Prognostic factors for the outcome of nonfunctioning pancreatic neuroendocrine tumors in MEN1: a systematic review of literature.

Metastatic duodenopancreatic neuro-endocrine tumors (dpNETs) are the most important disease-related cause of death in patients with multiple endocrine neoplasia type 1 (MEN1). Nonfunctioning pNETs (NF-pNETs) are highly prevalent in MEN1 and clinically heterogeneous. Therefore, management is controversial. Data on prognostic factors for risk stratification are limited. This systematic review aims to establish the current state of evidence regarding prognostic factors in MEN1-related NF-pNETs. We systematically searched four databases for studies assessing prognostic value of any factor on NF-pNET progression, development of distant metastases, and/or overall survival. In- and exclusion, critical appraisal and data-extraction were performed independently by two authors according to pre-defined criteria. Thirteen studies (370 unique patients) were included. Prognostic factors investigated were tumor size, timing of surgical resection, WHO grade, methylation, p27/p18 expression by immunohistochemistry (IHC), ARX/PDX1 IHC and alternative lengthening of telomeres. Results were complemented with evidence from studies in MEN1-related pNET for which data could not be separately extracted for NF-pNET and data from sporadic NF-pNET. We found that the most important prognostic factors used in clinical decision making in MEN1-related NF-pNETs are tumor size and grade. NF-pNETs <2 cm may be managed with watchful waiting, while surgical resection is advised for NF-pNETs ≥2 cm. Grade 2 NF-pNETs should be considered high risk. The most promising and MEN1-relevant avenues of prognostic research are multi-analyte circulating biomarkers, tissue-based molecular factors and imaging-based prognostication. Multi-institutional collaboration between clinical, translation and basic scientists with uniform data and biospecimen collection in prospective cohorts should advance the field.

Radiomic mapping model for prediction of Ki-67 expression in adrenocortical carcinoma.

AIM: To determine the value of contrast-enhanced computed tomography (CT)-derived radiomic features in the preoperative prediction of Ki-67 expression in adrenocortical carcinoma (ACC) and to detect significant associations between radiomic features and Ki-67 expression in ACC. MATERIALS AND METHODS: For this retrospective analysis, patients with histopathologically proven ACC were reviewed. Radiomic features were extracted for all patients from the preoperative contrast-enhanced abdominal CT images. Statistical analysis identified the radiomic features predicting the Ki-67 index in ACC and analysed the correlation with the Ki-67 index. RESULTS: Fifty-three cases of ACC that met eligibility criteria were identified and analysed. Of the radiomic features analysed, 10 showed statistically significant differences between the high and low Ki-67 expression subgroups. Multivariate linear regression analysis yielded a predictive model showing a significant association between radiomic signature and Ki-67 expression status in ACC (R2=0.67, adjusted R2=0.462, p=0.002). Further analysis of the independent predictors showed statistically significant correlation between Ki-67 expression and shape flatness, elongation, and grey-level long run emphasis (p=0.002, 0.01, and 0.04, respectively). The area under the curve for identification of high Ki-67 expression status was 0.78 for shape flatness and 0.7 for shape elongation. CONCLUSION: Radiomic features derived from preoperative contrast-enhanced CT images show encouraging results in the prediction of the Ki-67 index in patients with ACC. Morphological features, such as shape flatness and elongation, were superior to other radiomic features in the detection of high Ki-67 expression.

HEREDITARY ENDOCRINE TUMOURS: CURRENT STATE-OF-THE-ART AND RESEARCH OPPORTUNITIES: MEN1-related pancreatic NETs: identification of unmet clinical needs and future directives.

