Brian R. Untch

Well Differentiated Neuroendocrine Tumors with a Morphologically Apparent High Grade Component: A Pathway Distinct from Poorly Differentiated Neuroendocrine Carcinomas

Purpose: Most well-differentiated neuroendocrine tumors (WD-NET) of the enteropancreatic system are low-intermediate grade (G1, G2). Elevated proliferation demonstrated by either a brisk mitotic rate (>20/10 high power fields) or high Ki-67 index (>20%) defines a group of aggressive neoplasms designated as high-grade (G3) neuroendocrine carcinoma (NEC). High-grade NEC is equated with poorly differentiated NEC (PD-NEC) and is associated with a dismal outcome. Progression of WD-NETs to a high-grade neuroendocrine neoplasm very rarely occurs and their clinicopathologic and molecular features need to be characterized. Experimental Design: We investigated 31 cases of WD-NETs with evidence of a component of a high-grade neoplasm. The primary sites included pancreas, small bowel, bile duct, and rectum. Histopathology of the cases was retrospectively reviewed and selected IHC and gene mutation analyses performed. Results: The high-grade component occurred either within the primary tumor (48%) or at metastatic sites (52%). The clinical presentation, radiographic features, biomarkers, and the genotype of these WD-NETs with high-grade component remained akin to those of G1–G2 WD-NETs. The median disease-specific survival (DSS) was 55 months (16–119 months), and 2-year and 5-year DSS was 88% and 49%, respectively—significantly better than that of a comparison group of true PD-NEC (DSS 11 months). Conclusions: Mixed grades can occur in WD-NETs, which are distinguished from PD-NECs by their unique phenotype, proliferative indices, and the genotype. This phenomenon of mixed grade in WD-NET provides additional evidence to the growing recognition that the current WHO G3 category contains both WD-NETs as well as PD-NECs. Clin Cancer Res; 22(4); 1011–7. ©2015 AACR.

Surgeon-Performed Ultrasound Is Superior to 99Tc-Sestamibi Scanning to Localize Parathyroid Adenomas in Patients with Primary Hyperparathyroidism: Results in 516 Patients over 10 Years

BACKGROUND Surgeon-performed cervical ultrasound (SUS) and 99Tc-sestamibi scanning (MIBI) are both useful in patients with primary hyperparathyroidism (PHPT). We sought to determine the relative contributions of SUS and MIBI to accurately predict adenoma location. STUDY DESIGN We performed a database review of 516 patients undergoing surgery for PHPT between 2001 and 2010. SUS was performed by 1 of 3 endocrine surgeons. MIBI used 2-hour delayed anterior planar and single-photon emission computerized tomography images. Directed parathyroidectomy was performed with extent of surgery governed by intraoperative parathyroid hormone decline of 50%. RESULTS SUS accurately localized adenomas in 87% of patients (342/392), and MIBI correctly identified their locations in 76%, 383/503 (p < 0.001). In patients who underwent SUS first, MIBI provided no additional information in 92% (144/156). In patients who underwent MIBI first, 82% of the time (176/214) SUS was unnecessary (p = 0.015). In 32 patients SUS was falsely negative. The reason for these included gland location in either the deep tracheoesophageal groove (n = 9) or the thyrothymic ligament below the clavicle (n = 5), concurrent thyroid goiter (n = 4), or thyroid cancer (n = 1). In 13 cases, the adenoma was located in a normal ultrasound-accessible location but was missed by the preoperative exam. In the 32 ultrasound false-negative cases, MIBI scans were positive in 21 (66%). Of the 516 patients, 7.6% had multigland disease. Persistent disease occurred in 4 patients (1%) and recurrent disease occurred in 6 (1.2%). CONCLUSIONS When performed by experienced surgeons, SUS is more accurate than MIBI for predicting the location of abnormal parathyroids in PHPT patients. For patients facing first-time surgery for PHPT, we now reserve MIBI for patients with unclear or negative SUS.

