Showing papers by "Niki Karavitaki published in 2014"

BRAF V600E mutations are characteristic for papillary craniopharyngioma and may coexist with CTNNB1-mutated adamantinomatous craniopharyngioma

Abstract: Craniopharyngiomas are epithelial, sellar tumours comprising two subtypes: adamantinomatous (aCP) and papillary (pCP). aCPs contain mutations in CTNNB1, encoding β-catenin: a component of the adherens junction and mediator of Wnt signalling. Reported frequency of CTNNB1 mutations varies widely (16–100 %) [6, 7]. Recently, it was reported that pCPs contain BRAF p.V600E mutations in 95 % of cases [2] and that CTNNB1 and BRAF mutations are mutually exclusive and specific to tumour subtype. We examined the relationship between mutation in CTNNB1 and BRAF and subcellular location of β-catenin in a series of 37 craniopharyngiomas. The region of BRAF exon 15 containing codon 600 was sequenced, as was exon 3 of CTNNB1. Immunohistochemistry (IHC) for β-catenin was used to examine its subcellular location and an antibody specific for the BRAF V600E mutation (clone VE1) was used to complement the sequencing findings in all aCP and pCPs. Methods are reported in Online Resource 1. We found BRAF V600E mutations in 81 % (17 of 21) pCPs by targeted Sanger sequencing and in 86 % (18 of 21) pCPs by IHC. Although there was agreement between methods in 95 % (20 out of 21) of cases, interpretation of anti-BRAF V600E staining was challenging due to occasional non-specific reactivity. aCP cases were selected for the study on the basis of their CTNNB1 mutation status [6 wild type and 10 mutant (9 T41I, 1 D32N)]. In all aCPs, translocation of β-catenin from membrane to cytosol/nucleus was observed, confirming the utility of β-catenin translocation as a diagnostic tool. Of 16 aCP cases, 14 (88 %) were BRAF wild type by sequencing and IHC. We observed BRAF V600E mutation in two aCP cases. This finding was validated by careful diagnostic review of morphology and comparison with IHC findings. Further validation was obtained by sequencing in forward and reverse directions from two DNA samples extracted on different occasions. In both these specimens, CTNNB1 mutation was also present (T41I) (Fig. 1). Fig. 1 BRAF V600E mutations in adamantinomatous craniopharyngioma. Two cases are shown (a–e and f–j). a, f Classical features of aCP (wet keratin, stellate reticulum, palisaded epithelium). b, g Translocation of β-catenin is shown in ... Sequencing of bulk tumour revealed no relationship between CTNNB1 mutation and cytosolic/nuclear accumulation of β-catenin. However, our study did not search for mutations at other loci, which could have led to an under-estimation of the proportion of specimens harbouring CTNNB1 mutations. In other studies on FFPE tissue that used Sanger dideoxy sequencing to search for CTNNB1 mutation, the rate was also not 100 % [3, 5, 7], suggesting that this method is not sufficiently sensitive to detect the presence of a mutation in all samples. In contrast, Brastianos et al. [2] found CTNNB1 mutations in 96 % of aCPs using mass spectrometric genotyping. We found BRAF V600E mutations in 81 % of pCPs. Difficulties interpreting BRAF V600E staining have been reported previously and suggest that in specimens with a significant amount of epithelium, sequencing may be more reliable for determining mutational status of BRAF [1, 8]. A mutation in BRAF was found in two aCP cases, both of which had a coexisting CTNNB1 mutation, demonstrating that although the majority of aCPs do not contain BRAF mutations, they are not exclusive to pCPs and can exist with mutations in CTNNB1. In the majority of cases, however, mutations segregate with tumour subtype: CTNNB1 in aCPs and BRAF in pCPs. While inhibition of the Wnt pathway has proved challenging and effective inhibitors are still largely in development, inhibitors of mutant BRAF have shown efficacy as chemotherapeutic agents in the treatment of melanoma [4]. The finding that BRAF V600E is mutated in the majority of pCPs offers the possibility for targeted BRAF-inhibitor therapy for patients with this tumour type.

Clinical review: Functioning gonadotroph adenomas.

Abstract: Context: Functioning gonadotroph adenomas (FGAs) are pituitary tumors secreting biologically active gonadotropins. The published literature includes only small case series or individual case reports. This review summarizes the published data on this rare entity and, based on them, suggests guidance on the follow-up of these patients. Evidence Acquisition: A review of articles in English retrieved from the PubMed up to December 2013 was conducted. The following terms were used for the search: “functioning gonadotroph adenomas,” “FSH secreting adenomas,” “LH secreting adenomas,” “gonadotroph adenomas,” “ovarian hyperstimulation,” “macroorchidism,” “testicular enlargement,” and “precocious puberty.” Evidence Synthesis: All reported cases of FGA were assessed, and information on presenting manifestations, management approaches, and long-term outcome was reviewed. Conclusions: FGAs cause distinct manifestations and, based on the limited published literature, they are mostly macroadenomas. Their pathogenesis re...

