J Oral Maxillofac 48:1288-1292.
Surg
1990
for Squamous Cell Carcinoma-Antigen Detection of Squamous Cell and Mucoepidermoid Carcinoma After Primary Treatment: A Preliminary YASURO
Report
YOSHIMURA, DDS, PHD,* MASAFUMI OKA, DDS, PHD,t AND TOSHIO HARADA, DDS, PHD*
This study evaluated the efficacy of using the periodic measurement of the serum level of squamous cell carcinoma antigen (SCC-antigen) for determining the local recurrence and/or metastasis of squamous cell and mucoepidermoid carcinomas after primary treatment. It was found that at the time of clinical recognition of recurrence, the SCC-antigen level was normal, but metastasis to regional lymph nodes or to remote organs generally was accompanied by an increase of SCC-antigen. Changes in the SCCantigen level with mucoepidermoid carcinoma seemed to be less sensitive than with squamous cell carcinoma.
amine the value of measuring serum SCC-antigen levels in patients with SCC and mucoepidermoid carcinoma during the follow-up period.
Although inspection and palpation, as well as imaging techniques, are still the mainstays for determining the presence of head and neck tumors, recently the application of tumor markers also has been accepted as a valuable tool for diagnosis, predicting tumor extent, and determining parameters of treatment efficacy and prognosis.’ Since the discovery of SCC (squamous cell carcinoma)-antigen, the establishment of its measurement by Kato,2 and its recognition as a excellent tumor marker for SCC, reports on its use have appeared in the literature.3’4 However, the prognostic implications in the head and neck region have not been well examined. Therefore, this investigation was undertaken to ex-
Materials and Methods This study involved a total of 32 patients with SCC and 2 with mucoepidermoid carcinoma who had already been treated in the Department of Oral and Maxillofacial Surgery, Shimane Medical University. The anatomic sites of the SCCs were the tongue (12), maxillary sinus (8), gingiva (7), floor of the mouth (3), buccal mucosa (l), and oropharynx (1). The SCC patients were divided into three groups. Group A contained 17 patients completely free from cancer for more than 1 year after the last treatment. Group B was composed of 13 patients with evidence of tumor. In the latter group, there were three cases with only bcal recurrence (B-l group), four with no local recurrence but with regional lymph node or remote organ metastasis (B-2 group), and six with local tumors and concomitant metastasis to regional lymph nodes or to remote organs (B-3 group). Group C consisted of seven patients show-
Received from the Department of Oral and Maxillofacial Surgery, Shimane Medical University. * Professor. t Lecturer. $ Lecturer. Address correspondence and reprint requests to Dr Yoshimura: Denartment of Oral and Maxillofacial Surgery. - _. Shimane Medici University, 89-1, Enya Chd, Izumo City, Shimane (693) Japan. 0 1990 American
Association
of Oral and Maxillofacial Sur-
geons
0278-2391 I9014812-0008$3.00/O
1288
YOSHIMURA
1289
ET AL
ing no response to cancer treatment. Five patients overlapped both groups B and C. The two cases of mucoepidermoid carcinoma included in this study originated from the right sublingual gland (T2NlMO) and from the left maxillary sinus (T3NOMO), respectively. The description of the cancers followed the general rules for clinical and pathologic studies of head and neck cancer presented by the Union Internationale Contre le Cancer (UICC, 1987).5 As a rule, monitoring of EC-antigen in each patient was carried out beginning within the first 30 days after treatment and continuing for about 20 months, with, at most, 3-month intervals between these examinations. The estimation of SCC-antigen in serum was carried out by radioimmunoassay in the Special Reference Laboratory Inc, Tokyo.’ The upper normal limit of the SCC-antigen was 1.7 ng/mL in our series.4 Results Serum XC-antigen levels of SCCpatients in various conditions after primary treatment. Group A, in which patients showed neither recurrence nor metastasis more than 1 year after primary treat-
a
A
0
B C A FIGURE 1. SCC-antigen levels in the various oromaxiliary SCC patients after primary treatment. 0, Local recurrence without any other tissue involvement; A, primary tumor-free, but lymph node or remote organ metastases; m, local recurrence with lymph node or remote organ metastases; 0, tumor-free or deceased patient. A, Tumor-free patients; B, tumor-bearing patients; c, deceased patients (the value plotted in group C is the lowest after primary treatment).
