Jessica E. Maxwell

Liver-directed surgery of neuroendocrine metastases: What is the optimal strategy?

INTRODUCTION Neuroendocrine tumors (NETs) frequently metastasize to the liver. Operative debulking offers symptomatic relief and improved survival; however, the frequent presence of multifocal, bilobar disease and high recurrence rates introduces doubt regarding their optimal management. Parenchyma-sparing debulking (PSD) procedures (ablation, enucleation, wedge resections) may offer similar survival improvements as resection while minimizing morbidity and preserving functional liver tissue. METHODS Clinicopathologic variables from 228 patients with small bowel or pancreatic NETs managed operatively at one institution were collected. Liver-directed surgery was carried out when substantial debulking was deemed feasible. Survival was assessed by use of the Kaplan-Meier method. RESULTS A total of 108 patients with pancreatic NET or small bowel NET underwent liver-directed surgery with primarily PSD procedures. Nearly two-thirds of patients achieved 70% cytoreduction and 84% had concurrent resection of their primary. The median number of lesions treated was 6 (range, 1-36). There were no 30-day operative mortalities. The 30-day major complication rate was 13.0%. Patients who achieved 70% cytoreduction enjoyed improved progression free (median 3.2 years) and overall survival (median not reached). CONCLUSION PSD procedures are safe and can achieve significant cytoreduction, which is associated with improved survival. Lowering the debulking target threshold to 70% may benefit NET patients by increasing eligibility for cytoreduction.

Medical management of metastatic medullary thyroid cancer.

Medullary thyroid cancer (MTC) is an aggressive form of thyroid cancer that occurs in both heritable and sporadic forms. Discovery that mutations in the rearranged during transfection (RET) proto‐oncogene predispose to familial cases of this disease has allowed for presymptomatic identification of gene carriers and prophylactic surgery to improve the prognosis of these patients. A significant number of patients with the sporadic type of MTC and even those with familial disease still present with lymph node or distant metastases, making surgical cure difficult. Over the past several decades, many different types of therapy for metastatic disease have been attempted with limited success. Improved understanding of the molecular defects and pathways involved in both familial and sporadic MTC has resulted in new hope for these patients with the development of drugs targeting the specific alterations responsible. This new era of targeted therapy with kinase inhibitors represents a significant step forward from previous trials of chemotherapy, radiotherapy, and hormone therapy. Although much progress has been made, additional agents and strategies are needed to achieve durable, long‐term responses in patients with metastatic MTC. This article reviews the history and results of medical management for metastatic MTC from the early 1970s up until the present day. Cancer 2014;120:3287–3301.

A Practical Method to Determine the Site of Unknown Primary in Metastatic Neuroendocrine Tumors

INTRODUCTION The site of a primary neuroendocrine tumor (NET) tumor is unknown before treatment in approximately 20% of small bowel (SBNET) and pancreatic (PNET) cases despite extensive workup. It can be difficult to discern a PNET from an SBNET on hematoxylin and eosin stains, and thus, more focused diagnostic tests are required. Immunohistochemistry (IHC) and gene expression profiling are two methods used to identify the tissue of origin from biopsied metastases. METHODS Tissue microarrays were created from operative specimens and stained with up to seven antibodies used in the NET-specific IHC algorithm. Expression of four genes for differentiating between PNETs and SBNETs was determined by quantitative polymerase chain reaction and then used in a previously validated gene expression classifier (GEC) algorithm designed to determine the primary site from gastrointestinal NET metastases. RESULTS The accuracy of the IHC algorithm in identifying the primary tumor site from a set of 37 metastases was 89%, with only one incorrect call. Three other samples were indeterminate as the result of pan-negative staining. The GECs accuracy in a set of 136 metastases was 94%. The algorithm identified the primary tumor site in all cases in which IHC failed. CONCLUSION Performing IHC, followed by GEC for indeterminate cases, identifies accurately the primary site in SBNET and PNET metastases in virtually all patients.

Biochemical Diagnosis and Preoperative Imaging of Gastroenteropancreatic Neuroendocrine Tumors.

Neuroendocrine tumors are a group of neoplasms that can arise in a variety of locations throughout the body and often metastasize early. A patients only chance for cure is surgical removal of the primary tumor and all associated metastases, although even when surgical cure is unlikely, patients can benefit from surgical debulking. A thorough preoperative workup will often require multiple clinical tests and imaging studies to locate the primary tumor, delineate the extent of the disease, and assess tumor functionality. This review discusses the biomarkers important for the diagnosis of these tumors and the imaging modalities needed.

Elevated pancreatic polypeptide levels in pancreatic neuroendocrine tumors and diabetes mellitus: causation or association?

