Squamous Cell Carcinoma Antigen (SCC Ag) in the Diagnosis and
Prognosis of Lung Cancer*
julio Sanchez De Cos, M.D.; Fernando Masa, M.D.;
Jose L. de la Cruz, M.D.; Carlos Disdier, M.D.:
and Cannen Vergara , M.D.
Objective: We have studied the usefulness of squa- mous cell carcinoma antigen (SCC Ag) in diagnosis and prognosis of lung cancer (LC).
Material and Method.: We have measured the serum SCC Ag levels in 388 subjects: 69 healthy persons;
103 with nonmalignant lung diseases (NMLD); 24 with lung metastasis of extrapulmonary origin (LMEO); and 192 with LC (88, with squamous cell carcinoma [SCC] type). In 55 with SCC, we analyzed the survival time.
Results: Serum SCC Ag was above 2.5 nglml in 1.4 percent of healthy persons; 2.9 percent of those with NMLD; 8.3 percent of those with LMEO; and 27.6 percent of those with LC. Such percentage was 47.7 percent in SCC. In this type, there were significant differences according to the extent of disease (61.6 percent in advanced stages, and 26.5
I n the last few years, many tumor markers with potential utility in the clinical management of several neoplasias have arisen.
1With regard to lung cancer (LC), some markers have a good sensitivity and specificity in the small cell subtype (small-cell lung cancer [SCLC]), like the neuron-specific eno- lase2·4 or the B-B creatine kinase.
4However, with regard to non-small-cell lung can- cer (NSCLC) subtypes, the well-known markers (basically, carcinoembryonic antigen [CEA]) are not sufficiently sensitive or specific.
5•6Recently, some authors have investigated the utility in LC of the new tumor marker, squamous cell carcinoma antigen (SCC Ag) a substance that has been used successfully for diagnosis and detec- tion of recurrence in cervical squamous cell carci- noma (SCC).' The first results suggest a good speci- ficity of SCC Ag for SCC of the lung and also a possible usefulness in the follow-up and control of treatment of that disease.
8·9The objective of this work is to evaluate the clinical usefulness of SCC Ag in LC, by the serum determinations of this marker in patients with such neoplasia, and also in healthy people and patients with other lung disorders.
*From the Unit of Pneumology, Hospital "San Pedro de Alcantara," Caceres, Spain.
Manuscript received July 30, 1992; revision accepted August 5, 1993.
percent in localized stages, p
=
0.002). In the other types, the sensitivity was substantially lower. The initial SCC Ag has prognostic significance (p • 0.02) in the univariate analysis, but it loses such signifi- cance in a multivariate model, including the stage.Concluaiom: Therefore, we do not recommend this marker in the clinical management of patients with LC, even it can be useful in the differential diagno- sis if used in combination with other markers.
(Cheat 1994; 105: 773-76)
CEA " carcinoembryonic antigen; LC = lung cancer;
LMEO • lung metastasis of extrapulmonary orircfn;
NMLD • nonmalignant lung diseases; NSCLC • l'lron- small-cell lung cancer;
sec •
squamous cell carci- noma; SCC Ag • squamous cell carcinoma antigen; SCLC • small-cell lung cancerMATERIAL AND METHODS
We have carried out the measurements of SCC Ag by an enzyme immunoassay in 415 serum samples collected from 388 subjects: 69 healthy persons (volunteers from the sanitary and nonsanitary staff of our institution) and 316 patients consecu- tively diagnosed in our institution between November 1989 and July 1991. They were classified as follows: (la) healthy (lf"TSOns (69 cases); (lb) patients with nonmalignant lung disorders (NMLD) (tuberculosis, pneumonia, chronic obstructive pulmo- nary disease, hidatyd cyst, etc) (103 cases); (lc) patients with lung metastasis of extrapulmonary origin (LMEO) (mamma, colon, stomach, prostate, lymphoma, myeloma) (24 cases); and (2) Patients with LC ( 192 cases): SCC, 88 cases; SCLC, 54 cases;
adenocarcinoma, 35 cases; and large-cell lung cancer, 15 cases.
The patient's characteristics concerning age, sex, and stage are shown in Table 1. In relation to the stage, the patients were classified only in two groups: Stage A includes (1) patients with SCLC and limited disease; and (2) patients with NSCLC and stages I, II, and IliA of the TNM staging system.10 Stage B includes (1) patients with SCLC and extensive disease; and (2) patients with NSCLC and stages IIIB and IV of the TNM staging system.
