Considering Postoperative Functional Hypoaldosteronism after Unilateral Adrenalectomy.

Conn's Syndrome is an uncommon condition. Patients who have undergone adrenalectomy in the early postoperative period can demonstrate biochemical hypoaldosteronism. Given the rare nature of this phenomenon we investigated its incidence and whether it translated to clinical findings. A single-institution retrospective review of all patients with biochemically proven hyperaldosteronism from 2005 to 2014 that underwent unilateral adrenalectomy. A total of 29 patients fit the inclusion criteria. Functional hypoaldosteronism had appreciated in 18/29 (62%) patients, whereas 11 patients (38%) had normal postoperative aldosterone. No significant differences between diagnostic groups were found in terms of clinical outcomes (length of stay, postoperative symptomatology, and readmissions P = 0.669, 0.154, and 0.268, respectively). Two (7%) patients required medical therapy. Biochemical evidence of functional hypoaldosteronism was identified in two-thirds of patients undergoing unilateral adrenalectomy. Although contralateral aldosterone suppression can be anticipated, the phenotypic response varied and the outcomes were similar to patients with normal aldosterone levels. Current guidelines make no formal recommendations for assessment of hypoaldosteronism after adrenalectomy, resulting in varying practice paradigms. Surgeons should consider the risk of postoperative hypoaldosteronism in these patients and counsel patients accordingly. Prospective investigations should be performed to assist in development of an outcomes-based care delivery model for these patients.

Pancreaticoduodenectomy Can Be Performed Safely with Rare Employment of Surgical Drains.

Use of drain remains frequent following pancreaticoduodenectomy (PD) due to concern for postoperative pancreatic fistula (POPF) and anastomotic leak development. Despite controversy, a recent randomized trial suggested omitting drainage would result in a large increase in operative mortality. This study sought to comprehensively examine the effects of forgoing drainage in the large cohort of patients undergoing PD. A prospective cohort study of two consecutive groups undergoing PD was constructed. The initial group had operative drains placed in cases subjectively concerning for POPF development; the second cohort did not undergo operative drainage. Outcomes including POPF incidence, need for reintervention, and overall morbidity were examined. A total of 106 patients were evaluated in two consecutive cohorts of 53; in the first group, 30 per cent had operative drains placed; 22.6 per cent developed POPF versus 7.5 per cent of patients in the no drainage group (P = 0.06). Despite this, no significant difference in major morbidity (Clavien ≥3, 20.8% versus 17.0%) or need for procedural reintervention (18.9% versus 15.1%) was observed. A subsequent validation cohort of 237 additional patients where drains were used only in exceptional circumstances was examined. Operative drains were placed in only 3 per cent of patients (n = 7) and 90-day mortality was 1.3 per cent (n = 3). Incidence of POPF was 8.0 per cent and the overall major complication rate was 14.8 per cent. Given such findings, it appears that drainage after PD can be avoided resulting in acceptable operative morbidity and mortality in most cases.

Loss of DPC4/SMAD4 expression in primary gastrointestinal neuroendocrine tumors is associated with cancer-related death after resection.

BACKGROUND: Gastrointestinal neuroendocrine tumors have frequent loss of DPC4/SMAD4 expression, a known tumor suppressor. The impact of SMAD4 loss on gastrointestinal neuroendocrine tumors aggressiveness or cancer-related patient outcomes is not defined. We examined the expression of SMAD4 in resected gastrointestinal neuroendocrine tumors and its impact on oncologic outcomes. METHODS: Patients who underwent complete curative operative resection of gastrointestinal neuroendocrine tumors were identified retrospectively (n = 38). Immunohistochemical staining for SMAD4 expression was scored by a blinded pathologist and correlated with clinicopathologic features and oncologic outcomes. RESULTS: Twenty-nine percent of the gastrointestinal neuroendocrine tumors were SMAD4-negative and 71% SMAD4-positive. Median overall survival was 155 months (95% confidence interval, 102-208 months). Loss of SMAD4 was associated with both decreased median disease-free survival (28 months; 95% confidence interval, 16-40) months compared with 223 months (95% confidence interval, 3-443 months) for SMAD4-positive patients (P = .03) and decreased median disease-specific survival (SMAD4: 137 [95% confidence interval, 81-194] months versus SMAD4-positive: 204 [95% confidence interval, 143-264] months; P = .04). This translated into a decrease in median overall survival (SMAD4-negative: 125 (95% confidence interval, 51-214) months versus SMAD4-positive: 185 (95% confidence interval, 138-232) months; P = .02). CONCLUSION: Consistent with the known biology of the DPC4/SMAD4 gene, an absence of its protein expression in primary gastrointestinal neuroendocrine tumors was negatively associated with outcomes after curative operative resection.