The PanNET Working Group of the 16th International Multiple Endocrine Neoplasia Workshop (MEN2019) convened in Houston, TX, USA, 27-29 March 2019 to discuss key unmet clinical needs related to PanNET in the context of MEN1, with a special focus on non-functioning (nf)-PanNETs. The participants represented a broad range of medical scientists as well as representatives from patient organizations, pharmaceutical industry and research societies. In a case-based approach, participants addressed early detection, surveillance, prognostic factors and management of localized and advanced disease. For each topic, after a review of current evidence, key unmet clinical needs and future research directives to make meaningful progress for MEN1 patients with nf-PanNETs were identified. International multi-institutional collaboration is needed for adequately sized studies and validation of findings in independent datasets. Collaboration between basic, translational and clinical scientists is paramount to establishing a translational science approach. In addition, bringing clinicians, scientists and patients together improves the prioritization of research goals, assures a patient-centered approach and maximizes patient involvement. It was concluded that collaboration, research infrastructure, methodologic and reporting rigor are essential to any translational science effort. The highest priority for nf-PanNETs in MEN1 syndrome are (1) the development of a data and biospecimen collection architecture that is uniform across all MEN1 centers, (2) unified strategies for diagnosis and follow-up of incident and prevalent nf-PanNETs, (3) non-invasive detection of individual nf-PanNETs that have an increased risk of metastasis, (4) chemoprevention clinical trials driven by basic research studies and (5) therapeutic targets for advanced disease based on biologically plausible mechanisms.

Metastatic pheochromocytoma and paraganglioma: focus on therapeutics.

Metastatic pheochromocytomas and paragangliomas are rare and challenging tumors. The tumor burden, combined with excessive catecholamine production, predispose to a broad spectrum of complications that range from spinal cord compression to any organ damage, all of which may lead to decreased quality of life and overall survival. Current therapies include surgery, systemic chemotherapy and radiopharmaceutical agents. Surgery is often a preferred therapy because it may cure or allow a long-term remission in patients with locoregional or isolated resectable distant metastases. Additionally, surgery can palliate symptoms related to tumor burden or catecholamine excess. However, in patients for whom surgery is not an option, systemic chemotherapy and radiopharmaceutical agents are preferred options. Systemic chemotherapy and radiopharmaceutical agents such as 131I-Metaiodobenzylguanidine (131I-MIBG) may cause partial responses or stabilization of disease with better blood pressure control and symptomatic and performance status improvement. However, as these therapies are only palliative, patients' quality of life and personal preferences should always be considered. The recognition of molecular pathways involved in the pheochromocytoma and paraganglioma tumorigenesis has driven the development of new therapeutic options. Agents such as tyrosine kinase, MAPK, PI3K, or hypoxia inducible factor inhibitors, alone or in combination, may represent novel therapeutic strategies that could be evaluated in prospective clinical trials. Transcriptional profiling and the development of personalized cancer medicine will help to pave the way for more specific therapeutic approaches and combinations.

CT features and quantification of the characteristics of adrenocortical carcinomas on unenhanced and contrast-enhanced studies.

AIM: To describe the morphological and contrast-agent washout characteristics of adrenocortical carcinomas (ACCs) on computed tomography (CT). MATERIALS AND METHODS: Forty-one patients with histopathologically proven ACCs were retrospectively evaluated. The morphological characteristics of the ACCs were documented and compared with surgical and histopathological findings. The percentage of contrast agent enhancement washout (PEW) and relative PEW (RPEW) were calculated for 17 patients who had the combination of unenhanced, portal venous, and 15 min delayed phase images. RESULTS: Characteristic imaging findings of ACCs included large size (38 of 41 tumours were >6 cm), well-defined margin with a thin enhancing rim (25 patients), and central stellate area of low attenuation on contrast-enhanced CT images (21 patients). Tumour extension into the inferior vena cava (IVC) with associated thrombus was identified on CT in six (14.6%) patients. Of 17 tumours evaluated, 12 (71%) had a PEW value of ≤60%, and 14 (82%) had an RPEW value of ≤40%. CONCLUSION: Large size, a well-defined margin with a thin enhancing rim, central low attenuation, and a predilection for extension into the IVC are typical morphological characteristics of ACC on CT. The contrast-washout characteristics of ACCs, in concordance with their malignant nature, share those of non-adenomas rather than adenomas.

A current review of the etiology, diagnosis, and treatment of pediatric pheochromocytoma and paraganglioma.

