JBJS | Dedifferentiated Chondrosarcoma in Albright Syndrome. A Case Report and Review of the Literature*

The Journal of Bone & Joint Surgery, Volume 79, Issue 10

Case Reports | October 01, 1997

Dedifferentiated Chondrosarcoma in Albright Syndrome. A Case Report and Review of the Literature*

TOSHIFUMI OZAKI, M.D.†; NORBERT LINDNER, M.D.‡; SEBASTIAN BLASIUS, M.D.‡, MÜNSTER, GERMANY

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Investigation performed at the Department of Orthopaedics, University of Münster, Münster

The Journal of Bone & Joint Surgery. 1997; 79:1545-51

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Introduction

Introduction | Case Report | Discussion | References

Fibrous dysplasia is a developmental condition in which the skeleton fails to mature normally. Albright syndrome, which was first reported in 1937 by McCune and Bruch²³ and by Albright¹, is characterized by polyostotic fibrous dysplasia, endocrine disorders, and brown patches on the skin (café-au-lait spots)^3,17,25. It is seen more often in female than in male patients³⁵. Malignant transformation in fibrous dysplasia was noted, in 1945, by Coley and Stewart⁵, and since then it has been reported in more than 100 patients^12,19,33,43. The most common secondary malignant lesion in fibrous dysplasia is osteosarcoma, followed by fibrosarcoma and chondrosarcoma^{6,9,15,18,33,42}. The prevalence of malignant transformation in fibrous dysplasia is only 0.4 per cent (six of 1517 patients)³⁶. However, the prevalence of malignant transformation in Albright syndrome is 4 per cent (four of 100 patients³⁶), which is higher than that in other forms of fibrous dysplasia³⁶. To our knowledge, we are the first to report the case of a patient who had a dedifferentiated chondrosarcoma secondary to Albright syndrome.

*No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article. No funds were received in support of this study.

†Department of Orthopaedic Surgery, Okayama University Medical School, 2-5-1 Shikata-cho, Okayama 700, Japan.

‡Departments of Orthopaedics (N. L.) and Pathology (S. B.), Westfälische Wilhelms-University, 48129 Münster, Germany.

*No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article. No funds were received in support of this study.

†Department of Orthopaedic Surgery, Okayama University Medical School, 2-5-1 Shikata-cho, Okayama 700, Japan.

‡Departments of Orthopaedics (N. L.) and Pathology (S. B.), Westfälische Wilhelms-University, 48129 Münster, Germany.

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Fig. 1 Anteroposterior and lateral radiographs showing multifocal radiolucent areas, several osteolytic lesions (arrowheads indicate the largest lesion), ballooning, and deformity of the tibia.

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Fig. 2 Whole-body bone scan revealing polyostotic lesions and osseous deformity.

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Fig. 3 Computed tomography scan showing an osseous lesion, disruption of the tibial cortex, and an extraskeletal tumor mass (arrowheads).

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Fig. 4 Resected specimen of the proximal and diaphyseal region of the tibia, showing mainly cartilaginous tumor tissue in the proximal aspect of the tibia. There is complete destruction of the cortex by hemorrhagic tumor tissue with extraosseous extension of the tumor into the soft tissue on the medial side (arrowheads).

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Fig. 5 Photomicrograph of a specimen taken from an area of fibrocartilaginous dysplasia, showing highly differentiated cartilaginous tissue with marginal ossification, consistent with enchondroma-like nodules (x 64).

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Fig. 6-A: Photomicrograph showing low-grade (highly differentiated) chondrosarcoma (x 400).

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Fig. 6-B: Photomicrograph showing an area of osteosarcoma with osteoid production (x 400).

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Fig. 7-A Photomicrograph showing the sharp transition between low-grade chondrosarcoma and high-grade sarcoma, which is a characteristic feature of dedifferentiated chondrosarcoma (x 100).

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Fig. 7-B High-magnification photomicrograph of the area of transition (x 200).