Study Protocol In Patients With LC
We practiced clinical examination, laboratory analysis (com- plete blood cell counts, biochemistry, serum electrophoretic protein, and urinanalysis), chest radiograph, electrocardiogram, fiberoptic bronchoscopy with bronchial biopsy, and extent study by means of abdominal echography. In patients with suggestive symptoms or candidates for surgery, we also practiced complete radionuclide bone scan, and skull, chest, and superior abdomen computed tomography.
CHEST /105/3/ MARCH, 1994 773
Table 1 -Patient Characteristic•
Sex, % Age, yr.
n Mean (Range) M F Healthy subjects 69 43.05 (30-68) 53.6 46.4 Nonmalignant lung diseases 103 63.80 {17-90) 81.1 18.9 Metastatic lung 24 63.30 (29-87) 57.7 42.3
malignancies
Lung cancer 192 65.70 (35-88) 98.4 1.6 Lung Cancer. Histologic Subtypes, and Stage
Squamous cell Small cell Adenocarcinoma Large cell
Stage A, Stage B,
n(%) n(%)
34 (38.6) 22 (40.7) 9 (25.7) 2 (13.3)
54 (61.4) 32 (59.3) 26 (74.3) 13 (86.7)
Me1J811rements of Serum SCC Ag
Total, n (%) 88 (100) 54 (100) 35 (100) 15 (100)
The SCC Ag is a fraction of the tumor antigen TA-4, a new tumor marker that was extracted from
sec
tissue of the uterine cervix. The serum measurements have been performed by means of enzyme immunoassay of microparticles (Imxsec
Assay, Abbot).
We carried out SCC Ag determinations before treatment in all the patients included in the study.
Follow-up
After diagnosis, and/or treatment, the patients were reviewed in an outpatient clinic with 3 months interval until death. On finishing the study, 44 patients were dead. The period of follow- up for the other patients was from 9 to 24 months.
Statistical Methods
The comparison of percentages was carried out by means of X2 test, and the comparison of mean numbers, by the Wilcoxon test.
Survival distributions were compared by the log-rank test.
The proportional hazard model" was used to test the pretreat- ment variables. This provides information on independent prog- nostic factors.
RESULTS
Diagnostic Value
As you can see in Table 2, the serum SCC Ag concentrations were elevated only in 1.4 percent of healthy subjects. There were not significant differ- ences between male and female subjects.
Table 2 - Sen~m SCC Ag Concentrationa
Healthy subjects
Nonmalignant lung diseases Metastatic lung malignancies Lung cancer (total)
Squamous cell Small cell Adenocarcinoma Large cell
774
SCC Ag, nglml, Mean (Range) 0.62 (0.01-3.2) 0.78 (0.1-7.6) 1.53 (0.01-19.3) 4.27 (0.01-105) 6.98 (0.01-105) 1.24 (0.01-10) 1.69 (0.01-13.9) 5.35 (0.1-70)
sec
Ag>2.5 nglml,%
1.4 2.9 8.3 27.6 47.7 9.3 14.3 6.7
In patients with NMLD, only 2.9 percent had a high level of SCC Ag (specificity, 97.1 percent).
In the group with LMEO, 8.9 percent had a high value of SCC Ag.
The highest concentrations were observed in those with LC, not only with regard to mean numbers, but with regard to the percentage above the adopted threshold (27.6 percent).
In the LC group, there were important differ- ences according to the histologic subtype. The highest percentages of elevated serum SCC Ag numbers were registered in the sec type
(47percent). In the other types, such percentages were substantially lower.
For SCC subtype, the serum concentrations ac- cording to the stage are shown in Table 3. These concentrations were significantly higher in advanced stages (stage
B),not only with regard to mean numbers, but with regard to the percentage above 2.5 ng/ml.
Survival
First, we analyzed the variables "stage" and "se- rum SCC Ag number," by the univariate test (log- rank test) . As you can see in Figure I, the patients with initial SCC Ag less than 2.5 nglml had a longer survival (p
=0.02). Stage A was also associated with a better prognosis (p
=0.006) (this result is not shown in the figure).
Then, these two variables ("stage" and "SCC Ag number") were evaluated together by a multivariate model (the multivariate proportional hazard test) , and this test did not support a significant additional contribution of SCC Ag to prognosis.
DISCUSSION
It
has been demonstrated that the SCC Ag is useful in the control of treatment and detection of recurrence in cervical SCC.
7•12•13Afterwards, the value of this marker has been investigated in sec
type of other origins (larynx, esophagus, oral and facial tumors, etc) and the first results suggest a moderate usefulness in the follow-up of patients, even though the sensitivity is not high.
