Dwarfs and Giants of Parathyroid Adenomas-No Difference in Outcome After Parathyroidectomy.

BACKGROUD: This study compares the outcome of parathyroidectomy for primary hyperparathyroidism (PHPT) in patients whose adenomas' weights were at the extremes of the distribution curve. As the size of parathyroid adenomas influences the success rate of localization studies for PHPT, it is possible that a difference in cure rate could be observed between subgroups of patients. MATERIALS AND METHODS: Data were retrieved from a prospective database maintained in a large university hospital. RESULTS: From a cohort of 519 patients who underwent parathyroidectomy for PHPT, two subgroups of patients were identified based on the extreme 10% of the distribution curve for adenomas' weight: adenomas <300 mg ("dwarfs", n = 100, median 200 mg) and >3000 mg ("giants", n = 56, median 4300 mg). In comparison with giant adenomas, dwarf adenomas were associated with less severe hypercalcemia (median 2.84 versus 3.00 mmol/L, P < 0.001) and lower PTH (median 11.7 versus 25.6 pmol/L, P < 0.001). The occurrence of dwarf adenomas showed no trend during the study period (23/173 [13%] in 2000-2004 versus 36/217 [17%] in 2007-2011). Scan-directed parathyroidectomy was feasible in more patients with giant adenomas (59% versus 38%). Persistent disease was diagnosed in three patients with dwarf adenomas. Patients with giant adenomas had no recurrence during a follow-up of 40 mo even though eight patients had histological features suggestive of atypical/malignant tumors. CONCLUSIONS: Preoperative biochemistry is a poor predictor of adenomas' size even at the extremes of the distribution curve. Cure can be achieved in all patients with "dwarf" adenomas. Even in the presence of suspicious histological features, "giant" adenomas did not show malignant behavior.

Risk of adrenocortical carcinoma in adrenal tumours greater than 8 cm.

BACKGROUND: Adrenocortical cancer (ACC) is a rare malignancy. In the absence of metastatic disease, the suspicion of ACC is based on size and radiological appearance. The aim of this study was to analyse the long-term outcome of patients with large adrenal cortical tumours (>8 cm). METHODS: A prospective database recorded clinical, biochemical, operative and histological data on patients operated for cortical adrenal tumours between January 2000 and February 2013. Out of 130 patients operated for cortical adrenal tumours, analysis was restricted to 37 cortical tumours >8 cm. RESULTS: There were 31 (84 %) ACCs and 6 (16 %) benign adenomas (p < 0.01). The most common presentation was that of an abdominal mass [17 (55 %) vs. 3 (50 %), ACC vs. benign, respectively]. There was no difference in size between stage II and stage III-IV tumours; however, there was a trend for tumours to be heavier in advanced stages (920 ± 756 vs. 1,435 ± 1,022 g, p = 0.08, stage II vs. stage III-IV, respectively). No mortality was observed in patients with benign tumours during a median follow-up of 70 months (range 36-99 months). Mortality in the ACC group occurred in 17/31 (55 %) patients. Mitotane was administered in 12 (71 %) patients with stage III-IV ACCs with a 5-year survival rate 25 % compared to 20 % in patients who did not receive Mitotane. In stage II ACC, eight (57 %) patients received Mitotane with a 50 % mortality at 5 years. CONCLUSIONS: The high incidence of ACC in cortical tumours >8 cm underlines the need for adequate surgical resection via open surgery aiming to avoid local recurrence. Beyond surgery, the impact of other therapies is not fully characterised and the efficacy of adjuvant Mitotane treatment is yet to be proven.

Familial isolated primary hyperparathyroidism caused by mutations of the MEN1 gene.

BACKGROUND: Familial isolated primary hyperparathyroidism (FIHP) is an autosomal dominant disorder that can represent an early stage of either the multiple endocrine neoplasia type 1 (MEN1) or hyperparathyroidism-jaw tumor (HPT-JT) syndromes; alternatively, the condition can be caused by an allelic variant of MEN1 or HRPT2 (hyperparathyroidism 2 gene), or caused by a distinct entity involving another locus. We have explored these possibilities in a patient with primary hyperparathyroidism, whose mother had a history of renal calculi and primary hyperparathyroidism. INVESTIGATIONS: Serum biochemistry and radiological investigations for primary hyperparathyroidism, MEN1 and HPT-JT, and genetic testing for MEN1 and HRPT2 mutations were undertaken. DIAGNOSIS: FIHP with primary hyperparathyroidism as the sole endocrinopathy due to a previously unreported heterozygous missense germline MEN1 mutation, Tyr351Asn. In addition, another unreported heterozygous missense germline MEN1 mutation, Trp220Leu, was identified in an unrelated male patient with FIHP, whose mother and sister also had primary hyperparathyroidism. DNA from a parathyroid tumor from the sister revealed a loss of heterozygosity in which the mutant allele was retained. This is consistent with Knudson's 'two-hit' model of hereditary cancer and a tumor suppressor role for MEN1 in FIHP. MANAGEMENT: The patient underwent parathyroidectomy and has remained normocalcemic over a follow-up period of 6 years. The other four patients have remained normocalcemic for a follow-up period of 4-15 years following parathyroidectomy. None has developed abnormalities of the MEN1 syndrome, providing further support that FIHP is a distinct genetic variant of the MEN1 syndrome.

