The overall management of GEP-NETs is summarized in Figure 1 [4]. The goals of initial evaluation are the diagnosis of GEP-NETs, localization of the tumor, and staging [1]. Approximately 15–30% of GEP-NETs are functioning tumors with hormone-related symptoms, and 70–85% of GEP-NETs are nonfunctioning and detected incidentally or because the patient has symptoms of local mass effect or metastasis [1]. Once GEP-NETs are suspected, laboratory and imaging examinations are performed systematically as summarized in Table 2. Multiphasic contrast-enhanced abdominal and pelvic CT or MRI is recommended for all patients with suspected GEP-NETs [4]. Endoscopy or endoscopic ultrasound evaluation is recommended as appropriate for detection of GEP-NETs of the stomach, duodenum, and rectum. An octreotide scan can be used as the first imaging tool, especially in cases in which CT or endoscopic ultrasound findings are inconclusive [3, 4]. Fluorine-18–labeled FDG PET/CT can be used for evaluation of high-grade tumors, but the applicability of FDG PET/CT to low-grade GEP-NETs is limited because of the lower metabolic activity of low-grade tumors. Thus the 2012 NCCN guidelines do not include PET/CT for this purpose [8]. Pathologic diagnosis and grade determination are essential in the management of GEP-NETs. Imaging-guided biopsy of the primary tumor or metastatic sites should be performed if possible [3].

In the initial evaluation of GEP-NETs, it is crucial to divide resectable locoregional tumors from unresectable locoregional and metastatic tumors because the management and prognosis of the two categories differ markedly [9]. Imaging plays an important role in this determination. The seventh edition of the American Joint Committee on Cancer TNM staging system is used [10]. NETs of the stomach; duodenum, jejunum, and ileum; colon and rectum; and appendix have separate staging systems, and pancreatic NET shares the staging system with pancreatic adenocarcinoma [11].

For locoregional GEP-NETs, the primary goal is complete surgical resection, which can have an excellent outcome [4, 12]. For peripherally located small pancreatic insulinomas and gastrinomas, enucleation may be considered, but for most other GEP-NETs and deep-seated tumors, conventional pancreatectomy is recommended. For most NETs of the bowel, conventional surgical bowel resection should be considered. At times, endoscopic resection may be considered for small localized tumors in the stomach and rectum. Regional lymphadenectomy is recommended because GEP-NETs are associated with risk of nodal metastasis, even of small tumors [4, 13].

The management of unresectable and metastatic GEP-NETs is complex and continues to evolve. The most common site of distant metastasis is the liver (85%), followed by peritoneum (18%), bones (8%), and lungs (4%) [14]. For patients with limited metastatic (mostly liver) disease and resectable primary tumor, surgical resection of both metastatic and primary tumors should be considered first if complete resection is possible. For asymptomatic low-volume disease with an indolent course, observation or octreotide treatment is recommended with surveillance until clinically significant disease progression occurs. In cases of significant tumor-related symptoms, tumor burden, or disease progression, several options can be considered, including MTT (everolimus or sunitinib), cytotoxic chemotherapy, octreo-tide, and liver-directed therapy (chemoembolization or radioembolization, ablative therapy, or cytoreductive surgery) [4, 9] (Table 3).

In the 2012 NCCN guidelines, MTTs were added to the recommended treatment of unresectable and metastatic pancreatic NETs with category 2A evidence (Table 3). MTTs for unresectable and metastatic NETs in gastrointestinal tract, however, were recommended with category 3 evidence. Liver-directed therapies require category 2B evidence for treatment of clinically significant hepatic metastases from GEP-NETs [4]. Considering these evidence levels, the use of MTTs for pancreatic NETs, either alone or in combination with other therapies, will continue to increase. Radiologists, as part of multidisciplinary teams, should understand these trends in clinical management and be familiar with the various therapeutic modalities and the effects of these treatments on imaging findings.

