Medical and Pediatric Oncology 6:115-119 (1979)
Ectopic Production of Human Chorionic Gonadotropin: A Case Report Charles Erlichman, MD, J. F. Pringle, MB, FRCP(C), and 1. C. Quirt, MD, FRCP(C) Department of Radiation Oncology (J.F.P.) and Departmentof Medicine (I.C.Q., C.E.), Princess Margaret Hospital, Toronto
The ectopic production of the 0-subunit of human chorionic gonadotropin (hCG) is described in a patient with an anaplastic carcinoma. After chemotherapy the marker decreased in a logarithmic fashion to undetectable levels but the neoplasm progressed and the patient died. The specificity of the &subunit of hCG is discussed. Discordance of the marker and clinical disease is pointed out, and several possible explanations are outlined. The lack of specificity of the &subunit of hCG and the discordance that it may exhibit means that its use in diagnosing and following disease progression may be limited. Key words: anaplastic carcinoma, ectopic hormone production, tumour marker, p-subunit of hCG
INTRODUCTION
There has been a recent proliferation of publications on the use of human chorionic gonadotropin (hCG) in the diagnosis, prognosis, and treatment of human malignancies. The radioimmunoassay for the 0-subunit of hCG [ l ] is very specific for this hormone, and it was hoped that this would prove to be a useful tumor marker. As more and more disease states were screened, it became obvious that its specificity was not limited to the first trimester of pregnancy, and t o trophoblastic and testicular tumours. The production of hCG has been reported in a wide variety of malignancies [2-51 and in some nonmalignant disease states [ 5 ] . Therefore this marker is not specific for one type of tumour. Another approach would be t o examine the marker quantitatively and thereby hopefully limit its specificity. By obtaining a quantitative value for the marker, one might be able to define an upper limit, above which benign diseases would not exceed. We report this case because of the implications its quantitative values have and the discordance in response to therapy of the tumour and the marker. Address reprint requests to Dr. J.F. Pringle, Department of Radiation Oncology, Princess Margaret Hospital, 500 Sherbourne Street, Toronto, ON M4X 1K9,Canada.
0098-1532/79/0602-0115$01.40 0 1979 Alan R. Liss, Inc.
116
Erlichman, Pringle, and Quirt
CASE REPORT
Mrs. H.C., a 32-year-old gravida 4, para 4 Jamaican female, was admitted to another hospital in August 1976 for the investigation of amenorrhea lasting six months. An examination under anaesthesia at that time revealed an irregularity along the right side of the pelvis, and a dilatation and curettage showed chronic endometritis. Her menses occurred normally subsequent to this. If February 1977 she developed a sharp pain in her right hip which radiated down the right leg. This pain progressed until she could not walk. During the eight months prior to admission to the hospital she lost 9 kg. On admission she was found to have a hard mass fixed to the right pelvic side wall. An intravenous pyelogram (IW) showed displacement of the bladder to the left pelvic wall and a pelvic ultrasound confirmed a solid mass adherent to the right pelvic wall. On August 25, 1977, an exploratory laparotomy was performed. This revealed a mass located midway between the anterior superior spine and the symphysis pubis fixed to the iliac wing. This was removed. The ovaries, fallopian tubes, and uterus were normal to inspection and palpation. Pathologic examination showed an anaplastic carcinoma in a lymph node mass. Postoperatively, two urinary hemagglutination tests for human chorionic gonadotropin were positive. A subsequent dilatation and curettage revealed a late secretory endometrium. The patient was referred to Princess Margaret Hospital in moderate distress because of pain in her hip and leg. There was no peripheral lymphadenopathy. Chest and cardiovascular examination were