Physical Address
304 North Cardinal St.
Dorchester Center, MA 02124
Hepatic metastasis from neuroendocrine cancers
Overview
The liver is the most common site of metastasis for all neuroendocrine neoplasms and second only to regional lymph nodes as the dominant site of metastases from all gastrointestinal (GI) tract malignancies. In patients with neuroendocrine liver metastases (NELMs) the cause of death is from local progression in the liver resulting in liver failure. The progress made and the accumulated experience documenting the survival potential of hepatic resection for selected patients with colorectal metastases has driven the investigation of this approach for other malignancies metastatic to the liver; there are fundamental biological differences in neuroendocrine tumors (NETs), and evidence for a similar approach in NELMs has not yet been proven. As yet, no randomized prospective data (or level 1 evidence) has evaluated liver-directed therapies (resection, transplantation, ablation, intra-arterial therapy) for patients with NELM. Consensus guidelines have been developed, ; however, because of a paucity of level 1 data, recommendations have weak evidentiary support and appropriate patient selection for the various therapies continues to be debated. Clinical decisions therefore are based on experience, and guidelines are based on a lower level of evidence. Published data also originate in high-volume centers of excellence, and the generalizability is not proven. The role of the multidisciplinary team (MDT) is essential in individualizing patient care.
The recent advances in imaging have been valuable in both the morphologic and functional characterization of the disease. Contrast-enhanced ultrasound (US), contrast-enhanced dynamic computed tomography (CT), and magnetic resonance imaging (MRI) with diffusion-weighted imaging and liver-specific contrast have improved the diagnosis and characterization of NELM (see Chapter 15 ). Isotope scanning with positron emission tomography (PET)/CT has progressed significantly and become the standard against which other modalities will be compared (see Chapter 18 ).
Despite the absence of level 1 data, accumulated clinical experience suggests that cytoreduction through liver-directed therapies is beneficial for symptom control and survival. Furthermore, cytoreduction has been demonstrated to be safe (see Chapter 101 ).
Liver-directed therapy of NELM is appealing because GI NET has a route of metastatic dispersal similar to colorectal metastases, through the portal venous system; moreover, the natural history of NETs is typically prolonged compared with other GI tract malignancies and, in fact, with other solid tumors. Initial experience with hepatic resection for metastatic NET suggested that patients might benefit in terms of survival and symptom relief from clinical endocrinopathies when antihormonal and antineoplastic therapies were ineffective. In addition to the prolonged natural history of NET and the clinically significant endocrinopathies, several other observations have supported further assessment of liver-directed therapies: (1) the prolonged presence of intrahepatic disease before evidence of extrahepatic progression, (2) the impression that the severity of clinical endocrinopathy correlates with the intrahepatic volume of metastatic disease, (3) the resectability of the primary and regional NET despite metastatic disease, and (4) the presence of normal, nonmetastatic liver. Finally, it is important to note that much of the experience quoted in this chapter has not incorporated the newer classifications, including grade and differentiation, into the analysis of the data. This is common in the studies evaluating the use of systemic therapies, including targeted therapies, peptide receptor radionuclide therapy (PRRT), and somatostatin analogues (SSAs) (see Chapter 65 ). The use of the classification system facilitates the understanding of the different first-, second-, or third-line therapies in the development of treatment algorithms. This chapter details the clinical data supporting liver-directed therapy for NELM and presents the current outcomes for resection, transplantation, and intraarterial, ablative, and systemic therapies for NELM.
Classification of gastroenteropancreatic neuroendocrine tumors
Most NELMs are of GI or pancreatic origin, so-called gastroenteropancreatic (GEP) tumors (see Chapter 65 ).
The GEP NETs have been divided into two broad types: functional and nonfunctional, either of which may or may not be associated with hormone production that causes a clinical endocrinopathy. Regardless of origin, NETs are similar histopathologically. Many histologic and morphologic features are shared by both benign and malignant tumors. Importantly, only the confirmed presence of metastases confers an unequivocal diagnosis of malignancy.