Subclinical Cushing syndrome: a review.

Owing to its diagnostic challenges, subclinical Cushing syndrome (SCS) is likely to be highly underdiagnosed and undertreated, and the overall incidence may be as high as 5% to 20% in patients with adrenal incidentalomas. The diagnosis can be established by a systematic and thorough biochemical evaluation. SCS has been associated with significant morbidity, which at least partly may be reversed by surgery. Given the low rates of complications and the possibility to reverse the detrimental effects of elevated cortisol secretion, minimally invasive adrenalectomy is recommended for patients with biochemically proven or suspected SCS who are appropriate surgical candidates.

Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism.

Adrenal aldosterone-producing adenomas (APAs) constitutively produce the salt-retaining hormone aldosterone and are a common cause of severe hypertension. Recurrent mutations in the potassium channel gene KCNJ5 that result in cell depolarization and Ca(2+) influx cause ∼40% of these tumors. We identified 5 somatic mutations (4 altering Gly403 and 1 altering Ile770) in CACNA1D, encoding a voltage-gated calcium channel, among 43 APAs without mutated KCNJ5. The altered residues lie in the S6 segments that line the channel pore. Both alterations result in channel activation at less depolarized potentials; Gly403 alterations also impair channel inactivation. These effects are inferred to cause increased Ca(2+) influx, which is a sufficient stimulus for aldosterone production and cell proliferation in adrenal glomerulosa. We also identified de novo germline mutations at identical positions in two children with a previously undescribed syndrome featuring primary aldosteronism and neuromuscular abnormalities. These findings implicate gain-of-function Ca(2+) channel mutations in APAs and primary aldosteronism.

Comprehensive re-sequencing of adrenal aldosterone producing lesions reveal three somatic mutations near the KCNJ5 potassium channel selectivity filter.

BACKGROUND: Aldosterone producing lesions are a common cause of hypertension, but genetic alterations for tumorigenesis have been unclear. Recently, either of two recurrent somatic missense mutations (G151R or L168R) was found in the potassium channel KCNJ5 gene in aldosterone producing adenomas. These mutations alter the channel selectivity filter and result in Na(+) conductance and cell depolarization, stimulating aldosterone production and cell proliferation. Because a similar mutation occurs in a mendelian form of primary aldosteronism, these mutations appear to be sufficient for cell proliferation and aldosterone production. The prevalence and spectrum of KCNJ5 mutations in different entities of adrenocortical lesions remain to be defined. MATERIALS AND METHODS: The coding region and flanking intronic segments of KCNJ5 were subjected to Sanger DNA sequencing in 351 aldosterone producing lesions, from patients with primary aldosteronism and 130 other adrenocortical lesions. The specimens had been collected from 10 different worldwide referral centers. RESULTS: G151R or L168R somatic mutations were identified in 47% of aldosterone producing adenomas, each with similar frequency. A previously unreported somatic mutation near the selectivity filter, E145Q, was observed twice. Somatic G151R or L168R mutations were also found in 40% of aldosterone producing adenomas associated with marked hyperplasia, but not in specimens with merely unilateral hyperplasia. Mutations were absent in 130 non-aldosterone secreting lesions. KCNJ5 mutations were overrepresented in aldosterone producing adenomas from female compared to male patients (63 vs. 24%). Males with KCNJ5 mutations were significantly younger than those without (45 vs. 54, respectively; p<0.005) and their APAs with KCNJ5 mutations were larger than those without (27.1 mm vs. 17.1 mm; p<0.005). DISCUSSION: Either of two somatic KCNJ5 mutations are highly prevalent and specific for aldosterone producing lesions. These findings provide new insight into the pathogenesis of primary aldosteronism.

Identification of somatic mutations in parathyroid tumors using whole-exome sequencing.