Cost-effectiveness of scan-directed parathyroidectomy.

BACKGROUND: Concordant parathyroid localization with sestamibi and ultrasound scans allows minimally invasive parathyroidectomy (MIP) to be performed in patients with non-familial primary hyperparathyroidism (PHPT). AIM: To investigate the financial implications of scan-directed parathyroid surgery. METHODS: Analysis of hospital records for a cohort of consecutive unselected patients treated in a tertiary referral centre. RESULTS: Two hundred patients (138F:62M, age 18-91years) were operated for non-familial PHPT between Jan 2003 and Oct 2007. MIP was performed in 129 patients, with a mean operative time was 35 +/- 18min. Some 75 patients were discharged the same day and the others had a total of 72 in-patient days. Bilateral neck exploration (BNE) was performed in 71 patients with negative/non-concordant scans. Mean operative time was 58 +/- 25min. Only nine patients were discharged the same day and a total of 93 in-patient days were used ( approximately 1.3days/patient). The estimated total costs incurred were pound215,035 ( approximately 290,000). These costs would have been covered by the National Tariff ( pound2,170 per parathyroidectomy) but were higher than those possibly incurred if all 200 patients would have undergone BNE without any radiological investigations ( pound166,000 approximately 224,100euro). CONCLUSION: Shorter operative time and day-case admission for MIP generate costs savings that compensate only partially for the additional costs associated with parathyroid imaging studies.

Routine preoperative (123)I-MIBG scintigraphy for patients with phaeochromocytoma is not necessary.

BACKGROUND: Functional imaging using (123)I-meta-iodo-benzyl-guanetidine (MIBG) scintigraphy has alleged 100% specificity for phaeochromocytoma (PHAEO). Its benefit in patients with biochemical diagnosis of PHAEO is arguable when cross-sectional radiology can demonstrate the side-size of the adrenal tumours. MATERIALS AND METHODS: This is a retrospective review of clinical notes of patients undergoing adrenalectomy for PHAEO in a University centre. RESULTS: Between January 2000 and December 2007, adrenalectomy for PHAEO was performed on 66 patients (28 M and 38 F, aged 24-82 years). Diagnosis was demonstrated by raised 24-h urine catecholamines (n = 14) or metanephrines (n = 52). The side and size of adrenal tumours were demonstrated on computed tomography (n = 58) and/or magnetic resonance imaging (n = 20) scans. MIBG scans were performed in 38 patients. Four of these patients were found to have non-adrenal pathology (haemangioblastomas, haemangioma, a bronchogenic cyst and an angiomyolipoma); hence, the positive predictive value of MIBG scan was 90%. In a further five patients, MIBG raised the suspicion of local metastatic disease but this was not confirmed on operative findings and no recurrence was detected in these patients during 6-92-month follow-up. This led to an overall rate of false-positive rate of 23%. CONCLUSION: MIBG scintigraphy adds little to the routine preoperative management of patients with suspected PHAEO. Its use should be limited to the small minority of patients with negative cross-sectional imaging and those with recurrent or metastatic disease.

Routine genetic screening with a multi-gene panel in patients with pheochromocytomas.

PURPOSE: Several new gene mutations have been reported in recent years to be associated with a risk of familial pheochromocytoma. However, it is unclear as to whether extensive genetic testing is required in all patients. METHODS: The clinical data of consecutive patients operated for pheochromocytoma over a decade in a tertiary referral center were reviewed. Genetic screening was performed using a 10-gene panel: RET, VHL, SDHB, SDHD, SDHA, SDHC, SDHAF2, MAX, TMEM127 and FH. RESULTS: A total of 166 patients were analyzed: 87 of them had genetic screening performed (39 M: 44.8%, 48 F: 55.2%, age range 6-81 years, mean 45±16.8 years). In total, 22/87 (25.3%) patients had germline mutations, while 65/87 (74.7%) patients presented with apparently sporadic tumors. Germline VHL mutations were identified in 11.7% of patients, RET in 6.8% (five MEN2A/MEN2 and one MEN2B/MEN3), SDHD in 2.3%, MAX in 2.3%, SDHB in 1.1%, and TMEM127 in 1.1% of patients. At diagnosis, 15.1% of patients with unilateral non-syndromic pheochromocytoma showed germline mutations. We identified 19.7% of mutations in patients with unilateral-non-recurrent pheochromocytomas within 5 years vs. 50% in the recurrent-bilateral-metastatic group (p = 0.01). Germline mutations were more frequently seen with bilateral pheochromocytomas (p = 0.001): 80% of patients with bilateral disease had germline mutations (4 VHL, 3 RET, 1 MAX). CONCLUSIONS: The advent of rapid genetic screening using a gene-panel makes it feasible to screen large cohorts of patients and provides a valuable tool to contribute to the prediction of bilateral and malignant disease and to screen family members.

