Carcinoembryonic antigen in patients with intraeranial tumors

Transcription

1 J Neurosurg 53: , 980 Carcnoembryonc antgen n patents wth ntraeranal tumors YASUO SUZUKI, M.D., AND RvuIfm TANAKA, M.D. Department of Neurosurgery, Bran Research Insttute, Ngata Unversty, Ngata, Japan Carcnoembryonc antgen (CEA) n plasma, cerebrospnal flud (CSF), and tumor cyst flud obtaned from patents wth a varety of ntracranal tumors was determned by radommunoassay. Slghtly elevated levels of plasma CEA, rangng from 2.6 to 3.8 ng/ml, were noted n sx (4%) of 6 patents wth prmary bran tumors: n three glomas, two pneal tumors, and one acoustc neurnoma, respectvely. On the other hand, 7 (37%) of 46 patents wth metastatc bran tumors showed a defnte elevaton, and most of them had values hgher than 5.0 ng/ml. Of 37 patents wth prmary bran tumors, only one wth a pneal germnoma showed a sgnfcant elevaton of CEA n CSF, whereas eght (44%) of 8 patents wth metastatc bran tumors showed hgh values of CEA n CSF. All sx patents wth leptomenngeal carcnomatoss showed elevated CEA n CSF. Levels of CEA n tumor cyst flud were determned n 7 patents wth ntracranal tumors, ncludng 2 glomas, two cranopharyngomas, two metastatc tumors, and one menngoma; elevaton of CEA n tumor flud was noted n two cranopharyngomas and one metastatc tumor. Sequental determnaton of CEA n plasma or CSF revealed that the CEA levels were well correlated wth the actvty of bran tumors. Consequently, the determnaton of CEA n plasma or CSF s valuable for the dfferental dagnoss between prmary and metastatc bran tumors and for the management of CEA-producng tumors. KEY WORDS 9 carcnoembryonc antgen 9 ntracranal tumor 9 metastatc bran tumor 9 leptomenngeal carcnomatoss S INCE the frst report of Gold and Freedman 2 n 965 descrbng carcnoembryonc antgen (CEA) extracted from colonc carcnoma as a tumor-specfc antgen, numerous nvestgators have shown that a marked elevaton of plasma CEA levels can be recorded n patents wth varous other types of cancer, and that a moderate ncrease of plasma CEA levels can also be observed n several noncancerous condtons or n apparently healthy subjects? In spte of the lack of tumor and organ specfcty, CEA assay has been found useful n the management of cancer, ncludng evaluaton of treatment or detecton of recurrence, as well as n screenng for cancer? '2 However, the clncal sgnfcance of CEA assay n patents wth ntracranal tumors has not been establshed, although several reports have descrbed CEA values n a lmted number of patents wth ntracranal tumors. 5,~76 The purpose of the present paper s to evaluate the usefulness of CEA assays n plasma, cerebrospnal flud (CSF), and tumor cyst flud that were performed n a large number of patents wth a varety of ntracranal tumors. Clncal Materal Clncal Materal and Methods A total of 285 patents were ncluded n ths study. The patents tested for CEA are shown n Table. Plasma CEA was determned n 253 patents wth 388 assays, ncludng 6 cases of prmary bran tumor, 46 of metastatc bran tumor, and 46 of nonneoplastc dsease. The 67 glomas ncluded 36 anaplastc glomas, 26 astrocytomas, two olgodendroglomas, two medulloblastomas, and one ependymoma. The 2 pneal tumors ncluded eght germnomas, one teratoma, one embryonal carcnoma, one teratoblastoma, and one tumor hstologcally not verfed. The sx mscellaneous tumors ncluded two hemangoblastomas, one epdermod tumor, one chorod plexus paplloma, one retculum cell sarcoma, J. Neurosurg. / Volume 53 / September,