ment, showed values under 1.7 ng/mL of serum SCC (Fig 1). The three cases with only local recurrence (group B-l) also had levels within normal limits, although in the latter group, two out of the three cases had recurrences detected very early. Locally tumor-free patients with metastasis to lymph nodes or the lung (group B-2) showed higher values; more than 1.7 ng/mL in three of four patients. All patients with local recurrence and concomitant metastasis to lymph nodes or remote organs (group B-3), who had not responded well to their primary treatments, showed a value above 1.7 ng/mL (Fig 1). SCC-antigen levels of patients who subsequently died (group C) were higher than normal in five of seven patients. The plotted values in Figure 1 of each patient in group C were the lowest levels between the period of postprimary treatment and death. The mean values of group A, B-l, B-2, B-3, and C represented 1.O, 1.2, 2.0, 2.5, and 2.1 ng/mL, respectively. In two cases of suspected recurrence, which eventually proved to be free from tumor in the biopsy specimens, the SCC-antigen levels were 1.3 and 0.9 ng/mL, respectively. Changes of XC-antigen levels after primary treatment in SCC patients. The SCC-antigen levels of four good and four poor prognosis patients are shown as representative cases in Figure 2. The good prognosis cases had low levels of SCC-antigen. Generally, when recurrence or metastasis could be clinically detected, the serum level of SCC-antigen had risen above normal, but when good control of the cancers was obtained, it went down to normal or near-normal levels. Squamous cell carcinoma patients with poor prognosis (cases 1, 3, and 4) had high levels of SCC-antigen in the serum not only at the beginning of posttreatment, but also during the follow-up period. Before their death they showed the highest levels. The tongue cancer patient (case 5) who underwent primary resection and bilateral radical neck dissection at different times showed a slightly higher level of SCC-antigen at the time of recognition of lung metastasis. Measurements of SCC-antigen were not carried out afterwards because of his admission to a different department. He eventually died of respiratory failure originating from pulmonary metastatic lesions without having any local or regional lesions. SCC antigen levels after primaly treatment of mucoepidermoid carcinomas. No clear-cut findings were obtained as in patients with SCC; namely, the SCC-antigen levels did not precisely indicate the recurrence and/or metastasis in the early stages. However, when the recurrent tumor mass grew, the
1290
EFFICACY
20.0
I.
7OY
F
L-maxillary
2.
58Y
F
L-glngival
3.
59Y
M
L-maxillary
4.
SlY
F
L-maxillary
5.
58Y
M
R-tongue
6.
43Y
M
L-maxillary
7.
54Y
M
L-tongue
8.
49Y
M
L-Qingival
sinus
ca.
(TJNCMO)
the
mandible
sinus
ca.
(T4NIMll
sinus
ca.
(T4NCMO)
ca.
ca.
of
MEASUREMENT
lT2NlMOl
21 19
(TZNZb,.,O) sinus
ca.
OF XC-ANTIGEN
ca.
(T4NOMO)
(TPNOMOI /2
10.0
ca.
of
the
13
mandible
(T2NO+iO) P
8.0
*:
Deceased
6.0
4.0
2.0
FIGURE 2.
SW-antigen tendency
in the serum showed
SCC-antigen levels of eight XC
a high level or a
to increase.
Report of Cases Case
I
A 57-year-old patient underwent excision of cancer from the right floor of the mouth, hemimandibulectomy, and radical neck dissection on June 13, 1986, after a diagnosis of mucoepidermoid tumor (T2NlMO) by biopsy. He then underwent a left radical neck dissection on August 18, 1986, because of suspicion of contralateral cervical lymph node metastasis. Local recurrence was suspected because of a submentosubmandibular hard elastic swelling discovered in November 1987. From that period until September 1988, the patient did not attend our department regularly. When the patient visited our department in September 1988, the tumor had grown to an uncontrollable extent. Palliative treatment was undertaken with radiation therapy (total dose, 50 Gy), and intermittent administration of UFT [l-(tetrahydro-2-furanyl)-S-fluorouracil, 100 mg plus uracil, 224 mg; Taiho Pharmaceutical, Tokyo, Japan], in a dosage of four to six capsules per day. OK-432 (biological response modifier) was also administered intermittently. At first, the tumor appeared to shrink to some extent due to the therapy, but then it rapidly grew larger. He died of his disease on March 24,1989. At autopsy, one metastatic deposit in the lung was macroscopically recognized.
patients.