normal. Abdominal examination was unremarkable except for the induration noted in the right lower quadrant. Pelvic examination revealed a hard mass on the pelvic side wall. The right leg was edematous. Initial investigations revealed that hemoglobin level was 10.5 gm/dl, WBC was 13.2 X 109/liter with 74% polymorphonuclear leukocytes, alkaline phosphatase was 37.5 King-Armstrong units (KAU) (normal, 3-10), and G O T was 62 IU (normal, 10-32). A chest film was normal, but pelvic X-ray films revealed sclerosis of the right iliac bone. A liver scan showed hepatomegaly with no filling defects. An hCG /?-subunit determination by radioimmunoassay (Serono Laboratories, Boston) was 2,700 mIU/ml (normal, 0-5). Tissue was examined by immunoperoxidase stain for the /?-subunit of hCG and it stained nonspecifically. Staining for pregnancyspecific 01-glycoprotein was strongly positive. A decision was made to treat the patient with high doses of methotrexate with Leucovorin@rescue because of the elevated P-subunit of hCG in the range found in trophoblastic disease, the treatment of this tumour was most likely associated with a chance of cure, and a trophoblastic malignancy could not be completely ruled out. Between September and November 1977 the proband received four courses of methotrexate and Leucovorin rescue. Each course consisted of one gram of methotrexate infused over 16 hours followed six hours later by a bolus of 100 mg of Leucovorin IV. This was followed by lOOmg of Leucovorin by infusion over eight hours and then 25 mg IV every eight hours for six more doses. The patient attained relief of pain, return of the alkaline phosphatase and SCOT levels to normal, and a decline in the serum psubunit of hCG to normal (see Fig. 1). The pelvic mass did not change clinically or on ultrasound examination. The patient was lost to follow-up for one month but presented again in December with increasing right hip pain, especially when standing, and a fever for one week. There was right lower quadrant tenderness and the mass was unchanged on pelvic examination. Investigations revealed that the alkaline phosphatase was again elevated, at 13.8 KAU,
Ectopic Production of Human Chorionic Gonadotropin
117
I
\ \ "\ \ -_-
I
t Sepl.
Oct.
Nov.
Oec.
t W.I.
Fig. 1 . Serum psubunit of hCG level of proposita plotted logarithmically against time. ( t ) Date on which blood was drawn; (J) date on which methotrexate was given. Note that the last two blood samples had undetectable levels of the p-subunit of hCG, as expected by the linear plot.
SGOT was increased to 84 IU, and the 0-subunit of hCG was less than 1.5 mIU/ml. A renal scan showed a nonfunctioning right kidney. A pelvic ultrasound revealed the right pelvic mass to be cystic. A bone scan showed increased uptake in the ilium adjacent to the pelvic mass in the left sacrum and right femur. A fifth course of methotrexate was given, but it produced no improvement in the hip pain, alkaline phosphatase and SGOT levels, or the pelvic mass. Furthermore, the patient continued to spike fevers daily and no source of infection could be found. Concern regarding a pelvic abscess led to an examination under anaesthesia, dilatation and currettage, and posterior colpotomy with biopsy of the pelvic mass. The mass was again noted to be hard, fixed to the pelvis, and tying the cervix down. Pathologic examination of the endometrial currettage revealed midsecretory endometrium. The biopsy showed anaplastic carcinoma. There was no evidence of a pelvic abscess. A postoperative liver scan revealed that several space-occupying lesions had developed. She was then treated with 3,000 rads to the pelvis, in 20 treatments, for relief of pain. After completion of this regimen, she returned to Jamaica, where she died one month later. A postmortem was not obtained. DISCUSSION