Pancreatic neuroendocrine tumors (PNETs) that secrete primarily pancreatic polypeptide (PP) are rare and usually nonfunctional. There are approximately 2 dozen reports of PP-secreting PNETs, 3 of which have been associated with diabetes mellitus (DM). None suggest a mechanism for the association between PP-secreting PNETs and DM. We describe 5 patients with PP-producing tumors who were diagnosed with DM at the same time as their PNETs, review the literature on PP, and consider its role in the pathophysiology of DM. The cases discussed were extracted from our surgical neuroendocrine tumor database. We examined all patients with PP-predominant PNETs--both with DM (n = 5) and without (n = 8). The 5 patients with DM at the time of PNET diagnosis demonstrated improvement or resolution of their DM postoperatively. In the patients with PP-secreting PNETs but no diagnosis of DM preoperatively, 1 became hypoglycemic postoperatively, and 2 others developed postoperative DM. The 5 cases discussed in detail raise the question of whether the hypersecretion of PP in PNETs might be an important event leading to the development of DM. Although the literature does not provide a mechanism for this association, it may be related to the role of PP in hepatic glucose regulation.

Somatic alterations of CDKN1B are associated with small bowel neuroendocrine tumors

CDKN1B, a cyclin-dependent kinase inhibitor associated with G1 arrest, was recently proposed as an important tumor suppressor gene in small bowel neuroendocrine tumors (SBNETs). The rate of frameshift mutations in SBNET primaries are reportedly 7.4%, and hemizygous deletions are 6.7%. We set out to confirm the role of CDKN1B mutations and copy number variants (CNVs) in primary SBNETs, and whether these are also found in pancreatic neuroendocrine tumors (PNETs). Genomic DNA was isolated from 90 primary SBNETs and 67 PNETs. Coding exons of CDKN1B were amplified by PCR and sequenced. CNV analysis was performed by quantitative PCR, p27 expression was evaluated using immunohistochemistry. In SBNETS, three frameshifts, one missense mutation, and three CNVs were observed. The total rate of CDKN1B alterations was 7.0% (6 of 86; 95% confidence interval (CI) 3.2-4.4%). The frameshift rate was 3.5% (95% CI 1.1-9.8%). One SBNET patient had a hemizygous deletion of CDKN1B, and two patients had duplications (3.4%; 95% CI -0.41-7.2%). One PNET patient had a duplication, and two patients had hemizygous deletions (4.8%; 95% CI -0.44-10%). Alterations of cell-cycle control due to alterations in CDKN1B may be one mechanism by which SBNETs develop, which could have implications for new treatment modalities.

Identification of primary tumors in patients presenting with metastatic gastroenteropancreatic neuroendocrine tumors

Background. Patients with gastroenteropancreatic neuroendocrine tumors often present with metastases. Identification of the primary tumor is important for operative management, and therefore we sought to determine our success at identifying primary tumors with diagnostic testing and operative exploration. Methods. A clinical neuroendocrine tumor database was reviewed to identify patients presenting with metastases and primary tumor in situ. Results of radiologic, endoscopic, and operative procedures were evaluated to determine which correctly identified the primary tumor. Results. There were 197 patients presenting with metastases and unresected primaries, 134 who had an operation and 63 managed nonoperatively. Primaries were identified preoperatively in 168 (84%), at operative exploration in 7, and were not found in 22 patients. Computed tomography found 150/197 primary tumors, somatostatin‐receptor scintigraphy 88/155, and endoscopy 43/107. The sensitivity of computed tomography surpassed scintigraphy (76% vs 57%, P < .01). The primary was removed in 130/134 (97%) patients, and hepatic debulking was performed in 67%. Median survival for operative patients with small bowel and pancreatic tumors was 145 and 71 months, respectively. Conclusion. Imaging and endoscopy identified the primary tumor in most patients, and the majority of the others were found at exploration. Preoperative testing facilitated operative planning, allowing for resection of the primary and hepatic debulking in most patients.

Translational Diagnostics and Therapeutics in Pancreatic Neuroendocrine Tumors.

Pancreatic neuroendocrine tumors (PNET) are rare tumors, but have been increasing in incidence. Although typically thought of as indolent, more than half of patients present with metastatic disease. For many years, the only mutations commonly known in these tumors were those in the MEN1 gene. Recently, the genetics underlying PNETs have been further defined through exome sequencing. The most frequent alterations found in sporadic PNETs are in MEN1, DAXX/ATRX, and a variety of genes in the mTOR pathway. Confirmation of these mutations has prompted trials with a number of drugs active in these pathways, and two drugs were eventually approved in 2011—sunitinib and everolimus. New data additionally identify the MET and CD47 receptors as potential novel drug targets. Yet despite improvements in progression-free survival with sunitinib and everolimus, further studies defining when to use these agents and factors associated with limitations in their utility are needed. As more discoveries are made in the laboratory that elucidate additional molecular mechanisms important in the initiation and metastasis of PNETs, continued efforts to translate these discoveries into distinct new therapies will be needed to improve patient survival. Clin Cancer Res; 22(20); 5022–9. ©2016 AACR. See all articles in this CCR Focus section, “Endocrine Cancers: Revising Paradigms.”