Germline p53 Mutation in a Micronesian Child With Adrenocortical Carcinoma and Subsequent Osteosarcoma
Heather M. Delaney, MD,* Ronald D. Prauner, MD,* and Donald A. Person, MD*+
Summary: In 1990, an 18-month-old Micronesian girl was initially diagnosed with a right adrenocortical carcinoma. More than a decade later (2003), she was diagnosed with metastatic osteosarcoma with the primary in her right proximal fibula. Given this child’s remarkable history of malignancy, she underwent testing for a genetic mutation that is associated with increased cancer formation. One such cancer syndrome is called Li-Fraumeni syndrome where approximately 70% of patients carry a genetic mutation in the p53 tumor suppressor gene. Patients with LFS are at risk for developing cancers of the breast, soft tissues, brain, bone, adrenal gland, and blood cells. Mutational analysis of our patient did reveal the presence of a germline mutation of the p53 tumor suppressor gene. She was found to have a base pair change (A→C) at nucleotide 394 resulting in a lysine to glutamine amino acid change at codon 132 (K132Q), which remarkably has never been described in association with either adrenocortical carcinoma or osteosarcoma.
Key Words: adrenocortical carcinoma, osteosarcoma, p53 germline mutation
(J Pediatr Hematol Oncol 2008;30:803-806)
P atients with Li-Fraumeni syndrome (LFS) are at risk for developing certain types of cancers to include cancers of the breast, soft tissues, brain, bone, adrenal gland, and blood cells.1,2 Among families that fulfill the classic criteria for LFS, approximately 70% have been found to carry a genetic mutation in the p53 tumor suppressor gene.3 We describe a child from the remote islands of the Pacific with a remarkable history of childhood adrenocortical carcinoma (ACC) and osteo- sarcoma who was found to have a p53 tumor suppressor mutation not previously described in association with these 2 cancers.
From the *Department of Pediatrics, Tripler Army Medical Center; and ¡Department of Clinical Investigation, Pacific Island Health Care Project, Honolulu, HI.
The views expressed in this manuscript are those of the authors and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the US Government.
Reprints: Heather M. Delaney, MD, Department of Pediatrics, Tripler Army Medical Center, 1 Jarrett White Road, Tripler AMC, HI 96859-5000 (e-mail: heather.delaney@amedd.army.mil).
Copyright @ 2008 by Lippincott Williams & Wilkins
CASE REPORT
In 1990, an 18-month-old girl from Chuuk State, Federated States of Micronesia was referred through the Pacific Island Healthcare Project (PIHCP)4 to Tripler Army Medical Center (TAMC) for symptoms of weight gain, hirsuitism, clitoromegaly, cushingoid facies, and lethargy (Fig. 1). She had increased cortisol levels with loss of diurnal variation and markedly increased DHEA-sulfate levels. The patient was diagnosed with Cushing syndrome and an abdominal computed tomography scan revealed a right adrenal mass. She underwent a right adrenalectomy weighing 12.9g and measuring 4.3 × 2.6 ×2cm in size. Histopathologically, the tumor was an ACC as noted by focal capsular infiltration, high mitotic rate, abnormal mitotic figures, and prominent nucleoli. She did not receive any additional adjuvant therapy, and after recovery, she returned to her home.
When she was 11 years old, she was evaluated at the Chuuk State Hospital complaining of gradual enlargement of a right lower leg mass. The mass was initially noted to be the size of a marble and associated with “pricking pain.” She reportedly had some difficulty while walking. She was treated with unknown medications (likely traditional herbal), which afforded some temporary relief. The patient did not return for follow-up until 14 years of age when she returned with a right leg mass the size of a large orange associated with numbness and pain in the leg. She also complained of fatigue and loss of appetite. The circumference of her right lower leg was 45cm at its widest, compared with 29.5cm of the left lower leg. A radiograph obtained at that time in Chuuk revealed an ossifying mass extending into the soft tissue (Fig. 2) and she was again referred to TAMC under the PIHCP. When she arrived in late July 2003 she was wheelchair bound, ill appearing, and in severe pain.
