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Humoral Hypercalcemia Associated With a Dysgerminoma
Case Rep rt Humoral Hypercalcemia Associated With a Dysgerminoma
SHELLEY C. GIEBEL, M.D.,* C. ROBERT STANHOPE, M.D., GEORGE D. MALKASIAN, Jr., M.D., Department of Obstetrics and Gynecology; MARK F. SCHRAY, M.D., t Division ofRadiation Oncology; HUNTER HEATH III, M.D.,:\: Division ofEndocrinology/Metabolism and Internal Medicine; THOMAS A. GAFFEY, M.D., Section of Surgical Pathology
A 16-year-old girl sought medical attention at the Mayo Clinic because of a 4.5-kg weight loss, hypercalcemia, and a pelvic mass. Preoperatively, the level of the ~-subunit of human chorionic gonadotropin was 147 IUlIiter. After a brief period for observation and hydration, abdominal exploration revealed a stage III dysgerminoma; total abdominal hysterectomy and bilateral salpingooophorectomy were performed. Within the dysgerminoma, syncytial giant cells expressed human chorionic gonadotropin-positive immunostaining in the cytoplasm. Postoperatively, the value of the ~ subunit of human chorionic gonadotropin decreased rapidly. The patient received whole-abdomen irradiation 4 weeks postoperatively, after which the level of calcium returned to normal. The patient has been free of disease for more than 7 years.
Dysgerminoma, a germ cell tumor of ovarian origin, constitutes approximately 0.9 to 2% of all ovarian malignant lesions. I These tumors commonly are nonfunctioning; however, they occasionally secrete human chorionic gonadotropin. Herein we present a case that suggests that dysgerminomas also may secrete a factor or factors capable of causing hypercalcemia.
REPORT OF CASE A 16-year-old girl was assessed at our institution because of a pelvic mass, hypercalcemia, and an increased plasma concentration of the ~-subunit of human chorionic gonadotropin. She had felt lethargic during the preceding 6 months and had polyuria and polydipsia. Nausea and vomiting that persisted for 2 weeks had resulted in a 4.5-kg weight loss. The patient denied use of vitamin D or A, diuretics, or calcium supplements.
*Current address: Olmsted Medical Group, Rochester, Minnesota. tCurrent address: Emanuel Hospital, Portland, Oregon. :j:Current address: University of Utah Medical Center, Salt Lake City, Utah. Address reprint requests to Dr. C. R. Stanhope, Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, Mr-r 55905. Mayo Clin Proc 67:966-968,1992
On examination, we detected a mobile mass (15 by 15 ern) in the pelvic midline. Initial studies of the blood yielded the following results: calcium, 15.2 mg/dl (normal, 9.1 to 10.3); phosphorus, 2.9 mg/dl (normal, 3.1 to 4.7); alkaline phosphatase, 402 U/liter (normal, 133 to 573); creatinine, 2.1 mg/dl (normal, 0.6 to 0.9); hemoglobin, 11.0 g/dl (normal, 11.6 to 14.9); and 13-human chorionic gonadotropin, 147 lUI liter (normal, less than 5.0). Chest roentgenographic findings were unremarkable. After rehydration, the calcium level decreased to 14.0 mg/dl, and a celiotomy was performed. An ovarian mass (17 by U.S by 9 em) that weighed 1,185 g was removed along with a mass of right periaortic nodes (10 by 5.5 by 2 em). Further abdominal exploration revealed no palpable nodes beyond the periaortic chain, and the liver was free of involvement. Three palpable right external iliac nodes were removed, and a biopsy of the left ovary was performed. An examination of frozen sections disclosed an ovarian dysgerminoma with serosal involvement. The periaortic mass, right external iliac nodes, and left ovary contained dysgerminoma tissue. Because of the stage III dysgerminoma, total abdominal hysterectomy and bilateral salpingo-oophorectomy were performed. During the patient's recuperation period, a bone scan showed no metastatic involvement. The postop966
HUMORAL HYPERCALCEMIA ASSOCIATED WITH A DYSGERMINOMA
Mayo Clio Proc, October 1992, Vol 67
