Familial adenomatous polyposis (FAP) is an autosomal dominant disorder caused by mutation of the APC gene. It is characterised by the appearance of hundreds to thousands of colorectal adenomas in adolescence and the subsequent development of colorectal cancer. Various extracolonic malignancies are associated with FAP, including desmoids and neoplasms of the stomach, duodenum, pancreas, liver, and brain. We present a family affected by FAP with an exon 14 APC mutation displaying two rare extracolonic lesions, a hepatoblastoma and a myoepithelial carcinoma. The hepatoblastoma was found in a male patient aged 2 years. The second lesion, a myoepithelial carcinoma of the right cheek, was found in a female patient aged 14 years. Inactivation of the normal APC allele was demonstrated in this lesion by loss of heterozygosity analysis, thus implicating APC in the initiation or progression of this neoplasm. This is the first reported case of this lesion in a family affected by FAP.
- familial adenomatous polyposis
- APC gene
- loss of heterozygosity
- myoepithelial carcinoma hepatoblastoma
- FAP, familial adenomatous polyposis
- LOH, loss of heterozygosity
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For individuals who inherit the colorectal cancer predisposition syndrome, familial adenomatous polyposis (FAP), prophylactic colectomy has reduced the risk of death from colorectal cancer. However, in addition to the multiple adenomas that develop within the colorectum of these patients, extracolonic tumours are frequent, and these present additional challenges for surveillance, prevention, and treatment.1 The various tumours found in FAP include desmoids, upper gastrointestinal tract neoplasms, central nervous systm neoplasms, osteomas, and epidermoid cysts. Hepatoblastoma, a rare embryonal tumour of infancy, has been reported in young, predominantly male patients with FAP at a frequency significantly higher than that seen in the general population.2 In addition, young female patients with FAP may develop thyroid carcinomas.3 Both lesions occur in the offspring of affected patients with FAP at a rate of 1%.
FAP is caused by germline mutation of the APC tumour suppressor gene. A previous report has documented the inactivation of both copies of APC within a hepatoblastoma occurring in a patient with FAP, thus implicating APC in the genesis of this extracolonic tumour.4 In this report, we present a case of myoepithelial carcinoma occurring in a female patient with FAP aged 14 years. In this tumour both copies of APC were inactivated.
“Familial adenomatous polyposis is caused by germline mutation of the APC tumour suppressor gene”
CASE REPORT AND INVESTIGATIONS
Family FP008 consists of 17 affected individuals spanning four generations with an average age of onset of polyposis of 21 years. The family phenotype is characterised by profuse polyposis, congenital hypertrophy of the retinal pigment epithelium, osteomas, and upper gastrointestinal tract neoplasms. In addition, two rare extracolonic lesions have occurred in this family, a hepatoblastoma and a myoepithelial carcinoma. The first lesion was seen in a male patient aged 2 years. This lesion was of fetal subtype with clear margins, and was removed by left hepatic lobectomy. The second extracolonic lesion, a myoepithelial carcinoma of the right cheek, was found in a female patient aged 14 years. This report implicates the APC tumour suppressor gene in the genesis of this lesion and is the first case report of such a lesion in a family with FAP.
The specimen was received as a lesion of the right cheek and assumed to be an epidermoid cyst. It consisted of multiple fragments of cream and tan tissue measuring 30 × 24 × 14 mm. The largest of the fragments contained bright yellow foci. Microscopically, the tumour comprised compact nests and trabeculae separated by thin walled vessels and composed of round to oval shaped cells with eosinophilic to clear cytoplasm and indistinct cytoplasmic boundaries (fig 1). Nuclei were oval and vesicular, moderately pleomorphic, and contained the occasional small nucleolus. Apoptotic activity was conspicuous focally. Hyaline periodic acid Schiff positive material was present focally between the tumour nests. The mitotic rate was 21 mitoses/10 high power fields. No definite local invasion was seen but this was difficult to evaluate because of the extent of fragmentation. The tumour was positive for S100, smooth muscle actin, epithelial membrane antigen, and cytokeratin (CAM 5.2).
An inactivating mutation, 1751–1753 delC, in exon 14 of the APC gene, was previously detected in the germline of this family by the protein truncation assay, denaturing electrophoresis, and DNA sequencing. This mutation was found in the normal DNA of both individuals with the rare extracolonic lesions. DNA from the myoepithelioma was extracted from archival paraffin wax embedded tissue and loss of heterozygosity (LOH) analysis was performed using two polymorphic markers on chromosome 5q (D5S346 and MCC-CA), both of which are tightly linked to the APC locus. LOH in the myoepithelial tumour is shown in fig 2. A full haplotyping analysis using three APC intragenic and three tightly linked polymorphic markers had been included in the diagnostic procedures for this kindred. From the haplotyping analysis we were able to deduce that the wild-type allele had been lost from the tumour (fig 2).
Malignant myoepithelioma is rare and accounts for less than 1% of all salivary gland tumours.5,6 It occurs with the same frequency in both sexes. It arises from pre-existing benign lesions, such as pleomorphic adenomas and benign myoepitheliomas, but can also arise de novo. Four main histological variants of myoepithelioma are described, namely: spindle cell, plasmacytoid (hyaline), clear cell, and epithelioid. The neoplasm in our patient was classified as a myoepithelioma, clear to epithelioid cell type. Malignant myoepithelioma is distinguished from benign neoplasia on the basis of local invasion, with cytological abnormalities serving as a guide to aggressive local behaviour, although metastases occur in up to 30% of cases.7 In view of the cytological atypia, foci of tumour necrosis, and high mitotic count, our present case was regarded as malignant.6 Myoepithelioma is described as having solid, myxoid, and reticular growth.8 The tumour reported here was described as having a solid growth pattern. There were features of intracystic or intraluminal growth, which correlated with the surgeon's impression of a cystic tumour. The patient remains well two years after surgery.
Take home messages
This is the first report of myoepithelial carcinoma occurring in a patient with familial adenomatous polyposis
In this tumour both copies of APC were inactivated, implicating APC in the genesis of this extracolonic tumour
Biallelic inactivation of APC in hepatoblastoma has been reported previously. However, the involvement of APC in myoepithelial carcinomas has not been examined. Molecular analyses of pleomorphic adenomas of the salivary glands have shown no significant involvement of sequences on chromosome 5q, with a single report of 17% LOH.9 In our case, LOH was seen in the wild-type allele, thus demonstrating biallelic inactivation of APC, and implicating APC in the genesis of this lesion. The age of onset reported for myoepithelial carcinoma varies from 17 months to 81 years,5,6,10 although the disease is essentially reported as one of persons over 50 years of age.8 It is possible that a de novo mutation of APC may have been present in the cases reported in very young individuals. Such genetic events are common in FAP and would be unlikely to be excluded in the absence of a family history.
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