A bone scan revealed a large region of markedly intense uptake involving the proximal right tibia and fibula with extensive soft tissue component and multiple areas of increased uptake throughout the lungs (Fig. 3). Computed tomography scan of the chest revealed diffuse perihilar and mediastinal lymphadenopathy and multiple lung and soft tissue nodules consistent with metastatic disease. Magnetic resonance imaging confirmed an aggressive bony and soft tissue neoplastic process measuring 12.1 x 17.3 x 11.5cm centered about the proximal fibular metaphysis with extension into the adjacent tibia and distal femur (Fig. 4). Biopsy of the tumor was consistent with necrotic high-grade osteogenic osteosarcoma with osteoblastic histologic features and obliteration of the proximal fibular cortex.
Given this child’s history of ACC as an infant and the development of a second primary osteosarcoma, there was concern that this patient may carry a germline mutation of the p53 tumor suppressor gene placing her and potentially her family at risk for developing malignancies. Upon review of her family history, the patient’s aunt mentioned that a number of other family members had cancer at an early age and an aunt that
died of hepatic cancer in her early 20s. However, the circum- stances surrounding these malignancies were unknown secondary to the lack of modern medical care in Chuuk State. Analysis by direct sequencing at the Georgetown University Medical Center’s Institute for Molecular and Human Genetics revealed a hetero- zygous missense mutation of base pair change (AAG-CAG) at nucleotide 394 resulting in a lysine to glutamine amino acid change at codon 132 (K132Q).
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L L
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ANTERIOR
POSTERIOR
Lossy Compressed
This patient had an above-the-knee amputation and was treated with high-dose methotrexate as per modified POG protocol 9450 for her metastatic disease. After completing 11 months of therapy, she returned to her home in Chuuk. At last contact (mid 2007), the patient is alive and well.
DISCUSSION
We describe a patient who was treated as an infant with a primary ACC and in whom a second cancer, an osteosarcoma of the fibula, developed a decade later. The use of multiagent chemotherapy for the treatment of childhood malignancies, and treatment with radiotherapy seem to independently increase the risk for occurrence of a second primary malignant neoplasm.5,6 Our patient received no adjuvant chemotherapy or radiotherapy for treatment of her primary ACC. The association between this rare primary tumor and a second primary fibular osteosarcoma motivated an evaluation for the presence of a cancer syndrome associated with a germline mutation of the p53 tumor suppressor gene.
ACC is an extremely rare cancer in children, accounting for 0.002% of all childhood malignancies.7 It follows a bimodal age distribution with peaks in the first and fourth decades.8 ACC occurs at increased frequency in certain syndromes to include Beckwith- Wiedemann syndrome8 and in families with LFS.1 Therefore, children with ACC are at a substantially increased risk of developing a subsequent cancer. Our patient went on to develop osteosarcoma of the fibula nearly a decade after she was treated for her first malignancy.
Osteosarcoma is the most common malignant bone tumor of childhood and adolescence with almost 9 cases per million in patients younger than 20 years.9 Osteo- sarcomas most frequently present in the distal femur. Our patient had osteosarcoma of the proximal fibula, which makes up only 2% of all osteosarcomas. Not only is osteosarcoma a common primary malignancy, it also is the most common second primary malignant neoplasm in children. This tumor is typically described in patients with certain primary malignancies such as retinoblastoma, Hodgkin disease, and rhabdomyosarcoma, and has only rarely been associated with an ACC as the primary tumor.8,10 In addition, osteosarcoma has also been described in familial cancer syndromes such as LFS.
Individuals with the rare genetic disorder LFS have a high risk of developing childhood and adult malignant tumors at an unusually early age, often associated with a high mortality rate.2 The classic presentation of LFS identifies families where an individual, the proband, is diagnosed with sarcoma before 45 years of age, a first- degree relative with cancer before 45 years of age, and another first-degree or second-degree relative in the same lineage with any cancer before 45 years of age or with sarcoma at any age.11 Among the families that fulfill classic criteria for LFS, approximately 70% have been found to carry a genetic defect that involves a mutation in the protein p53 tumor suppressor gene located on chromosome 17p13.3
The types of tumors that occur in individuals with LFS include cancers of the breast, soft tissues, brain, bone, adrenal gland, and blood cells. Together these tumors account for greater than 50% of cancers in selected families with LFS.2 Although these tumors are rare at varying degrees among the general population, they are found at a greater incidence among families with classic LFS. In fact, the incidence of ACC in families with LFS is 100 times that of the general population11 and therefore it is not surprising that these individuals with ACC have a high incidence of germline p53 mutations.