Natural History and Tumor Volume Kinetics of Papillary Thyroid Cancers During Active Surveillance

Importance Active surveillance of low-risk papillary thyroid cancer (PTC) is now an accepted alternative to immediate surgery, but experience with this approach outside of Japan is limited. The kinetics (probability, rate, and magnitude) of PTC tumor growth under active surveillance have not been well defined. Objective To describe the kinetics of PTC tumor growth during active surveillance. Design, Setting, and Participants Cohort study of 291 patients undergoing active surveillance for low-risk PTC (intrathyroidal tumors ⩽1.5 cm) with serial tumor measurements via ultrasonography at a tertiary referral center in the United States. Intervention Active surveillance. Main Outcomes and Measures The cumulative incidence, rate, and magnitude of the change in tumor diameter or volume, as well as associations with patient and tumor characteristics. Results Of the 291 patients, 219 (75.3%) were women; mean (SD) age was 52 (15) years. During a median (range) active surveillance of 25 (6-166) months, growth in tumor diameter of 3 mm or more was observed in 11 of 291 (3.8%) patients, with a cumulative incidence of 2.5% (2 years) and 12.1% (5 years). No regional or distant metastases developed during active surveillance. In all cases, 3-dimensional measurements of tumor volume allowed for earlier identification of growth (median, 8.2 months; range, 3-46 months before increase in tumor diameter). In multivariable analysis, both younger age at diagnosis (hazard ratio per year, 0.92; 95% CI, 0.87-0.98; P = .006) and risk category at presentation (hazard ratio for inappropriate, 55.17; 95% CI, 9.4-323.19; P < .001) were independently associated with the likelihood of tumor growth. Of the tumors experiencing volume growth, kinetics demonstrated a classic exponential growth pattern, with a median doubling time of 2.2 years (range, 0.5-4.8 years; median r2 = 0.75; range, 0.42-0.99). Conclusions and Relevance The rates of tumor growth during active surveillance in a US cohort with PTCs measuring 1.5 cm or less were low. Serial measurement of tumor volumes may facilitate early identification of tumors that will continue to grow and thereby inform the timing of surveillance imaging and therapeutic interventions.

Severe obesity is associated with symptomatic presentation, higher parathyroid hormone levels, and increased gland weight in primary hyperparathyroidism.

CONTEXT A relationship between primary hyperparathyroidism (PHPT) and obesity has been observed but is incompletely understood. Furthermore, obesity has been associated with vitamin D deficiency, suggesting that the three conditions may be linked. OBJECTIVE We hypothesized that PHPT in morbidly obese patients is more severe and that the difference may be explained by vitamin D deficiency. DESIGN AND SETTING, PARTICIPANTS, AND OUTCOME MEASURES: Records of 196 patients with surgically treated PHPT and known body mass index (BMI) were examined. Patients were stratified into three BMI groups: group I (nonobese), BMI < 25 kg/m(2) (n = 54); group II (non-severely obese), BMI 25-34 kg/m(2) (n = 102); and group III (severely obese), BMI 35 kg/m(2) or greater (n = 40). RESULTS Preoperative PTH levels were higher in group ΙΙΙ compared with group Ι (181 ± 153 vs. 140 ± 80 pg/ml, p = 0.04). Group III patients had larger tumors on average compared with group I (1.8 ± 1.5 vs. 1.04 ± 1.5 g, P = 0.0002). In group III, BMI positively correlated with parathyroid tumor weight (r = 0.5, P = 0.002). Postoperative PTH was higher in group III compared with group Ι (61 ± 41 vs. 44 ± 28 pg/ml, P = 0.02). There was higher frequency of depression, musculoskeletal symptoms, weakness, and gastroesophageal reflux disease in group III patients. CONCLUSIONS BMI positively correlated with parathyroid tumor weight independent of vitamin D. Severely obese patients have larger parathyroid tumor weight, higher pre- and postoperative PTH, and greater symptoms.