This case illustrates two aspects of the use of the 0-subunit of hCG as a tumour marker. First, levels of the 0-subunit of hCG as high as those recorded here have in only a few case been reported in tumours of nontrophoblastic and nontesticular origin. Sussman et a1 [ 6 ] have reported two cases of large-cell carcinoma of the lung, one case of carcinoma of the stomach, one case of renal cell carcinoma, and one case of undifferentiated carcinoma with markedly elevated levels of the &subunit of hCG. Most other reports of ectopic
118
Erlichman, Pringle, and Quirt
hCG production state only whether the result is positive or negative. The importance of this point must be emphasized. Elevation of the &subunit of hCG is not specific for trophoblastic or testicular malignancies [2-5,7]. It has also been found in nonmalignant states [S] ,and recently the desialylated hCG has been demonstrated in nonneoplastic liver and colon homogenates [8], making the usefulness of the &subunit of hCG as a cancer marker doubtful. Furthermore, the quantitative assessment of the 0-subunit of hCG does not limit the specificity of the test. Second, in response to therapy, this patient’s &subunit of hCG decreased in a logarithmic fashion. Tumour cell kill by chemotherapeutic agents follows first-order kinetics. Therefore, if there was a stoichiometric relationship between the tumour cells and the marker, this logarithmic decrease in the P-subunit would be expected as a reflection of the tumour cell death. However, there was evidence of progression of disease, and the &subunit of hCG remained undetectable. This discordance in marker and tumour has been observed previously [ 4 , 9 ] . The implications are that one should be extremely wary of using this marker to follow progression of disease except in trophoblastic and testicular neoplasms. Several hypotheses can be formulated to explain this discordance: 1) The tumour may be made up of a heterogeneous group of cells, of which some produce the P-subunit of hCG while others do not. This possibility is supported by the positive staining for the pregnancy-specific 01-glycoprotein in the tumour. There does appear to be another group of cells that elaborate this hormone marker which do not stain for the &subunit of hCG. The chemotherapy may have selectively killed the &subunit of hCG-producing cells only. 2) There may not be a stoichiometric relationship between the tumour cells and the 0subunit of hCG. In this case the decrease in the marker would not reflect tumour burden. 3) The therapy may have stopped the production of the 0-subunit of hCG by the tumour cells. In this way the tumour could progress with undetectable marker being recorded [4]. There may have been a change in the metabolic clearance of the 0-subunit. This is supported by the work of Tsuruhara et a1 [ 101 and DuFau et a1 [ 1 11 . These workers have shown that the desialylated hCG maintains its activity in bioassays in vitro and in the radioimmunoassay but shows a loss of bioactivity in vivo. Clearance studies have shown that the desialylated hCG has a markedly increased clearance rate compared to intact hCG [lo, 121. These points imply that the sialic acid moiety is important in the metabolic clearance of the hCG. Thus, if a neoplasm began secreting desialylated hCG (as part of the natural evolution of the disease or as a direct effect of the chemotherapy), a marker might not be detected. 5) The clinical assessment of the tumour size may have been inaccurate. This would be unlikely, however, in this particular case. These possibilities have been mentioned before by Rosen et a1 [4]. In the case reported here, there is no definite evidence that favours one explanation over another. Thus in using tumour markers one must understand the h i t a t i o n s of sensitivity, specificity, and relationship to the tumour cell population [13].
ACKNOWLEDGMENTS
We would like to thank Dr. A. Malkin for performing the determinations of the 0-subunit of hCG and for his helpful suggestions, and express our appreciation to Miss Ellen Hoffman for typing this report.