CONTEXT: Pheochromocytomas and paragangliomas (PHEO/PGL) are neuroendocrine tumors that arise from sympathetic and parasympathetic paraganglia. Diagnosed rarely during childhood, PHEO/PGL are nonetheless important clinical entities, particularly given our evolving understanding of their pathophysiology. EVIDENCE ACQUISITION: We identified articles through the U.S. National Library of Medicine by using the search terms pheochromocytoma and paraganglioma. Results were narrowed to manuscripts that included children and studies related to the genetics of PHEO/PGL. Web-based resources for genetic disorders were also used. For all articles, we performed subsequent reference searches and verification of source data. EVIDENCE SYNTHESIS: Up to 20% of PHEO/PGL are diagnosed in children. Most are functional tumors, and clinical presentation includes symptoms related to catecholamine hypersecretion and/or tumor mass effect. Increasingly, PHEO/PGL are identified during presymptomatic screening in children with genetic syndromes associated with PHEO/PGL (multiple endocrine neoplasia type 2, von Hippel-Lindau disease, and the paraganglioma syndromes). Plasma and/or urine metanephrines are the best diagnostic test for a functional tumor, and the management of pediatric patients is similar to adults. Genetic counseling should be undertaken in all cases. Although most pediatric PHEO/PGL are benign, these tumors can occasionally metastasize, a condition for which no curative treatment exists. CONCLUSIONS: Although PHEO/PGL are rarely diagnosed during childhood, the pediatric provider should be able to recognize and screen for such tumors, particularly in the context of a known genetic predisposition. Optimal care of these children includes a multidisciplinary team approach at centers experienced in the evaluation and treatment of these uncommon yet fascinating endocrine neoplasms.

Impact of preoperative thyroid ultrasonography on the surgical management of primary hyperparathyroidism.

BACKGROUND: Primary hyperparathyroidism (PHPT) with coexisting thyroid disease has been considered a contraindication to minimally invasive parathyroidectomy (MIP). This study assessed the impact of thyroid ultrasonography and guided fine-needle aspiration (FNA) biopsy with cytological review of the aspiration in distinguishing patients eligible for MIP from those requiring open parathyroidectomy with thyroid surgery. METHODS: The records of 194 consecutive patients who had minimally invasive or open parathyroidectomy for sporadic PHPT were reviewed retrospectively. Thyroid ultrasonographic findings and FNA results were compared with surgical and pathology records. RESULTS: A total of 163 patients (84.0 per cent) were eligible for MIP based on ultrasonographic findings with or without FNA results. Ultrasonography detected concurrent thyroid disease in 163 patients (84.0 per cent). Thirty-nine (23.9 per cent) underwent FNA, of whom 16 had benign findings and were eligible for MIP; the remaining 23 had suspicious FNA results and had open parathyroidectomy combined with thyroid surgery. Postoperative thyroid histopathology confirmed malignancy in nine patients, eight of whom had disease detected ultrasonographically. Micronodular thyroid disease (less than 1 cm) accounted for four of nine malignancies. CONCLUSION: Most patients with PHPT are eligible for MIP. Experienced ultrasonographers can diagnose coexisting micronodular and macronodular thyroid disease, and identify patients eligible for MIP.

Accuracy of fine-needle aspiration cytology in patients with radiation-induced thyroid neoplasms.

BACKGROUND: Fine-needle aspiration cytology (FNAC) is useful for selecting patients with thyroid nodules for thyroidectomy. Its value in patients who have been exposed to low-dose therapeutic radiation is questionable because these patients have an increased risk of multifocal benign and malignant tumours, and thyroid cancer is common in such patients. METHODS: Between 1960 and 1999, 171 patients with one or more thyroid nodules who had a history of exposure to radiation underwent operation; 49 of these patients had preoperative FNAC. The cytology results in these 49 patients were compared with those of an age- and sex-matched control group of patients with thyroid nodules who did not have a history of radiation exposure. RESULTS: Of those who had been exposed to radiation, six of 20 patients with 'benign' cytology by FNAC and six of 16 patients with 'suspicious' cytology had thyroid cancer. All 13 specimens considered to be malignant on FNAC were indeed malignant. There was a higher rate of false-negative cytological examinations among patients with a history of irradiation that in those without. CONCLUSION: FNAC of thyroid nodules in patients with a history of irradiation is not as accurate as that in non-irradiated patients, primarily because of coexisting occult thyroid cancers.

HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome.

We report here the identification of a gene associated with the hyperparathyroidism-jaw tumor (HPT-JT) syndrome. A single locus associated with HPT-JT (HRPT2) was previously mapped to chromosomal region 1q25-q32. We refined this region to a critical interval of 12 cM by genotyping in 26 affected kindreds. Using a positional candidate approach, we identified thirteen different heterozygous, germline, inactivating mutations in a single gene in fourteen families with HPT-JT. The proposed role of HRPT2 as a tumor suppressor was supported by mutation screening in 48 parathyroid adenomas with cystic features, which identified three somatic inactivating mutations, all located in exon 1. None of these mutations were detected in normal controls, and all were predicted to cause deficient or impaired protein function. HRPT2 is a ubiquitously expressed, evolutionarily conserved gene encoding a predicted protein of 531 amino acids, for which we propose the name parafibromin. Our findings suggest that HRPT2 is a tumor-suppressor gene, the inactivation of which is directly involved in predisposition to HPT-JT and in development of some sporadic parathyroid tumors.

Incidental thyroid carcinoma identified by positron emission tomography scanning obtained for metastatic evaluation.

Positron emission tomography (PET) scanning is an emerging technology with substantial implications for patients with solid tumors. PET is useful in identifying sites of metastatic disease as well as primary malignancy and evaluating suspicious findings found via other imaging modalities. PET is becoming a standard modality for metastatic evaluation of a variety of malignancies. However, this imaging is not limited by histology and may reveal clinically occult second lesions. We present five cases of a clinically occult thyroid cancer found in patients who underwent PET scanning for metastatic evaluations. The principal diagnoses included two patients with malignant melanoma, one each with gastric, rectal, and colonic adenocarcinoma. None of the cases had findings on physical examination. Increased uptake in the region of the thyroid was evident on the PET scan, and fine-needle aspiration biopsy indicated papillary carcinoma of the thyroid in all five cases. Although evaluation of metastatic disease is the primary purpose for PET in this setting the discovery of occult thyroid malignancy is an additional benefit of such imaging. This emphasizes the importance of investigating suspicious areas found by PET and not simply assuming that these are all sites of metastatic disease. Furthermore incidental findings of uptake in the region of the thyroid make consideration of a primary carcinoma mandatory.

Intraoperative parathyroid aspiration and parathyroid hormone assay as an alternative to frozen section for tissue identification.

Most people would agree that successful parathyroidectomy depends on two important variables: the surgeon's recognition and excision of the abnormal parathyroid gland(s) and the pathologist's confirmation that the removed tissue is parathyroid tissue. Frozen section is usually employed to confirm the identity of parathyroid tissue, but occasionally confirmation cannot be made without a permanent section, as with intrathyroidal glands. This study proposes a new method of expeditious and easy confirmation of parathyroid tissue utilizing the immunoassay for quick measurement of intraoperative parathyroid hormone (IOPTH). By directly aspirating the suspected adenoma, the assay becomes a rapid diagnostic tool that can be used as an alternative to frozen section. In cases where the surgeon is already planning to employ the assay, the elimination of frozen section is cost-effective. Intraoperative aspiration of histologically confirmed parathyroid adenomas was performed on 12 consecutive patients undergoing parathyroid surgery. Parathyroid glands were aspirated with a 22-gauge syringe after gland excision. Aspirates were placed in 1 to 3 ml of buffered saline. A similar process was performed on 12 thyroid controls. Specimens were centrifuged, aliquotted, and stored at -70 degrees C. The parathyroid hormone value was analyzed electively by rapid assay and the values recorded. For all parathyroid aspirates, the rapid assay value was > 1500 pg/ml, exceeding the uppermost limit of the diagnostic chart. Values for thyroid aspirates ranged from 58 to 85 pg/ml (mean 75.7 pg/ml). In all cases tissue confirmation was achieved with permanent section. Values were 100% sensitive and specific. Measurement of PTH from intraoperative aspiration of suspected parathyroid adenomas is clinically useful in patients for whom frozen section would routinely be employed. Values > 1500 pg/ml secure the tissue diagnosis. There is no additional cost in cases where IOPTH monitoring is already being utilized to confirm cure. The elimination of frozen section could be cost-effective and, for some institutions, actually decrease the operating time as the IOPTH assay takes only 15 minutes. PTH assay is an accurate diagnostic technique and to date is 100% sensitive and specific for differentiating between parathyroid tumors and thyroid nodules.