9•14Recently, some authors have carried out several studies oriented to the clinical application of sec
Ag in LC.
Concerning the diagnostic value, the increased
Table 3-SCC of the Lung, Sen.m SCC Ag, and StageStage A Stage B
(n = 34) (n =54) p Value SCC Ag, nglml, range 0.01-84 0.2-105
SCC Ag, nglml, mean 3.62 9.2 0.009
SCC Ag> 2.5 nglml, % 26.4 61.1 0.002
SCC Ag in Diagnosis and Prognosis of Lung Cancer (Sanchez De Cos at a/)
nl >
>
....
::J
"'
10
80
. '-·-·
I I
.... ,
I I
... ,
I I t '--·
,,
tI I
--sec
Ag < 2.5 ng1m1----· sec
Ag>
2.5 ngtmlp
= a.u
~--\ T
'
-·--·
I'
zo
I •i I I' I
-- --- - - ---- - -.- .. -
u u
I I t I
11.2
time <months>
Figure 1. Kaplan-Meier survival curves for patients with squamous cell carcinoma. Curves represent patients with SGG Ag < 2.5 nwml (solid line) and patients with SCC Ag > 2.5 n!¥ml (dashed line).
serum levels of this marker seem fairly specific for malignant disease. So, Mino et al
9could not detect serum SCC Ag concentrations above the cut-off point in patients with benign diseases. Neverthe- less, more recently, Body et
al~found elevated values of SCC Ag (above 3 ng/ml) in 11.1 percent of 90 patients with benign pulmonary diseases. This specificity (88.9 percent) was equal to that of the
CEA . ~
In our work, we observed a better specificity. So, we found a high value of the marker (above 2.5 ngl ml) only in 2.9 percent of 103 patients with NMLD.
However, the sensitivity of SCC Ag in LC is not high . In our series, the sensitivity for LC was 27.6 percent. Other authors have found figures of sensi- tivity that vary from 33
percent'~to 78.4 percent;
16•17the differences depend on the analytical method and the normal range adopted. In the study of Body et
al,~the sensitivity was 35 percent for the squa- mous LC, and clearly lower for the other types; they found that CEA was more sensitive (56 percent) with a similar specificity (88.9 percent), but, impor- tantly, CEA and SCC Ag did not give redundant information. In a previous work, we found that, using a cut-off point of 5 ng/ml, the sensitivity of CEA in LC was 47.6 percent, and the specificity was 80.0
percent.'~Concerning the histologic subtype in LC, only Lorenz et al
19registered the highest sensitivity for the adenocarcinoma. Most of the works that com- prise large series agree in the higher affinity be- tween SCC Ag and SCC type. This higher affinity
has also been proved by means of immunohis- tochemical studies.
20We also found the highest sensitivity for the sec type (47.7 percent), with an important difference over the other types (14.3 percent for adenocarcinoma, 9.2 percent for SCLC, and 6.7 percent for large cell LC).
With respect to the stage, unlike Body et al,
8we found significant differences in the serum SCC Ag concentrations according to the extent of disease.
So, in localized disease (stages I, II, and IliA of the TNM system), only 26.4 percent of patients had SCC Ag elevated, as opposed to 61.1 percent in those with advanced disease (stages IIIB and IV).
Therefore, the SCC Ag does not seem useful for early diagnosis of LC. However, if the high specific- ity that we have found is supported by additional studies, this marker can be useful in the differential diagnosis of a patient with suggestive symptoms of LC, especially if used in combination with other more sensitive markers.
Survival
Just as other authors,
8we have found a significant association between the initial serum SCC Ag and the survival time. This association is not surprising, since the marker has a good correlation with tumor burden and stage. Nevertheless, after staging the patients with usual procedures-staging which is necessary and irreplaceable with a view to treat- ment-the prognostic value of the TNM classifica- tion does not increase significantly with the knowl- edge of the initial serum SCC Ag.
CHEST/105/3/MARCH,1994 775
To sum up, we consider that SCC Ag is not useful for early diagnosis of LC, in view of the low sensitiv- ity in localized stages.
Ithas, occasionally, a moder- ate value in differential diagnosis, since a high concentration of the marker is very specific. The serum SCC Ag concentrations have a good correla- tion with tumor burden; therefore, they have prog- nostic significance, but this marker is not an inde- pendent prognostic factor when used in combination with the stage. Therefore, we do not recommend this marker in the clinical management of patients with LC.