Ectopic Production of H u m a n Chorionic G o n a d o t r o p i n
119
REFERENCES 1 . Vaitukaitis JL, Braunstein GD, Ross GT: A radioimmunoassay which specifically measures human chorionic gonadotropin in the presence of human luteinizing hormone. Am J Obstet Gynecol 113:751-758,1972. 2. Braunstein GD, Vaitukaitis JL, Carbone PP: Ectopic production of human chorionic gonadotrophin by neoplasms. Ann Intern Med 78:39-45, 1973. 3. Goldstein DP, Kosasa TS, Skarim AT: The clinical application of a specific radioimmunoassay for human gonadotropin in trophoblastic and nontrophoblastic tumours. Surg Gynecol Obstet 138~747-751,1974. 4. Rosen SW, Wintraub BD, Vaitukaitis JL, Sussman HH, Hershman JM, Muggia FM: Placental proteins and their subunits as tumour markers. Ann Intern Med 82:71-83, 1975. 5 . Vaitukaitis JL, Ross GT, Braunstein GD,Rayford PL: Gonadotropins and their subunits: Basic and clinical studies. Rec Prog Horm Res 32:289-331, 1976. 6. Sussman HH, Weintraub BD, Rosen SW: Relationship of ectopic placental alkaline phosphatase to ectopic chorionic gonadotropin and placental lactogen. Cancer 33:820-823,1974. 7. Gailani S , Chu TM, Nussbaum A, Ostrander M, Christoff N: Human chorionic gonadotrophins (hCG) in non-trophoblastic neoplasms; assessment of abnormalities of hCG and CEA in bronchogenic and digestive neoplasms. Cancer 38:1684-1686,1976. 8. Yoshimoto Y, Wolfsen AR, Odell WD: Human chorionic gonadotropin-like substance in nonendocrine tissues of normal subject. Science 197:575-577, 1977. 9. Braunstein GD, McIntire KR, Waldmann TA: Discordance of human chorionic gonadotropin and alpha-fetoprotein in testicular teratocarcinoma. Cancer 31: 1065-1068, 1973. 10. Tsuruhara T, DuFau ML, Hickman J, Catt KJ: Biological properties of hCG after removal of terminal sialic acid and galactose residues. Endocrinology 91:296-301, 1972. 11. DuFau ML, Catt KJ, Tsuruhara T: Retention of in vitro biological activities by desialylated human luteinizing hormone and chorionic gonadotropin. Biochem Biophys Res Commun 44:1022-1029, 1971. 12. VanHall EV, Vaitukaitis JL, Ross GT, Hickman JW, Ashwell G: Effects of progressive desialylation on the rate of disappearance of immunoreactive hCG from plasma in rats. Endocrinology 89: 11-15, 1971. 13. Vaitukaitis JL: When isa tumour marker not a tumour marker? N Engl J Med 293:1370-1371, 1975.
Ectopic Production of Human Chorionic Gonadotropin: A Case Report Charles Erlichman, MD, J. F. Pringle, MB, FRCP(C), and 1. C. Quirt, MD, FRCP(C) Department of Radiation Oncology (J.F.P.) and Departmentof Medicine (I.C.Q., C.E.), Princess Margaret Hospital, Toronto
The ectopic production of the 0-subunit of human chorionic gonadotropin (hCG) is described in a patient with an anaplastic carcinoma. After chemotherapy the marker decreased in a logarithmic fashion to undetectable levels but the neoplasm progressed and the patient died. The specificity of the &subunit of hCG is discussed. Discordance of the marker and clinical disease is pointed out, and several possible explanations are outlined. The lack of specificity of the &subunit of hCG and the discordance that it may exhibit means that its use in diagnosing and following disease progression may be limited. Key words: anaplastic carcinoma, ectopic hormone production, tumour marker, p-subunit of hCG
INTRODUCTION
There has been a recent proliferation of publications on the use of human chorionic gonadotropin (hCG) in the diagnosis, prognosis, and treatment of human malignancies. The radioimmunoassay for the 0-subunit of hCG [ l ] is very specific for this hormone, and it was hoped that this would prove to be a useful tumor marker. As more and more disease states were screened, it became obvious that its specificity was not limited to the first trimester of pregnancy, and t o trophoblastic and testicular tumours. The production of hCG has been reported in a wide variety of malignancies [2-51 and in some nonmalignant disease states [ 5 ] . Therefore this marker is not specific for one type of tumour. Another approach would be t o examine the marker quantitatively and thereby hopefully limit its specificity. By obtaining a quantitative value for the marker, one might be able to define an upper limit, above which benign diseases would not exceed. We report this case because of the implications its quantitative values have and the discordance in response to therapy of the tumour and the marker. Address reprint requests to Dr. J.F. Pringle, Department of Radiation Oncology, Princess Margaret Hospital, 500 Sherbourne Street, Toronto, ON M4X 1K9,Canada.
