Significance of simultaneous determination of serum human chorionic gonadotropin (hcg) and hcg-b in testicular tumor patients

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1 International Journal of Urology (2000) 7, Original Article Significance of simultaneous determination of serum human chorionic gonadotropin (hcg) and hcg-b in testicular tumor patients SENJI HOSHI, KEN-ICHI SUZUKI, SHIGETO ISHIDOYA, CHIKARA OHYAMA, MAKOTO SATO, TAKASHIGE NAMIMA, SEIICHI SAITO AND SEIICHI ORIKASA Department of Urology, Tohoku University School of Medicine, Sendai, Japan Abstract Key words Background: Simultaneous determinations of human chorionic gonadotropin hormone (hcg) and hcg-b frequently produce discrepancies, that is when hcg or hcg-b is normal, the other is elevated. Accordingly, we examined the significance of simultaneous determination of serum hcg and hcg-b in testicular tumors. Methods: Simultaneous determination of hcg and hcg-b was performed in 54 patients with testicular seminoma and 74 with non-seminomatous testicular tumors. Results: For detection of seminoma patients, hcg-b was more effective than hcg because hcg-b was positive in 83% (45/54) of the patients and hcg was positive in 50% (27/54). In nonseminomatous testicular tumor cases, hcg-b was positive in 74% (55/74) and hcg was positive in 82% (61/74). The cases of hcg <1.0 miu/ml and HCG-b>0.1 ng/ml were significantly more frequently seen in patients with seminoma than in those with non-seminomatous testicular tumor (P < 0.001). Fourteen patients had recurrent tumor. At recurrence, only hcg was elevated in nine cases, only hcg-b was elevated in two cases and both in one case. For diagnosis of falsely positive hcg, testosterone administration was effective because after testosterone administration, serum hcg levels became undetectable (< 1.0 miu/ml) within one week in three examined cases. Conclusion: Human chorionic gonadotropin-b was a better marker of seminoma than hcg. For earlier detection of recurrence, both markers should be examined. For diagnosis of falsely positive hcg, testosterone administration was effective. human chorionic gonadotropin-b, serum hcg, testicular cancer. Introduction Fraction b of the human chorionic gonadotropin hormone (hcg-b) is believed to be a more sensitive testicular tumor marker than human chorionic gonadotropin hormone (hcg). 1,2 However, simultaneous examinations of hcg and hcg-b frequently produce discrepancies, that is when hcg or hcg-b is normal, the other Correspondence: Senji Hoshi MD, Department of Urology, Tohoku University School of Medicine, 1-1 Seiryomachi, Aobaku, Sendai , Japan. hoshi@uro.med.tohoku.ac.jp Received 27 April 1999; revision 31 January 2000; accepted 31 January is elevated. Accordingly, we examined the significance of simultaneous determination of serum hcg and hcg-b in testicular tumors. Methods From December 1991 to December 1998, 54 patients with testicular seminoma (stage I, 30; stage II, 18; stage III, 6) and 74 patients with non-seminomatous testicular tumor (stage I: 10, stage II: 21, stage III: 43) 3 were examined. The seminoma and non-seminomatous testicular tumors were diagnosed only by pathologic finding of testicular tumors. Pathologic diagnosis of testicular