The expression of somatostatin receptors (SSTRs) is a unique characteristic of NETs that enables targeted therapy and functional imaging. Somatostatin is a peptide that binds SSTRs and stimulates hormonal activity [6]. The expression of SSTR is especially elevated in well-differentiated NETs in comparison with poorly differentiated neuroendocrine carcinomas [15, 16]. Octreotide, which targets SSTRs, has been used to control hormone-related symptoms since FDA approval in 1987 (Fig. 2). The once-monthly long-acting depot (also called long-acting repeatable [LAR]) form of octreotide approved by the FDA in 1997 is widely used [11]. Lanreotide, another somatostatin analogue targeting SSTR, is similar to octreotide in clinical efficacy. Several studies [17–19] have shown that in addition to controlling the effects of hormonal symptoms, octreotide has tumor-stabilizing effects. According to results of the Placebo-Controlled, Double-Blind, Prospective Randomized Study on the Effect of Octreotide LAR in the Control of Tumor Growth in Patients With Metastatic Neuroendocrine Midgut Tumors (PROMID), the use of octreotide can have a survival advantage for patients with metastatic midgut carcinoid tumors [19].

Peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogues adds therapeutic radiation effects to somatostatin analogues and is an effective option in therapy for unresectable and metastatic GEP-NETs. Since 1992, when the first PRRT was administered with ¹¹¹In-labeled octreotide, PRRT agents such as ⁹⁰Y-labeled octreotide and ¹⁷⁷Lu-labeled octreotide have been developed. As of this writing, PRRT is not available in the United States [20].

The goal of MTT is inactivation of overexpressed or overactivated signaling cascades to inhibit tumor growth and various functions of tumors by targeting growth factors, growth factor receptors, receptor tyrosine kinases, and intracellular signaling cascades [8]. Several growth-promoting targets are overexpressed in GEP-NETs, including vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), and insulinlike growth factor 1 receptor (IGF-1R). The phosphatidylinositol-3′-kinase (PI3K)–Akt–mammalian target of rapamycin (mTOR) and the Ras–Raf–mitogen-activated protein extracellular signal-regulated kinase (MEK)-Erk1/2 intracellular signaling pathways are also important regulators of survival and proliferation of GEP-NETs activated by various growth factors [18] (Fig. 3).

Sunitinib is a multitargeted tyrosine kinase inhibitor with activity against VEGFR, PDGFR, c-Kit, and Flt-3. Everolimus is an mTOR inhibitor blocking the PI3K-Akt-mTOR signaling cascade (Fig. 3). Both everolimus and sunitinib have been confirmed to have anti-tumor activity and to improve progression-free survival among patients with advanced pancreatic NETs [3, 4]. In addition, many targeted agents, such as bevacizumab, temsirolimus, imatinib, and sorafenib, are being investigated in clinical trials.

Streptozocin-based chemotherapy for the treatment of pancreatic NETs was approved by the FDA in 1982. Streptozocin with 5-fluorouracil is still an effective option for unresectable and metastatic pancreatic NETs (category 2A), especially grade 2 tumors [11]. Commonly used regimens are streptozocin with 5-fluorouracil or doxorubicin, temozolomide with capecitabine, and cisplatin with etoposide [18]. However, cytotoxic chemotherapy has minimal benefit in the management of unresectable and metastatic gastrointestinal NETs (carcinoids) and is recommended if there is category 3 evidence (i.e., no other option is feasible) [4, 11].

Liver-directed therapies are cytoreductive surgery, ablative therapy (radiofrequency ablation, cryotherapy, microwave ablation), and transarterial embolization (TAE) therapy (chemoembolization, radioembolization). These therapies are recommended to patients with liver-predominant metastatic disease [4]. The rationale of these therapies is that aggressive debulking of the hepatic metastatic tumor volume has survival benefits despite the risks of invasive procedures and recurrence after treatment [21].