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TABLE I REVIEW OF THE LITERATURE

Study	Case	Gender, Age at Onset (Yrs.)	Polyostotic Fibrous Dysplasia		Secondary Sarcoma
Symptoms	Radiation Therapy	Age at Onset (Yrs.)	Affected Bone	Symptoms	Diagnosis	Treatment	Outcome
Snapper³⁸ (1949)	1	F, 7	Pathological fracture, precocious puberty, mental deficiency	No	14	Femur	Not reported	Osteosarcoma	Not reported	Died with metastasis at <12 mos.
Dustin and Ley¹¹ (1950)	2	F, 7	Pathological fracture, precocious puberty	Yes (femur, pelvis; total, 16 gray)	13	Pelvis	Pain, mass, dysuria	Osteosarcoma	None	Died with metastasis at <12 mos.
Parrini²⁹ (1957)	3	F, 6	Precocious puberty	No	8	Calvarium	Recurrent mass	Osteosarcoma	Resection	Not reported
Mogensen²⁷ (1958)	4	F, 19	Pigmented skin, acromegaly, delayed menarche	Yes (pituitary body)	36	Orbita	Visual impairment, exophthalmos	Not reported	Radiation	Died at 7 mos.
Jäger²¹ (1962)	5	F, 6	Pigmented skin, pathological fracture (femur)	Yes (femur)	22	Maxilla	Swelling	Osteosarcoma	Resection, radiation	Died with pulmonary metastasis at 9mos.
Bell and Hinds² (1967)	6	F, 6	Pigmented skin, sinusitis, bronchial pneumonia	No	16	Rib	Pain	Fibrosarcoma	Resection	Died, after local relapse, at 14 mos.
Roze et al.³² (1967)	7	F, infancy	Pigmented skin, myxoma	No	72	Tibia	Pain	Osteosarcoma	Radiation (20 gray), amputation, chemotherapy	Died with metastasis at 18 mos.
Pons et al.³⁰ (1974)	8	M, 12	Pigmented skin	No	21	Mandible	Swelling	Osteosarcoma	Resection, radiation	Died with pulmonary metastasis at 8 mos.
Hall et al.¹⁶ (1984)	9	M, 4	Pigmented skin, acromegaly, hyperthyroidism, pathological fracture	No	37	Mandible	Swelling	Osteosarcoma	Not reported	Not reported
Ruggieri et al.³⁴ (1995)	10	F, 7	Pathological fracture, pigmented skin, precocious puberty, hypertension	No	40	Ilium	Swelling, pain	Osteosarcoma	Radiation (63 gray)	Died with pulmonary metastasis at 5 mos.
Ozaki et al. (present study) (1997)	11	M, infancy	Pigmented skin, pathological fracture, precocious puberty	No	51	Tibia	Swelling, pain	Dedifferentiated chondrosarcoma	Amputation, chemotherapy	Alive with disease at 15 mos.

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TABLE I REVIEW OF THE LITERATURE