Parathyroid Carcinoma: Current Understanding and New Insights into Gene Expression and Intraoperative Parathyroid Hormone Kinetics

Parathyroid carcinoma is an indolent but ultimately life-threatening malignancy. Due to the lack of definitive diagnostic markers and overlapping clinical features of benign primary hyperparathyroidism (PHPT), this disease is often misdiagnosed as parathyroid adenoma. Therefore, a high index of suspicion preoperatively and early intraoperative recognition with en bloc surgical resection are crucial for favorable outcome. Owing to the rarity of the disease, little is known about the molecular pathogenesis of parathyroid carcinoma. Here, we review the literature to present current understanding of the disease and provide new information on gene expression and use of intraoperative parathyroid hormone (PTH) monitoring in the surgical management of this rare malignancy. Specifically, using microarray transcriptome analysis of an unequivocal case of parathyroid carcinoma and a biopsy from the same patients normal parathyroid gland, we identify APP, CDH1, KCNJ16, and UCHL1 as differentially expressed genes in parathyroid carcinoma. Further, using case records from four cases of unequivocal parathyroid carcinoma, we compared intraoperative PTH kinetics of these patients to 475 patients with benign PHPT, and show that intraoperative PTH monitoring is accurate in predicting postoperative normocalcemia in initial en bloc operations for parathyroid carcinoma.

NF2 Loss Promotes Oncogenic RAS-Induced Thyroid Cancers via YAP-Dependent Transactivation of RAS Proteins and Sensitizes Them to MEK Inhibition

UNLABELLED Ch22q LOH is preferentially associated with RAS mutations in papillary and in poorly differentiated thyroid cancer (PDTC). The 22q tumor suppressor NF2, encoding merlin, is implicated in this interaction because of its frequent loss of function in human thyroid cancer cell lines. Nf2 deletion or Hras mutation is insufficient for transformation, whereas their combined disruption leads to murine PDTC with increased MAPK signaling. Merlin loss induces RAS signaling in part through inactivation of Hippo, which activates a YAP-TEAD transcriptional program. We find that the three RAS genes are themselves YAP-TEAD1 transcriptional targets, providing a novel mechanism of promotion of RAS-induced tumorigenesis. Moreover, pharmacologic disruption of YAP-TEAD with verteporfin blocks RAS transcription and signaling and inhibits cell growth. The increased MAPK output generated by NF2 loss in RAS-mutant cancers may inform therapeutic strategies, as it generates greater dependency on the MAPK pathway for viability. SIGNIFICANCE Intensification of mutant RAS signaling through copy-number imbalances is commonly associated with transformation. We show that NF2/merlin inactivation augments mutant RAS signaling by promoting YAP/TEAD-driven transcription of oncogenic and wild-type RAS, resulting in greater MAPK output and increased sensitivity to MEK inhibitors.

Prophylactic central neck dissection in differentiated thyroid cancer: an assessment of the evidence.

An area of ongoing controversy in the management of patients with differentiated thyroid cancer is the role of prophylactic central neck dissection (pCND). This review describes the natural history of differentiated thyroid cancer and provides the limited data regarding the role of routine pCND. An evidence-based analysis was performed of the rationale for routine pCND was performed, including reduced rates of central neck recurrence, reduced morbidity with secondary central neck lymphadenectomy, improved rates of postoperative athyroglobulinemia, and improved stratification of radioactive iodine (RAI) dosage. A critical appraisal of the available literature demonstrates insufficient evidence to indicate that this extra procedure performed routinely leads to improvement in clinically meaningful end points.