The SCC antigen values of the patient were 1.1 ng/mL in the pretreatment period, and remained within normal levels for about 2 years after primary treatment. A high level first appeared in October 1988, when the tumor had become very large, and it decreased during palliative treatment. In a short time, the XC antigen levels again rose beyond the normal level (Fig 3).
Case 2 A mucoepidermoid carcinoma extending from the left maxillary sinus to the oral cavity was observed in a 78year-old man. Computed tomography imaging showed that the tumor had invaded the posterior sinus wall, into the left hard palate and alveolar bone inferiorly, and had destroyed the lateral maxillary sinus wall (T3NOMO). Radiation therapy (total dose, 50.4 Gy) combined with 5-FU administered through the left superficial temporal artery (total dose, 6,000 mg) was carried out. During the irradiation and infusion of 5-FU, tumor tissue vaporization using Nd-YAG and carbon dioxide lasers also was carried out three times. Aspiration of necrotic and necrobiotic tissues was aggressively undertaken. OK-432 was also administered after the completion of radiation. The tumor responded well to the treatment, disappearing completely. The patient has remained free from the tumor up to the present. Oral administration of UFT in a dosage of 3 capsules/day and interdermal injection of OK432 are being continued. The SCC antigen was 2.5 ng/mL at the first examina-
1291
YOSHIMURAET AL n9/ml
Intermittent of UFT@;
administration 4-6
capsules/day.
and
*Deceased
Continuous oral
administratIon
administratlcn
radical
of UFT@;
of CX-432;
3 capsules/day.
and
5KE
neck
I,
r
I
wlthin after
30 days
post
I
I
3M.
post 6M.
post SW.
,
I
I
post
IeM.
post
24M.
post
3oM.
primary
treatment
FIGURE 3. SCC-antigen levels of two patients with mucoepidermoid carcinoma after primary treatment. Case
1, Mucoepidermoid carcinoma of the right sublingual gland (TZNlMO). Cuse 2, Mucoepidermoid carcinoma of the left maxillary sinus (T3NOMO). The SCC value of case 1 stayed at a low level for a long time, and inspite of clinical recognition of recurrence, this level remained lower than 1.7 ng/mL. SCC-antigen did not rise until the tumor grew to be fairly large. Case 2 always remained at a normal level after primary treatment and the patient is now free from cancer.
tion on March 10, 1988, but the level has been in a normal range after treatment (Fig 3).
Discussion Detection of recurrence is sometimes difficult in the early stages, because operated or irradiated areas develop fibrotic scars. Furthermore, because reconstructive surgery changes anatomical arrangements, it prevents adequate inspection and palpation.6 However, if SCC-antigen levels are examined periodically and an upward tendency is detected, the possibility of recurrence and/or metastasis would seem to be great. It was generally shown in this study that SCC-antigen levels rose beyond normal levels or continuously remained above 1.7 ng/mL in the patients with metastasis to regional lymph nodes or remote organ metastasis in the follow-up period. There were three cases positive for local recurrence in spite of low serum levels of SCC-antigen. This would support the efficacy of using inspection over SCC-antigen level monitoring, although two of the three cases were at a very early stage of local
recurrence. It may be that XC-antigen produced by recurrent SCC is diluted in the circulation and, therefore, is not ready detected. On the other hand, two different cases of clinically detected local recurrence eventually proved to be suture abscess and dyskeratotic change, respectively, also showed low levels of SCC-antigen. Nine of 10 patients with metastatic deposits in the body, with or without local recurrence, showed a high level of SCC-antigen, ie, spread of the cancer brought about an elevation of SCC-antigens in the serum. Among seven deceased patients, the further advanced the disease, the higher the measurable SCC-antigen levels. Patients with mucoepidermoid carcinoma, which possesses SCC components in the cancer tissue, also showed high levels of WC-antigen in the serum; however, it was only ascertained in several advanced stages of recurrence. As shown, it is very beneficial to check SCCantigen serum levels periodically in patients with SCC and mucoepidermoid carcinoma; however, clinicians who treat head and neck cancer should not only determine recurrence or metastasis by use of
1292
DISCUSSION
tumor markers, but also by clinical imaging procedures.