Rathke's cleft cyst

Abstract: Rathke's cleft cysts are benign sellar and suprasellar lesions arising from epithelial remnants of Rathke's pouch with a peak incidence at 30-50 years of age. The majority are between 10 and 20mm in diameter and contain mucoid or gelatinous material encapsulated in a thin cyst wall of simple or pseudostratified cuboidal or columnar epithelium. Symptomatic cases are rare, but incidental lesions are found in 11% of unselected postmortem cases. The pathogenesis of these lesions is uncertain, but they may occasionally share histopathologic features with (papillary) craniopharyngiomas. The most common presenting symptoms include headaches, visual disturbance, and pituitary hormone abnormalities. MRI reveals well-demarcated homogenous lesions with variable intensity that is highly dependent on cyst contents, which can range from clear, CSF-like fluid to thick, mucoid material. Treatment is almost invariably surgical with the aim of draining the cyst contents and removing the surrounding capsule. The recurrence rate is uncertain due to a lack of studies with long follow-up periods, but risk factors associated with increased likelihood of recurrence include cyst size, presence of squamous metaplasia of the cyst wall, incomplete resection or intraoperative CSF leak, and the need for an abdominal fat graft or sellar packing.

Refractory hypercalcaemia secondary to parathyroid carcinoma: response to high-dose denosumab.

Abstract: Objective: Hypercalcaemia is an important cause of increased morbidity and mortality in patients with parathyroid carcinoma. Surgical resection is the mainstay of treatment but, equally, managing hypercalcaemia is of paramount importance. At present, few therapies have been shown to be effective in the most severe cases. This report describes the efficacy of denosumab in a patient with parathyroid carcinoma when conventional therapies had been shown to be relatively ineffective. Subject, methods and results: A 50-year-old man presented with symptomatic hypercalcaemia 1 year after the surgery for his parathyroid carcinoma. Investigations revealed raised serum calcium and parathyroid hormone concentrations consistent with the recurrence of the disease. Imaging failed to localise any surgically remediable foci. Medical management with loop diuretics, calcimimetics and bisphosphonates failed to provide a sustained response. Denosumab, as a monthly injection, led to a gradual decrement in his peak calcium concentrations with the values now persistently below 3 mmol/l. Conclusions: Denosumab, a fully human MAB that binds to the ‘receptor activator of nuclear factor kB ligand (RANKL)’, was shown to have a profound effect in modulating malignant hypercalcaemia. This medication should be considered as an effective option in patients with refractory hypercalcaemia secondary to parathyroid carcinoma.

Management of craniopharyngiomas

Abstract: Craniopharyngiomas are rare epithelial tumours arising along the path of the craniopharyngeal duct. Their pathogenesis remains uncertain and they can present with a variety of manifestations attributed to pressure effects to surrounding structures. The optimal management of craniopharyngiomas remains challenging mainly due to their sharp, irregular borders and their tendency to adhere to vital neurovascular structures making surgical manipulations potentially hazardous to vital brain areas. Non-aggressive surgery followed by radiotherapy is currently the most widely used option possibly achieving the most optimal long-term outcome. Other treatment modalities including intracystic irradiation, intracystic instillation of antineoplasmatic agents and stereotactic radiotherapy are also available in our armamentarium. The long-term morbidities related with the craniopharyngiomas and their treatment remain significant, with hypothalamic damage playing the protagonist role and requiring further studies to identify measures that will improve the prognosis of the patients.

Low rate of germline AIP mutations in patients with apparently sporadic pituitary adenomas before the age of 40: a single-centre adult cohort.