2 Y. Suzuk and R. Tanaka TABLE Patents tested for carcnoembryonc antgen Dsease Plasma CSF* Cystc Flud prmary bran tumor gloma ptutary adenoma 30 menngloma 28 acoustc neurnoma 2 2 pneal tumor 2 0 cranopharyngoma 6 2 other 6 3 metastatc bran tumor control cerebral aneurysm 0 2 ntracerebral hematoma 0 2 other total cases *CSF:cerebrospnal flud. and one chondroma. The 46 patents wth nonneoplastc dseases served as controls. Levels of CEA n CSF were determned wth 36 assays n 93 patents, ncludng 37 patents wth prmary bran tumor, 8 wth metastatc bran tumor, and 38 wth non-neoplastc dsease. The 9 glomas ncluded 5 anaplastc glomas, one astrocytoma, two medulloblastomas, and one ependymoma. The 0 pneal tumors ncluded eght germnomas, one embryonal carcnoma, and one tumor hstologcally not verfed. The three mscellaneous tumors ncluded two hemangoblastomas and one chorod plexus paplloma. Levels of CEA n tumor cyst flud were determned n 7 cases, ncludng 2 cases of gloma, one of menngoma, two of cranopharyngoma, and two of metastatc bran tumor. Cyst flud was obtaned at operaton n 3 patents, or sampled through a slcone tube placed n the cavty resultng from the partal extrpaton of tumor n four gloma patents. Method of Assay Samples were centrfuged at 3000 rpm for 5 mnutes, and the supernatants were stored frozen at -20~ untl use. Radommunoassay for CEA was performed by a one-step sandwch method 4 usng a Danabot CEA Kt.* A small number of samples were assayed by Z-gel method usng a Roche CEA Kt.:[: *Danabot CEA Kt manufactured by Danabot Radosotope Laboratory, Tokyo, Japan. troche CEA Kt manufactured by Nppon Roche, Ltd., Tokyo, Japan. TABLE 2 Prmary tumor stes n patents wth plasma carcnoembryonc antgen levels over 2.5 ng/ml Postve Total Prmary Ste Cases Cases lung breast stomach maxllary snus pancreas gall bladder colon unknown total Results 2 7 Carcnoembryonc Antgen n Plasma The plasma CEA levels of normal subjects have been reported to be less than 2.5 ng/ml n the assay by the one-step sandwch method usng the Danabot CEA Kt, and less than 5.0 ng/ml n that by the Roche CEA Kt. Snce the values n the assay by Danabot Kt are about half of those n the assay by Roche Kt, 4 the values obtaned by the Roche Kt n ths study were halved to correspond to the Danabot Kt values. Plasma CEA levels n 253 patents wth or wthout ntracranal tumors are plotted n Fg.. Slghtly elevated levels of plasma CEA were observed n sx (4%) of 6 patents wth prmary bran tumors: n three (4%) of 67 glomas, n one of 2 acoustc neurnomas, n one pneal germnoma, and n one embryonal carcnoma of the pneal regon. The ndvdual CEA values of the postve patents were 3., 3.2, and 3.8 ng/ml n the three glomas, respectvely, 2.6 ng/ml n the acoustc neurnoma, 3. ng/ml n the pneal germnoma, and 3.0 ng/ml n the embryonal carcnoma of the pneal regon (Fg. ). Repeated assays performed after about month revealed that the CEA values of all of the postve patents, except one wth pneal germnoma, returned to normal values of less than 2.5 ng/ml. On the other hand, 7 (37%) of 46 patents wth metastatc bran tumors showed a defnte elevaton of plasma CEA level. The CEA values of the 7 patents were between 2.6 and 5.0 ng/ml n fve patents, between 5. and 0.0 ng/ml n sx, and more than 0. ng/ml n sx (Fg. ). The prmary stes of the 7 postve patents were the lung n nne patents, the breast n one, the stomach n one, the maxllary snus n one, the pancreas n one, the gall bladder n one, the colon n one, and unknown stes n two (Table 2). Adenocarcnoma was the most frequent hstologcal fndng related to postve plasma CEA values; n total, seven of nne adenocarcnomas were postve. Seven among the 7 patents n whom the prmary stes had not been confrmed at the tme of admsson 356 J. Neurosurg. / Volume 53 / September, 980

