Elevated Alkaline Phosphatase Prior to Transarterial Chemoembolization for Neuroendocrine Tumors Predicts Worse Outcomes

Introduction

We hypothesized that an elevated preoperative alkaline phosphatase (AP) predicted worse outcomes for patients undergoing transarterial chemoembolization (TACE) for neuroendocrine tumor (NET) liver metastases.

Methods

We reviewed all patients who underwent TACE for metastatic NET between 2009 and 2013. Survival was evaluated using preprocedure variables.

Results

One hundred and nine patients underwent 210 TACE procedures. The average age was 57.7 years (range 20–78). Primary sites included pancreas (N?=?20), other gastrointestinal (N?=?52), lung (N?=?9), and unknown (N?=?28). The tumor was grade 1 in 68 (62 %), grade 2 in 21 (19 %), and grade 3 in 3 (3 %). Extrahepatic disease was present in 54 (50 %) and greater than 50 % hepatic tumor burden by imaging in 63 (58 %). Elevated bilirubin occurred in 8 (7 %), elevated AP in 22 (20 %), elevated ALT in 21 (19 %), and elevated AST in 41 (38 %). Univariate predictors included tumor grade (43 vs 27 vs 21 months, p?=?0.015), hepatic tumor burden (59 vs 37 months, p?=?0.009), and elevated AP (59 vs 23 months, p?<?0.001). On multivariate analysis, only elevated AP (p?=?0.001) predicted worse survival.

Conclusions

Elevated AP prior to TACE for metastatic NET portends a worse survival outcome, even more so than tumor grade or extent of hepatic disease.

     

Pancreatic Neuroendocrine Tumors

Pancreatic neuroendocrine neoplasms include well-differentiated pancreatic neuroendocrine tumors (PanNETs) and neuroendocrine carcinomas (NECs) with well-differentiated PanNETs accounting for most cases. Other pancreatic primaries and metastatic carcinomas from other sites can mimic pancreatic neuroendocrine neoplasms. Immunohistochemical studies can be used to aid in the differential diagnosis. However, no specific markers are available to differentiate PanNETs from NETs of other sites. Although NECs are uniformly deadly, PanNETs have variable prognosis. Morphology alone cannot predict the tumor behavior. Although some pathologic features are associated with an aggressive course, Ki67 is the only prognostic molecular marker routinely used in clinical practice.     

Pulmonary Neuroendocrine Tumors

Pulmonary neuroendocrine tumors represent a morphologic spectrum of tumors from the well-differentiated typical carcinoid tumor, to the intermediate-grade atypical carcinoid tumor, to the high-grade neuroendocrine carcinomas composed of small-cell carcinoma and large-cell neuroendocrine carcinoma. The addition of immunohistochemistry in diagnostics is helpful and often essential, especially in the classification of large-cell neuroendocrine carcinoma. The importance of the intermediate-grade atypical carcinoid group is underscored by the impact of this diagnosis on therapy. The distinction of pulmonary small-cell carcinoma from large-cell neuroendocrine carcinoma, despite both being in the high-grade group, is of relevance to the therapeutic approach to these tumor types.     

Multifocality in Small Bowel Neuroendocrine Tumors

Background

Neuroendocrine tumors (NETs) account for 30% of small bowel (SB) neoplasms. The objectives of this study were to evaluate the incidence of multifocality in primary small bowel neuroendocrine tumors (SBNETs) and to examine the associated outcomes.

Methods

Patients with multifocal SBNET were compared to those with a solitary lesion. Only patients who underwent diagnostic workup and surgical intervention at our institution were included in this study. The primary aim of our study was surgical outcomes and mortality and recurrence. The second aim of our study was to evaluate the utility of double-balloon enteroscopy (DBE) and capsule endoscopy.

Results

Of 178 patients with SBNETs during the study period, 85 met inclusion criteria. The mean age was 61.0 ± 12.6 years and 44.7% were male. The ileum was the primary tumor site for 66 patients (77.7%). Of DBE patients, 28 (62.2%) had additional lesions identified, of which 23 (82.1%) had NET confirmed on pathology. Average tumor size was 1.8 cm and most were well differentiated (89.9%), with Ki-67 of ≥ 2% (65.8%); 74.4% had nodal metastases and 51% of patients had stage IV disease. Forty-six patients (54.1%) had multifocal disease, of whom 37 (80.5%) had an ileal primary. No differences in survival or recurrence were seen for multifocal versus solitary disease.

Conclusions

SBNETs have a high incidence of multifocality. DBE can be used in the preoperative assessment to detect multifocal NET. Multifocality has no impact on survival or recurrence outcomes.

     

Pathologic Grade and Tumor Size are Associated with Recurrence-Free Survival in Patients with Duodenal Neuroendocrine Tumors

Background

Duodenal neuroendocrine tumors are rare and few studies exist to guide surgical management. This study identifies factors associated with recurrence after resection.