erative changes in the levels of calcium, phosphorus, and human chorionic gonadotropin are shown in Figure 1. Immediately postoperatively, the serum calcium value was within normal limits; however, by postoperative day 2, it increased. A downward trend was noted during the following weeks, but the level of calcium did not return to normal until the patient received radiotherapy. Since that time, the value has remained in the normal range. Four weeks postoperatively, adjuvant whole-abdomen irradiation was begun; a dose of 1,950 cGy was administered in 13 150-cGy fractions. Although the liver and kidneys were not shielded initially, 100% posteroanterior kidney blocks were used after the first 1,500 cGy. Subsequently, an additional 1,500 cGy in 10 150-cGy fractions was administered to the pelvic, periaortic, and diaphragmatic nodal regions; the total dose in these regions was 3,450 cGy. In view of the extensive periaortic adenopathy, 2,000 cGy in 10 200cGy fractions was administered to the mediastinum and bilateral supraclavicular regions. At the time of preparation of this report, the patient had been continuously free of disease for more than 7 years, and she had had no treatment-related morbidity. A review of the permanent sections of the samples of tissue also revealed dysgerminoma. Immunostaining for ~ human chorionic gonadotropin was localized to syncytial
giant cells in the dysgerminoma, both ovaries, and the metastatic lesions. DISCUSSION The first description of humorally mediated hypercalcemia in a patient with an ovarian cancer was reported by Plimpton and Gellhorn- in 1956. The reported incidence of hypercalcemia in patients with ovarian tumors ranges from 0.47 3 to 8.2%.4 Most such malignant lesions are epithelial in origin, as are those tumors commonly associated with humorally mediated hypercalcemia, including those in primary sites such as the lung and the head and neck. Stewart and associates' described a series of nine cases of gynecologic cancer associated with humorally mediated hypercalcemia in which mesonephromas and adenocarcinoma of the ovary were the most common tumors. In 1962, Breidahl and Ritchie" reported hypercalcemia in a patient with a dysgerminoma; however, after review of the tissue, Ferenczy and colleagues' disputed the conclusions of Breidahl and Ritchie and suggested that the tumor was a mucinous cystadenocarcinoma. Nelken and co-workers 7 and Stewart and associates' also reported single cases of humorally mediated hypercalcemia in patients with dysgerminomas. Clearly, hypercalcemia that accompanies some tumors is caused by circulating factors secreted by the tumors. One
14 12
Calcium
10
8 6 4
2 Weeks
7/ 7/ 7/ 7/ 7/ 7/ 7/ 7/ 7/ 7/ 8/ 9/ 11/ 11 4/ 7/ 10/ 2/ 6/ 9/ 17 18 19 20 21 22 23 24 25 26 13 10 8 17 23 28 20 27 16 23
I
ptstoperative
1985
967
RadiOthera~y
II
1986
I LJ 1987
Fig. 1. Laboratory findings in a 16-year-old girl after total abdominal hysterectomy and bilateral salpingo-oophorectomy for stage III dysgerminoma. hCG = human chorionic gonadotropin.
968
HUMORAL HYPERCALCEMIA ASSOCIATED WITH A DYSGERMINOMA
Mayo Clio Proc, October 1992,Vol67
Table I.-Postoperative Laboratory Values for a 16-Year-Old Girl Who Underwent Surgical Excision of a Dysgerminoma
of the patients in comparison with nonfunctioning dysgerminomas.
Date (1985)
Value
Normal range
Aug. 12
81
15-60
Aug. 13 Aug. 14 Aug. 14
104* 8.8 2.3
20-275 5-11 1.3-3.7
CONCLUSION Hypercalcemia associated with an ovarian malignant tumor is rare but should be considered when a patient has rapid onset of symptoms such as polydipsia, polyuria, weight loss, and fatigue. For our patient, the data suggested that the hypercalcemia was mediated by a humoral factor secreted by the tumor, as occurs in other malignant lesions. The presence of syncytiotrophoblastic giant cells in pure dysgerminomas can mimic intrauterine or ectopic pregnancies on initial evaluation but does not alter the associated prognosis, in contrast to mixed germ cell tumors that harbor components of embryonal cell or choriocarcinomas. Careful pathologic review is necessary for further management decisions.
