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Osteoblastic Osteogenic Sarcoma in a 35-month-old Girl Report of a Case G E N E P. S I E G A L , M.D., D A V I D C. D A H L I N , M.D., FRANKLIN H. SIM, M.D. Mayo Clinic and Mayo Foundation, Rochester, Minnesota ABSTRACT Siegal, Gene P., Dahlin, David C., and Sim, Franklin H.: Osteoblastic osteogenic sarcoma in a 35-month-old girl. Report of a case. Am J Clin Pathol 63: 886-890, 1975. A girl, aged 2 years, 11 months, who had pain and swelling of the proximal humerus, was found to have osteoblastic osteogenic sarcoma of the humerus. Among 937 consecutive patients with osteogenic sarcoma examined at the Mayo Clinic, she is the youngest child seen, as well as only the sixth child younger than 6 years of age in this series. (Key words: Osteosarcoma; Pediatric oncology; Neoplasm of bone; Osteogenic sarcoma; Cancer.) O S T E O G E N I C SARCOMAS are extremely rare in infants and children of preschool age. At the Mayo Clinic from January 1905 through J u n e 1974, a total of 937 cases of osteogenic sarcomas was recorded. This total includes 63 cases with the primary lesion located in either the mandible or the maxilla and 34 cases with the lesion classified as parosteal (juxtacortical) o s t e o s a r c o m a . Previously, the youngest patient in the entire series was a girl, aged 3 years, 11 months, with a sarcoma of the proximal end of the femur. Only four other cases of osteosarcoma in preschool-age children are to be found in the records of the Mayo Clinic; two of the tumors were in girls, aged 4!4 and 5 years, in both of whom the tumor involved the distal right femur, and two Received October 29, 1974; accepted for publication November 11, 1974. Address reprint requests to Dr. Siegal, c/o Section of Publications, Mayo Clinic, 200 First Street SW, Rochester, MN 55901. were in boys, also aged 4V2 and 5 years, in whom the tumor involved the distal right femur and the proximal right femur, respectively. In a large series reported from another center, 11 the youngest patient among 552 with osteogenic sarcoma was 4 years old; the median age of patients in the series was 26 years. Other reports 15,16,18,20 have given comparable age statistics. We now report a case of osteogenic sarcoma in a girl, aged 2 years, 11 months. She becomes the 937th in the Mayo Clinic series. When she was first seen at another hospital, the lesion was thought to be either an infectious process or Ewing's sarcoma. Osteogenic sarcoma was not considered in the differential diagnosis, ostensibly because of the patient's young age. We report this case to emphasize that, though extremely rare, osteogenic sarcoma does occur during the first 5 years of life. 886 June 1975 OSTEOGENIC SARCOMA IN A CHILD 887 FIG. 1 (left). Predominantly sclerosing, destructive lesion of proximal end of left humeral diaphysis. Note irregular destruction of cortex of most of shaft. FIG. 2 (right). Gross features of partially ossified osteogenic sarcoma of left humerus with greatest dimensions in proximal portion of humeral shaft. Report of a Case A Caucasian girl, aged 2 years, 11 months, was in her usual state of health until she awoke one night complaining of pain in the left shoulder and arm. There was no associated fever or chill. On the following morning, her father noticed swelling and induration over the painful area. Roentgenograms revealed a destructive lesion of the left proximal humeral metaphysis with sclerosis and periosteal reaction. She was referred to the Mayo Clinic 4 days later. T h e patient, the sixth child of a 37year-old woman, gravida 7, para 7, abortus 0, had been delivered at term as a normal infant by forceps. She had had no serious illness. There was no history of trauma or injury to the left shoulder or extremity. A review of the family history revealed that one sister had died as a premature neonate and that all her other siblings were living and well. There was a 888 SIEGAL, DAHLIN AND SIM A.J.C.P.