Study	Case	Gender, Age at Onset (Yrs.)	Polyostotic Fibrous Dysplasia		Secondary Sarcoma
Symptoms	Radiation Therapy	Age at Onset (Yrs.)	Affected Bone	Symptoms	Diagnosis	Treatment	Outcome
Snapper³⁸ (1949)	1	F, 7	Pathological fracture, precocious puberty, mental deficiency	No	14	Femur	Not reported	Osteosarcoma	Not reported	Died with metastasis at <12 mos.
Dustin and Ley¹¹ (1950)	2	F, 7	Pathological fracture, precocious puberty	Yes (femur, pelvis; total, 16 gray)	13	Pelvis	Pain, mass, dysuria	Osteosarcoma	None	Died with metastasis at <12 mos.
Parrini²⁹ (1957)	3	F, 6	Precocious puberty	No	8	Calvarium	Recurrent mass	Osteosarcoma	Resection	Not reported
Mogensen²⁷ (1958)	4	F, 19	Pigmented skin, acromegaly, delayed menarche	Yes (pituitary body)	36	Orbita	Visual impairment, exophthalmos	Not reported	Radiation	Died at 7 mos.
Jäger²¹ (1962)	5	F, 6	Pigmented skin, pathological fracture (femur)	Yes (femur)	22	Maxilla	Swelling	Osteosarcoma	Resection, radiation	Died with pulmonary metastasis at 9mos.
Bell and Hinds² (1967)	6	F, 6	Pigmented skin, sinusitis, bronchial pneumonia	No	16	Rib	Pain	Fibrosarcoma	Resection	Died, after local relapse, at 14 mos.
Roze et al.³² (1967)	7	F, infancy	Pigmented skin, myxoma	No	72	Tibia	Pain	Osteosarcoma	Radiation (20 gray), amputation, chemotherapy	Died with metastasis at 18 mos.
Pons et al.³⁰ (1974)	8	M, 12	Pigmented skin	No	21	Mandible	Swelling	Osteosarcoma	Resection, radiation	Died with pulmonary metastasis at 8 mos.
Hall et al.¹⁶ (1984)	9	M, 4	Pigmented skin, acromegaly, hyperthyroidism, pathological fracture	No	37	Mandible	Swelling	Osteosarcoma	Not reported	Not reported
Ruggieri et al.³⁴ (1995)	10	F, 7	Pathological fracture, pigmented skin, precocious puberty, hypertension	No	40	Ilium	Swelling, pain	Osteosarcoma	Radiation (63 gray)	Died with pulmonary metastasis at 5 mos.
Ozaki et al. (present study) (1997)	11	M, infancy	Pigmented skin, pathological fracture, precocious puberty	No	51	Tibia	Swelling, pain	Dedifferentiated chondrosarcoma	Amputation, chemotherapy	Alive with disease at 15 mos.

Case Report

Introduction | Case Report | Discussion | References

A fifty-two-year-old man who had had polyostotic fibrous dysplasia and many café-au-lait spots since he was an infant was seen at our hospital because of mild pain and increased swelling of the left knee. There was no family history of bone tumors, skin pigmentation, or precocious puberty. During childhood, he had sustained multiple fractures of the long bones of the lower limbs. When he was five years old, acne, growth of pubic hair, and an increase in the size of the penis and testes were observed. During adolescence and adulthood, more fractures of the lower limbs occurred. Neither the lower limbs nor the pituitary gland had been treated with radiation therapy. Since the age of fifty years, he had been confined to a wheelchair because of the marked deformities and risk of fractures of the lower extremities.

On admission to our hospital, six months after he was first seen, the patient reported constant pain in the proximal aspect of the left tibia and marked tenderness was noted. The findings of laboratory tests were normal except for the level of serum alkaline phosphatase, which was 420 international units per liter (normal, 0 to 170 international units per liter).

Radiographs of both femora revealed lesions with characteristics ranging from lytic to a ground-glass appearance to sclerotic. Both hips had severe varus deformity (shepherd's crook deformity), which is typical of fibrous dysplasia. In the proximal aspect of the left tibia, several large osteolytic lesions and areas of osseous destruction were noted (Fig. 1). A bone scan showed increased uptake of isotope in the skull, maxillae, mandible, humeri, shoulders, ribs, forearms, hands, vertebrae, pelvis, femora, tibiae, and feet (Fig. 2). Computed tomography revealed disruption of the posterior cortex of the left tibia and an extraskeletal tumor mass (Fig. 3). T1-weighted magnetic resonance imaging after injection of gadolinium-diethylenetriamine penta-acetic acid showed a heterogeneous bone tumor with a soft-tissue component as well as areas of low and high signal intensity. On the basis of these clinical and radiographic findings, malignant transformation of the polyostotic fibrous dysplasia was suspected. Radiographs and computed tomography scans of the chest revealed no evidence of pulmonary metastases.