Clinical behavior for NETs has ranged from an indolent to an aggressive clinical course with rapid cancer progression and death. For GEP NETs, two classification schemes have been used. , Broadly, these classifications stratify patients with malignant GEP NETs into low-grade (well-differentiated) or high-grade (poorly differentiated) NETs (World Health Organization [WHO] classification). In 2017 the WHO revised the classification system, which emphasizes the proliferation index and the tumor differentiation. In general, only patients with liver metastases from well-differentiated (low-grade) NETs, rather than poorly differentiated (high-grade) NETs, are approached surgically. Limited evidence is emerging suggesting that there may be a role for surgery in poorly differentiated NELMs.
The tumor-node-metastases (TNM) staging has been described, which correlated with survival. Another classification system is based on the number and extent (or pattern) of hepatic metastases identified on radiologic imaging: a single metastasis (type I) of any size or location, an isolated metastatic bulk accompanied by smaller lesions (type II), and disseminated metastatic spread through both liver lobes (type III) ( Fig. 91.1 ). The three groups reportedly differ significantly in regard to tumor-related characteristics and help determine a therapeutic approach that correlates with long-term survival. The published guidelines by the North American Neuroendocrine Tumors Society highlight the importance of a uniform approach to pathology reporting. This is especially relevant regarding differentiation and grade of individual tumors, which have a major impact on prognostication and choice of therapy.
GI NETs produce a variety of proteins and peptide hormones. , Almost all NETs are positive for neuroendocrine markers chromogranin A and neuron-specific enolase. The serum levels correlate poorly with prognosis ; however, they are useful for clinical follow-up. , Pancreatic NETs (pNETs) produce a wide variety of one or more peptides: gastrin, insulin, glucagon, and vasoactive intestinal polypeptide, among others. , Nonfunctional pNET implies the production of an inactive peptide or subclinical hormone or no peptide production.
Small intestinal carcinoids
Small intestinal carcinoids represent the most common GI carcinoid tumor and metastasize to the liver not infrequently.
It is important to recognize carcinoid heart disease in patients with GI carcinoids undergoing evaluation for resection. Approximately 20% of patients with carcinoid syndrome will have clinically evident carcinoid heart disease, and an even larger proportion will have occult heart disease detectable by echocardiography. The confirmation of carcinoid heart disease requires a thorough cardiac evaluation. The major consequence of carcinoid heart disease is the presence of right heart failure and the elevated systemic venous pressures that can cause a pulsatile liver (implying hepatic vein pressures >25 mm Hg), which precludes hepatic resection. The presence of clinically significant carcinoid heart disease dictates medical treatment, and occasionally valve replacement, before resection of the primary small intestinal carcinoid and the NELMs. Survival after surgical repair of carcinoid heart disease is improved compared with medical treatment, even without surgical treatment of hepatic metastases. Some patients may be candidates for hepatic resection after repair of carcinoid heart disease, depending on objective decreases in systemic venous hypertension and the degree of functional cardiac improvement. , Conversely, hepatic resection has been associated with decreased cardiac progression of the carcinoid heart disease and improved prognosis.
Any patient with carcinoid syndrome requires preoperative and intraoperative SSA therapy to prevent a carcinoid crisis, a clinical syndrome of life-threatening intraoperative hypotension or hypertension and severe flushing with or without concurrent bronchospasm or arrhythmias. To date, the frequency and factors predictive of this perianesthetic complication remain unknown. Prevention is essential, and appropriate treatment should be prescribed in all patients undergoing intervention for metastatic carcinoid tumors. Short-acting analogues are preferred, even if the patient has received the long-acting analogue within 30 days. Management should consist of subcutaneous short-acting SSA therapy immediately preoperatively, followed by intravenous infusion of the SSA throughout the operation and continued administration in the early postoperative period. Additional intraoperative increases in SSA infusion rates are appropriate for unexplained intraoperative hemodynamic instability.
The 5-year survival for localized small intestinal carcinoid ranges from 78% to 93% and in metastatic disease decreases to 19% to 38%.