0098-1532/79/0602-0115$01.40 0 1979 Alan R. Liss, Inc.
116
Erlichman, Pringle, and Quirt
CASE REPORT
Mrs. H.C., a 32-year-old gravida 4, para 4 Jamaican female, was admitted to another hospital in August 1976 for the investigation of amenorrhea lasting six months. An examination under anaesthesia at that time revealed an irregularity along the right side of the pelvis, and a dilatation and curettage showed chronic endometritis. Her menses occurred normally subsequent to this. If February 1977 she developed a sharp pain in her right hip which radiated down the right leg. This pain progressed until she could not walk. During the eight months prior to admission to the hospital she lost 9 kg. On admission she was found to have a hard mass fixed to the right pelvic side wall. An intravenous pyelogram (IW) showed displacement of the bladder to the left pelvic wall and a pelvic ultrasound confirmed a solid mass adherent to the right pelvic wall. On August 25, 1977, an exploratory laparotomy was performed. This revealed a mass located midway between the anterior superior spine and the symphysis pubis fixed to the iliac wing. This was removed. The ovaries, fallopian tubes, and uterus were normal to inspection and palpation. Pathologic examination showed an anaplastic carcinoma in a lymph node mass. Postoperatively, two urinary hemagglutination tests for human chorionic gonadotropin were positive. A subsequent dilatation and curettage revealed a late secretory endometrium. The patient was referred to Princess Margaret Hospital in moderate distress because of pain in her hip and leg. There was no peripheral lymphadenopathy. Chest and cardiovascular examination were normal. Abdominal examination was unremarkable except for the induration noted in the right lower quadrant. Pelvic examination revealed a hard mass on the pelvic side wall. The right leg was edematous. Initial investigations revealed that hemoglobin level was 10.5 gm/dl, WBC was 13.2 X 109/liter with 74% polymorphonuclear leukocytes, alkaline phosphatase was 37.5 King-Armstrong units (KAU) (normal, 3-10), and G O T was 62 IU (normal, 10-32). A chest film was normal, but pelvic X-ray films revealed sclerosis of the right iliac bone. A liver scan showed hepatomegaly with no filling defects. An hCG /?-subunit determination by radioimmunoassay (Serono Laboratories, Boston) was 2,700 mIU/ml (normal, 0-5). Tissue was examined by immunoperoxidase stain for the /?-subunit of hCG and it stained nonspecifically. Staining for pregnancyspecific 01-glycoprotein was strongly positive. A decision was made to treat the patient with high doses of methotrexate with Leucovorin@rescue because of the elevated P-subunit of hCG in the range found in trophoblastic disease, the treatment of this tumour was most likely associated with a chance of cure, and a trophoblastic malignancy could not be completely ruled out. Between September and November 1977 the proband received four courses of methotrexate and Leucovorin rescue. Each course consisted of one gram of methotrexate infused over 16 hours followed six hours later by a bolus of 100 mg of Leucovorin IV. This was followed by lOOmg of Leucovorin by infusion over eight hours and then 25 mg IV every eight hours for six more doses. The patient attained relief of pain, return of the alkaline phosphatase and SCOT levels to normal, and a decline in the serum psubunit of hCG to normal (see Fig. 1). The pelvic mass did not change clinically or on ultrasound examination. The patient was lost to follow-up for one month but presented again in December with increasing right hip pain, especially when standing, and a fever for one week. There was right lower quadrant tenderness and the mass was unchanged on pelvic examination. Investigations revealed that the alkaline phosphatase was again elevated, at 13.8 KAU,
Ectopic Production of Human Chorionic Gonadotropin
117
I
\ \ "\ \ -_-
I
t Sepl.
Oct.
Nov.
Oec.
t W.I.