CONTEXT: The underlying molecular alterations causing sporadic parathyroid adenomas that drive primary hyperparathyroidism have not been thoroughly defined. OBJECTIVE: The aim of the study was to investigate the occurrence of somatic mutations driving tumor formation and progression in sporadic parathyroid adenoma using whole-exome sequencing. DESIGN: Eight matched tumor-constitutional DNA pairs from patients with sporadic parathyroid adenomas underwent whole-exome capture and high-throughput sequencing. Selected genes were analyzed for mutations in an additional 185 parathyroid adenomas. RESULTS: Four of eight tumors displayed a frame shift deletion or nonsense mutation in MEN1, which was accompanied by loss of heterozygosity of the remaining wild-type allele. No other mutated genes were shared among the eight tumors. One tumor harbored a Y641N mutation of the histone methyltransferase EZH2 gene, previously linked to myeloid and lymphoid malignancy formation. Targeted sequencing in the additional 185 parathyroid adenomas revealed a high rate of MEN1 mutations (35%). Furthermore, this targeted sequencing identified an additional parathyroid adenoma that contained the identical, somatic EZH2 mutation that was found by exome sequencing. CONCLUSION: This study confirms the frequent role of the loss of heterozygosity of chromosome 11 and MEN1 gene alterations in sporadic parathyroid adenomas and implicates a previously unassociated methyltransferase gene, EZH2, in endocrine tumorigenesis.

Comprehensive DNA methylation analysis of benign and malignant adrenocortical tumors.

The molecular pathogenesis of benign and malignant adrenocortical tumors (ACT) is incompletely clarified. The role of DNA methylation in adrenocortical tumorigenesis has not been analyzed in an unbiased, systematic fashion. Using the Infinium HumanMethylation27 BeadChip, the DNA methylation levels of 27,578 CpG sites were investigated in bisulfite-modified DNA from 6 normal adrenocortical tissue samples, 27 adrenocortical adenomas (ACA), and 15 adrenocortical carcinomas (ACC). Genes involved in cell cycle regulation, apoptosis, and transcriptional regulation of known or putative importance in the development of adrenal tumors showed significant and frequent hypermethylation. Such genes included CDKN2A, GATA4, BCL2, DLEC1, HDAC10, PYCARD, and SCGB3A1/HIN1. Comparing benign versus malignant ACT, a total of 212 CpG islands were identified as significantly hypermethylated in ACC. Gene expression studies of selected hypermethylated genes (CDKN2A, GATA4, DLEC1, HDAC10, PYCARD, SCGB3A1/HIN1) in 6 normal and 16 neoplastic adrenocortical tissues (10 ACA and 6 ACC), displayed reduced gene expression in benign and malignant ACT versus normal adrenocortical tissue. Treatment with 5-aza-2'-deoxycytidine of adrenocortical cancer H-295R cells increased expression of the hypermethylated genes CDKN2A, GATA4, DLEC1, HDAC10, PYCARD, and SCGB3A1/HIN1. In conclusion, the current study represents the first unbiased, quantitative, genome-wide study of adrenocortical tumor DNA methylation. Genes with altered DNA methylation patterns were identified of putative importance to benign and malignant adrenocortical tumor development.

Evidence of a stabilizing mutation of ß-catenin encoded by CTNNB1 exon 3 in a large series of sporadic parathyroid adenomas.

Aberrant accumulation of ß-catenin plays an important role in a variety of human neoplasms. This can be caused by stabilizing mutation of ß-catenin (CTNNB1, exon 3) or by mutation or deregulated expression of other components of the WNT/ß-catenin signaling pathway. Accumulation of non-phosphorylated active ß-catenin has been reported to commonly occur in parathyroid adenomas from patients with primary hyperparathyroidism (pHPT), either due to the aberrantly spliced internally truncated WNT receptor LRP5 (LRP5Δ) or to a stabilizing mutation of ß-catenin. The S37A mutation was reported to occur in 7.3 % in a single study of parathyroid adenomas, while in other studies no stabilizing mutations of ß-catenin exon 3 were identified. The aim of this study was to determine the mutational frequency of the CTNNB1 gene, specifically exon 3 in a large series of parathyroid adenomas. One hundred and eighty sporadic parathyroid adenomas were examined for mutations in exon 3 of CTNNB1 by direct DNA sequencing, utilizing previously published primer sequences. The mutation S33C (TCT>TGT) was detected by direct-DNA sequencing of PCR fragments in 1 out of 180 sporadic parathyroid adenomas (0.68 %). Like serine 37, mutations of serine 33 have been reported in many neoplasms with resulting ß-catenin stabilization, enhanced transcription, and oncogenic activities. Immunohistochemical analysis revealed an overexpression of the ß-catenin protein in the lone mutant tumor. Taking also previous studies into account we conclude that activating mutations of the regulatory GSK-3ß phosphorylation sites serine 33 and 37, encoded by CTNNB1 exon 3, rarely occur in parathyroid adenomas from patients with pHPT.

