Ann McCormack

Aggressive pituitary tumours: the role of temozolomide and the assessment of MGMT status

Eur J Clin Invest 2011; 41 (10): 1133–1148

Salvage therapy with temozolomide in patients with aggressive or metastatic pituitary adenomas: experience in six cases

OBJECTIVE The prognosis of either pituitary carcinoma or aggressive pituitary adenoma resistant to standard therapies is poor. We assessed the efficacy of treatment with temozolomide, an oral second-generation alkylating agent, in a consecutive series of six patients with aggressive pituitary adenomas. DESIGN This was a 1-year prospective study of temozolomide therapy in six consecutive patients with pituitary carcinoma (one case) or atypical pituitary adenoma (five cases) resistant to standard therapies. There were three males and three females. Age at enrollment ranged between 52 and 64 years. Temozolomide was given orally at a dose of 150-200 mg/m(2) per day for 5 days every 4 weeks for a maximum of 12 cycles. METHODS Response assessment was based on measurable change in tumor size, as assessed on magnetic resonance imaging, and hormone levels. Response was defined as reduction of at least 50% of tumor size and hormone levels. RESULTS Four patients completed the 12 cycles of temozolomide treatment, as planned. Two patients stopped the drug after 3 and 6 months respectively because of the progression of disease. Two patients responded to temozolomide, while the remaining two patients had stable disease. Immunohistochemistry for O(6)-methylguanine-DNA methyltransferase (MGMT) in tumor sample showed a partial association with treatment response. CONCLUSIONS Temozolomide treatment has a wide range of efficacy in patients with pituitary carcinoma or locally aggressive pituitary adenoma. Positive staining for MGMT seems likely to predict a lower chance of response.

European Society of Endocrinology Clinical Practice Guidelines for the management of aggressive pituitary tumours and carcinomas

BACKGROUND Pituitary tumours are common and easily treated by surgery or medical treatment in most cases. However, a small subset of pituitary tumours does not respond to standard medical treatment and presents with multiple local recurrences (aggressive pituitary tumours) and in rare occasion with metastases (pituitary carcinoma). The present European Society of Endocrinology (ESE) guideline aims to provide clinical guidance on diagnosis, treatment and follow-up in aggressive pituitary tumours and carcinomas. METHODS We decided upfront, while acknowledging that literature on aggressive pituitary tumours and carcinomas is scarce, to systematically review the literature according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. The review focused primarily on first- and second-line treatment in aggressive pituitary tumours and carcinomas. We included 14 single-arm cohort studies (total number of patients = 116) most on temozolomide treatment (n = 11 studies, total number of patients = 106). A positive treatment effect was seen in 47% (95% CI: 36-58%) of temozolomide treated. Data from the recently performed ESE survey on aggressive pituitary tumours and carcinomas (165 patients) were also used as backbone for the guideline. SELECTED RECOMMENDATION: (i) Patients with aggressive pituitary tumours should be managed by a multidisciplinary expert team. (ii) Histopathological analyses including pituitary hormones and proliferative markers are needed for correct tumour classification. (iii) Temozolomide monotherapy is the first-line chemotherapy for aggressive pituitary tumours and pituitary carcinomas after failure of standard therapies; treatment evaluation after 3 cycles allows identification of responder and non-responder patients. (iv) In patients responding to first-line temozolomide, we suggest continuing treatment for at least 6 months in total. Furthermore, the guideline offers recommendations for patients who recurred after temozolomide treatment, for those who did not respond to temozolomide and for patients with systemic metastasis.