Fig. 1 . Serum psubunit of hCG level of proposita plotted logarithmically against time. ( t ) Date on which blood was drawn; (J) date on which methotrexate was given. Note that the last two blood samples had undetectable levels of the p-subunit of hCG, as expected by the linear plot.
SGOT was increased to 84 IU, and the 0-subunit of hCG was less than 1.5 mIU/ml. A renal scan showed a nonfunctioning right kidney. A pelvic ultrasound revealed the right pelvic mass to be cystic. A bone scan showed increased uptake in the ilium adjacent to the pelvic mass in the left sacrum and right femur. A fifth course of methotrexate was given, but it produced no improvement in the hip pain, alkaline phosphatase and SGOT levels, or the pelvic mass. Furthermore, the patient continued to spike fevers daily and no source of infection could be found. Concern regarding a pelvic abscess led to an examination under anaesthesia, dilatation and currettage, and posterior colpotomy with biopsy of the pelvic mass. The mass was again noted to be hard, fixed to the pelvis, and tying the cervix down. Pathologic examination of the endometrial currettage revealed midsecretory endometrium. The biopsy showed anaplastic carcinoma. There was no evidence of a pelvic abscess. A postoperative liver scan revealed that several space-occupying lesions had developed. She was then treated with 3,000 rads to the pelvis, in 20 treatments, for relief of pain. After completion of this regimen, she returned to Jamaica, where she died one month later. A postmortem was not obtained. DISCUSSION
This case illustrates two aspects of the use of the 0-subunit of hCG as a tumour marker. First, levels of the 0-subunit of hCG as high as those recorded here have in only a few case been reported in tumours of nontrophoblastic and nontesticular origin. Sussman et a1 [ 6 ] have reported two cases of large-cell carcinoma of the lung, one case of carcinoma of the stomach, one case of renal cell carcinoma, and one case of undifferentiated carcinoma with markedly elevated levels of the &subunit of hCG. Most other reports of ectopic
118
Erlichman, Pringle, and Quirt
hCG production state only whether the result is positive or negative. The importance of this point must be emphasized. Elevation of the &subunit of hCG is not specific for trophoblastic or testicular malignancies [2-5,7]. It has also been found in nonmalignant states [S] ,and recently the desialylated hCG has been demonstrated in nonneoplastic liver and colon homogenates [8], making the usefulness of the &subunit of hCG as a cancer marker doubtful. Furthermore, the quantitative assessment of the 0-subunit of hCG does not limit the specificity of the test. Second, in response to therapy, this patient’s &subunit of hCG decreased in a logarithmic fashion. Tumour cell kill by chemotherapeutic agents follows first-order kinetics. Therefore, if there was a stoichiometric relationship between the tumour cells and the marker, this logarithmic decrease in the P-subunit would be expected as a reflection of the tumour cell death. However, there was evidence of progression of disease, and the &subunit of hCG remained undetectable. This discordance in marker and tumour has been observed previously [ 4 , 9 ] . The implications are that one should be extremely wary of using this marker to follow progression of disease except in trophoblastic and testicular neoplasms. Several hypotheses can be formulated to explain this discordance: 1) The tumour may be made up of a heterogeneous group of cells, of which some produce the P-subunit of hCG while others do not. This possibility is supported by the positive staining for the pregnancy-specific 01-glycoprotein in the tumour. There does appear to be another group of cells that elaborate this hormone marker which do not stain for the &subunit of hCG. The chemotherapy may have selectively killed the &subunit of hCG-producing cells only. 2) There may not be a stoichiometric relationship between the tumour cells and the 0subunit of hCG. In this case the decrease in the marker would not reflect tumour burden. 3) The therapy may have stopped the production of the 0-subunit of hCG by the tumour cells. In this way the tumour could progress with undetectable marker being recorded [4]. There may have been a change in the metabolic clearance of the 0-subunit. This is supported by the work of Tsuruhara et a1 [ 101 and DuFau et a1 [ 1 11 . These workers have shown that the desialylated hCG maintains its activity in bioassays in vitro and in the radioimmunoassay but shows a loss of bioactivity in vivo. Clearance studies have shown that the desialylated hCG has a markedly increased clearance rate compared to intact hCG [lo, 121. These points imply that the sialic acid moiety is important in the metabolic clearance of the hCG. Thus, if a neoplasm began secreting desialylated hCG (as part of the natural evolution of the disease or as a direct effect of the chemotherapy), a marker might not be detected. 5) The clinical assessment of the tumour size may have been inaccurate. This would be unlikely, however, in this particular case. These possibilities have been mentioned before by Rosen et a1 [4]. In the case reported here, there is no definite evidence that favours one explanation over another. Thus in using tumour markers one must understand the h i t a t i o n s of sensitivity, specificity, and relationship to the tumour cell population [13].