Death related to propofol use in an adult patient.

OBJECTIVE: To report an adult trauma patient fatality related to propofol administration. DESIGN: Retrospective case review. SETTING: Trauma intensive care unit (ICU) in a level one trauma center. PATIENT: An 18-yr-old man involved in a motor vehicle crash. INTERVENTIONS: Treatment for multiple trauma injuries and propofol sedation. MEASUREMENTS AND MAIN RESULTS: Posttrauma ICU monitoring was performed. The patient developed cardiac arrhythmia, metabolic acidosis, and cardiac failure, which resulted in death. CONCLUSION: Death related to propofol infusion can occur in adults as well as in pediatric patients.

Classification and treatment of follicular thyroid neoplasms are discordant between and within medical specialties.

BACKGROUND: The histologic criteria to classify follicular thyroid neoplasms are controversial. Criteria used for diagnosis and treatment varies both within and between specialty groups. This discordance makes it difficult to compare disease and management practice. This is especially problematic in issues concerning reoperations and survival. To determine the degree of disparity, we surveyed 3 groups of specialists. METHODS: A questionnaire describing 10 histologic scenarios was sent to an equal number of thyroidologists, endocrine surgeons, and endocrine pathologists. Individuals were randomly selected from rosters of 3 corresponding societies. Each item asked for a rating of a diagnosis and treatment. Questionnaires were distributed and received by facsimile, and responses were kept confidential. The response rate was 60%. RESULTS: Responses were analyzed by nonparametric statistical tests. Two scenarios had significant disagreement among specialties in both diagnosis and treatment: one scenario involved the assessment of neoplasms with minimal capsular invasion; the other scenario involved Hürthle cell features. In both scenarios pathologists tended to be more conservative in assigning the term carcinoma and recommending total thyroidectomy. Significant disagreement within specialty groups was also noted. Two other scenarios dealt with the distinction between minimally and widely invasive carcinoma; significantly, pathologists viewed tumors as less invasive. CONCLUSIONS: This study indicates that much disparity exists among specialists in pathology, endocrinology, and surgery and among experts in each of these disciplines. It highlights that there is no uniform classification. If multicenter trials to evaluate treatment options are to occur, a universal classification must be accepted.

Reoperative parathyroid surgery in the era of sestamibi scanning and intraoperative parathyroid hormone monitoring.

HYPOTHESIS: Results of reoperative parathyroid surgery (RPS) have improved with the advent of sestamibi parathyroid subtraction scanning and intraoperative parathyroid hormone (IOPTH) monitoring. DESIGN: Retrospective review of patient histories, preoperative localization studies, operative data, including IOPTH monitoring, and outcomes for patients undergoing recent RPS at a single institution. Follow-up was complete (mean, 20 months). SETTING: Tertiary care referral center. PATIENTS: All patients undergoing RPS for benign persistent or recurrent primary hyperparathyroidism during the period 1989 to 1997. MAIN OUTCOME MEASURES: Overall cure rate and operative morbidity from RPS; sensitivity and accuracy of preoperative localization studies; and prediction of cure from IOPTH monitoring. RESULTS: The study group included 124 patients (87 women and 37 men). Hypercalcemia was corrected in 109 patients (88%). Permanent recurrent laryngeal nerve injury occurred in 0.8% and permanent hypoparathyroidism in 13% of patients. Test sensitivities and accuracies, respectively, were as follows: ultrasound with biopsy, 90% and 82%; sestamibi parathyroid subtraction scanning, 82% and 67%; and ultrasound alone, 75% and 65%. Level of IOPTH was predictive of cure in all patients with a 70% or greater fall from baseline at 20 minutes after excision. Persistent multigland disease was the major cause for reoperative failure (73%). CONCLUSIONS: Neither cure rates nor operative morbidity have changed appreciably over the past 2 decades, despite the introduction of sestamibi parathyroid subtraction scanning and IOPTH monitoring. Multigland disease continues to represent the principal cause of failure in RPS despite the routine use of preoperative localization studies. Thus far, increasing the stringency of IOPTH monitoring from a 50% to 70% decline from baseline levels has been predictive of cure, even in multigland disease. Most missed abnormal glands reside in normal anatomic locations, and the need for multiple operations, not just the reoperation, results in the increased morbidity seen with RPS.