examination
and
References 1. Waldmann TA, Herberman RB: Tumor markers in diagnosis and in monitoring therapy, in Hollander JF, Frei E (eds): Cancer Medicine ted 21. Philadelnhia. Lea & Febiger. _ _ 1982 pp 1068-1089. 2. Kato H, Torigoe T: Radioimmunoassay for tumor antigen of human cervical squamous cell carcinoma. Cancer 40: 1621, 1977
J Oral Maxillofac
3. Maruo T, Shibata K, Kimura A, et al: Tumor-associated antigen, TA-4, in the monitoring of the effects of therapy for squamous cell carcinoma of the uterine cervix. Serial determinations and tissue localization. Cancer 56:302. 1985 4. Yoshimura Y, Harada T, Oka M, et al: Squamous cell carcinoma antigen in the serum of oromaxillary cancer. Int J Oral Maxillofac Surg 17:49, 1988 5. Hermanek P, Sobin LH: UICC International Union Against Cancer: TNM classification of malignant tumours (ed 4). Berlin, Springer-Verlag, 1987, pp 13-22, 27-32 6. Ikeda H, Nishiyama K, Inoue T, et al: The role of computed tomography in the follow-up of cancers of the head and neck. Jpn J Cancer Clin 32:8, 1986
Surg
48:1292-1293,lwo
Discussion Squamous Cell Carcinoma-Antigen for Detection of Squamous Cell and Mucoepidermoid Carcinoma After Primary Treatment: A Preliminary Report Charles N. Bertolami, DDS, DMedSc, and Dianna V. Messadi, BDS, MMedSc, DMedSc UCLA School of Dentistry, Los Angeles, California
SCC (squamous cell carcinomatantigen is a subfraction of tumor antigen TA-4 isolated from cervical SCCs. Elevated SCC-antigen levels (defined as greater than 2.5 ng/mL) have been reported in 4% of normal controls and 76% of women with recurrent cervical SCC. The positivity rate of the antigen has been correlated with tumor stage and lymph node involvement.’ The purpose of the present investigation was to ascertain whether serum levels of SCC-antigen are positively correlated with recurrence and/or metastasis of oral SCC and mucoepidermoid carcinoma. The study concludes that recurrence of SCC alone is not associated with a change in serum SCCantigen levels; however, antigen levels do increase in the event of metastasis. Little can be said about the value of SCC-antigen determination for patients with mucoepidermoid carcinoma inasmuch as only two subjects were studied and, for 11 of 14 determinations, their antigen levels were within the normal range (below 1.7 ng/mL). Admittedly, obtaining sufficient numbers of clinical patients to allow unequivocal conclusions is immensely difficult; however, the present investigation is compromised because of few subjects (34) and a large number of separate variables (eg, freedom from tumor, no local recurrence but with metastasis locally, local recurrence and metastasis, nonresponsiveness to treatment). The data in Figure 1 are encouraging, provided they are not overinterpreted. Figure 2 is especially problematic because the presented patients are described as “representative” but no criteria for “representativeness” are given. Four patients were selected as a so-called “good” responder group and four as a “poor responder” group. How do the investigators know if the chosen subset of
patients is representative unless they have comparable plots for all 34 patients? If such plots exist, why are they not presented? Doing so could certainly strengthen the assertion of correlation between high SCC-antigen levels and poor prognosis. If the selection process was based on choosing three patients who died and four who did well and then plotting results back to their starting SCCantigen levels, the data would have no real prognostic value because only patients who fit the desired “prognostication” outcome ahead of time were included. Even if, at the outset, the investigators selected four patients whose starting SCC-antigen level was above 1.7 ng/mL and whose values subsequently increased (the poor prognosis group) for comparison with four whose starting value was below 1.7 ng/mL (the good prognosis group), the conclusion still would be invalid unless there is comparable information for the other 26 patients in the study. Equally important, not all the survivors were observed for the same period of time. In fact, none of the survivors was observed for as long as patient 1, who died in month 20. Who can guess the fate of any of the so-called survivors, when one third of those who died did so at 18 to 20 months and none of the survivors were observed beyond 18 months? One survivor (patient 7) was followed for only 11 months. Had the study been stopped at this point (or at any time up to 19 months), an argument against prognostic significance could have been made. Certainly, by following patients for different periods of time, the investigators are vulnerable to the accusation that they stopped the study when the data yielded the conclusion they were looking for. Patient 5 is a particular problem because this individual is identified in Figure 2 as a “good prognosis” case but, in fact, died as a consequence of pulmonary metastasis. Figure 3 simply has too few patients to draw any conclusions and so the statement that “it is very beneficial to check SCC-antigen serum levels in patients with SCC and mucoepidermoid carcinoma periodically” is not substantiated by the data presented. Although the present study has an insufficient data base to draw meaningful conclusions, the use of SCC-antigen levels for diagnosis and prognostication is an interesting
Surg
1990
for Squamous Cell Carcinoma-Antigen Detection of Squamous Cell and Mucoepidermoid Carcinoma After Primary Treatment: A Preliminary YASURO
Report
YOSHIMURA, DDS, PHD,* MASAFUMI OKA, DDS, PHD,t AND TOSHIO HARADA, DDS, PHD*
This study evaluated the efficacy of using the periodic measurement of the serum level of squamous cell carcinoma antigen (SCC-antigen) for determining the local recurrence and/or metastasis of squamous cell and mucoepidermoid carcinomas after primary treatment. It was found that at the time of clinical recognition of recurrence, the SCC-antigen level was normal, but metastasis to regional lymph nodes or to remote organs generally was accompanied by an increase of SCC-antigen. Changes in the SCCantigen level with mucoepidermoid carcinoma seemed to be less sensitive than with squamous cell carcinoma.
