BRIEF REPORT Rhabdomyosarcoma, Osteosarcoma, and Adrenocortical Carcinoma in a Child With a Germline p53 Mutation
Catherine M. Khayat and Donna L. Johnston, MD*
A child with an unusual association of cancers is described. The patient first presented with a rhabdomyosarcoma of the right scapular muscle, and was successfully treated with chemotherapy. Six years after diagnosis of the first malignancy, the child presented with two synchronous malignancies: osteosarcoma of the jaw and adrenocortical carcinoma. Genetic mutation analysis was performed and revealed
a germline p53 mutation of CGT>CAT at codon 273. The family history was negative for any other cancer consistent with the Li-Frau- meni syndrome. This case highlights the need for close surveillance of patients with p53 mutation for malignancy and describes the occurrence of two malignancies synchronously. Pediatr Blood Cancer 2004;43:683-686. @ 2004 Wiley-Liss, Inc.
Key words: adrenocortical carcinoma; Li-Fraumeni syndrome; osteosarcoma; p53 mutation; rhabdomyosarcoma
INTRODUCTION
We describe a patient who was initially treated for rhabdomyosarcoma and subsequently presented with an osteosarcoma of the jaw and an adrenocortical carcinoma occurring synchronously. The occurrence of second mali- gnant neoplasms has been well documented in patients treated with multiagent chemotherapy. Furthermore, the combination of chemotherapy and high dose radiotherapy appears to significantly increase this risk [1]. Osteosar- coma is known to occur as a second malignancy in patients successfully treated for rhabdomyosarcoma [2]. However, adrenocortical carcinoma appears to be unrelated to treatment of a primary neoplasm, and was never reported to occur at the same time as osteosarcoma. Such an unusual association of malignancies prompted a search for a germline genetic mutation.
CASE REPORT
The patient first presented at the age of 19 months with a 2-week history of swelling located at the level of the right scapula. Physical exam was otherwise unremarkable. Radiography of the area revealed a soft tissue mass of uniform appearance adjacent to the lateral border of the scapula with no calcification. Magnetic resonance imag- ing (MRI) showed a 4 cm by 4 cm by 2.5 cm thick soft tissue mass within the muscle fascial plane of the poster- ior aspect of the right scapular muscle with no bony involvement of the tumor (Fig. 1). No laboratory data abnormalities were detected.
Wide resection of the lesion was performed and pathology revealed a rhabdomyosarcoma of embryonal (spindle cell variant) type, and also alveolar (solid variant) type. Unfortunately, cytogenetics were not able to be performed on the tissue. Chest radiograph, abdominal ultra-sound, computerized tomography (CT) of the chest, abdomen and pelvis, bone scan, bone marrow aspirate and biopsy were found to be all normal as part of the staging work up. The patient was treated with 14 courses of vincristine, actinomycin-D, and cyclophosphamide according to the Protocol POG D-9602-VAC (Intergroup RMS) IRS-V for low risk rhabdomyosarcoma.
Close medical surveillance and frequent imaging studies failed to reveal any abnormalities until the age of 7 years. The child then presented with a few-day history of right cheek swelling associated with a mild cough. The lesion was described as a 2 cm by 3 cm swelling of the jaw, anterior to the right ear. There was no fever or other cons- titutional symptoms. Laboratory data (complete blood count and amylase) were normal. A radiograph of the mandible failed to reveal evidence of stones suggesting
Department of Pediatrics, Children’s Hospital of Eastern Ontario, Ottawa, Ontario, Canada
*Correspondence to: Dr. Donna L. Johnston, Children’s Hospital of Eastern Ontario, Division of Hematology/Oncology, 401 Smyth Rd, Ottawa, Ontario K1H 8L1, Canada. E-mail: djohnston@cheo.on.ca
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sialolithiasis as an etiology of the swelling, and the patient was discharged home on antibiotics. The swelling per- sisted and further imaging studies were done. A CT scan showed a bony spiculated mass arising from the ramus of the right mandible with new bone formation and periosteal reaction consistent with osteogenic sarcoma (Fig. 2). The child then underwent a work up for evidence of meta- stases. Bone scan demonstrated increased uptake in the posterior body and ramus of the right mandible. CT of the chest was normal. Abdominal CT revealed a large right upper quadrant mass (6.4 cm by 4.8 cm by 5.5 cm) of inhomogeneous echogenicity anterior to the right kidney
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and displacing it posteriorly, without invading it (Fig. 3). The inferior vena cava was compressed, laterally and posteriorly displaced but showed no sign of invasion. No large lymph node was identified. Previous abdominal ultra-sound 10 months prior was normal.
