LETTERS TO THE EDITOR
Adrenocortical carcinoma: an unusual genetic cause!
A 55-year-old Jehovah’s Witness was simultaneously referred by his general practitioner (GP) to the gastroenterologist and endo- crinologist with elevated alkaline phosphatase 150 IU/l (normal 30-130), but otherwise normal liver function tests, and raised adjusted calcium 2.77 mm (normal 2.18-262) with normal phosphate. His parathyroid hormone level was 15 pM (normal 1.3-6.8). He had a history of hypertension, well controlled with ramipril and bendroflumethiazide. Despite occasional mild abdominal discomfort, the patient reported feeling well. Body mass index was 32.6 kg/m2 and clinical examination was unre- markable. He did not drink alcohol and was a nonsmoker.
Ultrasound (Fig. 1a) and dual-phase sestamibi of the parathy- roids (Fig. 1b) were obtained revealing a parathyroid adenoma inferiorly and posteriorly to the right thyroid lobe. An abdomi- nal ultrasound showed a diffuse increase in liver echogenicity suggestive of a fatty liver but also a 6.8 x 7 cm well-defined right adrenal mass was identified. Magnetic resonance imaging of his adrenals showed a large 9-4 x 8 x 7.7 cm heteroge- neously enhancing right adrenal lesion (Fig. 1c), which was of predominantly intermediate signal on T1-weighted imaging. There was an irregular patchy enhancement following intrave- nous gadolinium although there was no change in signal charac-
teristics in the in/out phase imaging. The overall appearances were consistent with a neoplastic lesion, most likely an adreno- cortical carcinoma (ACC), metastasis or a phaeochromocytoma. The other abdominal viscera were unremarkable. Computed tomography appearance of the chest, abdomen and pelvis revealed nil of note. Subsequent functional assessment with 24-h urinary metanephrines was negative, and there was failure of suppression of an overnight dexamethasone suppression test, 9 AM cortisol 233 nm (normal < 50 nM).
Elective combined surgery was planned with removal of a right inferior parathyroid gland and an open right adrenalec- tomy. The parathyroid adenoma measured 26 x 15 x 9 mm. The right adrenal gland removed measured 11 x 8.2 x 6-4 cm and weighed 286 g. The entire gland had been replaced by a tumour which had a variegated cut surface with firm grey/white areas and areas of yellowish necrosis. Histology showed a malig- nant tumour with extensive areas of necrosis and vascular and capsular invasion (Fig. 1d). At least 15 mitoses per 50 high power fields were seen including atypical forms. The morpholog- ical and immunohistochemical appearances were consistent with an ACC (with a Ki-67 proliferation index of 40-50%). Accord- ing to the European Network for the Study of Adrenal Tumours (ENSAT) classification, the burden of disease represented stage
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II disease (T2N0M0) (Fig. 1d). After multidisciplinary team dis- cussion, the patient was started on adjuvant mitotane and oral hydrocortisone replacement. Clinical and radiological surveil- lance 2 years later has shown evidence of recurrence with multi- ple liver metastases.
At his initial presentation to the endocrine clinic, there was no documented family history of endocrine disorders. However, during post-operative referral to the clinical geneticist for con- sideration of multiple endocrine neoplasia type 1 (MEN1), the patient revealed that his younger daughter, age 29 years, had previously been diagnosed with carcinoma of the breast. The Department of Clinical Genetics assessed his older daughter, and while the result of the MEN1 test was awaited, she was diag- nosed with breast cancer, aged 30 years. Testing of the TP53 gene was arranged on the patient’s younger affected daughter and a pathogenic mutation was identified (exon 7 c.734G>A) confirming a diagnosis of Li-Fraumeni syndrome (LFS). Genetic testing of the index case confirmed that he had the same hetero- zygous TP53 mutation. His 13-year-old son from another rela- tionship has thus far declined testing.