A study by Varley et al8 analyzed 14 cases of childhood ACC and identified a p53 germline mutation in greater than 80% making this the highest known incidence of germline mutation in a tumor suppressor gene in any cancer. Additionally, it has also been reported that among patients with a multiple cancer history, the combination of childhood osteosarcoma and ACC as primary tumors carries the highest incidence of a p53 germline mutation.3,12-14
By identifying this gene defect and its link to tumor development, individuals in families with LFS who carry this mutation can be monitored for early cancer recogni- tion. Although our patient’s family history was largely unknown, anecdotally there was a family history of cancer to include an aunt who died of hepatic cancer in her early 20s. Hepatic carcinoma is not a commonly described cancer among families with LFS. However, the cancer burden in the Pacific is high15 and chronic hepatitis B virus infections are common.
Mutational analysis by direct sequencing did reveal the presence of a germline mutation of the p53 tumor suppressor gene in our patient. Without a known “classic” family history consistent with LFS, this muta- tion may represent a de novo mutation. Typically, the p53 mutation presenting with LFS tumors at exceptionally young ages has a high degree of penetrance in LFS families. However, it has been reported that individuals with certain p53 mutations, notably those presenting with ACC,8 may have low penetrance because these patients will often not meet criteria for classic LFS. This may be the case with our patient.
According to a database of mutations in the p53 tumor suppressor genes, this particular genetic mutation (K132Q) has only been described as a somatic mutation in 15 cases to include prostate, larynx, hematologic malignancies, pancreas, lymph nodes, colon, breast, ovary, and brain cancer.16 Not only has this mutation never been described in the context of ACC or osteosarcoma, this is also the first reported case of this specific p53 germline mutation. Additionally, this muta- tion was also reported as a heterozygous mutation, whereas germline mutations are typically described as having loss of heterozygosity. A study by Trkova et al17 in 2003 reviewed all published cases of tumors in germline p53 mutation carriers where loss of heterozygosity data were available. They identified 84 tumors with loss of the wild-type allele, 57 tumors with retention of heterozy- gosity, and 9 tumors with loss of the allele harboring the
germline mutation. They reported a significant difference in the fraction of tumors showing p53 protein accumula- tion between the tumors with loss of the wild-type allele and those with retention of p53 heterozygosity providing support to the idea that the pathogenesis of tumors in germline p53 mutation carriers does not have to be associated with loss of the wild-type p53 allele. They went on to hypothesize that the product of the normal allele can potentially be inactivated by a variety of other mechanisms or that many of these tumors may even preserve the activity of the wild-type p53 protein.17
Given that our patient carries a germline p53 mutation, places her and potentially her family and descendents at extreme risk for developing malignancies throughout their lifetime. Although, the patient and her family were counseled regarding this increased risk of cancer formation, it is unknown how this information will influence this family’s follow-up in the future given the limited access to medical care in the Islands of Chuuk State. Given the remote location of this family in the Pacific, it alone is remarkable how this patient was discovered and received treatment through the PIHCP not once but twice. This program, a web-based consulta- tion and referral system, was established in 1989 as a means of providing the residency training programs at TAMC with unique patients from the United States Associated Pacific Islands (USAPIs) so as to enhance Graduate Medical Education.4,15,18 The PIHCP has been instrumental in TAMC’s ability to care for more than 6000 indigenous patients from the developing world of the USAPIs, which include 3 flag territories (American Samoa, Guam, and the Commonwealth of the Northern Mariana Islands) and 3 freely associated jurisdictions including the Republic of the Marshall Islands, the Federated States of Micronesia (including Chuuk, Kos- rae, Pohnpei, and Yap States), and the Republic of Palau. Given the inherent restrictions under the PIHCP, further testing of family members for this genetic mutation was not available and likely impossible through their local healthcare network. Further study needs to be done to look into the incidence of p53 mutation in Micronesian families with malignancy to determine the demand for increased access to medical care and prompt follow-up for early cancer recognition.
ACKNOWLEDGMENTS
The authors thank Dr Adam Kanis, geneticist, and Dr Lynne Ruess, pediatric radiologist, for their contributions with this manuscript.
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