Skeletal Radiol (2004) 33:473–476 DOI 10.1007/s00256-004-0771-0
Paul C. Jutte Renato Rosso Massimiliano de Paolis Costatino Errani Elisabetta Pasini Laura Campanacci Gaetano Bacci Franco Bertoni Mario Mercuri
Received: 10 November 2003 Revised: 17 February 2004 Accepted: 18 February 2004 Published online: 25 May 2004 ISS 2004 P. C. Jutte · M. de Paolis · C. Errani · E. Pasini · L. Campanacci · G. Bacci · F. Bertoni ()) · M. Mercuri Istituti Orthopedici Rizzoli, Via Pupilli 1, 40136 Bologna, Italy e-mail:
[email protected] P. C. Jutte University Medical Center Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands R. Rosso Anatomia Patologica Universit di Pavia, via Forlanini 16, 27100 Pavia, Italy
CASE REPORT
Osteosarcoma associated with hyperparathyroidism
Abstract The fourth case in the literature is presented of a patient with the rare association of hyperparathyroidism and osteosarcoma. A 56year-old woman presented with hyperparathyroidism and a lesion in the tibia. Initial diagnosis was brown tumor. Histology, however, revealed osteosarcoma, and the patient was treated accordingly. The experimental induction of osteosarcoma by parathormone in rodent studies makes this finding alarming, considering the increasing use of parathormone in the treatment of osteoporosis. The mechanism by which osteosarcoma is induced in humans cannot
be explained based on current knowledge of mechanisms of action of parathyroid hormone. Keywords Hyperparathyroidism · Osteosarcoma · Parathormone · Radiographs
Introduction
Case description
The association of hyperparathyroidism and osteosarcoma is very rare. The present paper describes the fourth case in the English literature. Smith et al. reported two patients [1]. The first case was a dedifferentiated chondrosarcoma with a sarcomatous component in the tibia, and the second, an osteosarcoma of the mandible. Recently Betancourt et al. reported another patient with an osteosarcoma (proximal femur) with coexisting hyperparathyroidism [2]. Although the association has seldom been reported in humans, there have been alarming reports of rodents developing osteosarcoma if exposed to high levels of parathormone [3, 4, 5]. In light of the increased use of parathormone for treating osteoporosis and experimental work in which osteosarcoma was induced with parathormone, we feel it is important to report this case. The possibility of a causal relationship between the two conditions is discussed.
A 56-year-old woman came from another hospital with a 2-month history of pain on weight-bearing in the right leg. For 6 months she had suffered from polydipsia and fatigue. Otherwise, she had always been healthy. On physical examination the proximal tibia was tender on palpation, without any soft tissue mass. The range of motion of the knee was normal. Radiographs of the right tibia showed a lytic lesion in the diaphyseal area with some destruction of the cortex (Fig. 1). Radiographs of the right femur revealed an irregular osteolytic lesion in the diaphysis without cortical destruction. The diagnosis of myeloma was suspected. Bone marrow biopsy was negative. Additional skeletal radiographs revealed small osteolytic areas in the distal phalangeal areas of both thumbs, and a characteristic small round lytic area in the subchondral area of the distal part of the right index finger (Fig. 2). Laboratory findings were compatible with hyperparathy-
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Fig. 2 Small osteolytic areas in the proximal part of the distal phalangeal areas of both thumbs, and a characteristic small round lytic area in the subchondral area of the distal part of the right index finger
Fig. 1 AP and lateral radiographs of the right tibia showing an osteolytic lesion in the diaphyseal area with some destruction of the cortex
roidism: grossly elevated parathormone 290 pg/ml (range 11–64), hypercalcemia 12.2 mg/dl (range 8.1–10.4), gross elevation of alkaline phosphatase 553 U/l (range 100– 280), and hypercalciuria 450 mg/24 h (range 100–300). Ultrasonography showed enlargement of the right lower parathyroid gland. Suspected diagnosis was hyperparathyroidism with accompanying brown tumors. Excision of the enlarged parathyroid gland was done. Histologic examination revealed hyperplasia of the chief cells, compatible with benign adenoma. Incisional biopsy and cementing of the lucent area of the proximal left tibia was performed; histology showed undifferentiated spindle and polymorphic anaplastic cells producing osteoid matrix in a lace-like arrangement. A diagnosis of grade 4 osteoblastic osteosarcoma was made (Fig. 3). She was referred to our institute for oncologic treatment. In the meantime, she experienced a remarkable remission of pain, and both lesions were clinically and radiologically stable. The diagnosis of osteosarcoma of the tibia was not clinically supported, and a biopsy was repeated of the right tibia. A biopsy was done of the right
Fig. 3 Initial biopsy showing undifferentiated spindle and polymorphic anaplastic cells producing osteoid matrix in a lace-like arrangement, compatible with grade 4 osteoblastic osteosarcoma
femur as well. Both lesions were histologically characterized by irregular slim bony trabeculae embedded in a spindle cell stroma without any cytologic atypia as seen in brown tumors. The patient was carefully followed by our clinicians with the diagnosis of brown tumors accompanying hyperparathyroidism. Parathormone levels reached withinnormal range within 4 months after the parathyroidectomy. The level of alkaline phosphatase, however, increased to 707 U/l (100–280) at this time, after an initial drop. The osseous lesions in the right femur and both hands had not substantially changed. At this time she experienced pain and swelling in the right tibia as well. Radiographs showed large lucent areas around the cement
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Fig. 6 Biopsy specimen showing undifferentiated oval and polymorphic anaplastic cells producing osteoid matrix in a lace-like arrangement (grade 4 osteoblastic osteosarcoma); same characteristics as the first biopsy
Fig. 4 AP and lateral radiographs of the right tibia showing large lucent areas around the cement extending proximally and distally
(Fig. 4). MRI showed a large lesion with soft tissue involvement (Fig. 5). Biopsy revealed grade 4 osteoblastic osteosarcoma, with the same characteristics as the first biopsy (Fig. 6). Staging revealed no further lesions. Chemotherapy was started according to osteosarcoma protocol. Wide resection and reconstruction with an allograft were subsequently performed. The percentage of tumor necrosis was 90%. There were no traces of hyperparathyroidism in the resected specimen. At present, after a follow-up of 18 months, she is doing well without signs of recurrence or metastasis.
