Composite Adrenocortical Carcinoma and Neuroblastoma in an Infant With a TP53 Germline Mutation: A Case Report and Literature Review
Yue-Jia Tang, MD, Ting-Ting Yu, MD, Jing Ma, MD, Ying Zhou, MD, Min Xu, MD, and Yi-Jin Gao, MD
Summary: Li-Fraumeni syndrome is a kind of hereditary cancer predisposition syndromes, and is caused by TP53 gene mutation. Adrenocortical carcinoma (ACC) is commonly described as the most closely related tumor with this disease. Here, we present a case of a male infant with composite ACC and neuroblastoma who inherited a TP53 gene mutation from his mother, a 20-year-old carrier without any tumor to date. This TP53 gene mutation may be pathogenic and lead to composite malignancies of ACC and neuroblastoma.
Key Words: TP53 gene mutation, Li-Fraumeni syndrome, compo- site malignancies, adrenocortical carcinoma, neuroblastoma
(J Pediatr Hematol Oncol 2018;00:000-000)
L i-Fraumeni syndrome (LFS, OMIM 151623) is charac- terized by high cancer risk. Among all tumors related to LFS, soft tissue sarcoma, osteosarcoma, premenopausal breast cancer, brain tumors, and adrenocortical carcinoma (ACC) are the most common ones.1 Mutations in the TP53 gene (OMIM 191170, 17q13.1) lead to LFS, and various
TP53 gene mutations have been reported since first descri- bed. A male infant with composite ACC and neuroblastoma (NB) who inherited a TP53 gene mutation from his mother is presented in this article.
CASE REPORT
The patient was born full-term by spontaneous vaginal delivery. Of 4 prenatal ultrasounds, the last was done at week 38 and was unremarkable. His birthweight was 2.8 kg. The baby was well until age 6 months when parents noted abdominal distension.
An abdominal computed tomography scan revealed a mass arising from the left adrenal gland. The mass crossed the midline with extension into the right renal hilum. The left kidney was well- defined and compressed downward. Several enlarged retro- peritoneal lymph nodes were identified. A tumor thrombus was identified in the inferior vena cava. Echocardiography revealed another tumor thrombus in the superior vena cava. The lung was clear. The bone scan and marrow analysis were normal. No chro- mosome analysis was performed on the patient.
At the time of surgery, a 12 cmx10 cm×10 cm mass was removed. Regional lymph nodes were dissected. The 2 tumor thrombus were not removed. Histologic examination showed pleo- morphic tumor cells (Fig. 1). A metastatic retroperitoneal lymph
A
B
the patient
To
mother
node contained small round cells (Fig. 1). By immunohistochemical analysis the pleomorphic tumor cells were positive for synapto- physin, steroidogenic factor, AE1/AE3, and negative for chromog- ranin A, A103 (MelanA/Mart-1), inhibin, HMB45. The small round tumor cells showed positive staining for synaptophysin, Ki-70 (70%+), weak positive staining for PGP9.5, and negative staining for SOX-10, AE1/AE3, CD45. Consequently, a histopathologic diagnosis of composite ACC and NB was made. Fluorescence in situ hybridization showed no N-MYC amplification.
The patient was treated with chemotherapy (vincristine, cyclophosphamide, carboplatin, doxorubicin, and etoposide) for NB after the first surgery. Then, he underwent 2 times of embo- lectomy. And histologic examination showed ACC.
Because TP53 gene mutations are common in ACC, genetic testing was performed on the family members.2 With the family’s agreement, we collected peripheral blood from the patient and his parents. Whole-exomes sequencing was performed and a TP53 germline mutation, c.801dupG, p.Asn268Glufs*4, was identified in the patient and his mother (Fig. 2). Both of them are heterozygotes. The father was wild type. Although we did not evaluate this new TP53 variant for function, or perform p53 staining to assess accu- mulation of protein, Alamut Visual (Interactive Biosoftware, France) predicted the possible pathogenicity of the mutation and it showed that the process of transcription can be destroyed, or the function of mRNA may be damaged because of the mutation. It is also classified as a “likely pathogenic” variation according to American College of Medical Genetics and Genomics (ACMG).