Variable 1,25-Dihydroxyvitamin D (pg/ml) Urinary calcium (mgI24-h specimen) Total thyroxine (ug/dl) Urinary cAMPt (nmolldl)
*Only 434 ml in the urine specimen. tcAMP =cyclic adenosine monophosphate.
possible factor is 1,25-dihydroxyvitamin D; another is the newly discovered parathyroid hormone-related peptide." Pertinent postoperative laboratory values for our patient are shown in Table 1. Our patient's plasma level of 1,25dihydroxyvitamin D was not sufficiently increased to have caused the hypercalcemia. No assay for parathyroid hormone-related peptide was available when this patient was examined. Postoperative parathyroid hormone assay yielded a value of 34!!1 eq/ml (normal, 50 or less). Thus, we cannot say which of these variables caused hypercalcemia in our patient, but we believe that the dysgerminoma was responsible because the hypercalcemia resolved after the dysgerminoma was removed and radiation therapy was instituted. Thus, our patient probably had humorally mediated hypercalcemia associated with a malignant process. The syncytiotrophoblastic giant cells found in the current case have prognostic significance. Distinguishing between pure dysgerminomas and those of mixed origin is important. Both the prognosis associated with and the management of dysgerminomas depend on the histologic types identified within the tumor mass. This subtype of pure dysgerminoma-that is, one with syncytiotrophoblastic giant cells--can mimic an intrauterine or ectopic pregnancy on initial evaluation. Apparently, the titer of gonadotropin is proportional to the mass of syncytiotrophoblastic giant cells in the tumor. Zaloudek and colleagues?reported six cases of pure dysgerminomas with syncytiotrophoblastic giant cells. In these investigators: experience, the presence of syncytiotrophoblastic giant cells did not alter the prognosis
REFERENCES 1. Norris HJ, AdamAE: Malignant germ cell tumors of ovary. In Gynecologic Oncology: Fundamental Principles and Clinical Practice. Vol 2. Edited by M Coppleson. Edinburgh, Churchill Livingstone, 1981, pp 680-696 2. Plimpton CH, Gellhorn A: Hypercalcemia in malignant disease without evidence of bone destruction. Am J Med 21:750759, 1956 3. Ferenczy A, Okagaki T, Richart RM: Para-endocrine hypercalcemia in ovarian neoplasms: report of mesonephroma with hypercalcemia and review ofliterature. Cancer 27:427433, 1971 4. Smith JP, Boronow RC, Moure JMD: Hypercalcemia accompanying ovarian mesonephroma without skeletal metastasis. South MedJ 61:375-378,1968 5. Stewart AF, Romero R, Schwartz PE, Kohorn EI, Broadus AE: Hypercalcemia associated with gynecologic malignancies: biochemical characterization. Cancer 49:2389-2394, 1982 6. Breidahl HD, Ritchie BC: Hypercalcaemia due to malignant ovarian tumour: a case report. Med J Aust 1:208-210, 1962 7. Nelken RP, Nieburg PI, Bergstrom WH, Richman RA: Dysgerminoma presenting as a calcified abdominal mass with hypercalcemia. Pediatrics 61:791-793,1978 8. Broadus AE, Mangin M, Ikeda K, Insogna KL, Weir EC, Burtis WJ, Stewart AF: Humoral hypercalcemia of cancer: identification of a novel parathyroid hormone-like peptide. N Engl J Med 319:556-563,1988 9. Zaloudek CJ, Tavassoli FA, Norris HJ: Dysgerminoma with syncytiotrophoblastic giant cells: a histologically and clinically distinctive subtype of dysgerminoma. Am J Surg Pathol 5:361-367, 1981
SHELLEY C. GIEBEL, M.D.,* C. ROBERT STANHOPE, M.D., GEORGE D. MALKASIAN, Jr., M.D., Department of Obstetrics and Gynecology; MARK F. SCHRAY, M.D., t Division ofRadiation Oncology; HUNTER HEATH III, M.D.,:\: Division ofEndocrinology/Metabolism and Internal Medicine; THOMAS A. GAFFEY, M.D., Section of Surgical Pathology