Frequent germ-line mutations of the MEN1, CASR, and HRPT2/CDC73 genes in young patients with clinically non-familial primary hyperparathyroidism.

Familial primary hyperparathyroidism (FPHPT) may occur due to an underlying germ-line mutation in the MEN1, CASR, or HRPT2/CDC73 genes. The disease may be undiagnosed in the absence of a history suggestive of FHPT. Young PHPT patients (≤45 years of age) are more likely to harbor occult FPHPT. A total of 1,161 (136 were ≤45 years of age) PHPT patients underwent parathyroidectomy from 2001 to 2009. Thirty-four patients declined participation. Sixteen patients were diagnosed in the clinical routine with FPHPT (11 MEN1, four MEN2A, and one HPT-JT) and were not included in the genetic analysis. Eighty-six young (≤45 years of age) patients with clinically non-syndromic PHPT underwent genetic analysis. Sanger sequencing of all coding regions of the MEN1, CASR, and the HRPT2/CDC73 genes was performed. Eight of 86 (9.3%) young patients with clinically non-familial PHPT displayed deleterious germ-line mutations in the susceptibility genes (4 MEN1, 3 CASR, and 1 HRPT2/CDC73). There was one insertion, one deletion, two nonsense, and four missense mutations, all predicted to be highly damaging to protein function and absent in 3,244 control chromosomes. Germ-line mutations in known susceptibility genes within young patients with PHPT, including those diagnosed in the clinical routine, was 24/102 (23.5%; 15 MEN1, four RET, three CASR, and two HRPT2/CDC73). We demonstrate that germ-line inactivating mutations in susceptibility genes are common in young patients with clinically non-familial PHPT. Thus, enhanced use of genetic analysis may be warranted in clinically non-familial young PHPT patients.

Parathyroid four-dimensional computed tomography: evaluation of radiation dose exposure during preoperative localization of parathyroid tumors in primary hyperparathyroidism.

BACKGROUND: Parathyroid four-dimensional computed tomography (4DCT) provides greater sensitivity than sestamibi with single photon emission CT (SPECT, or SeS) for preoperative localization of parathyroid tumors in patients with primary hyperparathyroidism (PHPT). The radiation dose imparted to the patient during preoperative parathyroid imaging, however, has not been analyzed. METHODS: Patients with biochemically unequivocal PHPT referred for minimally invasive parathyroidectomy underwent 4DCT or SeS. 4DCT was performed using a 64 detector row CT scanner, and SeS used a standardized protocol of 20 mCi of technetium-99m followed by planar and SPECT imaging. The CT radiation dose was estimated using the Imaging Performance Assessment of CT Scanners (ImPACT) calculator, and the SeS dose was estimated using the US Nuclear Regulatory Commission Regulation (NUREG) method. RESULTS: The calculated effective doses of 4DCT and SeS were 10.4 and 7.8 mSv, respectively, in contrast to an estimated annual background radiation exposure of approximately 3 mSv. The dose to the thyroid with 4DCT, however, was about 57 times higher (92.0 vs. 1.6 mGy) than that with SeS. Based on age- and sex-dependent risk factors, the calculated risk of 4DCT-related thyroid cancer developing in a 20 year old woman was 1,040/million (i.e., about 0.1%). CONCLUSIONS: 4DCT, a superior preoperative imaging modality for locating parathyroid tumors, imparts a significantly higher thyroid radiation dose than SeS. Given the enhanced risk of thyroid cancer in individuals with radiation exposure at a young age, 4DCT should be used judiciously in young PHPT patients.

Stump appendicitis: a surgeon's dilemma.