Regulator of G Protein Signaling 5 Is Highly Expressed in Parathyroid Tumors and Inhibits Signaling by the Calcium-Sensing Receptor

The molecular mechanisms responsible for aberrant calcium signaling in parathyroid disease are poorly understood. The loss of appropriate calcium-responsive modulation of PTH secretion observed in parathyroid disease is commonly attributed to decreased expression of the calcium-sensing receptor (CaSR), a G protein-coupled receptor. However, CaSR expression is highly variable in parathyroid adenomas, and the lack of correlation between CaSR abundance and calcium-responsive PTH kinetics indicates that mechanisms independent of CaSR expression may contribute to aberrant calcium sensing in parathyroid disease. To gain a better understanding of parathyroid tumors and the molecular determinants that drive parathyroid adenoma development, we performed gene expression profiling on a panel of 64 normal and neoplastic parathyroid tissues. The microarray data revealed high-level expression of genes known to be involved in parathyroid biology (PTH, VDR, CGA, CaSR, and GCM2). Moreover, our screen identified regulator of G protein signaling 5 (RGS5) as a candidate inhibitor of CaSR signaling. We confirmed RGS5 to be highly expressed in parathyroid adenomas relative to matched-pair normal glands. Transient expression of RGS5 in cells stably expressing CaSR resulted in dose-dependent abrogation of calcium-stimulated inositol trisphosphate production and ERK1/2 phosphorylation. Furthermore, we found that RGS5-nullizygous mice display reduced plasma PTH levels, an outcome consistent with attenuated opposition to CaSR activity. Collectively, these data suggest that RGS5 can act as a physiological regulator of calcium sensing by CaSR in the parathyroid gland. The abnormally elevated expression of RGS5 observed in parathyroid adenomas could thus represent a novel mechanism of CaSR desensitization in patients with primary hyperparathyroidism.

The Surgical Management of Small Bowel Neuroendocrine Tumors: Consensus Guidelines of the North American Neuroendocrine Tumor Society

Abstract Small bowel neuroendocrine tumors (SBNETs) have been increasing in frequency over the past decades, and are now the most common type of small bowel tumor. Consequently, general surgeons and surgical oncologists are seeing more patients with SBNETs in their practices than ever before. The management of these patients is often complex, owing to their secretion of hormones, frequent presentation with advanced disease, and difficulties with making the diagnosis of SBNETs. Despite these issues, even patients with advanced disease can have long-term survival. There are a number of scenarios which commonly arise in SBNET patients where it is difficult to determine the optimal management from the published data. To address these challenges for clinicians, a consensus conference was held assembling experts in the field to review and discuss the available literature and patterns of practice pertaining to specific management issues. This paper summarizes the important elements from these studies and the recommendations of the group for these questions regarding the management of SBNET patients.

Treatment Response and Outcomes of Grade 3 Pancreatic Neuroendocrine Neoplasms Based on Morphology: Well Differentiated Versus Poorly Differentiated.

Objectives Emerging data suggest that not all grade 3 (G3) pancreatic neuroendocrine neoplasms (panNENs) behave the same; tumor differentiation may predict outcome. Methods Patients with G3 panNENs treated at our institution between 1999 and 2014 were identified. Demographics, response to therapy, and overall survival were determined. Results Forty-five patients were identified, 16 with G3 well differentiated pancreatic neuroendocrine tumors (WD-panNETs) and 29 with poorly differentiated neuroendocrine carcinomas (PDNEC). Median overall survival in G3 WD-panNET patients was 52.2 months (95% confidence interval, 19.3–86.9 months) compared with 10.1 months (95% confidence interval, 6.9–12.4 months) in PDNEC patients (P = 0.0009). Response rate to platinum agents was 10% in G3 WD-panNETs and 37% in PDNEC. Response rate to alkylating agents was 50% in G3 WD-panNETs and 50% in PDNEC. Conclusions Both G3 WD-panNETs and PDNEC responded to platinum and alkylating agents. Overall survival was significantly greater in G3 WD-panNETs compared with PDNEC. These findings challenge current classification and suggest that G3 panNENs should be classified by morphology.