ACKNOWLEDGMENT: Nuria de Ia Montana, B.A., assisted with the English translation.
REFERENCES
Bates SE. Clinical applications of serum tumor marker. Ann Intern Med 1991 ; 115:623-38
2 Burghuber OC, Worofka B, Schrnthaner C, Vetter N, Neumann M, Dudczak P, et al. Serum neuron specific enolase is a useful tumor marker for small cell lung cancer.
Cancer 1990; 65:1386-90
3 Jorgensen LCH, Hansen HH, Cooper EH. Neuron specific enolase, carcinoembryonic antigen and lactate dehydroge- nase as indicators of disease activity in small cell lung cancer.
Eur J Cancer Clin Oncol 1989; 25:123-28
4 Jaques C. Bepler C, Holle R, Wolf M, Hannich TH, Cropp C, et al. Prognostic value of pretreatment carcinoembryonic antigen, neuron specific enolase and creatine-kinase BB levels in sera of patients with small cell lung cancer. Cancer 1988; 62:125-34
5 Dent PB, McCulloch PB, Wesley-James 0 , MacLaren R, Muirhead W, Dun net CW. Measurements of carcinoembryonic antigens in patient with bronchogenic carcinoma. Cancer 1978; 42:1484-91
6 Stahel RA, Martz C. Prognostic and diagnostic usefulness of serum markers in lung cancer. Eur J Cancer Clin Oncol 1985; 25:1461-66
7 Kato H. Tarnai K, Morioka H, Nagai M, Nagaya M, Torigoe I. Tumor-antigen T A-4 in the detection of recurrence in cervical squamous cell carcinoma. Cancer 1984; 54:1544-46
776
8 Body
JJ,
Sculier JP, Haymakers N, Paesmans M, Ravez P, Libert P, et al. Evaluation of squamous cell carcinoma antigen as a new marker for lung cancer. Cancer 1990;65:1552-56
9 Mino N, Atsushi 110, Hamamoto K. Availability of tumor- antigen 4 as a marker of squamous cell carcinoma of the lung and other organs. Cancer 1988; 62:730-34
10 Mountain CF. A new international staging system for lung cancer. Chest 1986; 89:225S-33S
11 Cox DR. Regression models and life tables. JR Stat Soc 1972; 34:187-220
12 Duk JM . de Bruijn HW, Croenier KH, Hollema H, Ten Hoor KA, Krans M, et al. Cancer of the uterine cervix:
sensitivity and specificity of serum squamous cell carcinoma antigen determinations. Cancer 1990; 65:1830-37
13 Scambia C , Panici PB, Baiocchi C , Amoroso M, Foti E, Creggi S, et al. The value of squamous cell carcinoma antigen in patients with locally advanced cervical cancer undergoing neoadjuvant chemotherapy. Am J Obstet Cynecol 1991 ; 164:631-36
14 Fischbach W, Meyer T , Barthel K. Squamous cell carcinoma antigen in the diagnosis and treatment follow-up of oral and facial squamous cell carcinoma. Cancer 1990; 65:1321-24 15 Mizushima Y, Hirata H. Izumi S, Hoshino K, Konishi K,
Morikage T. Clinical significance of the number of positive tumor markers in assisting the diagnosis of lung cancer with multiple tumor marker assay. Oncology 1990; 47:43-8 16 Ebert W, Kayser K, Buelzebruck H, Vogt-Moykopfic. Diag-
nostic validity of the
sec
antigen assays in squamous cell carcinoma of the lung. J Tumor Marker Oncol 1988; 3:35-44 17 Ebert W, Welper-Rigling CH , Drings P. Utility of serum and pleural effusionsec
antigen assays for diagnosis of lung squamous cell carcinoma [abstract]. Eur Respir J 1990;3:218S
18 Sanchez de Cos
J.
Clinical utility of the tumor markers in lung cancer, Thesis. University of Extremadura, Spain, 1991 19 Lorenz J, Cillmann-Bium D, Jensen M, Kreinberg R. Neu-ron specific enolase (NSE) and squamous cell carcinoma antigen (SCC) as serum markers in the diagnosis of bronchial carcinoma. Pneumologie 1990; 44:1259-63
20 Mino-Miyagawa N, Kimura Y, Hamamoto K. Tumor-Antigen 4: its immunohistochemical distribution and tissue and se- rum concentrations in squamous cell carcinoma of the lung and esophagus. Cancer 1990; 66:1505-12
sec Ag in Diagnosis and Prognosis of Lung cancer (Sanchez De Cos st a/)