Incisional biopsies were performed on the left tibia, and core biopsy specimens were taken from different sites of tumor involvement in the right tibia and in both femora to exclude the diagnosis of polyostotic malignant transformation and to decide on a safe level of amputation. The histological findings revealed a malignant tumor only in the left tibia, and a through-the-knee amputation was performed. The initiation of chemotherapy was delayed at the request of the patient, and adjuvant chemotherapy was started two months after the operation according to the COSS-86 (Cooperative Osteosarcoma Study) protocol⁴¹. Pulmonary metastases developed fourteen months after the operation. At the time of writing, fifteen months after the initial operation, the patient was alive with disease.

Pathological Findings

The sectioned surfaces of the amputated specimen revealed multiple grayish-white granular lesions in the tarsus, first metatarsal, and phalanges. The proximal aspect of the tibia had a glossy blue-white cartilaginous tumor, measuring twelve by six centimeters, extending from the epiphysis into the diaphysis (Fig. 4). A white soft-tissue mass was seen in the posterior region of the proximal metaphysis and diaphysis, and a cystic lesion that measured four by five centimeters was found in the anteromedial region of the proximal part of the diaphysis. The distal part of the diaphysis had a lobulated area of firm cartilaginous tissue.

On histological examination, the tissue taken from the tarsus, metatarsals, and phalanges had the characteristic morphology of fibrous dysplasia with islands of woven bone in a fibrous stroma. Examination of the tibia revealed fibrous dysplasia as a pre-existing lesion in all areas that were not infiltrated by the tumor. Enchondroma-like nodules with a diameter of about two centimeters were found in the distal diaphyseal region, indicating a chondroid differentiation in fibrous dysplasia (Fig. 5)²⁰. These observations suggested that our patient had fibrocartilaginous dysplasia rather than typical fibrous dysplasia. The main lesion in the proximal aspect of the tibia was composed of cartilaginous tumor with low-to-moderate cellularity. At the periphery of the cartilaginous tumor, a destructive growth pattern was evident as the tissue had infiltrated cortical bone and the pre-existing fibrous dysplasia. In addition to the infiltrating growth pattern of the cartilaginous tumor, the findings included mild-to-moderate nuclear atypia, double nuclei, and some mitotic figures, which are features of a grade-1 or grade-2 chondrosarcoma (Fig. 6-A). The white soft-tissue area that was located posteriorly in the cartilaginous lesion in the proximal part of the diaphysis showed osteosarcomatous differentiation (Fig. 6-B), and the lytic lesion located anteromedially was a high-grade anaplastic sarcoma. These areas of high-grade sarcoma were immediately adjacent to the low-grade chondrosarcoma (Figs. 7-A and 7-B). This growth pattern led to the diagnosis of dedifferentiated chondrosarcoma with anaplastic osteosarcomatous components.

Discussion

Introduction | Case Report | Discussion | References

The dedifferentiated chondrosarcoma in our patient developed in an area of pre-existing fibrocartilaginous dysplasia. In rare cases of fibrous dysplasia, the cartilage elements may be large and reach several centimeters in diameter^20,39. The fibro-osseous lesion adjacent to the cartilage islands is the most important diagnostic criterion for fibrocartilaginous dysplasia^39,40. Most dysplasias of this type involve the proximal part of the femoral shaft⁴⁰. The main part of the tumor in our patient consisted of a low-grade chondrosarcoma juxtaposed with a high-grade anaplastic sarcoma or osteosarcoma. These histopathological features meet the definition of dedifferentiated chondrosarcoma as initially described, in 1971, by Dahlin and Beabout⁷.

The main problem in the case of our patient was the differential diagnosis between dedifferentiated chondrosarcoma and chondroblastic osteosarcoma. The lesion first was regarded as chondrosarcoma because of the cytological findings of a low-to-moderate grade of malignancy, including double nuclei, and then because of the permeative growth pattern at the tumor margins. Chondroblastic osteosarcoma was unlikely because there were mostly areas of low-grade chondrosarcoma. In chondroblastic osteosarcoma, irregular neoplastic osteoid usually is intermixed with high-grade chondrosarcoma that has no grossly separated malignant elements¹⁴. The sharp transition between high-grade sarcoma and low-grade chondrosarcoma seen in our patient is typical of dedifferentiated chondrosarcoma.

