrence of disease and this is in accordance with the findings of other authors who failed to find a clear correlation of CEA with recurrence (Table 2). Although it has frequently been reported that elevated CEA levels return to normal after successful therapy,9.10.1"16 this might also be due to the fact that many patients stop smoking and this in itself is known to allow levels to return to normal.'' In conclusion, because of the low sensitivity and specificity, CEA determination is not useful for the diagnosis. screening and monitoring of head and neck cancer. Furthermore, it appears that the serum CEA level in patients with head and neck cancer does not provide prognostic information and is most probably determined by the smoking habits of the patient.

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SILVERMAN N.A., ALEXANDER J.C. & CHIUXIEN P.B. (1976) CEA levels in head and neck cancer. Cuncer 37, 2204-221 I YANAGAWAT., HAYASHI Y.. NlSHlDA T., YC6HlVA H., Y U R A Y.. AZUMA M. & SATO M. (1986) Immunohistochemical demonstration of carcinoembryonic antigen (CEA) on tissue sections from squamous cell head and neck cancer and plasma CEA levels of the patients. I n / . 1. O r d Surg. 15, 296306

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Carcinoembryonic antigen and head and neck cancer.

Carcinoembryonic antigen (CEA) concentrations were determined in the sera of 45 patients with a head and neck squamous cell carcinoma and of 13 contro...
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