—Vol.63 FIG. 3. Microscopic appearance of sarcoma. Alt h o u g h it is p r e d o m i nantly "spindling" in this area, note chondroid and osteoid matrix production. Hematoxylin and eosin. x250. strong family history of malignancy of tissues other than bone. There was also a family history of diabetes mellitus, heart disease, and mental retardation. Results of system review were unremarkable. T h e patient's height was 94 cm. (37 inches), and her weight was 14.25 kg. (31.5 lb.); both height and weight were in the 50th percentile for her age. The temperature was 36.7 C. (98.2 F.), pulse rate 88 per min., and blood pressure 98/72 mm Hg. T h e left upper arm was swollen and tender; a large firm mass was palpated in the proximal humerus. There was no axillary or cervical adenopathy. Results of routine blood counts and urinalysis were within normal limits, as were the calcium and phosphorus values. T h e serum alkaline phosphatase concentration, however, was greatly increased, to 2,100 U. per 1. (normal, 87 to 250 U. per 1.). Roentgenograms revealed a malignant neoplasm of the proximal metaphysis of the left humerus (Fig. 1). A skeletal survey yielded no evidence of metastasis. Stereoscopic anteroposterior and lateral chest roentgenograms and whole-lung tomograms appeared normal. Frozen sec- tions revealed high-grade osteogenic sarcoma, and the patient immediately underwent interscapulothoracic (forequarter) amputation. Centered in the upper metaphysis of the humerus was a grade 4 osteoblastic osteogenic sarcoma, measuring 14 by 5 by 5 cm. It extended into the soft tissues circumferentially to a maximum distance of 2 cm. The tumor also extended into the medullary canal and subperiosteal areas as far as the distal end of the humerus. Approximately one-third of the upper epiphysis was filled with tumor (Fig. 2). The lymph nodes and major veins were not affected. Microscopically, the tumor was an osteoblastic osteogenic sarcoma (Fig. 3). Recovery was uneventful. An adjunctive chemotherapy program was started 3 weeks after operation; this consisted of administration of vincristine, adriamycin, and methotrexate (in high doses), with citrovorum rescue. Discussion Bone cancer is a rare form of neoplasia. T h e age-adjusted death rate for Ameri- June 1975 OSTEOGENIC SARCOMA IN A CHILD can white females is 0.7480/100,000 population 1 ; in other words, approximately 800 American females die each year of bone cancer. 19 Osteogenic sarcomas constitute 20 to 60% of all bone tumors and, with the possible exception of myeloma, are the most common primary malignant neoplasms of bone. They develop most commonly in bone that is growing rapidly (i.e., the metaphyseal region of the long bones of the extremities). 5,13 This is one explanation of the high incidence of osteogenic sarcoma in adolescence—the pubertal growth spurt. However, increased growth is also evident in preschool children, and one would therefore anticipate an even higher incidence in children of preschool age than is actually reported. The patient whose case we have described presented initially with the classic symptoms and signs of osteogenic sarcoma, and the roentgenographic appearance was completely consistent with that diagnosis. Despite these features, the diagnosis might have been missed solely because the patient was only 2 and not 12 years old. We are unable to confirm the existence of the report of an osteogenic sarcoma in a child of similar age or in a younger child but, because many authors have not specifically stated the ages of their patients, the true frequency of osteogenic sarcomas in children of preschool age cannot be determined. One of us (D.C.D.) has seen in consultation the slides of a 2-year-old girl with sclerosing osteogenic sarcoma of the right femur. In light of the sclerotic lesion visualized roentgenographically and of decreased abduction and external rotation of the right hip, this child was followed by her home pediatrician for more than a month because the diagnosis of osteogenic sarcoma seemed impossible. We are confident that other young children, similarly affected, do occasionally present to the clinician. It is obviously 889 imperative that the clinician be alert to the possibility of osteogenic sarcoma in children of this age group. Because there are so few cases of osteogenic sarcoma in children aged 5 years or younger, we have been unable to gather a large enough series for statistical analysis of 5-year survival and prognosis. Overall, though, it appears that 5-year survival is in the range of 20%2-4-7,8-10'14-21 and that age probably does not influence prognosis. 9 Age, however, does appear to affect the onset of pulmonary metastasis 10 in that the younger the patient, the more rapid the onset of metastasis. Associated diseases, especially other malignant neoplasms and diabetes mellitus, have often been reported to occur in families of patients with osteogenic sarcoma. 