It is probable that the dedifferentiated chondrosarcoma originated from fibrocartilaginous dysplasia with enchondroma-like nodules²⁵, which developed into chondrosarcoma and finally resulted in dedifferentiated chondrosarcoma. The interpretation that the enchondroma-like nodules transformed into chondrosarcoma is supported by the presence of enchondroma-like nodules in the distal part of the tibia, in which there was no tumor. To our knowledge, there have been only eight reported cases of malignant cartilaginous components in a sarcoma (usually an osteosarcoma^{26,28,31,33,43} but also a chondrosarcoma⁴²) secondary to fibrous dysplasia.

The prevalence of malignant transformation in fibrous dysplasia has been reported to be 0.4 per cent (six of 1517 patients)³⁶, and most of the patients were more than thirty years old when a sarcoma developed. Yabut et al.⁴² analyzed the cases of eighty-three patients who had malignant transformation of fibrous dysplasia. Of the seventy-three patients for whom the histological diagnosis was described, forty had osteosarcoma; twenty-two, fibrosarcoma; and eleven, chondrosarcoma. The mean period of survival for the eighty-three patients was thirty-six months⁴². Ruggieri et al.³³ reported that, in twenty-eight patients who had malignant transformation of fibrous dysplasia, the secondary sarcoma was osteosarcoma (nineteen patients), fibrosarcoma (five), chondrosarcoma (three), or malignant fibrous histiocytoma (one). The most frequent sites of secondary sarcomas in these two reports were the craniofacial bone followed by the femur.

As far as we know, there have been only eleven reports, including our report, of malignant degeneration in a patient who had Albright syndrome (Table I)^{2,11,16,21,27,29,30,32,34,38}. All of the patients had Albright syndrome according to the reports, but the triad of the syndrome (polyostotic fibrous dysplasia, areas of pigmented skin, and precocious puberty) was noted in only two patients (Cases 10 and 11). Eight of the patients had secondary osteosarcoma; one, fibrosarcoma; and one (our patient), dedifferentiated chondrosarcoma. The type of sarcoma was not known for the eleventh patient. Two patients (Cases 2 and 4) had sarcoma in a previously irradiated area.

Early recognition of malignant transformation in fibrous dysplasia depends mainly on an accurate clinical history of symptoms such as pain and swelling³³. As lesions of fibrous dysplasia show a high uptake of isotope^10,13, a bone scan has limited value for revealing malignant transformation. Unless a malignant change occurs^22,25,37,42, fibrous dysplasia usually remains contained within the bone²¹. Radiographically, the most constant feature of malignant transformation of fibrous dysplasia is infiltration of the tumor into the surrounding soft tissues³³. If extraskeletal tumor growth is identified on computerized tomography or magnetic resonance imaging, malignant transformation should be strongly suspected.

The prognosis for patients who have a malignant lesion secondary to fibrous dysplasia is virtually the same as that for patients who have the corresponding primary tumor³³. Dedifferentiated chondrosarcoma is likely to be followed by pulmonary metastasis, and the prognosis is poor^4,8,24. After operative resection, our patient received chemotherapy with methotrexate, cisplatin, Adriamycin (doxorubicin), and ifosfamide and had no sign of recurrent disease or metastases for thirteen months. However, pulmonary metastases developed fourteen months after the operation. The prognosis may be improved by early diagnosis and adequate treatment.

References

Introduction | Case Report | Discussion | References

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Bell, W. H., and Hinds, E. C.: Fibrosarcoma complicating polyostotic fibrous dysplasia. Oral Surg., Oral Med., and Oral Pathol.,23: 299-310, 1967.23299 1967

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Enneking, W. F.: Clinical Musculoskeletal Pathology. Ed. 3, pp. 267-272. Gainesville, Florida, University of Florida Press, 1990.