A biopsy of the mandibular mass was performed and confirmed the diagnosis of osteogenic sarcoma. Ultra- sound guided biopsy of the abdominal mass revealed an adrenocortical tumor but the specimen was too small to determine whether the lesion was benign or malignant. The child then underwent resection of the mass. Pathology confirmed the diagnosis of adrenocortical carcinoma, with infiltration of the renal capsule and soft tissues adjacent to the hilum of the adrenal gland. The patient was then treated with Mitotane, up to 1,500 mg bid, along with mineralocorticoid and glucorticoid replacement to coun- teract the adrenal suppression caused by Mitotane.
Unfortunately, 2 months after the initiation of che- motherapy, the osteosarcoma was found to be unrespon- sive to chemotherapy. The adrenocortical carcinoma had completely resolved on abdominal ultra-sound and MRI. The following month, chemotherapy was stopped to allow the patient to enjoy the remainder of her life without having to deal with the side effects of chemotherapy that were most bothersome to her (nausea and vomiting). The patient subsequently developed liver metastases and died 7 months later.
Testing for p53 mutation by DNA sequence analysis yielded a positive result of a CGT >CAT mutation at codon 273 (Arg > His) which is a mutation that has previously been reported [3]. An extensive pedigree was
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obtained and there was no family history of any other malignancies documented in this family.
DISCUSSION
We describe the case of an unusual association of cancers in a child with germline p53 mutation and no family history of cancer. Germline p53 mutations are most often associated with characteristic family histories of cancer. Li and Fraumeni first described this association of familial features, now called Li-Fraumeni syndrome, in 1969 [4,5]. The classic syndrome is usually defined as follows: there is a proband with a sarcoma under the age of 45, a first degree relative with any cancer before the age of 45, and another first or second degree relative with any cancer under the age of 45, or with sarcoma at any age [6]. This rare familial syndrome is associated with soft tissue sarcomas, osteosarcomas, brain tumors, breast malignan- cies, lymphoid and non-lymphoid leukemias, and adre- nocortical carcinoma [7-10]. It is a highly penetrant autosomal disorder, associated with a 40% risk of mali- gnancy before the age of 16, high mortality rates, and second primary malignancies [10,11].
According to a 1992 study that looked at a sample of 59 patients, 6% of patients with second malignancies and no familial features of Li-Fraumeni syndrome have a germline p53 mutation [12]. When specific cancers are looked at, germline p53 mutations with no familial features of Li-Fraumeni syndrome are identified in 50- 80% of children with adrenocortical carcinoma [13], 10% of children with osteosarcoma [14], and 10% of children with rhabdomyosarcoma [15].
Rhabdomyosarcoma is the most common soft tissue malignancy in the pediatric population under the age of 15. It is the third most common extracranial solid tumor (after neuroblastoma and Wilms tumor), and represents 60% of the soft tissue sarcomas seen in children [16]. Somatic mutations of the p53 gene are seen in as many as 50% of cases [17], however germline mutations are much less common and tend to be associated with a lower age (average age 22 months) at presentation [15].
Osteosarcoma is known to occur as a second malig- nancy after treatment of rhabdomyosarcoma, yet the incidence has not been clearly established. It is the most common malignant bone tumor of adolescence and child- hood [18]. Approximately 3% of patients carry a germline p53 mutation [14]. A small number of osteosarcomas (0.5-6.5%) occur at the level of either jaw, the mandible being more common than the maxilla [19]. The most common sites for metastases are by far the lungs, followed less commonly by other bones and soft tissues [18].
Adrenocortical carcinoma and osteosarcoma have never been reported to occur synchronously before. Adrenocortical carcinoma is an extremely rare tumor in the general population. It accounts for 0.2% of all child-
hood malignancies. A high frequency of germline mutations has been reported in children with adrenocor- tical carcinoma [20,21]. Most tumors are hormonally active in children (80-100%), with 2/3 showing as virilization because of increased DHEA and DHEA-S production. Absence of evidence of hyperactivity is associated with poor prognosis, because of the advanced stage of the tumor at diagnosis [22]. In the case of our patient, the level of DHEA-S was mildly elevated at the time of diagnosis, however, there was no clinical evidence of virilization.
It is this unusual association of malignancies and the co-occurrence of osteosarcoma and adrenocortical carci- noma that prompted the search for a genetic mutation in our patient. The absence of a positive family history of malignancies compatible with the Li-Fraumeni syndrome strongly suggests a de novo mutation. However, it brings up important ethical issues in terms of predictive testing of unaffected family members. In this case counseling was offered to the family but declined. It was recommended that they undergo close follow up with their primary care physician for any evidence of malignancy. Examining their genetic material may be useful for determining who is at increased risk of developing early malignancies. This should, however, be weighed against the anxiety provoked by a positive result and the potential for curative measures once a malignancy has been identified.
ACKNOWLEDGMENT
The authors thank David Malkin, MD for performing the p53 mutation analysis.
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