A 16-year-old girl sought medical attention at the Mayo Clinic because of a 4.5-kg weight loss, hypercalcemia, and a pelvic mass. Preoperatively, the level of the ~-subunit of human chorionic gonadotropin was 147 IUlIiter. After a brief period for observation and hydration, abdominal exploration revealed a stage III dysgerminoma; total abdominal hysterectomy and bilateral salpingooophorectomy were performed. Within the dysgerminoma, syncytial giant cells expressed human chorionic gonadotropin-positive immunostaining in the cytoplasm. Postoperatively, the value of the ~ subunit of human chorionic gonadotropin decreased rapidly. The patient received whole-abdomen irradiation 4 weeks postoperatively, after which the level of calcium returned to normal. The patient has been free of disease for more than 7 years.
Dysgerminoma, a germ cell tumor of ovarian origin, constitutes approximately 0.9 to 2% of all ovarian malignant lesions. I These tumors commonly are nonfunctioning; however, they occasionally secrete human chorionic gonadotropin. Herein we present a case that suggests that dysgerminomas also may secrete a factor or factors capable of causing hypercalcemia.
REPORT OF CASE A 16-year-old girl was assessed at our institution because of a pelvic mass, hypercalcemia, and an increased plasma concentration of the ~-subunit of human chorionic gonadotropin. She had felt lethargic during the preceding 6 months and had polyuria and polydipsia. Nausea and vomiting that persisted for 2 weeks had resulted in a 4.5-kg weight loss. The patient denied use of vitamin D or A, diuretics, or calcium supplements.
*Current address: Olmsted Medical Group, Rochester, Minnesota. tCurrent address: Emanuel Hospital, Portland, Oregon. :j:Current address: University of Utah Medical Center, Salt Lake City, Utah. Address reprint requests to Dr. C. R. Stanhope, Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, Mr-r 55905. Mayo Clin Proc 67:966-968,1992
On examination, we detected a mobile mass (15 by 15 ern) in the pelvic midline. Initial studies of the blood yielded the following results: calcium, 15.2 mg/dl (normal, 9.1 to 10.3); phosphorus, 2.9 mg/dl (normal, 3.1 to 4.7); alkaline phosphatase, 402 U/liter (normal, 133 to 573); creatinine, 2.1 mg/dl (normal, 0.6 to 0.9); hemoglobin, 11.0 g/dl (normal, 11.6 to 14.9); and 13-human chorionic gonadotropin, 147 lUI liter (normal, less than 5.0). Chest roentgenographic findings were unremarkable. After rehydration, the calcium level decreased to 14.0 mg/dl, and a celiotomy was performed. An ovarian mass (17 by U.S by 9 em) that weighed 1,185 g was removed along with a mass of right periaortic nodes (10 by 5.5 by 2 em). Further abdominal exploration revealed no palpable nodes beyond the periaortic chain, and the liver was free of involvement. Three palpable right external iliac nodes were removed, and a biopsy of the left ovary was performed. An examination of frozen sections disclosed an ovarian dysgerminoma with serosal involvement. The periaortic mass, right external iliac nodes, and left ovary contained dysgerminoma tissue. Because of the stage III dysgerminoma, total abdominal hysterectomy and bilateral salpingo-oophorectomy were performed. During the patient's recuperation period, a bone scan showed no metastatic involvement. The postop966
HUMORAL HYPERCALCEMIA ASSOCIATED WITH A DYSGERMINOMA
Mayo Clio Proc, October 1992, Vol 67
