Staging and Classification
Multiple classification and grading systems have been proposed over the last few decades in an effort to better categorize NETs according to their clinical behavior; these have emphasized grade and differentiation. The older systems have been refined into the current grading classifications (Table 2) and TNM staging systems, including those adapted by the European Neuroendocrine Tumor Society (ENETS) in 2006, by the American Joint Committee on Cancer (AJCC) in 2009, and by WHO in 2010.
Although there has been significant progress in refining NET staging, the current systems are not perfect. Several authors have questioned whether poorly differentiated neuroendocrine carcinomas (NECs) and high-grade tumors are equivalent. Using the current staging system, a subset of patients may be classed as grade 2 on the basis of mitotic rate but have a high proliferation rate ( Ki-67 index ≥ 20%), typically associated with grade 3 disease; the behavior of such grade-discordant tumors is not well understood. For the most part, discordant tumors fall into a gray zone for which there are few data regarding treatment, with additional research needed to clarify optimal therapy.
Patients with poorly differentiated tumors (grade 3) may be further stratified on the basis of whether their Ki-67 index is between 20% and 55% or is > 55%. Patients with a Ki-67 index > 55% have a worse prognosis but respond to cisplatin-based chemotherapy for a longer period. Future staging strategies may need to account for heterogeneity in poorly differentiated NECs.
The only known cure for functional or nonfunctional PNETs is surgical resection. Unfortunately, most patients present with or develop advanced disease, for which the goal of treatment is often longevity with quality of life. Tumor functionality, grade, and stage are factors that help determine which of the various treatment options may be considered in patients with PNETs (Figure 2). Several treatment options exist for advanced PNETs, although the optimal sequence of therapies has not been well established. At times, observation may be prudent. Treatment of patients with advanced disease is usually multimodal. Details regarding the treatment of poorly differentiated NEC will not be discussed here, except to say that chemotherapy is the mainstay of treatment, and that surgery is rarely indicated in these patients.
Surgical resection is the gold standard for all locoregional PNETs ≥ 2 cm. Even when major vascular construction is needed, surgical resection may often cure or prolong survival in patients with PNETs. For small tumors (< 2 cm), treatment remains controversial and includes formal oncologic resection, enucleation, or observation, depending on patient factors, location, grade, functionality, and risk of disease dissemination.
Oncologic resection. An oncologic resection is necessary for PNETs ≥ 2 cm and includes pancreaticoduodenectomy or distal pancreatectomy with or without splenectomy. Central pancreatectomy is not an ideal operation for PNETs, since the lymphatic drainage typically favors either the pancreatic head or tail.
For lesions < 2 cm, the risk of positive lymph nodes or disease dissemination remains an argument for an oncologic resection. Patients with positive lymph nodes do worse than those with negative nodes, with some studies suggesting a significant 10-year difference in median survival (4.6 vs 14.6 years, respectively), although this discrepancy remains controversial. While small (< 1.5–2 cm) PNETs may have positive lymph nodes at a rate of 12% to 13%,[35,36] some population-based studies have questioned the prognostic value of lymphadenopathy. Preoperative risk evaluation of lymph nodes is often unreliable and correlates poorly with tumor size[38,39]; therefore, factors associated with lymph node positivity, such as tumor location (head), high Ki-67 index, and lymphovascular invasion, should be considered in surgical planning.
Enucleation. A patient is an ideal candidate for enucleation when the pancreatic duct is not in close proximity to the tumor. In patients with functional PNETs that have low malignant risk, such as insulinomas or gastrinomas, enucleation is a treatment option when deemed surgically appropriate. In properly selected patients with small (< 2 cm) PNETs, risk of recurrence is low and oncologic outcomes are acceptable.[37,40] When possible, lymphadenectomy should be performed in patients undergoing enucleation for nonfunctional PNETs.