2 Serum hcg and hcg-b in testicular tumor patients 219 tumors was done in at least three different parts of the testicular tumor. In some cases of stage II or III with high level of serum hcg and hcg-b and low level of alpha-fetoprotein (AFP) and the testicular tumor was pathologic diagnosis of seminoma, we defined these cases as seminoma. Serum hcg was determined by Delfia hcg (Pharmacia Upjohn, Tokyo, Japan) and serum hcg-b was determined by Bole ELISA. F-b-hCG (CIS Diagnostics, Tokyo, Japan). From 15 November 1991, the reference normal level of hcg was changed to < 1.0 miu/ml and normal level of hcg-b was changed to < 0.1 ng/ml. Cross reactivities of the Delfia hcg kit with lutenizing hormone (LH), follicle stimulating hormone (FSH) and hcg-b were < 0.5, 0.2 and 2.4%, respectively. Cross reactivities of Bole ELISA. F-bhCG kit with LH, FSH and hcg were not detected. The c 2 test was used to assess differences. Results In pretreatment cases, both hcg and hcg-b were undetectable in seven (13%) of the 54 seminoma cases and in 11 (15%) of the 74 cases of non-seminomatous testicular tumors. In patients with seminoma, both markers were detectable in 25 (46%) cases and only hcg-b was detected in 20 (37%) cases and only hcg was detected in two (4%) cases (Fig. 1). In non-seminoma, both markers were detectable in 53 (72%) cases and only hcg-b was detectable in two (3%) cases and only hcg in eight (11%) cases (Fig. 2). There were discrepancies between hcg and hcg-b in 41% of seminoma and in 14% of non-seminoma. The cases with hcg < 1.0 miu/ ml and hcg-b >0.1 ng/ml were significantly more in seminoma than in non-seminomatous testicular tumors (P < 0.001). Accordingly, hcg-b was a more sensitive marker of seminoma than hcg. However, only hcg was detectable in eight cases of non-seminoma and only HCG-b in two cases of seminoma. Human chorionic gonadotropin was a more sensitive marker of non-seminoma. Human chorionic gonadotropin hormone and hcgb levels were determined every month after orchiectomy for stage I tumor patients and after chemotherapy and/or tumor extirpation for stage II or III tumor patients. Fourteen patients (four seminoma and 10 non-seminoma) had recurrent tumors. Nine (two seminoma and seven non-seminoma) changed from stage I to stage II or III, one from IIB to IIA and three (one seminoma and two non-seminoma) from stage II to stage III. One patient with stage I seminoma experienced recurrence in the contra-lateral testis. At recurrence, in nine cases only hcg was elevated, in two cases only hcg-b was elevated and in one case both hcg and hcg-b were elevated. Both markers were not detectable in two cases (Table 1). In three recurrent non-seminoma cases, hcg elevation was detected 2 3 months earlier than hcg-b elevation (Fig. 3). In a recurrent seminoma and a non-seminomatous testicular tumor patient, hcg-b was 18 ng/ml and 0.16 ng/ml, respectively and hcg in both cases was <1.0 miu/ml, when recurrent retroperitoneal lymph node metastases were found hcg-b (ng/ml) n=20 n=25 n=7 n= hcg (miu/ml) Fig. 1 Pretreatment serum human chorionic gonadotropin (hcg) and hcg-b in 54 seminoma patients. Twenty patients were hcg-b positive and hcg negative. Two patients were hcg-b negative and hcg positive. hcg-b (ng/ml) n=2 n=11 n=8 n= hcg (miu/ml) Fig. 2 Pretreatment serum human chorionic gonadotropin (hcg) and hcg-b in 74 non-seminomatous testicular tumor patients. Two patients were hcg-b positive and hcg negative. Eight patients were hcg-b negative and hcg positive.

3 220 S Hoshi et al. Table 1 Human chorionic gonadotropin (hcg) and hcg-b at recurrence of testicular tumor Case no. Pathology of Stage hcg at recurrence hcg-b at recurrence AFP at recurrence (age) testicular tumor primary Æ recurrent (normal < miu/ml) (normal < 0.1 ng/ml) (normal < 20 ng/ml) 1. (31) S, E I Æ IIA 5.8 < (52) S I Æ IIA 1.3 < (17) E, imm T I Æ IIA (27) S I Æ IIB < (52) E, mt I Æ IIIB1 < 1 < (27) E, imm T I Æ IIIC 27.5 < (28) S, imm T I Æ IIIB2 < 1 < (21) E, mt I Æ IIIC 59.1 < (27) E I Æ IIIC 1.9 < (28) S I Æ I 9.2 < (contra-lateral testis) 11. (38) E IIB Æ IIA < (43) S IIIA Æ IIIO 5 < (45) E IIIB Æ IIIB 42 < (24) C, E IIIC Æ IIIC 6.1 < S, seminoma; E, embryonal carcinoma; imm T, immature teratoma; mt, mature teratoma; C, choriocarcinoma. Fig. 3 Three non-seminoma cases of recurrent testicular tumors. In three recurrent non-seminoma cases (case nos 6, 8 and 13 in Table 1), hcg elevation was detected 2 3 months earlier than hcg-b elevation. Case 14 in Table 1 had lung and brain metastases and was treated with PVP (cisplatin, vinblastine, peplomycin). Human chorionic gonadotropin and hcg-b became undetectable and brain metastasis disappeared. Lung metastasis also decreased but small nodules persisted. Pulmonary resection for metastatic testicular tumor was performed. The pathologic diagnosis of the pulmonary tumor was all necrosis. Just after the lung operation, hcg was elevated to 6.1 miu/ ml but hcg-b was normal. Because we suspected another metastasis, whole body CT was performed and a new brain metastasis was found. The patient was treated with the g-knife and one course of PE (cisplatin, etoposide). After this treatment brain metastasis disappeared, hcg was normalized and HCG-b continued at the normal level. No evidence of disease has continued now for 5 years. In this case we suspected a recurrence because of hcg elevation; brain metastasis was detected in the early phase and successful treatment performed. Falsely positive hcg was observed because of a cross reaction with LH. For diagnosis of falsely positive HCG, administration of 250 mg testosterone was effective. After testosterone administration, the serum hcg level became undetectable (< 1.0 miu/ml) within 1 week in three examined cases (Table 2). Case 3 in Table 2 complained of slight nausea continuing for 2 days after testosterone administration. Case Report Case 1 was a 26-year-old man with a mixed germ cell tumor (embryonal carcinoma, immature teratoma and choriocarcinoma) of the left testis. The metastatic evaluation revealed a 3-cm retroperitoneal metastasis but no pulmonary metastasis and the disease was diagnosed as stage IIA. Tumor marker studies 3 weeks after orchiectomy revealed a normal AFP level, elevated hcg of miu/ml and hcg-b of ng/ml. After subsequent treatment with five courses of PE (cisplatin, etoposide), the hcg-b level was no longer abnormally high, but hcg was detectable (> 1mIU/ ml). His hcg level did not become undetectable after five courses of PE and we have experienced hcg