Pancreatic neuroendocrine tumors
An aggressive operative approach is generally warranted for pNETs (see Chapter 65 ). , Resection remains the treatment of choice for patients with localized NET of the pancreas and for selected patients with hepatic metastases. Resection of the primary NET and the regional lymph nodes is generally possible despite their often large size. The extent and type of pancreatectomy is dictated by the site of the primary NET; pancreatoduodenectomy is used for NETs of the head of the pancreas (see Chapters 117A and 127C ) and distal pancreatectomy/splenectomy for NETs of the body and tail of the pancreas (see Chapters 117B and 127B ). Alternatively, enucleation may be used selectively for small (<1–2 cm) superficial NETs. For patients with NETs invading adjacent structures or the GI tract, en-bloc resection is recommended. Laparoscopic pancreatectomy currently is applicable for resection of many pNETs. , Concurrent laparoscopic resection of the primary pNET and hepatic metastases may be feasible selectively. Concurrent resection of primary pNET and hepatic metastases can be performed safely, although staged resections may be preferable, particularly in patients with involvement of the head of the pancreas, to avoid the development of hepatic abscesses. Overall actuarial 5-year survival rates for pNETs range from 45% to 63%, with a median survival of about 4 years.
Epidemiology of neuroendocrine tumors
NETs are more common in woman than in men and are associated with a high socioeconomic status. Localized disease has the best prognosis, with 5-year survivals ranging between 78% and 93%. In metastatic NETs the 5-year survival is poor, at 19% to 38%, although survival has increased in the last two decades. , , This improvement in survival is likely due to refinement in surgical techniques and newer novel targeted agents that have been introduced into the management of these tumors. NETs metastatic to the liver have the worst prognosis. Poorly differentiated NETs and rapidly progressive NELMs (>25% volume increase on two consecutive CT scans within 3 months) negatively affected survival. Until now, no series of liver resections has reported the proliferation index, the differentiation and the degree of liver involvement, which makes it difficult to ascertain the overall survival in each category within the WHO 2017 classification.
The Surveillance, Epidemiology, and End Results (SEER) database showed that 27% of NETs at presentation were associated with distant metastases. This is in contrast with European databases, which show that distant metastases are present in 44% to 73% of patients presenting to specialized centers. Metastases are generally found in the liver and lymph nodes and in less than 15% of patients, metastases are found in the bones. However, bony metastases are generally grossly underestimated because of the lack of adequate imaging.
Overall the metastatic potential of NETs is lower than that of adenocarcinomas. Similar to that of carcinoid tumors, the 5-year survival of patients with pNETs ranges from 30% to 40%, with a median survival of approximately 40 months. Up to 75% of patients who present with midgut or hindgut tumors are likely to have liver metastases, in particular, the nonfunctioning group and those with a pancreatic primary tumors (likely to be high grade) have the highest rate of liver involvement. In a series of 35 patients with hepatic metastases, 60% of which were metastatic gastrinomas, the 5-year survival was approximately 70%. With more than 75% tumor replacement the 5-year survival was only 24%, whereas 5-year survival approached 80% for less than 50% tumor replacement.
Radiologic assessment of neuroendocrine liver metastasis
The radiologic assessment of NELMs is essential in diagnosis planning and management. There is an increasing need to individualize patient care and make clinical decisions based on guidelines; therefore the information from the radiologic assessment is important for the MDT evaluation (see Chapters 15 and 18 ). It is important to establish the site, number, and extent of lesions, as well as the relationship to the vasculature and biliary structures. As with any liver resection, the future liver remnant must be determined (see Chapter 102 ). Imaging is important in determining the pattern of liver disease because this affects treatment decisions and also may have prognostic value. Three patterns of liver disease are described (also mentioned under the classification section, see Fig. 91.1 ). The simple, or type I, pattern refers to a single liver metastasis of any size and location, the complex, type II, pattern refers to a bulk of disease in one liver lobe with smaller lesions in the other lobe, and the diffuse, or type III, pattern describes disseminated multifocal spread through both liver lobes. Type III represents the majority (70%–80%) of patients who are also not candidates for curative hepatectomy. There are two broad groups of investigations: anatomic and functional imaging. US and contrast-enhanced CT (CECT) are predominantly anatomic, and MRI can combine both. Radioisotope scanning is functional imaging, but the addition of high-quality PET/CT can provide some anatomic detail.
Ultrasound
The appearance of NELM on US is variable and ranges from a hypoechoic to hyperechoic lesion, although a mixed type is more common (see Chapter 15 ). A central cystic appearance also may be present. Even though the hypervascular nature of these lesions can be demonstrated on color Doppler, this is best demonstrated with contrast-enhanced US (CEUS). CEUS can also identify lesions not usually seen on US; however, it is currently not available for routine use.