amine the value of measuring serum SCC-antigen levels in patients with SCC and mucoepidermoid carcinoma during the follow-up period.
Although inspection and palpation, as well as imaging techniques, are still the mainstays for determining the presence of head and neck tumors, recently the application of tumor markers also has been accepted as a valuable tool for diagnosis, predicting tumor extent, and determining parameters of treatment efficacy and prognosis.’ Since the discovery of SCC (squamous cell carcinoma)-antigen, the establishment of its measurement by Kato,2 and its recognition as a excellent tumor marker for SCC, reports on its use have appeared in the literature.3’4 However, the prognostic implications in the head and neck region have not been well examined. Therefore, this investigation was undertaken to ex-
Materials and Methods This study involved a total of 32 patients with SCC and 2 with mucoepidermoid carcinoma who had already been treated in the Department of Oral and Maxillofacial Surgery, Shimane Medical University. The anatomic sites of the SCCs were the tongue (12), maxillary sinus (8), gingiva (7), floor of the mouth (3), buccal mucosa (l), and oropharynx (1). The SCC patients were divided into three groups. Group A contained 17 patients completely free from cancer for more than 1 year after the last treatment. Group B was composed of 13 patients with evidence of tumor. In the latter group, there were three cases with only bcal recurrence (B-l group), four with no local recurrence but with regional lymph node or remote organ metastasis (B-2 group), and six with local tumors and concomitant metastasis to regional lymph nodes or to remote organs (B-3 group). Group C consisted of seven patients show-
Received from the Department of Oral and Maxillofacial Surgery, Shimane Medical University. * Professor. t Lecturer. $ Lecturer. Address correspondence and reprint requests to Dr Yoshimura: Denartment of Oral and Maxillofacial Surgery. - _. Shimane Medici University, 89-1, Enya Chd, Izumo City, Shimane (693) Japan. 0 1990 American
Association
of Oral and Maxillofacial Sur-
geons
0278-2391 I9014812-0008$3.00/O
1288
YOSHIMURA
1289
ET AL
ing no response to cancer treatment. Five patients overlapped both groups B and C. The two cases of mucoepidermoid carcinoma included in this study originated from the right sublingual gland (T2NlMO) and from the left maxillary sinus (T3NOMO), respectively. The description of the cancers followed the general rules for clinical and pathologic studies of head and neck cancer presented by the Union Internationale Contre le Cancer (UICC, 1987).5 As a rule, monitoring of EC-antigen in each patient was carried out beginning within the first 30 days after treatment and continuing for about 20 months, with, at most, 3-month intervals between these examinations. The estimation of SCC-antigen in serum was carried out by radioimmunoassay in the Special Reference Laboratory Inc, Tokyo.’ The upper normal limit of the SCC-antigen was 1.7 ng/mL in our series.4 Results Serum XC-antigen levels of SCCpatients in various conditions after primary treatment. Group A, in which patients showed neither recurrence nor metastasis more than 1 year after primary treat-
a
A
0
B C A FIGURE 1. SCC-antigen levels in the various oromaxiliary SCC patients after primary treatment. 0, Local recurrence without any other tissue involvement; A, primary tumor-free, but lymph node or remote organ metastases; m, local recurrence with lymph node or remote organ metastases; 0, tumor-free or deceased patient. A, Tumor-free patients; B, tumor-bearing patients; c, deceased patients (the value plotted in group C is the lowest after primary treatment).