Confusing genes: a patient with MEN2A and Cushing's disease

We report a patient with Cushing’s disease and primary hyperparathyroidism who subsequently developed medullary thyroid carcinoma (MTC) and bilateral phaeochromocytomas. Genetic testing for multiple endocrine neoplasia type 1 (MEN1) was negative, but a characteristic multiple endocrine neoplasia type 2A (MEN2A) RET-mutation was identified. Our case suggests that in patients with Cushing’s disease who have other evidence of endocrine neoplasia, if MEN1 is excluded then MEN2 should be considered. A 68-year-old man had presented with classical Cushingoid features at the age of 48 years. Biochemical investigation was compatible with ACTH-dependent Cushing’s syndrome. Bilateral inferior petrosal sinus (BIPSS) sampling demonstrated a central source, confirming pituitary-dependent Cushing’s syndrome, Cushing’s disease. He had attempted transsphenoidal adenomectomy (TSA), and although no adenoma was confirmed on histology, his cortisol level became undetectable (serum cortisol at 09.00 h <50 nmol/l (<1.8 lg/dl), all his clinical symptoms and signs gradually disappeared; indicating remission. He then remained well for 10 years, when he was noted to have hypercalcaemia with a corresponding elevated serum PTH, indicative of primary hyperparathyroidism (PHPT). He was offered conservative management with regular monitoring of his serum calcium. In the light of the diagnoses of primary hyperparathyroidism and the past history of a pituitary tumour, Cushing’s disease, he was tested for MEN1, but no mutation was found. His parents were deceased and he had no siblings, but he had single child, a 20-year-old son who had been diagnosed with primary hyperparathyroidism: following parathyroidectomy in the son, parathyroid hyperplasia was confirmed on histology. Our patient was therefore reviewed at regular intervals with a diagnosis of mutation-negative MEN1. He was noted to be Cushingoid in appearance some 15 years after the initial surgical cure, and on BIPPS was confirmed to have a recurrence of his Cushing’s disease. He had a transsphenoidal hypophysectomy, and again while no tumour was confirmed on surgical pathology, he went into clinical and biochemical remission with a postoperative serum cortisol at 09.00 h of <50 nmol/l. He was now panhypopituitary and pituitary hormone replacement therapy was commenced including hydrocortisone, thyroxine and testosterone. At the age of 66 years, he developed osteoporosis and at this stage parathyroidectomy was offered. Ultrasound scanning of his thyroid showed a thyroid nodule: fine needle aspiration of the thyroid nodule gave rise to suspicions of a medullary thyroid carcinoma (MTC). Plasma calcitonin level was massively elevated at 27,500 ng/l (normal<15 ng/l). Radionuclide scanning with FDG-PET revealed extensive FDG-avid disease in the thyroid with additional avid uptake in the liver and bone, strongly suggestive of metastatic MTC (Fig. 1). Furthermore, the FDG-PET also showed FDG-avid adrenal uptake (Fig 1); coincident CT scanning demonstrated bilateral adrenal nodules, 2.0–2.3 cm in maximal diameter, which in retrospect had been noted many years previously and were without any interval change on serial scans. Assessment of 24-h urinary metanephrines had been normal. However, 24-h urinary metanephrines were now abnormal (urine metanephrines 5.94 lmol/24 h, reference range 0.00–1.90; normetanephrine 2.12 lmol/24-h reference range 0.00–4.50), while plasma metanephrine was also highly elevated (plasma metanephrine 2125 pmol/l, reference range 80–510 pmol/l; plasma normetanephrine 1092 pmol/l, reference range 120–1180). Further questioning failed to reveal any evidence of paroxysmal symptoms, and he was normotensive. He was therefore diagnosed as having asymptomatic bilateral phaeochromocytomas. He was started on aand then b-adrenoceptor blockade, and was assessed at a multidisciplinary team meeting. It was decided to remove his MTC in the first instance, and to operate on the phaeochromocytoma(s) at a

Treatment of aggressive pituitary tumours and carcinomas: Results of a European Society of Endocrinology (ESE) survey 2016

OBJECTIVE To collect outcome data in a large cohort of patients with aggressive pituitary tumours (APT)/carcinomas (PC) and specifically report effects of temozolomide (TMZ) treatment. DESIGN Electronic survey to ESE members Dec 2015-Nov 2016. RESULTS Reports on 166 patients (40 PC, 125 APT, 1 unclassified) were obtained. Median age at diagnosis was 43 (range 4-79) years. 69% of the tumours were clinically functioning, and the most frequent immunohistochemical subtype were corticotroph tumours (45%). Ki-67 index did not distinguish APT from PC, median 7% and 10% respectively. TMZ was first-line chemotherapy in 157 patients. At the end of the treatment (median 9 cycles), radiological evaluation showed complete response (CR) in 6%, partial response (PR) in 31%, stable disease (SD) in 33% and progressive disease in 30%. Response was more frequent in patients receiving concomitant radiotherapy and TMZ. CR was seen only in patients with low MGMT expression. Clinically functioning tumours were more likely to respond than non-functioning tumours, independent of MGMT status. Of patients with CR, PR and SD, 25, 40 and 48% respectively progressed after a median of 12-month follow-up. Other oncological drugs given as primary treatment and to TMZ failures resulted in PR in 20%. CONCLUSION This survey confirms that TMZ is established as first-line chemotherapeutic treatment of APT/PC. Clinically functioning tumours, low MGMT and concurrent radiotherapy were associated with a better response. The limited long-term effect of TMZ and the poor efficacy of other drugs highlight the need to identify additional effective therapies.