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Halawa, M., and Aziz, A. A.: Chondrosarcoma in fibrous dysplasia of the pelvis. A case report and review of the literature. J. Bone and Joint Surg.,66-B(6): 760-764, 1984.66-B(6)760 1984

Hall, M. B.; Sclar, A. G.; and Gardner, D. F.: Albright's syndrome with reactivation of fibrous dysplasia secondary to pituitary adenoma and further complicated by osteogenic sarcoma. Report of a case. Oral Surg., Oral Med., and Oral Pathol.,57: 616-619, 1984.57616 1984

Huvos, A. G.: Bone Tumors: Diagnosis, Treatment, and Prognosis. Ed. 2, pp. 30-48. Philadelphia, W. B. Saunders, 1991.

Huvos, A. G.; Higinbotham, N. L.; and Miller, T. R.: Bone sarcomas arising in fibrous dysplasia. J. Bone and Joint Surg.,54-A: 1047-1056, July 1972.54-A1047 1972

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McCune, D. J., and Bruch, H.: Osteodystrophia fibrosa. Report of a case in which the condition was combined with precocious puberty, pathologic pigmentation of the skin and hyperthyroidism, with a review of the literature. Am. J. Dis. Child.,54: 806-848, 1937.54806 1937

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Simpson, A. H. R. W.; Creasy, T. S.; Williamson, D. M.; Wilson, D. J.; and Spivey, J. S.: Cystic degeneration of fibrous dysplasia masquerading as sarcoma. J. Bone and Joint Surg.,71-B(3): 434-436, 1989.71-B(3)434 1989

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Fig. 1 Anteroposterior and lateral radiographs showing multifocal radiolucent areas, several osteolytic lesions (arrowheads indicate the largest lesion), ballooning, and deformity of the tibia.

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Fig. 2 Whole-body bone scan revealing polyostotic lesions and osseous deformity.

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Fig. 3 Computed tomography scan showing an osseous lesion, disruption of the tibial cortex, and an extraskeletal tumor mass (arrowheads).

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Fig. 6-A: Photomicrograph showing low-grade (highly differentiated) chondrosarcoma (x 400).

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Fig. 6-B: Photomicrograph showing an area of osteosarcoma with osteoid production (x 400).

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Fig. 7-A Photomicrograph showing the sharp transition between low-grade chondrosarcoma and high-grade sarcoma, which is a characteristic feature of dedifferentiated chondrosarcoma (x 100).

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Fig. 7-B High-magnification photomicrograph of the area of transition (x 200).

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TABLE I REVIEW OF THE LITERATURE

Study	Case	Gender, Age at Onset (Yrs.)	Polyostotic Fibrous Dysplasia		Secondary Sarcoma
Symptoms	Radiation Therapy	Age at Onset (Yrs.)	Affected Bone	Symptoms	Diagnosis	Treatment	Outcome
Snapper³⁸ (1949)	1	F, 7	Pathological fracture, precocious puberty, mental deficiency	No	14	Femur	Not reported	Osteosarcoma	Not reported	Died with metastasis at <12 mos.
Dustin and Ley¹¹ (1950)	2	F, 7	Pathological fracture, precocious puberty	Yes (femur, pelvis; total, 16 gray)	13	Pelvis	Pain, mass, dysuria	Osteosarcoma	None	Died with metastasis at <12 mos.
Parrini²⁹ (1957)	3	F, 6	Precocious puberty	No	8	Calvarium	Recurrent mass	Osteosarcoma	Resection	Not reported
Mogensen²⁷ (1958)	4	F, 19	Pigmented skin, acromegaly, delayed menarche	Yes (pituitary body)	36	Orbita	Visual impairment, exophthalmos	Not reported	Radiation	Died at 7 mos.
Jäger²¹ (1962)	5	F, 6	Pigmented skin, pathological fracture (femur)	Yes (femur)	22	Maxilla	Swelling	Osteosarcoma	Resection, radiation	Died with pulmonary metastasis at 9mos.
Bell and Hinds² (1967)	6	F, 6	Pigmented skin, sinusitis, bronchial pneumonia	No	16	Rib	Pain	Fibrosarcoma	Resection	Died, after local relapse, at 14 mos.
Roze et al.³² (1967)	7	F, infancy	Pigmented skin, myxoma	No	72	Tibia	Pain	Osteosarcoma	Radiation (20 gray), amputation, chemotherapy	Died with metastasis at 18 mos.
Pons et al.³⁰ (1974)	8	M, 12	Pigmented skin	No	21	Mandible	Swelling	Osteosarcoma	Resection, radiation	Died with pulmonary metastasis at 8 mos.
Hall et al.¹⁶ (1984)	9	M, 4	Pigmented skin, acromegaly, hyperthyroidism, pathological fracture	No	37	Mandible	Swelling	Osteosarcoma	Not reported	Not reported
Ruggieri et al.³⁴ (1995)	10	F, 7	Pathological fracture, pigmented skin, precocious puberty, hypertension	No	40	Ilium	Swelling, pain	Osteosarcoma	Radiation (63 gray)	Died with pulmonary metastasis at 5 mos.
Ozaki et al. (present study) (1997)	11	M, infancy	Pigmented skin, pathological fracture, precocious puberty	No	51	Tibia	Swelling, pain	Dedifferentiated chondrosarcoma	Amputation, chemotherapy	Alive with disease at 15 mos.

