The 3PAs: An Update on the Association of Pheochromocytomas, Paragangliomas, and Pituitary Tumors.

Pituitary adenomas (PA) and pheochromocytomas/paragangliomas (PHEO/PGL) are rare tumors. Although they may co-exist by coincidence, there is mounting evidence that genes predisposing in PHEO/PGL development, may play a role in pituitary tumorigenesis. In 2012, we described a GH-secreting PA caused by an SDHD mutation in a patient with familial PGLs and found loss of heterozygosity at the SDHD locus in the pituitary tumor, along with increased hypoxia-inducible factor 1α (HIF-1α) levels. Additional patients with PAs and SDHx defects have since been reported. Overall, prevalence of SDHx mutations in PA is very rare (0.3-1.8% in unselected cases) but we and others have identified several cases of PAs with PHEOs/PGLs, like our original report, a condition which we termed the 3 P association (3PAs). Interestingly, when 3PAs is found in the sporadic setting, no SDHx defects were identified, whereas in familial PGLs, SDHx mutations were identified in 62.5-75% of the reported cases. Hence, pituitary surveillance is recommended among patients with SDHx defects. It is possible that the SDHx germline mutation-negative 3PAs cases may be due to another gene, epigenetic changes, mutations in modifier genes, mosaicism, somatic mutations, pituitary hyperplasia due to ectopic hypothalamic hormone secretion or a coincidence. PA in 3PAs are mainly macroadenomas, more aggressive, more resistant to somatostatin analogues, and often require surgery. Using the Sdhb +/- mouse model, we showed that hyperplasia may be the first abnormality in tumorigenesis as initial response to pseudohypoxia. We also propose surveillance and follow-up approach of patients presenting with this association.

A 13-Steroid Serum Panel Based on LC-MS/MS: Use in Detection of Adrenocortical Carcinoma.

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare malignancy, with an annual incidence of 1 or 2 cases per million. Biochemical diagnosis is challenging because up to two-thirds of the carcinomas are biochemically silent, resulting from de facto enzyme deficiencies in steroid hormone biosynthesis. Urine steroid profiling by GC-MS is an effective diagnostic test for ACC because of its capacity to detect and quantify the increased metabolites of steroid pathway synthetic intermediates. Corresponding serum assays for most steroid pathway intermediates are usually unavailable because of low demand or lack of immunoassay specificity. Serum steroid analysis by LC-MS/MS is increasingly replacing immunoassay, in particular for steroids most subject to cross-reaction. METHODS: We developed an LC-MS/MS method for the measurement of serum androstenedione, corticosterone, cortisol, cortisone, 11-deoxycorticosterone, 11-deoxycortisol, 21-deoxycortisol, dehydroepiandrosterone sulfate, pregnenolone, 17-hydroxypregnenolone, progesterone, 17-hydroxyprogesterone, and testosterone. Assay value in discriminating ACC from other adrenal lesions (phaeochromocytoma/paraganglioma, cortisol-producing adenoma, and lesions demonstrating no hormonal excess) was then investigated. RESULTS: In ACC cases, between 4 and 7 steroids were increased (median = 6), and in the non-ACC groups, up to 2 steroids were increased. 11-Deoxycortisol was markedly increased in all cases of ACC. All steroids except testosterone in males and corticosterone and cortisone in both sexes were of use in discriminating ACC from non-ACC adrenal lesions. CONCLUSIONS: Serum steroid paneling by LC-MS/MS is useful for diagnosing ACC by combining the measurement of steroid hormones and their precursors in a single analysis.

How and when to use temozolomide to treat aggressive pituitary tumours.

Temozolomide is an oral chemotherapy used to treat aggressive pituitary tumours since 2006. It is inexpensive and well tolerated, the main side effects are fatigue, nausea and cytopenia. Overall the studies demonstrate approximately 70% response rate for temozolomide, if response is defined radiologically as complete, partial response or stable disease. Using the more stringent criteria of complete or partial response, the success rate is near 40%. Functioning tumours respond more frequently than non-functioning tumours. Tumours which are depleted of methyl guanine methyltransferase (MGMT), as assessed by immunohistochemistry, also are more likely to respond. Temozolomide has an established role in treating pituitary tumours which have demonstrated metastases or which are refractory and progressing, despite all conventional treatment (so-called salvage treatment). The challenge is to offer temozolomide earlier in the pathway if appropriate. Tumours which demonstrate aggressive clinical behaviour (defined as clinically relevant growth despite optimal treatment) should be considered for temozolomide. One common situation when this might occur is tumour progression after surgery and radiotherapy. It is unnecessary to wait until salvage treatment is required. Anticipated (but not yet demonstrated) aggressive behaviour can be regarded as a potential indication for temozolomide, but there is currently insufficient evidence to recommend this. Ideally a trial should assess this potential indication. Early treatment could be considered in selected cases when high levels of proliferation and invasion were demonstrated, causing significant clinical concern.

GLP-1 and glucagon secretion from a pancreatic neuroendocrine tumor causing diabetes and hyperinsulinemic hypoglycemia.

CONTEXT: Glucagon-like peptide-1 (GLP-1) is a gut peptide that promotes insulin release from pancreatic ß-cells and stimulates ß-cell hyperplasia. GLP-1 secretion causing hypoglycemia has been described once from an ovarian neuroendocrine tumor (NET) but has not been reported from a pancreatic NET (pNET). OBJECTIVE: A 56-yr-old male with a previous diagnosis of diabetes presented with fasting hypoglycemia and was found to have a metastatic pNET secreting glucagon. Neither the primary tumor nor metastases stained for insulin, whereas the resected normal pancreas showed histological evidence of islet cell hyperplasia. We provide evidence that GLP-1 secretion from the tumor was the cause of hyperinsulinemic hypoglycemia. METHODS: GLP-1 levels were determined in the patient, and immunohistochemistry for GLP-1 was performed on the tumor metastases. Ex vivo tissue culture and a bioassay constructed by transplantation of tumor into nude mice were performed to examine the tumor secretory products and their effects on islet cell function. RESULTS: The patient had high levels of glucagon and GLP-1 with an exaggerated GLP-1 response to oral glucose. Immunohistochemistry and primary tissue culture demonstrated secretion of glucagon and GLP-1 from the tumor metastases, whereas insulin secretion was almost undetectable. Ex vivo coculture of the tumor with normal human islets resulted in inhibition of insulin release, and transplanted mice developed impaired glucose tolerance. CONCLUSIONS: This is the first description of glucagon and GLP-1 secretion from a metastatic pNET causing sequential diabetes and hypoglycemia. Hypoglycemia was caused by insulin secretion from hyperplastic ß-cells stimulated by tumor-derived GLP-1.