Thyroid cancer in patients with familial adenomatous polyposis.

The association between thyroid cancer and familial adenomatous polyposis (FAP), albeit rare, is well known. It has been suggested that the thyroid tumors have unique histologic characteristics and may be follicular in origin. Because of their rarity, treatment and long-term prognosis are uncertain. Twelve such patients (prevalence 399/100,000) seen during 1949-1995 were retrospectively reviewed. Histology was independently re-reviewed by two pathologists. There were 11 female patients (two sisters) and 1 male patient, with a mean age of 28 years (range 15-61 years). Eight patients (66%) had multicentric tumors and five (42%) bilateral disease. Average tumor diameter was 1.8 cm (range 0.2-5.0 cm). Regional nodal metastases were present in two patients. All 12 thyroid cancers in this series were papillary. The one male patient demonstrated "typical" histology with variable papillary and follicular architecture, whereas the 11 female patients had tumors with unusual histology as described by Harach. Five patients (41%) were treated by total thyroidectomy, five with near-total thyroidectomy, and two with lobectomy alone. Mean follow-up was 142 months (range 7 months to 30 years). Regional recurrent disease occurred in two patients, one of whom died of the disease. The 5- and 20-year survivals were 90% and 77%, respectively. The results indicated that all tumors in this study were papillary, although atypical histology was encountered in 91%. The mean age (28 years) is younger than that of patients with sporadic disease. Multicentricity and bilateral disease are common. In view of this finding, total thyroidectomy should be strongly considered. Long-term prognosis is excellent. The finding of unusual histology in a young patient with papillary thyroid carcinoma should arouse the suspicion of FAP.

An immunohistochemical survey for neuroendocrine cells in regional pancreatic lymph nodes: a plausible explanation for primary nodal gastrinomas? Mayo Clinic Pancreatic Surgery Group.

BACKGROUND: The existence of primary gastrinomas in lymph nodes continues to be controversial, because distinction from metastases from occult or regressed primary tumors may be difficult to exclude with certainty. If primary nodal gastrinomas do indeed occur, precursor neuroendocrine cells should be identifiable within lymph nodes. In a effort to detect these cells we undertook an immunohistochemical survey of regional pancreatic lymph nodes by using antibody against chromogranin, a highly specific marker for mature neuroendocrine cells. METHODS: We retrospectively identified consecutive cases from five surgeons in which Whipple resections had been performed for nonendocrine pathologic conditions. All formalin-fixed, paraffin-embedded lymph nodes were identified from these 106 cases, excluding lymph nodes with metastases. Immunoperoxidase staining with monoclonal antibody against chromogranin A was performed on single tissue sections. All slides were reviewed by a single pathologist; chromogranin-positive cells were identified and, when possible, further evaluated immunohistochemically with additional neuroendocrine markers, including sequential synaptophysin staining. RESULTS: A total of 1026 lymph nodes were available for review. Although well-formed intranodal chromogranin-positive nests were not identified, six nodes from three patients contained 13 strongly chromogranin-positive cells representing putative neuroendocrine cells. Mast cells showed weak nonspecific staining with chromogranin but were morphologically distinct. Perinodal adipose tissue contained a single paraganglion and several small neuroendocrine clusters. CONCLUSIONS: Putative neuroendocrine cells are rarely (less than 1%) found in regional pancreatic lymph nodes. Although these may be embryonic rests and might represent precursors of primary nodal gastrinomas, specific hormones have yet to be identified in these cells. Although these data provide support for the concept of primary nodal gastrinomas, this remains a diagnosis of exclusion.