Familial adenomatous polyposis (FAP) is a disease of significant morbidity and risk of early mortality caused by colorectal or periampullary cancer, or noncancerous desmoid tumors. In the pediatric and adolescent FAP population, precancerous and cancerous tumors of the colon, thyroid, liver, and central nervous system have been described, with rare reports in other locations. FAP-associated death in the pediatric and adolescent population is rare. We report a 12-year-old girl with FAP and Cushing syndrome secondary to right adrenocortical carcinoma, who died of metastatic disease unresponsive to therapy. The patient first presented for genetic screening at age 10 years and was found to have the same APC mutation as her mother, 453delA. She was lost to follow-up until the age of 12 years, when she was found to have a dramatic weight gain of 52 lb (body mass index of 34 kg/m2) and hypertension with a blood pressure of 157/89 mmHg. At endocrinology consultation, she reported daily chest and side pain with dyspnea on exertion. She was premenarchal. Physical examination revealed truncal obesity and a moon face. Her blood pressure was162/112 mmHg; height 146.6 cm; weight 72.5 kg, and growth velocity 3.7 cm/year during the last 2 years. Examination was notable for moderate acne, acanthosis nigricans, mild violaceous abdominal striae, Tanner stage-4 pubic hair, and lipomastia without true breast tissue. Abdominal examination showed no masses or organomegaly. The remainder of her physical examination was normal. Endocrine studies obtained as a result of virilization and features of Cushing syndrome showed normal electrolytes, normal thyroid-stimulating hormone, and free T4 and elevated testosterone, dehydroepiandrosterone sulfate, and androstenedione. The cortisol level did not suppress with 1 mg dexamethasone. The baseline was 18.2 μg/dL and 8 AM was 17.3 μg/dL. Computerized tomography of the abdomen/pelvis identified a right upper-quadrant suprarenal mass consistent with adrenal carcinoma measuring 14 × 10 × 8.6 cm with suspected lung metastases (Fig. 1). Further gastrointestinal evaluation was suspended at this time. Needle core biopsies of the mass showed a high-grade atypical lesion with extensive necrosis. This confirmed the diagnosis of adrenocortical carcinoma and she started receiving chemotherapy according to the Children's Oncology Group protocol, ARA0332. Her chemotherapy included cisplatin, doxorubicin, etoposide, and escalating doses of mitotane. Maintenance hydrocortisone in anticipation of the development of adrenal insufficiency secondary to mitotane therapy was also initiated.FIGURE 1: Scan at diagnosis demonstrating the right adrenal mass.Following 4 cycles of chemotherapy, she was taken to surgery for attempted gross total resection, but was found at exploration to have extensive metastatic disease to her liver, which had not been visible on preoperative imaging. She underwent right adrenalectomy with resection of the primary mass (Fig. 2). The liver metastases were biopsied, but were unresectable because of their diffusing nature. Histopathology of the primary mass showed 50% viable tumor with 50% necrosis. The pathology from the liver biopsy confirmed metastatic carcinoma. The lesional cells were highlighted by immunohistochemical stains melan A, inhibin, cytokeratin, and calretinin. The tumor cells were not highlighted by Myf-4. Disease progression was noted after 6 cycles, so she then received 2 cycles of gemcitabine, capecitabine, and mitotane. At completion of these 2 cycles, she developed cardiomyopathy with further metastatic disease progression. After further discussion with the patient and family, she was transitioned to palliative care and died 2 months later, approximately 10 months after diagnosis.FIGURE 2: Gross specimen after resection of adrenal tumor.DISCUSSION There are several well-described intestinal and extraintestinal consequences of FAP. Although surveillance recommendations for the prevention of intestinal malignancies in FAP are well established, guidelines for surveillance of the extraintestinal malignancies have not been created. Recommendations that do exist include screening children of patients with FAP for hepatoblastoma with α-fetoprotein and abdominal ultrasound, annual physical examination to evaluate for soft tissue or bone lesions, and thyroid examination to identify any nodules (1). The majority of these recommendations are nonspecific and no consensus exists regarding periodic testing. Adrenal adenomas are a frequently occurring extraintestinal manifestation of FAP, with >50 cases reported (1). Many of these patients were asymptomatic and discovered at autopsy. In a retrospective study of the FAP database at the Cleveland Clinic, Marchesa et al (2) found a 7% prevalence of "incidentalomas" in patients with FAP as compared with 3% in the general population. Smith et al (3) prospectively studied 107 patients with FAP and found the prevalence of adrenal masses to be 13%. Although adrenal adenomas are common, adrenal carcinomas in patients with FAP are rare and only a few have been reported in the literature (1–4). Of these patients, only 1 was <20 years. In the non-FAP population, adrenocortical carcinomas are rare (4–12/million) (5) and are poorly responsive to chemotherapy. The prognosis is poor, especially when metastases are present. Early discovery is imperative for complete surgical resection. Adrenocortical tumors in patients with FAP have traditionally been found incidentally when screening for other complications. The present recommendation for identification of these tumors is early recognition of the physical signs of glucocorticoid excess such as weight gain, hypertension, hypokalemia, and diabetes mellitus because nearly 20% of adults with tumors have mild hormonal dysfunction (1). Radiologic and/or hormonal surveillance is not recommended at this time (1,4). Michalkiewicz et al (6) described 254 pediatric patients with adrenal cortical tumors without FAP and found that the majority of patients younger than 20 years had clinical signs of excess virilization as the most common presenting sign. Our study indicates that children with adrenocortical tumors and FAP present with findings of both glucocorticoid and androgen excess. Unfortunately, earlier detection was not possible given our patient's poor follow-up, and she presented with advanced stage disease Adrenocortical carcinoma is a rare, often fatal entity, which has been reported in association with FAP in older adolescents and adults. Hormone-secreting adrenocortical tumors in children are usually symptomatic, indicating that clinicians caring for children with FAP should be routinely monitoring for signs such as virilization, rapid weight gain, and hypertension, with the goal of identifying these patients at an early stage when surgical resection is possible.