DISCUSSION
About 29% of patients meeting the standard of the revised version of the Chompret criterion of LFS are sup- posed to have TP53 gene mutations.3 The criterion was elaborated by the French LFS working group in 2001 and revised by Tina and colleagues in 2009.4,5 ACC is commonly described as the most closely related tumor with TP53 gene mutation.6 More than 80% of patients under the age of 15 to 18 years have TP53 germline mutations.7 Therefore, all the patients with ACC are recommended to undergo genetic testing.8 In contrast to ACC, NB is seldom thought to be related to LFS.
The occurrence of multiple malignancies in LFS patients is estimated to be as high as 50%.9 Secondary malignancies account for most of it while simultaneous malignancies are rarely reported. And the etiology of it is elusive. The variation in our case has only been identified in a patient with mantle cell lymphoma.10 It has never been reported in patients with ACC, NB or multiple malignancies. We then searched PubMed and theInternational Agency for Research on Cancer (IARC) TP53 database11 for TP53 gene mutation carriers with simultaneous or composite ACC and NB. Five cases with 3 different variations have been reported before (Table 1).7,12-14 The variation in our case is different from all of them. More cases are required to formulate a better understanding of the mechanisms of TP53 gene mutations in multiple malignancies of ACC and NB.
Family cancer history is also an important clue for TP53 gene mutation screening. Almost all TP53 gene mutation carriers will develop at least 1 tumor in their lives according to National Cancer Institute (NCI).15 However, no other tumor has been reported in the family members in our case. The low penetrance of the TP53 gene mutation in the family may be explained by the loss of heterozygosity. According to the Knudson16 2-hit hypothesis of tumorigenesis, 2 genetic events are sufficient to inactivate tumor suppressor genes. For the patient, the allele with a TP53 gene mutation was inher- ited from his mother. The remaining copy of the wild type TP53 gene inherited from his father was inactivated by a somatic mutation, leaving no wild type TP53 gene to protect the body. Then the tumor developed.17,18
Several studies have revealed that specific TP53 gene mutations are associated with either a poorer prognosis or a poor response to treatment.19 Besides, TP53 gene mutation carriers are prone to all kinds of genotoxic agents, especially radiation.20 And it is advisable for patients with TP53 gene mutation to have regular whole-body magnetic resonance imaging to get better outcomes before the neoplasm is unresectable.21 With these results, the patient and his mother were cautioned to be alert about their gene condition.
| Case Number | Location | Year* | Sex/Age (mo)} | Family History | Variations§ | Exon | Inherited From | References |
|---|---|---|---|---|---|---|---|---|
| 1 | USA|| | 1998 | Female/18 | + | p.R248W (45,X) | 7 | Father | 12 |
| 2 | USA | 2008 | Female/10 | + | p.R248W | 7 | / | 13 |
| 3 | Brazil | 2015 | / | / | p.R337H | 10 | / | 14 |
| 4 | Brazil | 2015 | / | / | p.R337H | 10 | / | 14 |
| 5 | USA | 2015 | Male/8 | / | p.I162F | 5 | / | 7 |
| 6 | China | 2017 | Female/6 | + | p.N268E | 8 | Mother | This study |
*The time when the case was reported.
¡Months of age at diagnosis.
¿Family histories of tumors within 3 generations.
§Gene testing results from blood samples.
||The male infant in the United States in 1998 was also a Turner syndrome patient.
/ indicates not clearly described in the articles; ACC, adrenocortical carcinoma; NB, neuroblastoma.
CONCLUSIONS
We report a case of a patient with composite malignancies of ACC and NB during his infancy. A TP53 germline muta- tion, c.801dupG, p.Asn268Glufs*4, was identified. The muta- tion is probably pathogenic and may predispose the mutation carriers to composite malignancies of ACC and NB.
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