erative changes in the levels of calcium, phosphorus, and human chorionic gonadotropin are shown in Figure 1. Immediately postoperatively, the serum calcium value was within normal limits; however, by postoperative day 2, it increased. A downward trend was noted during the following weeks, but the level of calcium did not return to normal until the patient received radiotherapy. Since that time, the value has remained in the normal range. Four weeks postoperatively, adjuvant whole-abdomen irradiation was begun; a dose of 1,950 cGy was administered in 13 150-cGy fractions. Although the liver and kidneys were not shielded initially, 100% posteroanterior kidney blocks were used after the first 1,500 cGy. Subsequently, an additional 1,500 cGy in 10 150-cGy fractions was administered to the pelvic, periaortic, and diaphragmatic nodal regions; the total dose in these regions was 3,450 cGy. In view of the extensive periaortic adenopathy, 2,000 cGy in 10 200cGy fractions was administered to the mediastinum and bilateral supraclavicular regions. At the time of preparation of this report, the patient had been continuously free of disease for more than 7 years, and she had had no treatment-related morbidity. A review of the permanent sections of the samples of tissue also revealed dysgerminoma. Immunostaining for ~ human chorionic gonadotropin was localized to syncytial
giant cells in the dysgerminoma, both ovaries, and the metastatic lesions. DISCUSSION The first description of humorally mediated hypercalcemia in a patient with an ovarian cancer was reported by Plimpton and Gellhorn- in 1956. The reported incidence of hypercalcemia in patients with ovarian tumors ranges from 0.47 3 to 8.2%.4 Most such malignant lesions are epithelial in origin, as are those tumors commonly associated with humorally mediated hypercalcemia, including those in primary sites such as the lung and the head and neck. Stewart and associates' described a series of nine cases of gynecologic cancer associated with humorally mediated hypercalcemia in which mesonephromas and adenocarcinoma of the ovary were the most common tumors. In 1962, Breidahl and Ritchie" reported hypercalcemia in a patient with a dysgerminoma; however, after review of the tissue, Ferenczy and colleagues' disputed the conclusions of Breidahl and Ritchie and suggested that the tumor was a mucinous cystadenocarcinoma. Nelken and co-workers 7 and Stewart and associates' also reported single cases of humorally mediated hypercalcemia in patients with dysgerminomas. Clearly, hypercalcemia that accompanies some tumors is caused by circulating factors secreted by the tumors. One
14 12
Calcium
10
8 6 4
2 Weeks
7/ 7/ 7/ 7/ 7/ 7/ 7/ 7/ 7/ 7/ 8/ 9/ 11/ 11 4/ 7/ 10/ 2/ 6/ 9/ 17 18 19 20 21 22 23 24 25 26 13 10 8 17 23 28 20 27 16 23
I
ptstoperative
1985
967
RadiOthera~y
II
1986
I LJ 1987
Fig. 1. Laboratory findings in a 16-year-old girl after total abdominal hysterectomy and bilateral salpingo-oophorectomy for stage III dysgerminoma. hCG = human chorionic gonadotropin.
968
HUMORAL HYPERCALCEMIA ASSOCIATED WITH A DYSGERMINOMA
Mayo Clio Proc, October 1992,Vol67
Table I.-Postoperative Laboratory Values for a 16-Year-Old Girl Who Underwent Surgical Excision of a Dysgerminoma
of the patients in comparison with nonfunctioning dysgerminomas.
Date (1985)
Value
Normal range
Aug. 12
81
15-60
Aug. 13 Aug. 14 Aug. 14
104* 8.8 2.3
20-275 5-11 1.3-3.7
CONCLUSION Hypercalcemia associated with an ovarian malignant tumor is rare but should be considered when a patient has rapid onset of symptoms such as polydipsia, polyuria, weight loss, and fatigue. For our patient, the data suggested that the hypercalcemia was mediated by a humoral factor secreted by the tumor, as occurs in other malignant lesions. The presence of syncytiotrophoblastic giant cells in pure dysgerminomas can mimic intrauterine or ectopic pregnancies on initial evaluation but does not alter the associated prognosis, in contrast to mixed germ cell tumors that harbor components of embryonal cell or choriocarcinomas. Careful pathologic review is necessary for further management decisions.