3 I Carenoembryone antgen wth ntraeranal tumors (ng/ml Prmary Gloma Ig -, - - Bran Tumor non-gloma Metastatc Bran Tumor L 28.5 I 58.5 r Control IglB'* 9 FIG.. Plasma carcnoembryonc antgen levels n 207 ntracranal tumor patents and 46 control patents. showed elevated plasma CEA levels. In a group of control subjects, one patent wth polyneurts had a CEA value of 2.6 ng/ml, and one wth cerebral aneurysm, 3. ng/ml. Carcnoembryonc Antgen n Cerebrospnal Flud No normal values of CEA n CSF have been descrbed. In the present study, all of the 38 patents wth non-neoplastc dseases showed CEA levels n CSF of less than 0.5 ng/ml n the assay by the onestep sandwch method usng the Danabot Kt, and the values of 34 of the 38 patents were 0 ng/ml. Therefore, an upper lmt of normal CSF CEA levels by the one-step sandwch method has been proposed to be 0.5 ng/ml. The results of CEA assay n CSF are shown n Fg. 2. Of the 37 patents wth prmary bran tumors, only one wth pneal germnoma showng a spnal metastass revealed a sgnfcant elevaton of CEA level n CSF (6.0 ng/ml). In contrast to prmary bran tumors, eght (44%) of 8 metastatc bran tumors presented hgh levels of CEA n CSF. The clncal summary of the nne postve patents s shown n Table 3. Among the eght metastatc bran tumors wth elevated CEA levels n CSF, sx were leptomenngeal carcnomatoss and two were parenchymal metastass. All sx cases of leptomenngeal carcnomatoss assayed for CEA n CSF n ths study showed elevated CEA levels. In ths study, CSF cytology was performed n 2 patents wth <0,5 5 I0 5 (ng/ml) Prmary Bran Tumor Glomo t non-gomo! Metastatc Bran Tumor C ontro} FIG. 2. Carcnoembryonc antgen levels n the cerebrospnal flud of 55 ntracranal tumor patents and 38 control patents. J. Neurosurg. / Volume 53 / September,

4 Case No. Y. Suzuk and R. Tanaka TABLE 3 Summary of patents wth carcnoembryonc antgen (CEA) levels n cerebrospnal flud of over 0.5 ng/ml Cerebrospnal Flud Plasma Dagnoss, Prmary Ste, Hstology (mg/dl) Proten (mg7 Sugar dl) Cell Count Cytology* (ng/ml) CEA (ng/ml) CEA leptomenngeal carcmomatos~s, gall bladder, not verfed leptomenngeal carcmomatos~s, breast, adenocarcnoma leptomenngeal carcnomatoss stomach, not verfed leptomenngeal carcmomatos~s, stomach, adenocarcnoma leptomenngeal carcmomatos~s, unknown prmary ste leptomenngeal carcmomatosls, lung, adenocarcnoma parenchymal metastass, stomach, medullary carcnoma parenchymal metastass, lung, small-cell carcnoma germnoma wth spnal metastass *+ = Postve fndng of tumor cells; -- = no tumor cells found. ) / / / / <25 308/ /3 + ~400 <25 72/ metastatc bran tumors. All fve patents wth postve tumor cells (Cases, 3, 4, 5, and 6; Table 3) showed postve CEA levels n CSF, and two of seven patents wth negatve tumor cells (Cases 2 and 8) were also postve n CSF CEA (Table 3). No sgnfcant correlaton was noted between CSF CEA levels and other consttuents of CSF. Three of nne patents wth hgh CSF CEA levels (Cases 3, 7, and 9) showed normal plasma CEA levels, and the CSF CEA levels n another four patents (Cases 4, 5, 6, and 8) were hgher than ther plasma CEA level. Carcnoembryonc Antgen n Tumor Cyst Flud The CEA levels n the tumor flud of 2 gloma "- "< 35 patents ranged from 0.4 to 2.5 ng/ml, wth a mean w : value of ng/ml. A sgnfcant elevaton was u 5 noted n two patents wth cranopharyngoma (8.6 and.0 ng/ml, respectvely), and n one wth metastatc bran tumor from breast carcnoma (750 ng/ml). One menngoma and one metastatc bran lo tumor showed values of less than 0.5 ng/ml. the CEA levels seemed to be well correlated wth the tumor actvty. Fgure 3 shows seral CEA levels of a patent wth bran metastass of a small-cell carcnoma of the lung. The patent was admtted for the treatment of a huge metastatc tumor n the rght pareto-occptal regon. Before treatment, CEA levels n plasma and CSF were 3.0 and 36.0 ng/ml, respec- \. Radotherapy I 0 Chemotherapy eme Plasma CEA o~o CSF CEA Seral Carcnoembryonc Antgen Assays Levels of CEA were determned repeatedly n some patents durng or after treatment of ther tumors. The results of seral CEA determnatons n plasma or CSF revealed that CEA could be a useful parameter for the evaluaton of treatment or detecton of recurrences of CEA-producng tumors. The followng are representatve patents n whom ~e' ~ e I I r, O ~ Months after Dagnoss FIG. 3. Seral carcnoembryonc antgen (CEA) levels n plasma and cerebrospnal flud(csf) of a patent wth bran metastass of a small-cell carcnoma of the lung. 358 J. Neurosurg. / Volume 53 / September, 980