4 Serum hcg and hcg-b in testicular tumor patients 221 Table 2 Changes of hormone concentrations pre- and post-testosterone administration in three cases of falsely positive human chorionic gonadotropin (hcg) Case no. LH FSH Testosterone hcg hcg-b (age) ( miu/ml) ( mlu/ml) ( ng/dl) (< 1.0 miu/ml) (< 0.1 ng/ml) 1. (26) 86.3 Æ Æ Æ Æ<1.0 < 0.1 Æ< (38) 26.7 Æ Æ Æ Æ<1.0 < 0.1 Æ< (28) 18.8 Æ Æ Æ Æ<1.0 < 0.1 Æ<0.1 Fig. 4 Case of falsely positive human chorionic gonadotropin (hcg) after completion of chemotherapy. Testosterone administration (250 mg) decreased lutenizing hormone (LH), from 86.3 miu/ml to 8.5 miu/ml, follicle stimulating hormone (FSH) from miu/ml to 44.9 miu/ ml, testosterone from ng/ dl to ng/dl and hcg from 2 miu/ml to < 1.0 miu/ml. Human chorionic gonadotropin levels continued to be in the normal range 9 months after testosterone administration. PE, cisplatin, etoposide; VIP, etoposide, ifosfamide, cisplatin; EMA, etoposide, methotrexate, actinomycin D. elevation without hcg-b elevation in the recurrent testicular cancer patients. Accordingly we think this patient is refractory for standard chemotherapy. Another eight courses of VIP (etoposide, ifosfamide, cisplatin) and EMA (etoposide, methotrexate, actinomycin D) 4 chemotherapies were given, but hcg was still 2 3 miu/ml. At that time serum testosterone was ng/dl (normal ), LH was 86.3 miu/ ml (normal ) and FSH was miu/ml (normal ). Falsely positive hcg was suspected because of a high level of the LH. The patient then received 250 mg of testosterone enanthate to suppress LH secretion. A week later repeat analysis revealed a testosterone concentration of ng/dl, LH 8.5 miu/ml, FSH 44.9 miu/ml and a normal hcg level (< 1.0 miu/ml). The patient received no further treatment and the normal hcg level continued even after 9 months (Fig. 4).