Variable 1,25-Dihydroxyvitamin D (pg/ml) Urinary calcium (mgI24-h specimen) Total thyroxine (ug/dl) Urinary cAMPt (nmolldl)
*Only 434 ml in the urine specimen. tcAMP =cyclic adenosine monophosphate.
possible factor is 1,25-dihydroxyvitamin D; another is the newly discovered parathyroid hormone-related peptide." Pertinent postoperative laboratory values for our patient are shown in Table 1. Our patient's plasma level of 1,25dihydroxyvitamin D was not sufficiently increased to have caused the hypercalcemia. No assay for parathyroid hormone-related peptide was available when this patient was examined. Postoperative parathyroid hormone assay yielded a value of 34!!1 eq/ml (normal, 50 or less). Thus, we cannot say which of these variables caused hypercalcemia in our patient, but we believe that the dysgerminoma was responsible because the hypercalcemia resolved after the dysgerminoma was removed and radiation therapy was instituted. Thus, our patient probably had humorally mediated hypercalcemia associated with a malignant process. The syncytiotrophoblastic giant cells found in the current case have prognostic significance. Distinguishing between pure dysgerminomas and those of mixed origin is important. Both the prognosis associated with and the management of dysgerminomas depend on the histologic types identified within the tumor mass. This subtype of pure dysgerminoma-that is, one with syncytiotrophoblastic giant cells--can mimic an intrauterine or ectopic pregnancy on initial evaluation. Apparently, the titer of gonadotropin is proportional to the mass of syncytiotrophoblastic giant cells in the tumor. Zaloudek and colleagues?reported six cases of pure dysgerminomas with syncytiotrophoblastic giant cells. In these investigators: experience, the presence of syncytiotrophoblastic giant cells did not alter the prognosis
REFERENCES 1. Norris HJ, AdamAE: Malignant germ cell tumors of ovary. In Gynecologic Oncology: Fundamental Principles and Clinical Practice. Vol 2. Edited by M Coppleson. Edinburgh, Churchill Livingstone, 1981, pp 680-696 2. Plimpton CH, Gellhorn A: Hypercalcemia in malignant disease without evidence of bone destruction. Am J Med 21:750759, 1956 3. Ferenczy A, Okagaki T, Richart RM: Para-endocrine hypercalcemia in ovarian neoplasms: report of mesonephroma with hypercalcemia and review ofliterature. Cancer 27:427433, 1971 4. Smith JP, Boronow RC, Moure JMD: Hypercalcemia accompanying ovarian mesonephroma without skeletal metastasis. South MedJ 61:375-378,1968 5. Stewart AF, Romero R, Schwartz PE, Kohorn EI, Broadus AE: Hypercalcemia associated with gynecologic malignancies: biochemical characterization. Cancer 49:2389-2394, 1982 6. Breidahl HD, Ritchie BC: Hypercalcaemia due to malignant ovarian tumour: a case report. Med J Aust 1:208-210, 1962 7. Nelken RP, Nieburg PI, Bergstrom WH, Richman RA: Dysgerminoma presenting as a calcified abdominal mass with hypercalcemia. Pediatrics 61:791-793,1978 8. Broadus AE, Mangin M, Ikeda K, Insogna KL, Weir EC, Burtis WJ, Stewart AF: Humoral hypercalcemia of cancer: identification of a novel parathyroid hormone-like peptide. N Engl J Med 319:556-563,1988 9. Zaloudek CJ, Tavassoli FA, Norris HJ: Dysgerminoma with syncytiotrophoblastic giant cells: a histologically and clinically distinctive subtype of dysgerminoma. Am J Surg Pathol 5:361-367, 1981