Contrast-enhanced computed tomography scanning
CECT has been the routine cross-sectional imaging modality of choice for NELMs, but this is changing (see Chapter 15 ). Not only will CECT identify more lesions than CEUS but it is also very useful in elucidating the vascular anatomy. Because of the hypervascular nature of the NELM, multiphase contrast CT is indeed essential.
Magnetic resonance imaging
MRI is rapidly becoming the imaging modality of choice for NELMs because it combines morphologic identification with some functional modalities (see Chapter 15 ). Using hepatic arterial-phase and fat-suppression T2-weighted images, more lesions are identified than with CECT, particularly lesions smaller than 5 mm. Diffusion-weighted MRI (DWI) and liver-specific contrast use the biologic nature of NETs and the physics of DWI combined with apparent diffusion coefficient mapping to enhance the ability of this imaging modality to identify more lesions in the liver.
Radioisotope scanning
The technology of radioisotope scanning in imaging NELMs has evolved over a relatively short period (see Chapter 18 ). Using the presence of somatostatin receptors (SSTRs) on the tumor cell surface, especially SSTR subtype 2, octreoetide radiolabeled scanning, or the octreoscan, was introduced to identify and functionally characterize NETs. Unfortunately the early technology suffered from poor image quality and spatial resolution. Nonetheless, over the past two decades numerous chelator-conjugated SSAs were developed, specifically DOTA-conjugate peptides such as DOTA-TATE, DOTANOC, and DOTATOC ( Fig. 91.2 ) These short amino acid–chelator conjugates demonstrated a greater affinity for the SSTR compared with that of an octreoscan. DOTA agents can be labeled with gallium-68 ( 68 Ga), a generator-eluted positron emitter that enables PET imaging and thus provides improved image quality and spatial resolution. 68 Ga-DOTA–conjugated somatostatin binds SSTR-expressing tumors and can identify lesions with a resolution of less than 5 mm. These 68 Ga-conjugated radiopharmaceuticals have become the reference standard imaging modality for NELM with a sensitivity of 82% to 100% and a specificity of 67% to 100% in low-grade NETs. In addition, it may identify extrahepatic disease (sensitivity and specificity 85%–96% and 67%–90%, respectively) especially subcentimeter bone metastasis in low-grade NETs. ,
This modality has been shown to alter the treatment decisions in up to 60% of patients by escalating or deescalating treatment options. , In a recent systematic review and meta-analysis that reported on a total of 1561 patients, change in management occurred in 44% (range, 16%–71%) of NELM patients after SSTR PET/CT. In a subgroup who had an initial indium-111 octreoscan, after the addition of an SSTR PET/CT, the information led to a change in management in 39% (16%–71%), demonstrating the superiority of the PET/CT.
There is some suggestion that the use of dual imaging with both 68 GA-DOTA and 2-[ 18 F]fluoro-2-deoxy-D-glucose (FDG)–PET/CT may have the benefit of identifying high-grade lesions with Ki67 greater than 10%, the latter of which may have a reduced expression of SSTRs and therefore better identification by FDG, which will, in turn, predict worse prognosis. 18 F-FDG-PET provides complementary diagnostic information and is of value for NET patients with negative SSTRs findings or a high proliferation index. 68 Ga-somatostatin receptor PET/CT should therefore be used in grade 1/2 NETs. 2-[ 18 F]fluoro-2-deoxy-D-glucose (FDG)-PET/CT can be used to assess resectability of hepatic metastases in grade 2 NETs, and potentially in combination with 68 Ga-somatostatin receptor PET/CT.
There remains debate about the timing of SSTR scintigraphy in relation to the administration of SSA therapy. However, no recommendation is possible based on the current evidence.
The choice of imaging modality has significant ramifications for treatment decisions in some NELM patients. Having enough imaging data may influence the correct choice of treatment or even the extent of treatment. The combination of morphologic and functional imaging is crucial in decision making. Given the current value of peptide receptor radioisotope therapy in treatment, as defined by the Netter 1 trial, such functional imaging becomes even more essential when planning therapy.
You're Reading a Preview
Become a Clinical Tree membership for Full access and enjoy Unlimited articles
If you are a member. Log in here