BACKGROUND: Stump appendicitis is defined by the recurrent inflammation of the residual appendix after the appendix has been only partially removed during an appendectomy for appendicitis. Forty-eight cases of stump appendicitis were identified in the English literature. DATABASE: The institutional CPT codes were evaluated for multiple hits of the appendectomy code, yielding a total of 3 patients. After appropriate approval from an internal review board, a retrospective chart review was completed and all available data extracted. All 3 patients were diagnosed with stump appendicitis, ranging from 2 months to 20 years after the initial procedure. Two patients underwent a laparoscopic and the one an open completion appendectomy. All patients did well and were discharged home in good condition. CONCLUSION: Surgeons need a heightened awareness of the possibility of stump appendicitis. Correct identification and removal of the appendiceal base without leaving an appendiceal stump minimizes the risk of stump appendicitis. If a CT scan has been obtained, it enables exquisite delineation of the surrounding anatomy, including the length of the appendiceal remnant. Thus, we propose that unless there are other mitigating circumstances, the completion appendectomy in cases of stump appendicitis should also be performed laparoscopically guided by the CT findings.

Minimally invasive parathyroidectomy.

Minimally invasive parathyroidectomy (MIP) is an operative approach for the treatment of primary hyperparathyroidism (pHPT). Currently, routine use of improved preoperative localization studies, cervical block anesthesia in the conscious patient, and intraoperative parathyroid hormone analyses aid in guiding surgical therapy. MIP requires less surgical dissection causing decreased trauma to tissues, can be performed safely in the ambulatory setting, and is at least as effective as standard cervical exploration. This paper reviews advances in preoperative localization, anesthetic techniques, and intraoperative management of patients undergoing MIP for the treatment of pHPT.

The role of epigenetic alterations in papillary thyroid carcinogenesis.

Papillary thyroid carcinoma (PTC) accounts for over 80% of all thyroid malignancies. The molecular pathogenesis remains incompletely clarified although activation of the RET fusion oncogenes, and RAS and BRAF oncogenes, has been well characterized. Novel technologies using genome-wide approaches to study tumor genomes and epigenomes have provided great insights into tumor development. Growing evidence shows that acquired epigenetic abnormalities participate with genetic alterations to cause altered patterns of gene expression/function. It has been established beyond doubt that promoter cytosine methylation in CpG islands, and the subsequent gene silencing, is intimately involved in cancer development. These epigenetic events very likely contribute to significant variation in gene expression profiling, phenotypic features, and biologic characteristics seen in PTC. Hypermethylation of promoter regions has also been analyzed in PTC, and most studies have focused on individual genes or a small cohort of genes implicated in tumorigenesis.

The DNA methylome of benign and malignant parathyroid tumors.

The role of DNA methylation of CpG islands in parathyroid tumorigenesis has not been analyzed in an unbiased, systematic fashion. DNA was isolated from normal and pathologic parathyroid tissues, bisulphite modified and analyzed using the Infinium HumanMethylation27 BeadChip. Distinct hierarchical clustering of genes with altered DNA methylation profiles in normal and pathologic parathyroid tissue was evident. Comparing normal parathyroid tissue with parathyroid adenomas, 367 genes were significantly altered, while 175 genes significantly differed when comparing parathyroid carcinomas and normal parathyroid tissues. A comparison between parathyroid adenomas and parathyroid carcinomas identified 263 genes with significantly distinct methylation levels. Results were confirmed for certain genes in a validation cohort of 40 parathyroid adenomas by methylation-specific PCR. Genes of known or putative importance in the development of parathyroid tumors showed significant and frequent hypermethylation. DNA hypermethylation of CDKN2B, CDKN2A, WT1, SFRP1, SFRP2, and SFRP4 was associated with reduced gene expression in both benign and malignant parathyroid tumors. Treatment with 5-aza-2'-deoxycytidine of primary cell cultures restores expression of hypermethylated genes in benign and malignant parathyroid tumors. In conclusion, the unbiased, genome-wide study of the parathyroid tumor DNA methylome identified a number of genes with altered DNA methylation patterns of putative importance to benign and malignant parathyroid tumorigenesis.

Metastatic Colon Cancer to the Thyroid Gland in the Setting of Pathologically Diagnosed Papillary Thyroid Cancer: A Review and Report of a Case.

