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A Case Report of an 18-Month-Old Boy With No Family History of Cancer

* We describe a young patient with no known family history of cancer who presented at 18 months with 2 advanced primary tumors, choroid plexus carcinoma and adrenal cortical carcinoma. Immunohistochemical studies demonstrated high levels of nuclear p53 protein expression in both tumors, as well as in the adjacent normal-appearing adrenal cortical cell nuclei of the adrenal gland. The immunohistologic distribution of elevated p53 expression suggests that this individual has a de novo germline mutation affecting p53 gene expression.

(Arch Pathol Lab Med. 2002;126:70-72)

The p53 tumor suppressor gene is the most commonly mutated gene in human cancers. The p53 gene regulates cell proliferation and DNA repair by inhibiting the cell cycle at Gl/S, so that loss of function may lead to aberrant cell kinetics and tumor growth.1 Germline mutations in the p53 gene characterize patients with Li-Fraumeni syndrome (LFS), a rare, autosomal-dominant familial tumor syndrome commonly associated with sarcoma, breast cancer, brain tumors, leukemia, and adrenal cortical carcinoma.2 The criteria used to identify an LFS-affected individual before the advent of gene analysis techniques were occurrence of sarcoma before the age of 45 years and at least 1 first-degree relative younger than 45 years with cancer, or a close relative with cancer before the age of 45 years or a sarcoma at any age.3 These individuals are subject to development of multiple primary tumors throughout their lives.

The present report concerns a young patient with no known family history of malignancies, who presented at 18 months with 2 advanced primary tumors, choroid plexus carcinoma and adrenal cortical carcinoma. Immunohistochemical studies demonstrated p53 protein localization in cell nuclei of both tumors, as well as in the adjacent normal-appearing adrenal cortical cell nuclei. The pattern of p53 expression by immunohistochemical studies suggests this individual has a de novo germline mutation affecting p53 gene expression, which could be characterized as a Li-Fraumeni syndrome, even though the clinically defining criteria are not fulfilled.

REPORT OF A CASE

An 18-month-old Hispanic boy presented with a 1-week history of emesis, decreased activity, tactile fevers, and depressed mental status after mild head trauma. Initial computed tomographic scan of the head was remarkable for a 6-cm-diameter, uniformly enhancing mass attached to the inferior wall of the right lateral ventricle with marked hydrocephalus, right greater than left. The patient had otherwise been well and had demonstrated normal early development, walking, and speech. He had no siblings, but his parents, both in their early 20s, did not know of any cancers in first- or second-degree relatives. Subtotal resection of the ventricular mass was performed, with a diagnosis of choroid plexus carcinoma based on the marked cytologic atypia, high mitotic index, and invasion into the ventricular wall. Abdominal ultrasound was performed after insertion of a ventriculoperitoneal shunt to relieve the hydrocephalus during induction chemotherapy, and a large left adrenal mass was detected. The 7.0 X 6.5 x 4.0-cm mass was diagnosed as adrenal cortical carcinoma by fine-needle aspiration biopsy. He subsequently underwent subtotal resection, due to periaortic infiltration that prevented a total resection. The child completed a course of chemotherapy (VP-16, ifosfamide, mesna, and carboplatin). A second resection of the ventricular tumor from a posterior approach resulted in removal of 95% of the tumor, including most of the area of attachment to the ventricular wall. A follow-up magnetic resonance imaging study 6 months after the surgeries showed no interval increase in the size of the brain and abdominal tumors, although it did show significant hydrocephalus on the left. Shunt revision was performed without complications at that time. The patient is continuing on an episodic chemotherapeutic regimen and has resumed walking at age 36 months.

PATHOLOGIC FINDINGS

Histopathologic studies included staining with hematoxylin-eosin and frozen sections of tumor with osmium processing. Immunohistochemical staining of formalinfixed, paraffin-embedded sections was done with an avidin-biotin horseradish peroxidase labeling procedure using primary antibodies against the following antigens: p53 and MIB-1 (Dako Corporation, Carpinteria, Calif).

Light and electron microscopic examination of the child's 2 tumors demonstrated that they were clearly 2 primary tumors rather than metastatic spread of tumor. The cytologic smear of the ventricular tumor revealed irregular papillary architecture with a surface lining of cytologically malignant cells (Figure 1, A), surrounded by sheets of pleomorphic cells (Figure 1, B) with foci of necrosis and microcalcifications. Scattered mitotic figures, including atypical mitoses, were present. The immunohistochemical proliferation index (MIB-1) was 2% to 5% focally. Immunohistochemical analysis for p53 protein was performed on several sections (dilution 1:50) and revealed a spectrum of tumor nucleus-positive staining from 0 to 4+, with the majority of nuclei showing 2+ to 4+ localization of this antigen (Figure 1, C) and negative stain on the negative control. Normal tissue cells typically do not accumulate enough p53 protein to localize immunohistochemically, since a small number of copies are sufficient for normal function. Electron microscopic examination revealed groups of basal bodies, some with sprouting cilia in the brain tumor cells, indicating an epithelial origin, such as choroid plexus (Figure 1, D).

The resected left adrenal mass weighed 98 g and measured 7.0 X 6.5 X 4.0 cm. The cut surface of the encapsulated tumor was brown-tan with hemorrhagic and cystic changes (Figure 2). Light microscopy showed sheets of polygonal cells with round or bizarre nuclei and abundant eosinophilic and microvacuolar cytoplasm (Figure 3, A). The tumor included some larger anaplastic cells with bizarre lobated nuclei and displayed multifocal necrosis and occasional microcalcifications. The MIB-1 immunohisto-- chemical stain for the proliferation index showed localization in 5% of tumor cells. Expression of p53 protein varied from 1 + to 4 + in some of the tumor cell nuclei (Figure 3, B). Adjacent, residual, normal-appearing adrenal gland also displayed p53 positivity in the nuclei of adrenal cortical cells (Figure 3, C). No papillary architecture or epithelial element of cells was found in the adrenal tumor. Frozen sections of tumor with osmium processing indicated that the vacuolated cytoplasm of the tumor cells was positive for lipid content. Electron microscopic examination confirmed the diagnosis of adrenal cortical carcinoma by demonstration of tubular cristae of the mitochondria and droplets of cytoplasmic fat (Figure 3, D).

Molecular examination of tissues was performed for some known p53 gene mutations. Specimens of DNA from both tumors were isolated by proteinase K and phenol DNA extraction techniques. Probes for 4 of the most commonly identified p53 mutations4 were tested against the tissue DNA samples (exons 5-8). None of these mutations was detected in DNA extracted from either tumor. Further gene sequencing studies may reveal the specific mutation in this case, but if the mutation is in a regulatory or receptor gene for p53, rather than in exons 5 through 8, determination of the mutation may be difficult.

COMMENT

The p53 gene is located on the short arm of the human chromosome 17, band 13 (17p13) and has 11 exons that span approximately 20 kb. This gene yields a 2.8-kb messenger RNA transcript and encodes for a 53-kd nuclear phosphoprotein (hence, p53) of a 393-amino-acid sequence protein that is expressed at low levels in the wild type.3 p53 protein is a multifunctional transcription factor involved in the control of cell cycle progression and in determining the survival of cells exposed to DNA-damaging agents. DNA damage induces a transient nuclear accumulation and transcriptional activation of the p53 protein, accompanied by transcriptional activation of other target genes that are responsible for the induction of cell cycle arrest or apoptosis.5 Ineffective p53 protein would therefore result in continuous cell cycling without apoptotic disposal of defective cells, producing a tumor.