Adrenocortical carcinoma is a rare malignancy, although pre- cise information on the actual incidence and prevalence is lack- ing. Conservative estimates from the National Cancer Institute survey from the 1970s suggest 1-2 per million population per year.1 The disease carries a poor prognosis with only 16-38% of patients surviving for more than 5 years after diagnosis. The majority of ACCs are sporadic neoplasms but hereditary endo- crine syndromes should be considered such as MEN1, LFS, Car- ney complex, Beckwith-Wiedemann syndrome and congenital adrenal hyperplasia. Whilst surgical resection offers the only chance of definitive treatment, adjuvant medical management and irradiation may also be considered. Despite the paucity of evidence showing the efficacy of mitotane, it remains the only adrenal-specific agent for the treatment of ACC.2
Li-Fraumeni Syndrome is an autosomal dominant cancer pre- disposition syndrome characterized by the early onset of a vari- ety of tumours amongst family members. Li and Fraumeni first described classic LFS in 1969, characterized by five cancers: sar- coma, ACC, breast cancer, leukaemia and brain tumours in young children and adults.3 Subsequently, this condition was associated with germline mutations in the p53 gene which encodes the p53 tumour suppressor protein. Penetrance in LFS is high with women having a higher lifetime risk than men (93% and 68%, respectively), likely a result of female breast can- cer. Whilst childhood ACC is well reported as part of the LFS tumour spectrum, adult cases have been described. We could not find any evidence of an association between LFS and the parathyroid adenoma that we believe represents coincidental pathology in this patient.
In 2011, the National Comprehensive Cancer Network pub- lished guidance on criteria for diagnostic testing, and recom- mendations for surveillance in LFS, based on the predisposition to a wide spectrum of tumours with disease onset as early on as childhood.4 Although there is no clear consensus as to the opti- mal surveillance programme, offering surveillance may impor- tantly contribute to psychological well-being as well as aiming to
detect early-onset disease to improve prognosis. Because of the high incidence of cancers in LFS, some of which have no effec- tive surveillance programme, a clinical geneticist should always undertake genetic testing for LFS.
This case highlights the importance of a thorough family his- tory (which can evolve over time) and the critical involvement of dedicated clinical geneticists in such patients with endocrine neoplasia. Recognition of familial susceptibility to cancer enables discussion of genetic testing, risk counselling, education and psy- chosocial support to affected families. For younger patients (<40 year-old) with ACC, screening for TP53 germline muta- tions is recommended.5
E. Brown, R. Hardy, A. Weber, C. Daousi, H. Wieshmann, J. Sheard and D. J. Cuthbertson Department of Diabetes and Endocrinology, School of Clinical Sciences, University of Liverpool, Liverpool, UK E-mail: daniel.cuthbertson@liverpool.ac.uk
doi: 10.1111/j.1365-2265.2012.04377.x
References
1 National Cancer Institute. (1975) Third national cancer survey: incidence data. National Cancer Institute Monograph 41, 1-454.
2 Terzolo, M., Angeli, A., Fassnacht, M. et al. (2007) Adjuvant mitotane treatment for adrenocortical carcinoma. New England Journal of Medicine 356, 2372-2380.
3 Li, F.P. & Fraumeni Jr, J.F. (1969) Soft-tissue sarcomas, breast cancer, and other neoplasms: a familial syndrome? Annals of Inter- nal Medicine 71, 747-752.
4 National Comprehensive Cancer Network Guidelines. (2011) Genetic/Familial High-risk assessment: Breast and Ovarian.
5 Herrmann, L.J., Heinze, B., Fassnacht, M. et al. (2011) TP53 germline mutations in adult patients with adrenocortical carcinoma. Journal of Clinical Endocrinology and Metabolism 97, 476-485.
Cure of a thyrotrophin (TSH)-secreting pituitary adenoma by medical therapy
Dear Sir,
Thyrotrophin (TSH)-secreting pituitary adenomas account for approximately 1% of pituitary adenomas. The most common presentation is central hyperthyroidism in a patient with a pitui- tary macroadenoma.1 Although some TSH-secreting pituitary adenomas may co-secrete growth hormone or prolactin, the majority do not show any associated hypersecretion. In a series of 43 patients with TSH-secreting pituitary adenomas, acromeg- aly and hyperprolactinaemia were present in only 19% and 21%, respectively. Of note, basal serum TSH was elevated in 42% of these patients with a subnormal response to thyrotrophin releas- ing hormone (TRH) in 81%, while basal x-subunit («SU) was elevated in 30% with an over twofold TRH-stimulated «SU response in 44%.2 The most appropriate treatment for a patient with a thyrotrophinoma is transsphenoidal resection of the