ment, showed values under 1.7 ng/mL of serum SCC (Fig 1). The three cases with only local recurrence (group B-l) also had levels within normal limits, although in the latter group, two out of the three cases had recurrences detected very early. Locally tumor-free patients with metastasis to lymph nodes or the lung (group B-2) showed higher values; more than 1.7 ng/mL in three of four patients. All patients with local recurrence and concomitant metastasis to lymph nodes or remote organs (group B-3), who had not responded well to their primary treatments, showed a value above 1.7 ng/mL (Fig 1). SCC-antigen levels of patients who subsequently died (group C) were higher than normal in five of seven patients. The plotted values in Figure 1 of each patient in group C were the lowest levels between the period of postprimary treatment and death. The mean values of group A, B-l, B-2, B-3, and C represented 1.O, 1.2, 2.0, 2.5, and 2.1 ng/mL, respectively. In two cases of suspected recurrence, which eventually proved to be free from tumor in the biopsy specimens, the SCC-antigen levels were 1.3 and 0.9 ng/mL, respectively. Changes of XC-antigen levels after primary treatment in SCC patients. The SCC-antigen levels of four good and four poor prognosis patients are shown as representative cases in Figure 2. The good prognosis cases had low levels of SCC-antigen. Generally, when recurrence or metastasis could be clinically detected, the serum level of SCC-antigen had risen above normal, but when good control of the cancers was obtained, it went down to normal or near-normal levels. Squamous cell carcinoma patients with poor prognosis (cases 1, 3, and 4) had high levels of SCC-antigen in the serum not only at the beginning of posttreatment, but also during the follow-up period. Before their death they showed the highest levels. The tongue cancer patient (case 5) who underwent primary resection and bilateral radical neck dissection at different times showed a slightly higher level of SCC-antigen at the time of recognition of lung metastasis. Measurements of SCC-antigen were not carried out afterwards because of his admission to a different department. He eventually died of respiratory failure originating from pulmonary metastatic lesions without having any local or regional lesions. SCC antigen levels after primaly treatment of mucoepidermoid carcinomas. No clear-cut findings were obtained as in patients with SCC; namely, the SCC-antigen levels did not precisely indicate the recurrence and/or metastasis in the early stages. However, when the recurrent tumor mass grew, the
1290
EFFICACY
20.0
I.
7OY
F
L-maxillary
2.
58Y
F
L-glngival
3.
59Y
M
L-maxillary
4.
SlY
F
L-maxillary
5.
58Y
M
R-tongue
6.
43Y
M
L-maxillary
7.
54Y
M
L-tongue
8.
49Y
M
L-Qingival
sinus
ca.
(TJNCMO)
the
mandible
sinus
ca.
(T4NIMll
sinus
ca.
(T4NCMO)
ca.
ca.
of
MEASUREMENT
lT2NlMOl
21 19
(TZNZb,.,O) sinus
ca.
OF XC-ANTIGEN
ca.
(T4NOMO)
(TPNOMOI /2
10.0
ca.
of
the
13
mandible
(T2NO+iO) P
8.0
*:
Deceased
6.0
4.0
2.0
FIGURE 2.
SW-antigen tendency
in the serum showed
SCC-antigen levels of eight XC
a high level or a
to increase.
Report of Cases Case
I
A 57-year-old patient underwent excision of cancer from the right floor of the mouth, hemimandibulectomy, and radical neck dissection on June 13, 1986, after a diagnosis of mucoepidermoid tumor (T2NlMO) by biopsy. He then underwent a left radical neck dissection on August 18, 1986, because of suspicion of contralateral cervical lymph node metastasis. Local recurrence was suspected because of a submentosubmandibular hard elastic swelling discovered in November 1987. From that period until September 1988, the patient did not attend our department regularly. When the patient visited our department in September 1988, the tumor had grown to an uncontrollable extent. Palliative treatment was undertaken with radiation therapy (total dose, 50 Gy), and intermittent administration of UFT [l-(tetrahydro-2-furanyl)-S-fluorouracil, 100 mg plus uracil, 224 mg; Taiho Pharmaceutical, Tokyo, Japan], in a dosage of four to six capsules per day. OK-432 (biological response modifier) was also administered intermittently. At first, the tumor appeared to shrink to some extent due to the therapy, but then it rapidly grew larger. He died of his disease on March 24,1989. At autopsy, one metastatic deposit in the lung was macroscopically recognized.
patients.