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TABLE I REVIEW OF THE LITERATURE

Study	Case	Gender, Age at Onset (Yrs.)	Polyostotic Fibrous Dysplasia		Secondary Sarcoma
Symptoms	Radiation Therapy	Age at Onset (Yrs.)	Affected Bone	Symptoms	Diagnosis	Treatment	Outcome
Snapper³⁸ (1949)	1	F, 7	Pathological fracture, precocious puberty, mental deficiency	No	14	Femur	Not reported	Osteosarcoma	Not reported	Died with metastasis at <12 mos.
Dustin and Ley¹¹ (1950)	2	F, 7	Pathological fracture, precocious puberty	Yes (femur, pelvis; total, 16 gray)	13	Pelvis	Pain, mass, dysuria	Osteosarcoma	None	Died with metastasis at <12 mos.
Parrini²⁹ (1957)	3	F, 6	Precocious puberty	No	8	Calvarium	Recurrent mass	Osteosarcoma	Resection	Not reported
Mogensen²⁷ (1958)	4	F, 19	Pigmented skin, acromegaly, delayed menarche	Yes (pituitary body)	36	Orbita	Visual impairment, exophthalmos	Not reported	Radiation	Died at 7 mos.
Jäger²¹ (1962)	5	F, 6	Pigmented skin, pathological fracture (femur)	Yes (femur)	22	Maxilla	Swelling	Osteosarcoma	Resection, radiation	Died with pulmonary metastasis at 9mos.
Bell and Hinds² (1967)	6	F, 6	Pigmented skin, sinusitis, bronchial pneumonia	No	16	Rib	Pain	Fibrosarcoma	Resection	Died, after local relapse, at 14 mos.
Roze et al.³² (1967)	7	F, infancy	Pigmented skin, myxoma	No	72	Tibia	Pain	Osteosarcoma	Radiation (20 gray), amputation, chemotherapy	Died with metastasis at 18 mos.
Pons et al.³⁰ (1974)	8	M, 12	Pigmented skin	No	21	Mandible	Swelling	Osteosarcoma	Resection, radiation	Died with pulmonary metastasis at 8 mos.
Hall et al.¹⁶ (1984)	9	M, 4	Pigmented skin, acromegaly, hyperthyroidism, pathological fracture	No	37	Mandible	Swelling	Osteosarcoma	Not reported	Not reported
Ruggieri et al.³⁴ (1995)	10	F, 7	Pathological fracture, pigmented skin, precocious puberty, hypertension	No	40	Ilium	Swelling, pain	Osteosarcoma	Radiation (63 gray)	Died with pulmonary metastasis at 5 mos.
Ozaki et al. (present study) (1997)	11	M, infancy	Pigmented skin, pathological fracture, precocious puberty	No	51	Tibia	Swelling, pain	Dedifferentiated chondrosarcoma	Amputation, chemotherapy	Alive with disease at 15 mos.