Pituitary hyperplasia: case series and literature review of an under-recognised and heterogeneous condition

Summary Pituitary hyperplasia (PH) occurs in heterogeneous settings and remains under-recognised. Increased awareness of this condition and its natural history should circumvent unnecessary trans-sphenoidal surgery. We performed an observational case series of patients referred to a single endocrinologist over a 3-year period. Four young women were identified with PH manifesting as diffuse, symmetrical pituitary enlargement near or touching the optic apparatus on MRI. The first woman presented with primary hypothyroidism and likely had thyrotroph hyperplasia given prompt resolution with thyroxine. The second and third women were diagnosed with pathological gonadotroph hyperplasia due to primary gonadal insufficiency, with histopathological confirmation including gonadal-deficiency cells in the third case where surgery could have been avoided. The fourth woman likely had idiopathic PH, though she had concomitant polycystic ovary syndrome which is a debated cause of PH. Patients suspected of PH should undergo comprehensive hormonal, radiological and sometimes ophthalmological evaluation. This is best conducted by a specialised multidisciplinary team with preference for treatment of underlying conditions and close monitoring over surgical intervention. Learning points Normal pituitary dimensions are influenced by age and gender with the greatest pituitary heights seen in young adults and perimenopausal women. Pituitary enlargement may be seen in the settings of pregnancy, end-organ insufficiency with loss of negative feedback, and excess trophic hormone from the hypothalamus or neuroendocrine tumours. PH may be caused or exacerbated by medications including oestrogen, GNRH analogues and antipsychotics. Management involves identification of cases of idiopathic PH suitable for simple surveillance and reversal of pathological or iatrogenic causes where they exist. Surgery should be avoided in PH as it rarely progresses.

Germline variants in familial pituitary tumour syndrome genes are common in young patients and families with additional endocrine tumours

OBJECTIVE Familial pituitary tumour syndromes (FPTS) account for 5% of pituitary adenomas. Multi-gene analysis via next-generation sequencing (NGS) may unveil greater prevalence and inform clinical care. We aimed to identify germline variants in selected patients with pituitary adenomas using a targeted NGS panel. DESIGN We undertook a nationwide cross-sectional study of patients with pituitary adenomas with onset ≤40 years of age and/or other personal/family history of endocrine neoplasia. A custom NGS panel was performed on germline DNA to interrogate eight FPTS genes. Genome data were analysed via a custom bioinformatic pipeline, and validation was performed by Sanger sequencing. Multiplex ligation-dependent probe amplification (MLPA) was performed in cases with heightened suspicion for MEN1, CDKN1B and AIP mutations. The main outcomes were frequency and pathogenicity of rare variants in AIP, CDKN1B, MEN1, PRKAR1A, SDHA, SDHB, SDHC and SDHD. RESULTS Forty-four patients with pituitary tumours, 14 of whom had a personal history of other endocrine tumours and/or a family history of pituitary or other endocrine tumours, were referred from endocrine tertiary-referral centres across Australia. Eleven patients (25%) had a rare variant across the eight FPTS genes tested: AIP (p.A299V, p.R106C, p.F269F, p.R304X, p.K156K, p.R271W), MEN1 (p.R176Q), SDHB (p.A2V, p.S8S), SDHC (p.E110Q) and SDHD (p.G12S), with two patients harbouring dual variants. Variants were classified as pathogenic or of uncertain significance in 9/44 patients (20%). No deletions/duplications were identified in MEN1, CDKN1B or AIP. CONCLUSIONS A high yield of rare variants in genes implicated in FPTS can be found in selected patients using an NGS panel. It may also identify individuals harbouring more than one rare variant.

Aggressive pituitary tumours and carcinomas: two sides of the same coin?

The European Society of Endocrinology (ESE) survey reported on the largest cohort of 125 aggressive pituitary tumours (APT) and 40 pituitary carcinomas (PC). Whilst the survey focused on treatment effectiveness, all pathological data were not explored in detail. Here, we comment on some interesting pathological findings, notably the difference between APT and PC.

Optimising pituitary surgery outcomes in Australia: how much does size matter?