5 Carenoembryone antgen wth ntraeranat tumors tvely. After chemoradotherapy, the bran tumor completely dsappeared and the CEA level n CSF dropped to 0.6 ng/ml. Although the CEA level n CSF has remaned normal for 4 months, the plasma CEA level s stll above 2.5 ng/ml, and the patent has been recevng chemotherapy. Fgure 4 shows seral CEA levels of a patent wth pneal germnoma. The patent began to complan of paraplega and sensory mparments of the legs about 4 months after the complete remsson of a pneal germnoma by ntal treatments. The myelography and cytology of the CSF demonstrated spnal and leptomenngeal dssemnaton of the germnoma. At readmsson, the CEA levels n plasma and CSF were 0. I ng/ml and 6.0 ng/ml, respectvely. After rradaton to the whole spnal axs and bran, combned wth chemotherapy, the CEA levels n CSF decreased to 8.0 ng/ml, and fnally to 0. ng/ml, and the patent has recovered well. Dscusson Although several nvestgators have determned CEA levels n plasma 5,8," or CSF 5,x~ of a lmted number of patents wth ntracranal tumors, the clncal sgnfcance of CEA determnaton has not been suffcently demonstrated. The present study clearly shows that determnaton of CEA n plasma and CSF s very useful for the dfferental dagnoss between prmary and metastatc bran tumors, and that CEA mght be a useful parameter for the management of CEA-producng ntracranal tumors. The ncdence of postve plasma CEA fndngs was ~ 2O < "' 5 U 0 Radotherapy 0 Chemotherapy [ I eee Plasma CEA o~o CSF CEA, '-~ o-- B -'--'---'~'--o e I Months after Dagnoss FIG. 4. Seral carcnoembryonc antgen (CEA) levels n plasma and cerebrospnal flud (CSF) of a patent wth pneal germnoma showng spnal and leptomenngeal dssemnaton. 3% (four of 49 patents wth prmary bran tumors), excludng germ-cell tumors n the pneal regon. Ths ncdence was smlar to that n the control group. The CEA levels of these postve cases never exceeded 5.0 ng/ml, beng less than 3.8 ng/ml at most, and returned to normal values n the follow-up assays. On the other hand, 7 (37%) of 46 patents wth metastatc bran tumors showed elevated plasma CEA levels, and 2 (7%) of these 7 postve cases had levels hgher than 5.0 ng/ml. Smlar results have been reported by Kdo, et al.,5 who reported that an elevaton of plasma CEA levels was noted n seven (58%) of 2 metastatc bran tumors n ther seres, whereas all 28 prmary bran tumors showed normal levels. Consequently, determnaton of plasma CEA levels s valuable n the dfferental dagnoss between prmary and metastatc bran tumors, although t does not have a dagnostc value n prmary bran tumors. A hgh concentraton of CEA n CSF can be expected when CEA-producng tumor cells are drectly n contact wth CSF, as n other body fluds such as urne, 8 gastrc juces, feces, pleural effuson, or asctes 7 of patents wth cancers of other organs. However, the clncal sgnfcance of the determnaton of CEA n CSF has been nvestgated less than that n plasma? a~ There have been no prevous reports descrbng normal values of CEA n CSF. Snce the CEA levels n CSF of 38 patents wth non-neoplastc dseases were less than 0.5 ng/ml, and most were 0 ng/ml, an upper lmt of normal CEA values n CSF usng the Danabot Kt s suggested as 0.5 ng/ml. By ths crteron, of 37 prmary bran tumors, only one pneal germnoma showed an elevaton of CEA levels n CSF, and eght (44%) of 8 metastatc bran tumors presented sgnfcantly hgh levels, rangng from.7 to 36.0 ng/ml. Therefore, the determnaton of CEA n CSF has a dagnostc value, agan, for metastatc bran tumors. It s worth mentonng that sx of the eght metastatc bran tumors wth hgh values of CEA n CSF were n patents wth leptomenngeal carcnomatoss, and that the sx represented 00% of the cases of menngeal carcnomatoss n ths study. However, leptomenngeal dssemnaton of tumor not producng CEA does not seem to be the cause of elevaton of CEA n CSF, snce two medulloblastomas wth leptomenngeal dssemnaton showed normal values of CEA n CSF n ths study. The dagnoss of leptomenngeal carcnomatoss s dffcult when the cytology of CSF results s negatve. 8 The present study revealed that the determnaton of CEA n CSF s more senstve and more quanttatve than CSF cytology n the dagnoss of leptomenngeal carcnomatoss. The CEA levels n the fluds obtaned from the cyst of glomas never exceeded those n normal plasma. Ths fndng suggests that glomas, bengn or malgnant, are not CEA-producng tumors. The tumor flud obtaned from two cranopharyngomas that had en- J. Neurosurg. / Volume 53 / September,