Colon carcinoma metastases to the thyroid are a rare phenomena. Here we report a case of multiple malignant neoplasms where an incidental diagnosis of colon cancer was made after pathologic evaluation of the thyroid specimen.

4D parathyroid CT as the initial localization study for patients with de novo primary hyperparathyroidism.

BACKGROUND: Preoperative localization of parathyroid tumors of primary hyperparathyroidism (pHPT) is required for minimally invasive parathyroidectomy (MIP). Parathyroid four-dimensional computed tomography (4DCT) has mainly been used as an adjunct to other imaging modalities in the remedial setting. 4DCT was evaluated as the initial localization study in de novo patients with pHPT. MATERIALS AND METHODS: A total of 87 consecutive patients underwent parathyroidectomy for pHPT from August 2008 to November 2009. 4DCT was introduced as the preferred imaging modality instead of sestamibi with SPECT (SeS) in April 2009. Results of the imaging studies [4DCT, SeS, and ultrasonography (US)], operative and, pathologic findings, and biochemical measurements were evaluated. RESULTS: In this study, 84% of patients (73 of 87) underwent an US, 59.8% (52 of 87) a SeS, and 38.0% (33 of 87) had a 4DCT. 4DCT had improved sensitivity (85.7%) over SeS (40.4%) and US (48.0%) to localize parathyroid tumors to the correct quadrant of the neck (P < 0.005) as well as to localize (lateralize) the parathyroid lesions to one side of the neck (93.9% for 4DCT vs. 71.2% for US and 61.5% for SeS; P < 0.005). 4DCT correctly predicted multiglandular disease (MGD) in 85.7% (6 of 7) patients, whereas US and SeS were unable to detect MGD in any case. All patients achieved cure based on intraoperative parathyroid hormone (PTH) measurements and normalization of intact PTH and S-Ca during follow-up. CONCLUSIONS: 4DCT provides significantly greater sensitivity than SeS and US for precise localization of parathyroid tumors of pHPT. Additionally, it correctly predicted MGD in a majority of patients.

Clinical and histopathological characteristics of hyperparathyroidism-induced hypercalcemic crisis.

BACKGROUND: The clinical and pathological characteristics of hyperparathyroidism-induced hypercalcemic crisis (HIHC) are incompletely described. The present study was designed to elucidate the nature and effects of HIHC in patients undergoing parathyroidectomy in our unit. METHODS: A prospective database of 1,754 consecutive patients with primary hyperparathyroidism (PHPT) who underwent parathyroidectomy from 1991-2009 identified 67 (41 women) patients presenting with HIHC. Hyperparathyroidism-induced hypercalcemic crisis was defined as symptoms and signs of acute calcium intoxication with a concomitant total albumin corrected calcium level>13.5 mg/dl (range: 8.8-10.2 mg/dl). Clinical and pathological characteristics were evaluated. Data are expressed as mean±SEM. RESULTS: Mean age at presentation was 56.7±2.2 years. Twenty-four of 67 patients (35%) required preoperative in-hospital management. Of these, all were treated with saline resuscitation, whereas 20/24 (83%) were treated pharmacologically. Neurocognitive derangements and nephrolithiasis with associated hematuria were the most common presenting symptoms and signs. Preoperative serum calcium and the intact parathyroid hormone level (PTH) were 14.0±0.19 mg/dl and 393±43 pg/ml (reference range: 12-65 pg/ml), respectively. Minimally invasive parathyroidectomy under local cervical block was performed in 28/67 patients (42%); the remainder underwent standard cervical exploration. All patients had postoperative normalization of serum calcium and intact PTH. Hyperparathyroidism-induced hypercalcemic crisis was due to parathyroid carcinoma in 3/67 patients (4.5%), whereas the remainder of patients displayed a single parathyroid adenoma (n=57) or multiglandular hyperplasia (n=7). Histopathological evaluation from HIHC patients revealed a chief cell microcystic pattern in 15/21 (71.4%) of examined parathyroid tumors. CONCLUSIONS: Hyperparathyroidism-induced hypercalcemic crisis is most commonly due to a single parathyroid adenoma, often associated with a microcystic histopathological pattern. The condition is optimally managed with saline hydration and urgent parathyroidectomy.