When surgery seems unfeasible or a patient has inoperable disease, ablative therapy may be considered if there are fewer than five liver metastatic lesions and they are smaller than 5 cm [22]. Repeated sessions of TAE therapy may be considered for patients with widespread liver metastases [18]. Although many protocols of TAE therapy have been reported in uncontrolled series, no single protocol shows confirmed superiority. Radioembolization with ⁹⁰Y microspheres has been developed to combine a profound embolization effect with an internal radiation therapeutic effect. Currently, ⁹⁰Y microspheres are approved as a medical device for the treatment of patients with liver metastases from colon cancer or unresectable hepatocellular carcinoma (HCC). The superiority of radioembolization over TAE has not been proved [18].

The common and expected imaging response pattern of metastatic GEP-NETs to somatostatin analogues is stable disease with no unequivocal changes in tumor size or morphologic and enhancement patterns because of the indolent course of GEP-NETs and tumor-stabilizing effect of octreotide [25]. Octreotide occasionally causes mild reduction of tumor burden (Fig. 4). The common response pattern of metastatic GEP-NETs to cytotoxic chemotherapeutic regimens is a decrease in the size of the tumor or necrosis, which is identical to that of conventional chemotherapy (Fig. 5). Progression of disease during octreotide or cytotoxic chemotherapy is seen as an increase in the size or number of metastatic lesions.

GEP-NETs are primarily hypervascular tumors related to overexpression of VEGFR or PDGFR pathways. Sunitinib directly targets receptor tyrosine kinases of VEGFR and PDGFR; everolimus targets the common signaling cascades of these pathways; and both act as cytostatic agents [8]. Therefore, the typical CT response pattern to these targeted agents is a decrease in tumor attenuation and enhancement with treatment and a stable to mild decrease in tumor size. However, various treatment response patterns are frequently encountered, especially during assessment of the treatment response of liver metastatic lesions at contrast-enhanced CT. In our experience, there are three representative atypical response patterns and a feature of atypical progressive disease [28] (Table 4).

Increase in size with decrease in density—Sometimes tumors have decreased density suggestive of response to treatment but have increased size, which may lead to misinterpretation of tumor progression according to size criteria [27] (Fig. 6). These changes may be attributed to cystic change, intratumoral edema, or visualization of previously unidentified portions of isodense tumor [28].

Increase in size with increase in density—MTTs with antiangiogenic action sometimes cause intratumoral hemorrhage, which can result in an increase in density with a variable size change. If tumor size and density are increased by hemorrhage (usually earlystage hemorrhage), accurate interpretation of treatment response is difficult and may be confused with progression, even when new criteria such as the Choi criteria and mRECIST are used. Useful hints suggestive of intratumoral hemorrhage are intratumoral fluid-fluid levels and internal changes in tumor architecture (e.g., a homogeneous lesion becomes heterogeneous) (Fig. 7). Intratumoral hemorrhage can be confirmed with additional imaging with unenhanced CT or MRI. Earlystage intratumoral hemorrhage manifests itself as hyperattenuation on unenhanced CT images and hyperintensity on T1-weighted MR images. These lesions usually have decreased size and density at follow-up imaging but sometimes exhibit fluctuation in size and density due to recurrent or intermittent hemorrhage [28].

Appearance of previously inconspicuous liver lesions—Sometimes isodense hepatic metastasis unidentified because of lack of contrast with normal parenchyma at baseline can be revealed as new low-attenuation lesions after treatment with MTTs (Fig. 8). These seemingly new lesions tend to further decrease in size and density on follow-up images. This is a potential pitfall that frequently leads to misinterpretation of progressive disease (pseudoprogression) and premature cessation of the current regimen, which is actually effective [28].

Atypical but true tumor progression—Atypical but true tumor progression can manifest itself as a new intratumoral nodule or nodules, increased tumor attenuation, or reappearance of rim enhancement without an increase in the size of the lesions [27] (Fig. 7).