6 Y. Suzuk and R. Tanaka dodermal orgn showed a defntely hgh value of CEA. Thus, the determnaton of CEA n tumor fluds of cranopharyngomas can be a postoperatve confrmatve dagnoss of ths tumor, and can be useful n the management of ths tumor, ncludng evaluaton of treatment or follow-up studes. In concluson, the frequency of metastatc bran tumors has been ncreasng n recent years because of the mprovement of prognoss n patents wth cancers of other organs, and because of employment of computerzed tomography n the dagnoss of ntracranal tumors. However, the dfferental dagnoss between prmary bran tumors, especally malgnant glomas, and metastatc bran tumors s often very dffcult. For the purpose of ths dfferental dagnoss, determnaton of CEA n both plasma and CSF mght be of great value. Furthermore, as shown n the seral study of CEA, CEA levels could be a useful parameter for the management of CEA-producng ntracranal tumors, such as metastatc tumors, cranopharyngomas, or germ-cell tumors. Acknowledgments The authors would lke to acknowledge the contnung gudance and encouragement of Professor Kome Uek, Department of Neurosurgery of Bran Research Insttute. We are also deeply ndebted to Dr. Yoshak Sugyama, Department of Neurosurgery of Toyama Prefectural Central Hosptal, and Dr. Masao Watanabe, Department of Neurosurgery of Nagaoka Red Cross Hosptal, for provdng clncal materal, and to Mss Norko Tanaka and Mss Yuke Oyanag for techncal assstance. References. Fujmoto S, Ktsukawa Y, Itoh K: Carcnoembryonc antgen (CEA) n gastrc juce or feces as an ad n the dagnoss of gastrontestnal cancer. Ann Surg 89: 34-38, Gold P, Freedman SO: Demonstraton of tumorspecfc antgens n human colonc carcnomata by mmunologcal tolerance and absorpton technques. J Exp Med 2: , Hall RR, Laurence D Jr, Darcy D, et al: Carcnoembryonc antgen n the urne of patents wth urothelal carcnoma. Br Meal J 3:609-6, Hra H: A collaboratve clncal study of carcnoembryonc antgen n Japan. Cancer Res 37: , Kdo DK, Dyce B J, Haverback B J, et al: Carcnoembryonc antgen n patents wth untreated central nervous system tumors. Bull Los Angeles Neurol Soc 4:47-54, Laurence D Jr, Stevens U, Bettelhem R, et al: Role of plasma carcnoembryonc antgen n dagnoss of gastrontestnal, mammary, and bronchal carcnoma. Br Med J 3: , Loewensten MS, Rttgers RA, Kupchk HZ, et al: CEA assay of asctes and pleural effusons: an adjunct to cytology n the detecton of malgnancy. Cn Res 24:378A, 976 (Abstract) 8. Olson ME, Chernk NL, Posner JB: Infltraton of the leptomennges by systemc cancer. A clncal and pathologc study. Arch Neurol 30:22-37, Skarn AT, Delwche R, Zamcheck N, et al: Carcnoembryonc antgen: clncal correlaton wth chemotherapy for metastatc gastrontestnal cancer. Cancer 33: , Sntzer LS, McKnney EC, Tejada F, et al: Cerebral metastases and carcnoembryonc antgen n CSF. N Engl J Med 293:0, 975 (Letter) I I. Suzuk Y, Tanaka R, Sekguch K, et al: [Clncal evaluaton of carcnoembryonc antgen n ntracranal tumor.] lgaku Ayum 07:28-30, 978 (Jpn) 2. Vder M, Kashmr R, Meeker WR, et al: Carcnoembryonc antgen (CEA) montorng n the management of radotherapeutc and chemotherapeutc patents. Am J Roentgenol Radum Ther Nucl Med 24: , 975 Address reprnt requests to: Yasuo Suzuk, M.D., Department of Neurosurgery, Bran Research Insttute, Ngata Unversty, Asah-mach, Ngata Cty 95, Japan. 360 J. Neurosurg. / Volume 53 / September, 980