Abstract: AIM: To study the prevalence of germline mutations of the aryl-hydrocarbon receptor interacting protein (AIP) gene in a large cohort of patients seen in the Oxford Centre for Diabetes Endocrinology and Metabolism (OCDEM), UK, with apparently sporadic pituitary adenomas, who were either diagnosed or had relevant clinical manifestations by the age of 40 years. PATIENTS: We prospectively investigated all patients who were seen at Oxford University Hospital, OCDEM, and a tertiary referral centre, between 2012 and 2013, and presented with pituitary tumours under the age of 40 years and with no family history: a total of 127 patients were enrolled in the study. METHODS: Leukocyte-origin genomic DNA underwent sequence analysis of exons 1-6 and the flanking intronic regions of the AIP gene (NM_003977.2), with dosage analysis by multiplex ligation-dependent probe amplification. RESULTS: AIP variants were detected in 3% of the 127 patients, comprising four of 48 patients with acromegaly (8%), 0 of 43 with prolactinomas, 0 of the 20 patients with non-functioning adenomas, 0 of 15 with corticotroph adenomas and 0 of one with a thyrotroph adenomas. Definite pathogenetic mutations were seen in 2/4 variants, comprising 4.2% of patients with acromegaly. CONCLUSIONS: This prospective cohort study suggests a relatively low prevalence of AIP gene mutations in young patients with apparently sporadic pituitary adenomas presenting to a tertiary pituitary UK centre. Those with somatotroph macroadenomas have a higher rate of AIP mutation. These findings should inform discussion of genetic testing guidelines.

Diagnosis and management of prolactinomas and non-functioning pituitary adenomas.

Abstract: #### Summary points Pituitary tumours account for a major proportion of intracranial tumours; most are benign adenomas. The tumours present with a range of signs and symptoms. Although evidence suggests that they are diagnosed earlier than previously, some are still missed, often for years, with clues such as headache and visual problems not being picked up.1 Management by a multidisciplinary team improves outcomes and optimises resources. This article focuses on the diagnosis and management of prolactinomas and non-functioning pituitary adenomas, which are the commonest types of pituitary adenoma in clinical practice. #### Sources and selection criteria We searched PubMed to identify peer reviewed original articles and reviews. Search terms were “pituitary tumour”, “pituitary adenoma”, “pituitary neoplasm”, and “prolactinoma”. We only considered those papers that were written in English and published within the past 20 years. Pituitary adenomas are monoclonal benign tumours that arise from differentiated hormone expressing cells in the anterior pituitary. Five major cell types occur in the anterior pituitary: the lactrotroph, producing prolactin; the somatotroph, producing growth hormone; the corticotroph, producing adrenocorticotrophic hormone; the thyrotroph, producing thyroid stimulating hormone; and the gonadotroph, producing luteinising hormone and follicle stimulating hormone. Classification of pituitary adenomas is based in part on the cell type. Tumours that secrete hormones are called functioning adenomas …

Adrenal insufficiency in acute oral opiate therapy

Abstract: Opiate drugs such as morphine are in extensive use for pain relief and palliation. It is well established that these drugs can cause changes in endocrine function, but such effects are not always sufficiently appreciated in clinical practice, especially in relation to the hypothalamic–pituitary–adrenal (HPA) axis. Herein, we report on an 18-year-old man who was diagnosed with a slipped left femoral epiphysis following a long history of pain in his leg. On examination, he was thought to look relatively young for his age and therefore the orthopaedic surgeons arranged an endocrine assessment, which showed an undetectable concentration of serum cortisol and a suppressed concentration of testosterone; therefore, he was referred urgently with a diagnosis of hypopituitarism. We elicited a history that he had been treated with opiate analgesics for 3 days at the time of his original blood tests. Full endocrine assessment including a short Synacthen test revealed that he now had normal adrenal and pituitary function. We conclude that his morphine therapy had caused profound suppression of his HPA and pituitary–gonadal axes and suggest that clinicians should be aware of these significant changes in patients on even short-term opiate therapy. Learning points Therapy with opiates is the standard therapy for severe acute and chronic pain. Such drugs cause profound changes in endocrine function. Importantly, opiates suppress the HPA axis at a central level. Short-term therapy with morphine could be the cause of biochemical adrenocortical insufficiency. Morphine and related drugs also suppress the pituitary–gonadal axis. After discontinuation of therapy with such drugs, adrenal function improves.

Transsphenoidal pituitary surgery in the elderly is safe and effective.

Abstract: Object. With an increasingly ageing population, the number of elderly people diagnosed with pituitary tumours continues to rise. There is a concern that with increasing age and comorbidities, there is higher anaesthetic risk, as well as peri-operative morbidity and mortality from pituitary surgery. This study aimed to audit the benefits and complications of transsphenoidal surgery performed in a large pituitary centre in elderly patients. Methods. Data on all elderly patients (age: ≥ 70 years) undergoing transsphenoidal surgery at a large tertiary referral centre between November 2003 and August 2012 were collected retrospectively. Results. A total of 104 operations were performed on 102 patients during 106 months. Median age was 75.2 years (range: 70–94) and 63 (61%) of the patients were male. Median follow-up was 15.2 months (range: 2.3–84.4). The majority presented with either peripheral visual field defects (26.4%) or pituitary hormone deficits (17.9%). A significant number (21.7%) of tumours ...