Management of a thyroid "incidentaloma" in a patient with cancer: a case report.

The routine use of (18)F-fluorodeoxyglucose-positron emission tomography (PET)/computed tomography scans for staging and assessment of treatment response for cancer has resulted in a large number of thyroid abnormalities being detected as incidental findings ("incidentalomas"). Since most PET/CT scans are performed in the setting of a known nonthyroid malignancy, the need for "incidentalomas" to be further investigated and managed depends on the stage, prognosis, and current treatment plan for the known malignancy. We present a case describing the management of an incidental F-fluorodeoxyglucose-avid thyroid nodule detected in a patient with known metastatic colorectal cancer. On the basis of this case, we discuss the management of incidental PET-detected thyroid nodules in patients with metastatic cancer. Thyroid "incidentalomas" must be seen in the context of the prognosis and treatment plan for the known malignancy.

MEN 2 syndrome masquerading as MEN 1.

Patients with multiple endocrine neoplasia (MEN) type 2A develop medullary thyroid cancer, which is associated with poor prognosis in its metastatic stage. Hyperparathyroidism is a common finding in both MEN 1 and 2. We report a 68-year-old patient diagnosed clinically with MEN 1 based on the presence of hyperparathyroidism and pituitary Cushing's disease with no supporting genetic evidence. The hyperparathyroidism was later found to be part of MEN 2A with underlying metastatic medullary thyroid cancer. We highlight the importance of genetic confirmation before a diagnosis of MEN 1 is made as other more serious pathologies might be overlooked.

Whole-exome sequencing studies of nonhereditary (sporadic) parathyroid adenomas.

CONTEXT: Genetic abnormalities, such as those of multiple endocrine neoplasia type 1 (MEN1) and Cyclin D1 (CCND1) genes, occur in <50% of nonhereditary (sporadic) parathyroid adenomas. OBJECTIVE: To identify genetic abnormalities in nonhereditary parathyroid adenomas by whole-exome sequence analysis. DESIGN: Whole-exome sequence analysis was performed on parathyroid adenomas and leukocyte DNA samples from 16 postmenopausal women without a family history of parathyroid tumors or MEN1 and in whom primary hyperparathyroidism due to single-gland disease was cured by surgery. Somatic variants confirmed in this discovery set were assessed in 24 other parathyroid adenomas. RESULTS: Over 90% of targeted exons were captured and represented by more than 10 base reads. Analysis identified 212 somatic variants (median eight per tumor; range, 2-110), with the majority being heterozygous nonsynonymous single-nucleotide variants that predicted missense amino acid substitutions. Somatic MEN1 mutations occurred in six of 16 (∼35%) parathyroid adenomas, in association with loss of heterozygosity on chromosome 11. However, no other gene was mutated in more than one tumor. Mutations in several genes that may represent low-frequency driver mutations were identified, including a protection of telomeres 1 (POT1) mutation that resulted in exon skipping and disruption to the single-stranded DNA-binding domain, which may contribute to increased genomic instability and the observed high mutation rate in one tumor. CONCLUSIONS: Parathyroid adenomas typically harbor few somatic variants, consistent with their low proliferation rates. MEN1 mutation represents the major driver in sporadic parathyroid tumorigenesis although multiple low-frequency driver mutations likely account for tumors not harboring somatic MEN1 mutations.

Management of adrenal incidentaloma: size still matters.

A 56-year-old man was found to have an adrenal incidentaloma on a CT scan of the abdomen. Clinically and biochemically, the mass was not functional. MRI scan revealed a heterogeneously enhancing, T2-hyperintense, right-sided adrenal mass (4.5×6.5 cm). Meta-iodo-benzylguanidine scan was normal, making a diagnosis of pheochromocytoma unlikely. As the mass was larger that 4 cm, it was excised and histopathological examination revealed a rare, composite tumour: benign adrenal adenoma with haemangiomatous and myelolipomatous components. This case highlights the difficulties encountered by a clinician faced with investigating a potentially malignant adrenal mass (based on size) and correlates radiological findings with a rare histopathological specimen.