Methods

A retrospective, single institution review was performed between 1983 and 2011 on patients with a pathologic diagnosis of duodenal neuroendocrine tumor. Tumor grade was assigned based on WHO 2010 criteria (Ki-67 and mitotic rate).

Results

Seventy-five patients were identified that underwent curative resection. This included 12 patients with endoscopic mucosal resection, 34 that had local resection, and 29 that underwent pancreaticoduodenectomy. Two-year and 5-year recurrence-free survival was 84 and 81 %, respectively. There were 11 tumor recurrences (either local or distant), and four patients died of their disease (3/4 had high-grade lesions) with an overall median follow-up of 27 months. On univariate analysis, tumor size and tumor grade were identified as being associated with recurrence, but not intervention type, lymph node metastases, ampullary location, or margin status.

Conclusions

Tumor grade and size are associated with recurrence-free survival in duodenal neuroendocrine tumors. When feasible, a less aggressive surgical approach to treat low-grade and low-stage duodenal NETs should be considered.     

Parenchyma-Sparing Resections for Pancreatic Neuroendocrine Tumors

Background

Parenchyma-sparing pancreatectomy (PSP), including enucleation and central pancreatectomy, has been investigated as an alternative to standard resection for pancreatic endocrine neoplasm, but the benefit/risk of these procedures remains little known.

Methods

From 1998 to 2010, among 197 patients operated for well-differentiated pancreatic neuroendocrine tumors, 67 underwent PSP (45 enucleations and 22 central pancreatectomies) and 66 standard resections (35 pancreaticoduodenectomies and 31 distal pancreatectomies) for a tumor below 4?cm, without synchronous distant metastasis. Groups were compared regarding postoperative morbidity, mortality, long-term pancreatic function, and survival calculated using the Kaplan?CMeier method.

Results

Tumors operated by PSP had a median size of 15?mm, were mainly incidentally diagnosed (n?=?46, 69?%), and nonfunctioning (n?=?55, 82?%). Overall morbidity rate was higher after PSP than standard resection (SR) (76 vs 58?%, p?=?0.0028), including more frequent pancreatic fistulas (69 vs 42?%, p?=?0.003). Postoperative diabetes was less frequent following PSP than pancreaticoduodenectomy (5 vs 21?%; p?=?0.022) but equivalent to the one observed after distal pancreatectomy (4?%, p?=?1). Exocrine insufficiency was significantly less frequent after PSP than SR (3 vs 32?%; p?<?0.0001). The overall and recurrence-free 5-year survival after PSP for nonfunctioning tumors was 96 and 98?%, respectively.

Conclusion

In selected patients, with small and low-grade tumors, PSP are associated with excellent overall and recurrence-free survivals. These procedures are associated with an increased postoperative morbidity but an excellent postoperative pancreatic function. Therefore, they should be considered as a valid therapeutic option in selected well-differentiated pancreatic neuroendocrine tumors.     

Nuclear Medicine Applications for Neuroendocrine Tumors

Sensitive, specific radiopharmaceuticals are available for scintigraphic diagnosis and internal radiotherapy of neuroendocrine tumors. ¹²³I-MIBG (metaiodobenzylguanidine) scintigraphy is the examination of choice for visualizing tumor sites of pheochromocytoma. In the event of malignant pheochromocytoma or carcinoid tumor, this examination allows assessment of the presence or absence of tumor uptake and can guide radiotherapy with ¹³¹I-MIBG. The peptides secreted by neuroendocrine tumors can be radiolabeled for targeting of their specific receptors. Scintigraphy using a ¹¹¹In-labeled somatostatin analog (octreotide) is the examination of choice for diagnosis of the spread of gastroenteropancreatic and carcinoid tumors, as it is more sensitive than morphologic imaging techniques. It can also guide radiotherapy performed with the same pharmaceutical vector. These same two agents (MIBG and octreotide) can be used therapeutically by replacing ¹²³I with ¹³¹I and ¹¹¹In by ⁹⁰Y. A transient palliative effect is obtained for a variable number of tumors (most often large ones) that take up the radiopharmaceutic agent well. There is general consensus that, for relatively radioresistant solid tumors, this type of radiotherapy is efficient only in the event of small tumor targets (a few millimeters in diameter) whose uptake is maximal, allowing more homogeneous distribution than that achieved with large tumors. Thus for optimal control of the disease it is recommended first to use scintigraphic imaging to confirm that the tumor takes up the radiopharmaceutical agent in question (¹²³I-MIBG or ¹¹¹In-octreotide) and then reduce the tumor burden surgically before injecting high therapeutic activity (possibly with reinjection of peripheral stem cells). This treatment can be repeated three times every 3 months before evaluating the response. In these conditions, internal radiotherapy can be beneficial or even determinant for controlling disease progression.