ACKNOWLEDGMENTS
We would like to thank Dr. A. Malkin for performing the determinations of the 0-subunit of hCG and for his helpful suggestions, and express our appreciation to Miss Ellen Hoffman for typing this report.
Ectopic Production of H u m a n Chorionic G o n a d o t r o p i n
119
REFERENCES 1 . Vaitukaitis JL, Braunstein GD, Ross GT: A radioimmunoassay which specifically measures human chorionic gonadotropin in the presence of human luteinizing hormone. Am J Obstet Gynecol 113:751-758,1972. 2. Braunstein GD, Vaitukaitis JL, Carbone PP: Ectopic production of human chorionic gonadotrophin by neoplasms. Ann Intern Med 78:39-45, 1973. 3. Goldstein DP, Kosasa TS, Skarim AT: The clinical application of a specific radioimmunoassay for human gonadotropin in trophoblastic and nontrophoblastic tumours. Surg Gynecol Obstet 138~747-751,1974. 4. Rosen SW, Wintraub BD, Vaitukaitis JL, Sussman HH, Hershman JM, Muggia FM: Placental proteins and their subunits as tumour markers. Ann Intern Med 82:71-83, 1975. 5 . Vaitukaitis JL, Ross GT, Braunstein GD,Rayford PL: Gonadotropins and their subunits: Basic and clinical studies. Rec Prog Horm Res 32:289-331, 1976. 6. Sussman HH, Weintraub BD, Rosen SW: Relationship of ectopic placental alkaline phosphatase to ectopic chorionic gonadotropin and placental lactogen. Cancer 33:820-823,1974. 7. Gailani S , Chu TM, Nussbaum A, Ostrander M, Christoff N: Human chorionic gonadotrophins (hCG) in non-trophoblastic neoplasms; assessment of abnormalities of hCG and CEA in bronchogenic and digestive neoplasms. Cancer 38:1684-1686,1976. 8. Yoshimoto Y, Wolfsen AR, Odell WD: Human chorionic gonadotropin-like substance in nonendocrine tissues of normal subject. Science 197:575-577, 1977. 9. Braunstein GD, McIntire KR, Waldmann TA: Discordance of human chorionic gonadotropin and alpha-fetoprotein in testicular teratocarcinoma. Cancer 31: 1065-1068, 1973. 10. Tsuruhara T, DuFau ML, Hickman J, Catt KJ: Biological properties of hCG after removal of terminal sialic acid and galactose residues. Endocrinology 91:296-301, 1972. 11. DuFau ML, Catt KJ, Tsuruhara T: Retention of in vitro biological activities by desialylated human luteinizing hormone and chorionic gonadotropin. Biochem Biophys Res Commun 44:1022-1029, 1971. 12. VanHall EV, Vaitukaitis JL, Ross GT, Hickman JW, Ashwell G: Effects of progressive desialylation on the rate of disappearance of immunoreactive hCG from plasma in rats. Endocrinology 89: 11-15, 1971. 13. Vaitukaitis JL: When isa tumour marker not a tumour marker? N Engl J Med 293:1370-1371, 1975.