5-6,12,17 Our patient's family included one paternal uncle who had died from stomach cancer, one half-sister who had had breast cancer with metastases to the neck, and the patient's father who had had skin cancer; additionally, one maternal aunt had died of brain cancer and her maternal grandmother also had had breast cancer. All family members died elsewhere and, therefore, none of the cancers could be confirmed histologically. Whether there is some hidden environmental carcinogen or a genetic predisposition is at this point mere speculation. T h e great importance of a team approach to the diagnosis and treatment of the pediatric patient with bone disease merits emphasis. T h e pathologist needs the assistance of his clinical colleagues as well as the radiologist in reaching the final and correct diagnosis. ADDENDUM The patient did well for 14 weeks after her initial amputation. During the fifteenth week, roentgenograms of the chest showed changes consistent with bilateral pulmonary metastases. Exploration of the left chest and of the right chest two weeks later demonstrated seven isolated lesions, involving all lobes. These lesions 890 SIEGAL, DAHLIN AND SIM w e r e all successfully excised. T h e p a t i e n t was c o n s i d e r e d to be free of metastatic disease a n d was p l a c e d o n a t r a n s f e r factor p r o t o c o l . T h r e e weeks later, a n t e r i o r a n d p o s t e r i o r chest wall n o d u l e s , a left p l e u r a l effusion, a n d a m e d i a s t i n a l mass w e r e f o u n d . T h i s was clinically c o n s i s t e n t with r e c u r r e n t t u m o r from t h e p r i m a r y o s t e o g e n i c s a r c o m a . T h e patient's parents refused any further treatment, a n d the p a t i e n t d i e d 193 d a y s after h e r initial d i a g n o sis. A u t o p s y was n o t p e r f o r m e d . References 1. Burbank F: Patterns in cancer mortality in the United States: 1950-1967. Natl Cancer Inst Monogr 33:118-126, 1971 2. Copeland MM: Primary maligant tumors of bone. Cancer 20:738-746, 1967 3. Dahlin DC, Coventry MB: Osteogenic sarcoma: A study of six hundred cases. J Bone Joint Surg [Am] 49:101-110, 1967 4. Francis KC: Massive preoperative irradiation in the treatment of osteogenic sarcoma. Prog Clin Cancer 1:774-776, 1965 5. Glass AG, Fraumeni JF: Epidemiology of bone cancer in children. J Natl Cancer Inst 44: 187-199, 1970 6. Kenny FM, Hashida Y, Askari HA, et al: Virilizing tumors of the adrenal cortex. Am J Dis Child 115:445-458, 1968 7. Lee ES: Treatment of bone sarcoma. Proc R Soc Med 64:1179-1180, 1971 8. Lindbom A, Soderberg G, Spjut HJ: Osteosarcoma: A review of 96 cases. Acta Radiol 56: 1-19, 1961 9. Lockshin MD, Higgins I T T : Prognosis in osteogenic sarcoma. Clin Orthop 58:85-101, 1968 A.J.C.P. — Vol. 63 10. Marcove RC, Mike V. Hajek JV, et al: Osteogenic sarcoma under the age of twentyone: A review of one hundred and forty-five operative cases. J Bone Joint Surg [Am] 52: 4 1 1 - 4 2 3 , 1970 11. McKenna RJ, Schwinn CP, Soong KY, et al: Sarcomata of the osteogenic series (osteosarcoma, fibrosarcoma, chondrosarcoma, parosteal osteogenic sarcoma, and sarcomata arising in bone): an analysis of 552 cases. J Bone Joint Surg [Am] 48:1-26, 1966 12. Miller RW: Deaths from childhood cancer in sibs. N Engl J Med 279:122-126, 1968 13. Miller RW: Relation between cancer and congenital defects: An epidemiologic evaluation. J Natl Cancer Inst 40:1079-1085, 1968 14. Moore GE, Gerner RE, Brugarolas A: Osteogenic sarcoma. Surg Gynecol Obstet 136: 359-366, 1973 15. O'Hara JM, Hutter RVP, Foote FW Jr, et al: An analysis of thirty patients surviving longer than ten years after treatment for osteogenic sarcoma. J Bone Joint Surg [Am] 5 0 : 3 3 5 354, 1968 16. Price CHG, Jeffree GM: Metastatic spread of osteosarcoma. Br J Cancer 28:515-524, 1973 17. Robbins R: Familial osteosarcoma: fifth reported occurrence (letter to the editor). JAMA 202: 1055, 1967 18. Ross FGM: Osteogenic sarcoma. Br J Radiol 37:259-276, 1964 19. Silverberg E, Holleb Al: Cancer statistics 1973. „ CA 23:2-27, 1973 20. Skrovina B, Cervenansky J, Kossey P, et al: Primary osteosarcoma: A clinical evaluation of 73 cases. Neoplasma 18:377-393, 1971 21. Sweetnam R, Knowelden J, Seddon H: Bone sarcoma: Treatment by irradiation, amputation, or a combination of the two. Br Med J 2: 363-367, 1971