The SCC antigen values of the patient were 1.1 ng/mL in the pretreatment period, and remained within normal levels for about 2 years after primary treatment. A high level first appeared in October 1988, when the tumor had become very large, and it decreased during palliative treatment. In a short time, the XC antigen levels again rose beyond the normal level (Fig 3).
Case 2 A mucoepidermoid carcinoma extending from the left maxillary sinus to the oral cavity was observed in a 78year-old man. Computed tomography imaging showed that the tumor had invaded the posterior sinus wall, into the left hard palate and alveolar bone inferiorly, and had destroyed the lateral maxillary sinus wall (T3NOMO). Radiation therapy (total dose, 50.4 Gy) combined with 5-FU administered through the left superficial temporal artery (total dose, 6,000 mg) was carried out. During the irradiation and infusion of 5-FU, tumor tissue vaporization using Nd-YAG and carbon dioxide lasers also was carried out three times. Aspiration of necrotic and necrobiotic tissues was aggressively undertaken. OK-432 was also administered after the completion of radiation. The tumor responded well to the treatment, disappearing completely. The patient has remained free from the tumor up to the present. Oral administration of UFT in a dosage of 3 capsules/day and interdermal injection of OK432 are being continued. The SCC antigen was 2.5 ng/mL at the first examina-
1291
YOSHIMURAET AL n9/ml
Intermittent of UFT@;
administration 4-6
capsules/day.
and
*Deceased
Continuous oral
administratIon
administratlcn
radical
of UFT@;
of CX-432;
3 capsules/day.
and
5KE
neck
I,
r
I
wlthin after
30 days
post
I
I
3M.
post 6M.
post SW.
,
I
I
post
IeM.
post
24M.
post
3oM.
primary
treatment
FIGURE 3. SCC-antigen levels of two patients with mucoepidermoid carcinoma after primary treatment. Case
1, Mucoepidermoid carcinoma of the right sublingual gland (TZNlMO). Cuse 2, Mucoepidermoid carcinoma of the left maxillary sinus (T3NOMO). The SCC value of case 1 stayed at a low level for a long time, and inspite of clinical recognition of recurrence, this level remained lower than 1.7 ng/mL. SCC-antigen did not rise until the tumor grew to be fairly large. Case 2 always remained at a normal level after primary treatment and the patient is now free from cancer.
tion on March 10, 1988, but the level has been in a normal range after treatment (Fig 3).
Discussion Detection of recurrence is sometimes difficult in the early stages, because operated or irradiated areas develop fibrotic scars. Furthermore, because reconstructive surgery changes anatomical arrangements, it prevents adequate inspection and palpation.6 However, if SCC-antigen levels are examined periodically and an upward tendency is detected, the possibility of recurrence and/or metastasis would seem to be great. It was generally shown in this study that SCC-antigen levels rose beyond normal levels or continuously remained above 1.7 ng/mL in the patients with metastasis to regional lymph nodes or remote organ metastasis in the follow-up period. There were three cases positive for local recurrence in spite of low serum levels of SCC-antigen. This would support the efficacy of using inspection over SCC-antigen level monitoring, although two of the three cases were at a very early stage of local
recurrence. It may be that XC-antigen produced by recurrent SCC is diluted in the circulation and, therefore, is not ready detected. On the other hand, two different cases of clinically detected local recurrence eventually proved to be suture abscess and dyskeratotic change, respectively, also showed low levels of SCC-antigen. Nine of 10 patients with metastatic deposits in the body, with or without local recurrence, showed a high level of SCC-antigen, ie, spread of the cancer brought about an elevation of SCC-antigens in the serum. Among seven deceased patients, the further advanced the disease, the higher the measurable SCC-antigen levels. Patients with mucoepidermoid carcinoma, which possesses SCC components in the cancer tissue, also showed high levels of WC-antigen in the serum; however, it was only ascertained in several advanced stages of recurrence. As shown, it is very beneficial to check SCCantigen serum levels periodically in patients with SCC and mucoepidermoid carcinoma; however, clinicians who treat head and neck cancer should not only determine recurrence or metastasis by use of
1292
DISCUSSION
tumor markers, but also by clinical imaging procedures.