Discussion
Fig. 5 MRI demonstrating the cement in black, with a large lesion proximally and distally, and soft tissue involvement
The case of a 56-year-old woman with hyperparathyroidism associated with an osteosarcoma is presented. This is the fourth report in the literature of this association. It would be an alarming finding if the occurrence of an osteosarcoma in hyperparathyroid patients was linked to the high levels of parathormone, because of the increasing use of parathormone. Parathormone is presumed to be safe, well tolerated, and very effective in the treatment of osteoporosis [6, 7]. There have been some alarming reports of experimental studies in which synthetic parathormone rhPTH (teriparatide) (1-34) induced osteosarcoma in rats [3, 5]. The rats were given high doses (3 to 200 times higher than normal) for a prolonged period (95% of their lifetime). It remains unclear if this carcinogenic effect of synthetic PTH can be extrapolated to humans [4, 5]. In a large clinical trial, Neer et al. did not find any osteosarcoma in over 1,600 postmenopausal women [6]. However, given the low incidence of osteosarcoma, probably much larger numbers of patients are needed to establish safety in this regard. Since November 2002, the US Food
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and Drug Administration approved the use of teriparatide (Forteo) for the treatment of osteoporosis. However, given the uncertain clinical relevance of the findings in rodents, the FDA only approved its use for postmenopausal women, who are at high risk of fracture, and to increase bone mass in men with primary or hypogonadal osteoporosis [7, 8]. Regarding endogenous PTH, the literature reveals no reports of increased osteosarcoma incidence within the average lifespan of humans with high levels of endogenous PTH caused by chronic diseases. Specifically in the large group of patients with chronic renal failure who are being kept alive by maintenance hemodialysis, we were not able to find any descriptions of associated osteosarcoma in the literature.
The patient presented is a woman, as were the other three reported patients. The age of these patients, 34, 46, 56, and 69 years, is atypical for primary osteosarcoma. The possibility of a relationship between the two conditions cannot be totally excluded. Still, the association, if real, is very rare, and the mechanism by which parathormone would induce osteosarcoma in humans cannot be explained based on current knowledge of action mechanisms of the parathyroid hormone. Acknowledgements The authors thank Christina Ghinelli for her help in preparing the figures.
References 1. Smith J, Huvos AG, Chapman M, Rabbs C, Spiro RH. Hyperparathyroidism associated with sarcoma of bone. Skeletal Radiol 1997; 26:107–112. 2. Betancourt M, Wirfel KL, Raymond AK, Yasko AW, Lee J, VassilopoulouSellin R. Osteosarcoma of bone in a patient with hyperparathyroidism: a case report. J Bone Mineral Res 2003; 18(1):163–166. 3. Barbehenn EK, Lurie P, Wolfe SM. Osteosarcoma risk in rats using PTH 1–34. Trends Endocrinol Metab 2001; 12(9):383.
4. Kuijpers G, Schneider B, Stadel B, Colman E. Recombinant human parathyroid hormone: preclinical data on rat osteosarcoma were not dismissed. BMJ 2002; 324(7347):1218. 5. Vahle JL, Sato M, Long GG, Young JK, Francis PC, Engelhardt JA, et al. Skeletal changes in rats given daily subcutaneous injections of recombinant human parathyroid hormone (1–34) for 2 years and relevance to human safety. Toxicol Pathol 2002; 30(3):312–321.
6. Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001; 344:1434– 1441. 7. Reeve J. Recombinant human parathyroid hormone. BMJ 2002; 324:435–436. 8. Freeman TR. Teriparatide: a novel agent that builds new bone. J Am Pharm Assoc 2003; 43(4):535–537.