If there is uncertainty in characterizing the treatment response pattern or if an atypical treatment response is suspected, radiologists in concert with referring oncologists should use all available imaging and clinical information for the most comprehensive treatment assessment. We should also consider the overall trend of response pattern [28]. If the pattern is mixed, in which most of the masses have decreased size and density and a few masses have grown or increased in density, then the findings of increased size or density may well represent an atypical response to MTT. In the case of pseudoprogression of liver metastasis, it is helpful to correlate the response pattern with tumors outside the liver. For example, if an extrahepatic lesion such as a primary tumor or lymph node metastatic lesion has decreased in density or size, we should consider the possibility of pseudoprogression when evaluating newly apparent liver lesions. Clinical and biochemical correlation is also helpful in cases of atypical response patterns. Tumor markers in blood (chromogranin A) and urine (5-hydroxyindoleacetic acid) are frequently used in monitoring treatment response. If there are no immediate management-related implications, reassessment at follow-up imaging in 6–12 weeks can be an alternative means of assessing response, depending on the clinical circumstances, because NETs are generally indolent or slowly progressing tumors [28].

The response patterns of GEP-NETs to ablative or TAE therapy are identical to those of HCC and liver metastasis from colon cancer in that the treated portions of tumors exhibit complete or partial devascularization (lack of contrast enhancement), and residual or recurrent tumors are solid enhancing nodules or masses [29]. For quantitative response criteria, the European Association for the Study of the Liver (EASL) guidelines for assessment of locoregional HCC treatment can be used. In these guidelines foci of tumor enhancement on CT or MR images are considered viable, whereas nonenhancing regions reflect tissue necrosis. The EASL guidelines define complete response as the absence of enhancing areas; partial response as a greater than 50% decrease in the enhanced areas; progressive disease as a greater than 25% increase in the size of a single, measurable lesion or the appearance of new lesions; and stable disease as a tumor response between partial response and progressive disease [30].

An important radiologically evident adverse event in octreotide therapy is biliary calcium secretion and gallstone formation, which can result in calculous cholecystitis and cholangitis [31]. Radiologists should monitor the presence of gallstones and associated biliary dilatation or inflammation in patients treated with octreotide.

Somatostatin analogues are administered by subcutaneous injection (short-acting octreotide) or intramuscular injection (long-acting octreotide depot form). Octreotide injection can cause subcutaneous or intramuscular nodular opacities and accumulation of intralesional air in the anterior abdominal wall or gluteal area depending on the injection site. Local hemorrhage and, rarely, abscess formation can occur at the injection site, especially intramuscular injection sites of the long-acting octreotide depot form (Fig. 9).

In patients treated with cytotoxic chemotherapy, the radiologically evident drug toxicities are related to immunosuppression and include opportunistic infections and neutropenic colitis. Oral agents such as temozolomide can cause enterocolitis related to the route of administration [32].

In patients with GEP-NETs treated with sunitinib or everolimus, some overlapping and some separate radiologic patterns of drug toxicities are encountered (Table 4). Both sunitinib and everolimus have antiangiogenic activity and share toxicities related to ischemia and endothelial injury [32, 33]. Bowel complications such as ischemic colitis, pneumatosis intestinalis, and bowel perforation can occur as consequences of bowel-wall ischemia (Fig. 10). Less commonly, cholecystitis occurs as a consequence of gallbladder ischemia. Arterial and venous thromboembolic events also occur as a result of endothelial injury in patients treated with sunitinib. Noninfectious pneumonitis occurs in 2–36% of patients treated with everolimus (Fig. 11). This complication is dose dependent and is graded 1–4 [34]. These drug toxicities can be fatal when they are unrecognized and MTTs are continued. Early recognition by radiologists is extremely important for prompt management and to minimize complications [32].

The complications of TAE and ablative therapies, including abscess, cholangitis, cholecystitis, hemorrhage, and injury to adjacent organs, are well established and have been extensively reviewed [29, 30]. In case of transarterial radioembolization for liver metastasis, local radiation effects lead to peripheral ring enhancement around the radioembolized tumor. This enhancement may be incorrectly ascribed to disease progression of hypervascular metastasis. Additional MRI or reassessment with follow-up CT can be helpful [30].