examination
and
References 1. Waldmann TA, Herberman RB: Tumor markers in diagnosis and in monitoring therapy, in Hollander JF, Frei E (eds): Cancer Medicine ted 21. Philadelnhia. Lea & Febiger. _ _ 1982 pp 1068-1089. 2. Kato H, Torigoe T: Radioimmunoassay for tumor antigen of human cervical squamous cell carcinoma. Cancer 40: 1621, 1977
J Oral Maxillofac
3. Maruo T, Shibata K, Kimura A, et al: Tumor-associated antigen, TA-4, in the monitoring of the effects of therapy for squamous cell carcinoma of the uterine cervix. Serial determinations and tissue localization. Cancer 56:302. 1985 4. Yoshimura Y, Harada T, Oka M, et al: Squamous cell carcinoma antigen in the serum of oromaxillary cancer. Int J Oral Maxillofac Surg 17:49, 1988 5. Hermanek P, Sobin LH: UICC International Union Against Cancer: TNM classification of malignant tumours (ed 4). Berlin, Springer-Verlag, 1987, pp 13-22, 27-32 6. Ikeda H, Nishiyama K, Inoue T, et al: The role of computed tomography in the follow-up of cancers of the head and neck. Jpn J Cancer Clin 32:8, 1986
Surg
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Discussion Squamous Cell Carcinoma-Antigen for Detection of Squamous Cell and Mucoepidermoid Carcinoma After Primary Treatment: A Preliminary Report Charles N. Bertolami, DDS, DMedSc, and Dianna V. Messadi, BDS, MMedSc, DMedSc UCLA School of Dentistry, Los Angeles, California
SCC (squamous cell carcinomatantigen is a subfraction of tumor antigen TA-4 isolated from cervical SCCs. Elevated SCC-antigen levels (defined as greater than 2.5 ng/mL) have been reported in 4% of normal controls and 76% of women with recurrent cervical SCC. The positivity rate of the antigen has been correlated with tumor stage and lymph node involvement.’ The purpose of the present investigation was to ascertain whether serum levels of SCC-antigen are positively correlated with recurrence and/or metastasis of oral SCC and mucoepidermoid carcinoma. The study concludes that recurrence of SCC alone is not associated with a change in serum SCCantigen levels; however, antigen levels do increase in the event of metastasis. Little can be said about the value of SCC-antigen determination for patients with mucoepidermoid carcinoma inasmuch as only two subjects were studied and, for 11 of 14 determinations, their antigen levels were within the normal range (below 1.7 ng/mL). Admittedly, obtaining sufficient numbers of clinical patients to allow unequivocal conclusions is immensely difficult; however, the present investigation is compromised because of few subjects (34) and a large number of separate variables (eg, freedom from tumor, no local recurrence but with metastasis locally, local recurrence and metastasis, nonresponsiveness to treatment). The data in Figure 1 are encouraging, provided they are not overinterpreted. Figure 2 is especially problematic because the presented patients are described as “representative” but no criteria for “representativeness” are given. Four patients were selected as a so-called “good” responder group and four as a “poor responder” group. How do the investigators know if the chosen subset of
patients is representative unless they have comparable plots for all 34 patients? If such plots exist, why are they not presented? Doing so could certainly strengthen the assertion of correlation between high SCC-antigen levels and poor prognosis. If the selection process was based on choosing three patients who died and four who did well and then plotting results back to their starting SCCantigen levels, the data would have no real prognostic value because only patients who fit the desired “prognostication” outcome ahead of time were included. Even if, at the outset, the investigators selected four patients whose starting SCC-antigen level was above 1.7 ng/mL and whose values subsequently increased (the poor prognosis group) for comparison with four whose starting value was below 1.7 ng/mL (the good prognosis group), the conclusion still would be invalid unless there is comparable information for the other 26 patients in the study. Equally important, not all the survivors were observed for the same period of time. In fact, none of the survivors was observed for as long as patient 1, who died in month 20. Who can guess the fate of any of the so-called survivors, when one third of those who died did so at 18 to 20 months and none of the survivors were observed beyond 18 months? One survivor (patient 7) was followed for only 11 months. Had the study been stopped at this point (or at any time up to 19 months), an argument against prognostic significance could have been made. Certainly, by following patients for different periods of time, the investigators are vulnerable to the accusation that they stopped the study when the data yielded the conclusion they were looking for. Patient 5 is a particular problem because this individual is identified in Figure 2 as a “good prognosis” case but, in fact, died as a consequence of pulmonary metastasis. Figure 3 simply has too few patients to draw any conclusions and so the statement that “it is very beneficial to check SCC-antigen serum levels in patients with SCC and mucoepidermoid carcinoma periodically” is not substantiated by the data presented. Although the present study has an insufficient data base to draw meaningful conclusions, the use of SCC-antigen levels for diagnosis and prognostication is an interesting