5 222 S Hoshi et al. Discussion In patients with testicular tumor, hcg-b is thought to be a sensitive and specific marker of tumor activity. 1,2 For detection of seminoma patients, hcg-b was more effective than hcg because in 54 seminoma patients, hcg-b was positive in 83% (45/54) of the cases and hcg was positive in 50% (27/54). However, in respect to non-seminomatous testicular tumor, hcg-b was positive in 74% (55/74) and hcg was positive in 82% (61/74). Accordingly, hcg-b is sensitive in cases of seminoma, but not in cases of non-seminomatous testicular tumor. Almost the same results were observed from the large series by Saller et al. 5 For early detection of testicular tumor patients, simultaneous determination of hcg and hcg-b is necessary. Compared with previous articles, our detection rate of hcg-b in seminoma patients is relatively high (83%). In 1986, Tukamoto et al. stated that the hcg-b in the spermatic vein was elevated in 12 out of 14 seminoma patients (88.9%). 6 The improved hcg-b kit introduced in 1991 which can detect levels as low as 0.1 ng/ml. This new kit may contribute to the high detection rate of hcg-b in our seminoma patients. Of the 14 recurrent patients, hcg was elevated in 10 cases, hcg-b was elevated in three cases and both hcg and hcg-b were elevated in one case. In the three recurrent non-seminoma cases, hcg elevation was detected 2 3 months earlier than hcg-b elevation. However, in a recurrent seminoma and a nonseminomatous testicular tumor patient, hcg-b was 18 ng/ml and 0.16 ng/ml, respectively and hcg in both cases was < 1.0 miu/ml. Accordingly, for early detection of recurrence in testicular tumor, simultaneous determination of hcg and hcg-b was useful. Maeda et al. reported successfully treating recurrent testicular tumor patients in which hcg was elevated but hcg-b was normal and they also stated the significance of simultaneous determination of hcg and hcg-b. 7 Human chorionic gonadotropin and LH both have immunologic cross-reactivity, as they share a common a subunit and their b subunits are 80% homologous. 8 Concerning false positive hcg-b, Kovcin et al. suggested that with values of hcg-b over 100 U/L crossreaction with LH or FSH occurred. 9 In 1979 Catalona et al. suggested that the slight hcg elevations observed in patients with testicular tumors and experiencing hypogonadism, might be due to high levels of LH. 10 Chemotherapy for testicular tumors causes temporary or permanent iatrogenic hypogonadism and secondary plasmatic elevations of LH and FSH. Small but significant cross-reactions with LH have been observed, resulting in spurious elevations of hcg. Germa et al. reported that 12 patients with complete response showed high hcg follow-up levels between 1.7 and 7.8 miu/ml; 8 simultaneous determination of LH and FSH also revealed high levels, miu/ml and miu/ml, respectively. Administration of exogenous testosterone resulted in all cases in reduction of LH and FSH values and normalization of hcg. Through testosterone administration, therefore, the relationship between spurious elevations of hcg and the iatrogenic hypogonadism could be clarified. In three similar cases, we administered 250 mg testosterone enanthate to suppress serum LH activity. In all three patients the LH was suppressed to normal levels 1 week later and the falsely positive hcg results converted to negative 1 week after therapy. A side-effect of testosterone therapy was observed; grade I nausea continued for 2 days in one patient (case 3 in Table 2). In our case 1, it required much time to recognize the falsely positive elevation of hcg. If we had known the concept of falsely positive hcg elevation, we could have spared unnecessary chemotherapy. For diagnosis of falsely positive hcg, administration of 250 mg testosterone enanthate is effective. Conclusions Human chorionic gonadotropin-b was a better marker of seminoma than hcg. For earlier detection of recurrence, both markers should be examined. For diagnosis of falsely positive hcg, testosterone administration was effective. References 1 Cochran JS, Walsh PC, Porter JC, Nicholson TC, Madden JD, Peters PC. The endocrinology of human chorionic gonadotropin-secreting testicular tumors: New methods in diagnosis. J. Urol. 1975; 114: Fossa SD, Klepp O, Barth E, Aakvaag A, Kaalhus O. Endocrinological studies in patients with metastatic malignant testicular germ cell tumours. Int. J. Androl. 1980; 3: Japanese Urological Association and Japanese Pathological Society (eds). General Rules for Clinical and Pathological Studies on Testicular Tumors, 2nd edn. Kanehara Syuppan Inc, Tokyo, Soto-Wright V, Goldstein DP, Bernstein MR, Berkowitz RS. Gynecol. Oncol. 1997; 64: Saller B, Clara R, Spöttl G, Siddle K, Mann K. Testicular cancer secretes intact human choriogonadotropin (hcg) and its free b-subunit: Evidence that hcg (+hcg-b) assay are the most reliable in diagnosis and follow-up. Clin. Chem. 1990; 36:

6 Serum hcg and hcg-b in testicular tumor patients Tsukamoto T, Kumamoto Y, Ohmura K, Tsunekawa T, Yamazaki K. Clinical studies of testicular tumor. I. Analysis of 27 patients with seminoma: The clinical significance of hcg-beta determination and of retroperitoneal lymph node dissection for stage I patients. Acta Urol. Jpn 1986; 32: Maeda Y, Oyama H, Shishido T, Kin T, Izutani T, Yonese J, Fukui I. Successful management for chemorefractory testicular cancer with brain and lung metastases. Jpn J. Urol. 1998; 89: Germa JR, Arcusa A, Casamitjana R. False elevations of human chorionic gonadotropin associated to iatrogenic hypogonadism in gonadal germ cell tumors. Cancer 1987; 60: Kovcin VN, Jelic SB, Lvanovic SM, Babovic NL. Serum gonadotropin levels in patients with germ-cell tumors of the testis: Interrelations, possible crossreactions and interpretation of beta-hcg level. Int. J. Biol. Markers 1997; 12: Catalona WJ, Vaitukaitis JL, Fair WR. Falsely positive specific human chorionic gonadotropin assays in patients with testicular tumors. Conversion to negative with testosterone administration. J. Urol. 1979; 122:

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