Sequence analysis of the catalytic subunit of PKA in somatotroph adenomas.

Abstract: Objective The pathogenetic mechanisms of sporadic somatotroph adenomas are not well understood, but derangements of the cAMP pathway have been implicated. Recent studies have identified L206R mutations in the alpha catalytic subunit of protein kinase A (PRKACA) in cortisol-producing adrenocortical adenomas and amplification of the beta catalytic subunit of protein kinase A PRKACB in acromegaly associated with Carney complex. Given that both adrenocortical adenomas and somatotroph adenomas are known to be reliant on the cAMP signalling pathway, we sought to determine the relevance of the L206R mutation in both PRKACA and PRKACB for the pathogenesis of sporadic somatotroph adenomas. Design Somatotroph adenoma specimens, both frozen and formalin-fixed, from patients who underwent surgery for their acromegaly between 1995 and 2012, were used in the study. Methods The DNA sequence at codon 206 of PRKACA and PRKACB was determined by PCR amplification and sequencing. The results were compared with patient characteristics, the mutational status of the GNAS complex locus and the tumour granulation pattern. Results No mutations at codon 206 of PRKACA or PRKACB were found in a total of 92 specimens, comprising both WT and mutant GNAS cases, and densely, sparsely and mixed granulation patterns. Conclusions It is unlikely that mutation at this locus is involved in the pathogenesis of sporadic somatotroph adenoma; however, gene amplification or mutations at other loci or in other components of the cAMP signalling pathway, while unlikely, cannot be ruled out.

IGF2-induced hypoglycemia unresponsive to everolimus

Abstract: Large tumours, usually of mesodermal origin, can cause severe and often intractable hypoglycaemia in the presence of undetectable levels of insulin. This phenomenon, referred to as non-islet-cell tumour hypoglycaemia (NICTH), is now generally thought to be due to secretion by the tumour of insulin-like growth factor-2 (IGF-2). Various interactions of IGF-2 with different receptors have been described,1 but most of the biological actions of IGF-2 are thought to be mediated via the IGF-1 receptor (IGF-1R), the binding of which results in differentiation, malignant transformation and the regulation of cell–cell adhesion. Interaction with the IGF-2 receptor (IGF2-R) promotes endocytosis and degradation of extra-cellular IGF-2 and may play a role in the transport of lysosomal enzymes, but is unlikely to be pathologically important. However, IGF-2 has also been shown to have high affinity binding with the insulin receptor; binding to the A isoform predominantly leads to mitogenic effects, but it also has (low) affinity with the B isoform that is principally concerned with its metabolic effects, including hypoglycaemia. Usually, IGF-2 is extensively bound to its binding-protein BP-3, and thus very little has access to the extravascular space. In NICTH the secretory product is principally the precursor pro-IGF-2, which is unable to bind BP-3 and thus can access extra-vascular receptors such as the insulin receptor isoforms. Thus, it has been thought that the hypoglycaemia in this condition relates to IGF-2 occupation of the insulin receptor. Downstream signalling form the insulin receptor involves the mammalian target of rapamycin (mTOR) pathway, and several recent case reports have suggested that blockade of the mTOR pathway with everolimus can effectively treat the severe hypoglycaemia associated with …

Hypopituitarism, Causes, Diagnosis, Management and Mortality

Abstract: Hypopituitarism is characterized by complete or partial deficiency of pituitary hormones due to a variety of causes and results to significant morbidities, compromised quality of life and increased mortality. Patients with hypopituitarism exhibit clinical manifestations that depend on the severity and the number of hormone deficits, the underlying etiology and the rapidity of onset of pituitary dysfunction. Diagnosis is based on the measurement of the basal concentrations of the anterior pituitary and the target organ hormones, as well as on dynamic testing. The confirmation of hypotonic polyuria and a water deprivation test are valuable tools for the diagnosis of diabetes insipidus. Management includes appropriate hormone replacement therapy combined with addressing the underlying cause of hypopituitarism.

Nonfunctioning Tumors of Pituitary, Clinical Features, Diagnosis, and Management

Abstract: Numerous types of benign or malignant tumors can be found in the sellar/parasellar region, which often present diagnostic and therapeutic challenges. Many of these tumors are nonfunctioning and are diagnosed either incidentally or due to mass effect manifestations. Imaging is essential for the differential diagnosis of the tumors but in most of the cases the final diagnosis is established by pathological examination. Treatment depends on the type of the neoplasm and mainly includes surgical resection of the neoplasm, radiotherapy, and chemotherapy or combination of these.