Observation. Studies comparing observation with surgical resection are difficult because of the indolent nature of PNETs. Retrospective studies are limited by selection bias and short follow-up. With these limitations in mind, it is fair to say that observation of patients with small PNETs does not lead to more recurrences.[41,42] Observation should be considered in patients with a low risk of disease dissemination who are at higher risk of dying from competing causes or whose risk from surgery outweighs the risk of disease progression.
PNETs most often spread to the liver, and disease recurs in the majority of patients even with complete resection. Therefore, treatment is often directed at slowing progression and minimizing symptoms. Liver treatment depends on the status of the primary tumor, the presence of extrahepatic disease, and the volume of liver disease. A combination of surgery, radiologic interventions, and systemic therapies can often alleviate symptoms and extend survival for several years (Figure 3).
Primary tumor resection. Primary tumor resection combined with neuroendocrine liver metastasectomy improves survival and symptomatology.[43,44] The role of primary tumor resection in patients with unresectable neuroendocrine liver metastases is less clear, and randomized trials are needed to evaluate the role of primary tumor resection in this setting.
While primary tumor resection for small bowel NETs with unresectable metastases may prevent mesenteric fibrosis, bowel obstruction, and malnutrition, primary tumor resection for PNETs with unresectable metastases is more controversial. Overwhelmingly, retrospective studies support primary tumor resection (Table 3), although there is no way to eliminate selection bias from these studies. The median survival in patients undergoing primary tumor resection ranges from 36 to 111 months compared with 12 to 52 months without primary tumor resection.[46-50] There appears to be a benefit from primary tumor resection whether or not liver disease is treated. It may be hypothesized that even nonfunctional PNETs secrete active agents, and that primary tumor resection decreases local symptoms while preventing further spread of tumor. Primary tumor resection should be considered even in patients with unresectable metastases when surgical morbidity is considered low in experienced hands.
Despite the potential benefits of primary tumor resection in metastatic PNETs, care should be taken when considering this approach in pancreatic head tumors. Hepatic abscesses occur in up to 50% of patients who undergo hepatic artery embolization (HAE) after pancreaticoduodenectomy. Hepatic abscesses in this setting can be difficult to treat and may potentially lead to death. In a recent discussion by a panel of experts, the majority agreed that in patients with neuroendocrine liver metastases, primary tumor resection should not be performed with pancreaticoduodenectomy; however, the majority would pursue primary tumor resection in patients with body/tail lesions.
Cytoreduction of liver metastases. The majority of patients with PNETs present with or later develop metastases. Liver failure is the leading cause of death in patients with liver metastases from PNETs, and treatment is often aimed at reducing tumor burden. It is not uncommon for patients with neuroendocrine liver metastases to have unresectable disease at diagnosis; however, surgery is likely underutilized, as only one in four patients undergoes resection.
Surgical rates have improved as surgical techniques have been refined. A shift toward parenchymal-preserving operations has led to a decrease in morbidity and mortality, with excellent oncologic outcomes even in patients with significant disease burden in the liver (Table 4). Parenchymal-preserving liver surgery is ideal for these well-encapsulated tumors, which are often amenable to enucleation (Figure 4). Nonanatomic resections in combination with ablation offer comparable oncologic results in small tumors.
Many surgeons have advocated for a 70% threshold[43,44] for cytoreductive liver surgery (ie, proceeding to surgery if cytoreduction to at least 70% is deemed possible) instead of the traditional and more stringent 90% threshold, maintaining that there is a survival benefit. Despite more advanced disease and a lower threshold for operating, contemporary surgical series report a 5-year overall survival (OS) rate of 74% to 80% with optimal surgical debulking and in combination with other therapies, in comparison with a historical 5-year OS rate of 40%.[43,56,57] Concomitant primary tumor resection is associated with a longer time to liver progression and improvement in median survival up to 159 months.[58,59] With these excellent data, resection of neuroendocrine liver metastases, with or without primary tumor resection, should be considered in all patients with metastatic PNETs.
Liver transplantation. Liver transplant may be considered for isolated neuroendocrine liver metastases; however, this is still not considered standard of care. While outcomes are promising, disease will recur in most patients.[60,61]
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