Historically considered a rare disease, pituitary adenomas are now recognised to be more prevalent than previously thought. In imaging and autopsy studies, about one in six people has a pituitary adenoma. While many are incidental findings, 1 per 1000 of the population has a clinically significant pituitary tumour. In Australia, the ease of access to modern imaging results in the frequent detection of pituitary incidentalomas. When to operate is now as important a skill for a neurosurgeon to develop as embracing the evolution in pituitary surgical techniques. Combine this with the widening medical therapy options for managing pituitary disease and advances in the radiotherapy field and it becomes clear that the complexities of care for these patients require a multidisciplinary approach. Pituitary surgery is the initial treatment modality for most clinically significant pituitary tumours, excepting prolactinomas in which dopamine agonists are first-line therapy. Broadly, the goals of pituitary surgery for patients with a non-functioning adenoma are to relieve symptoms arising from mass effect, such as headache, and prevent visual loss resulting from compression of the optic pathway. For functioning tumours, control of hormonal hypersecretion is also imperative as both cortisol and growth hormone excess are associated with substantial morbidity and increased mortality. Moreover, it is critical to minimise perioperative mortality and morbidity, which can include long-term anterior and posterior pituitary dysfunction. Size and invasiveness of a pituitary adenoma are key factors affecting outcomes of pituitary surgery. However, the size of the neurosurgical centre and experience is also a major factor. Biochemical control of hormone excess is greater, and reduced surgical complications, length of hospital stay and mortality are reported when surgery is performed in high-volume centres. The father of neurosurgery, Harvey Cushing, recognised the need for neurosurgical specialisation back in 1905 when he lamented ‘In talking the matter over with my surgical friends, many of them have expressed themselves emphatically against any form of operative specialisation’. Since the late 1990s, the majority of UK centres have evolved into a 1–2 pituitary surgeon/centre model of care. This has been associated with improved nationwide outcomes. Most of the 34 UK neurosurgical units undertaking pituitary surgery perform 30–40 operations per year, with some units operating on more than 100 cases. It has recently been proposed that an individual surgeon ideally should be performing 50 pituitary surgeries per year. However, there is also evidence that a dedicated surgeon in a smaller hospital can also achieve good results. The degree of surgical experience in the UK has been harder to achieve in the USA and Australia. In a US-based study from 2005, on average, a neurosurgeon operated on less than five pituitary tumours per annum. There are no comparative data for Australia. However, a review of MBS records over a 5-year period, up till 2016, reveals an average of 343 pituitary surgeries in Australia per year (http://medicarestatistics.humanservices.gov.au). According to membership of the Neurosurgical Society of Australasia, there are more than 200 neurosurgeons in Australia, so the risk of case load dilution amongst surgeons is large. There are limited data available on the safety of pituitary surgery in Australia. In Australia, there is no requirement for neurosurgeons to report their complication rates for pituitary surgery, with morbidity and mortality only discussed within departments. In the UK, steps are being taken by The Society of British Neurological Surgeons to publish national databases of specialised surgery audits, including pituitary surgery. Internationally, recommendations for Pituitary Tumour Centres of Excellence are being led by The Pituitary Society. With greater access to Internet resources, patient organisations, such as the Australian Pituitary Foundation, are also pushing for change. It is in this context that Davis et al have audited outcomes over 2 years for pituitary surgery at Sir Charles Gairdner Hospital, Perth in this issue of Internal Medicine Journal. Contrasting most states in Australia, this centre is the only public hospital performing pituitary surgery in Western Australia, undertaking approximately 25 transsphenoidal hypophysectomies and two transfrontal craniotomies per annum. Operations are performed by three neurosurgeons, and both the endoscopic and microscopic approaches are utilised for transsphenoidal hypophysectomy. During the audit period, there were no deaths and few major perioperative complications; new anterior pituitary dysfunction was rare, and the rate of complete resection of tumour tissue was within the range reported in the literature. However, there was a relatively low rate of control of hormone hypersecretion in functioning tumours (33%) and a relatively high rate of permanent diabetes insipidus (13%).

Ectopic Cushing syndrome due to neuroendocrine prostatic cancer

2008; 3: 54–60. 21 Holtkamp FA, de Zeeuw D, Thomas MC, Cooper ME, de Graeff PA, Hillege HJ et al. An acute fall in estimated glomerular filtration rate during treatment with losartan predicts a slower decrease in long-term renal function. Kidney Int 2011; 80: 282–7. 22 Apperloo AJ, de Zeeuw D, de Jong PE. A short-term antihypertensive treatment-induced fall in glomerular filtration rate predicts long-term stability of renal function. Kidney Int 1997; 51: 793–7. 23 Ahmed AK, Kamath NS, El Kossi M, El Nahas AM. The impact of stopping inhibitors of the reninangiotensin system in patients with advanced chronic kidney disease. Nephrol Dial Transplant 2010; 25: 3977–82. 24 Einhorn LM, Zhan M, Hsu VD, Walker LD, Moen MF, Seliger SL et al. The frequency of hyperkalemia and its significance in chronic kidney disease. Arch Intern Med 2009; 169: 1156–62. 25 Adam WR. Hypothesis: a simple algorithm to distinguish between hypoaldosteronism and renal aldosterone resistance in patients with persistent hyperkalemia. Nephrology (Carlton) 2008; 13: 459–63.