APUDoma

Etiology

APUDomas or APUD tumors arise from APUD cells which have the ability of amine precursors uptake and intracellular decarboxylation, before converting them into active amines, hence the name, amine precursor uptake, and decarboxylation cells. These cells were originally described by Pearse in the 1960s, to arise from the neural crest.[2] This was then disproven by the concept of the origin of APUD cells from multipotent stem cells before being implanted in different body organs, hence the diffuse endocrine system. Although the exact cause of NETs remains unknown, many risk factors such as smoking, genetic defects, and immunomodulation have been implicated.[3][4]

Epidemiology

More than half of NETs arise from the gastrointestinal tract and pancreas, while about 25% originate from the bronchopulmonary tree. Other primary sites include the thymus, breasts, prostate, and skin. The prevalence of NETs in the US is estimated to be about 171,321 persons in 2014, and the total incidence is 3.56 per 100,000 every year.[1] Because of the recent advances in diagnostic modalities, the incidence of newly diagnosed patients has been rising in the last 3 decades. In terms of ethnicity, the Black population has had a higher incidence than Whites.[5] It has also been noted that people with a history of the disease in a first-degree family member are 3 times higher likelihood of having NETs.[6]

Pathophysiology

Different genetic mutations have been associated with the pathogenesis and tumor progression of various types of NETs. For example, mTOR pathway genes are observed in more aggressive tumors with higher proliferative activity and are found in about 15% of pancreatic NETs. However, they are rarely found in carcinoid tumors.[7][8] Another important factor identified in tumor progression is increased vascularity due to overexpressing proangiogenic factors, such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF).[9]

Histopathology

NETs are typically distinguished into well-differentiated NETs and poorly differentiated neuroendocrine carcinomas (NECs), depending on morphology and clinical prognosis. Both groups share common neuroendocrine histologic features. Well-differentiated NETs are composed of small cells organized in islets, gyriform, and trabeculae, with finely granular cytoplasm, commonly referred to as "salt and pepper" chromatin pattern. On the other hand, poorly differentiated NECs usually appear as sheets of pleomorphic cells with irregular nuclei and less granular cytoplasm. Furthermore, neuroendocrine cells typically have neurosecretory granules. Measurement of these granules in the blood is used to determine the degree of differentiation of NETs, such as only chromogranins and synaptophysin are present in the gastrointestinal tract and pancreas, while chromogranin, synaptophysin, and CD56 (neural cell adhesion molecule) are present in the lung NETs.[10] 

Tumor grade corresponds to the proliferative activity of tumors, which is measured by the Ki-67 index, a protein found in the nucleus during cell replication, and/or mitotic activity. Low grade (G1) tumors have a mitotic rate from 0 to 1 per 10 high power fields (HPF) or a Ki-67 index of less than 3%. Intermediate grade (G2) tumors have a mitotic rate from 2 to 20 per 10 HPF or a Ki-67 index from 3% -20%, and high grade (G3) tumors have a mitotic rate more than 20 per 10 HPF or a Ki-67 index higher than 20%.[11] A recent classification has been introduced by WHO that distinguishes between well-differentiated (low grade, intermediate grade, or high grade) NETs and poorly differentiated (high grade) NECs.

History and Physical

NETs mostly arise sporadically, but they also may arise as part of inherited familial syndromes such as multiple endocrine neoplasia type 1 (MEN-1), which include neoplasia of the anterior pituitary, parathyroid glands, and pancreas. NETs might be symptomatic (functioning) or silent (non-functioning) depending on hormonal secretion. NETs can originate from different organs and from different cell types. Gastroenteropancreatic NETs (GEP-NETs) are subdivided into carcinoid tumors of the luminal GI tract and pancreatic NETs.

Carcinoid Tumors of the Luminal GI Tract

Many functioning NETs secrete massive amounts of vasoactive peptides and amines, including serotonin and tachykinins, into the blood, causing symptoms called carcinoid syndrome. Classic symptoms include flushing (63%–94%), diarrhea (68%–84%), abdominal pain (10%–55%), and bronchoconstriction (3% to 19%).[12] Carcinoid syndrome typically manifests in cases of hepatic or systemic metastasis because serotonin is metabolized in the liver before reaching the systemic circulation. Exposure of the heart to a high level of active peptides causes carcinoid heart disease, characterized by fibrous thickening of the endocardium.

Pancreatic NETs

Pancreatic NETs cause different variable clinical syndromes depending on the type of hormones secreted. For example, beta-cell neoplasm or insulinoma, the most common GI NETs, secretes excess insulin causing hypoglycemia, with the relief of symptoms after glucose administration (Whipple triad) and hypokalemia. Zollinger-Ellison syndrome is caused by gastrinoma secreting gastrin hormone characterized by multiple peptic ulcers in atypical sites such as the duodenum and jejunum, typically resistant to proton pump inhibitors, diarrhea, and abdominal pain. Glucagonomas produce excess glucagon hormone, typically cause diabetes, dermatitis (necrolytic migratory erythema), deep vein thrombosis, and depression. VIPoma produces excess vasoactive intestinal peptide associated with voluminous watery diarrhea (10–15 L/day) and flushing.[13]

Evaluation

The diagnosis of NETs depends on a thorough history, clinical examination, hormone levels, imaging, and histological confirmation. Carcinoid syndrome should be diagnosed initially using the measurement of 24-hour urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA), which is the metabolite of serotonin, or the plasma level of 5-HIAA,[14] with a sensitivity of 73% and a specificity of 100% in predicting the presence of a midgut NET.[15] Whereas patients who present with suspected pancreatic NET (pNET) should undergo measurement of the corresponding hormone levels, for example, measurement of fasting gastrin blood level for gastrinoma. Additionally, patients with pNETs should be evaluated for MEN type 1 tumors of the pituitary and parathyroid glands.

The tumor extent and location can be determined using imaging, such as computed tomography (CT) or magnetic resonance imaging (MRI) scans using new techniques and contrast media that increase sensitivity and specificity of detecting various NETs.[13] Because GEP-NETs express somatostatin receptors (SSTRs) on their surfaces, somatostatin receptor scintigraphy (SRS) using radiolabeled octreotide, a somatostatin mimic, to bind somatostatin receptors thus allowing tumor detection, localization, and the existence of metastasis. The exception to this is insulinoma, which has a low level of somatostatin receptor expression.[16] Positron emission tomography (PET) scan with gallium-DOTATOC, if available, could replace SSR due to its higher sensitivity.[17]

Treatment / Management

Various options are available for managing such heterogeneous tumors. Surgical excision of the tumors, which is the only curative therapy, is typically restricted to localized NETs.[18] Surgery can also be a part of palliative treatment to reduce tumor burden. Because most NETs are diagnosed after the development of metastases, chemotherapy is used for high-grade and aggressive tumors. Another option that is used in patients with hepatic NETs is ablative measures, including trans-arterial embolization, chemoembolization, and radiation therapy.[19] Anti-proliferative medications, like somatostatin analogs and low-dose interferon, are approved for the treatment of low and intermediate NETs.[20](B3)

Differential Diagnosis

• Irritable bowel syndrome
• Malignant neoplasms of the small intestine
• Medullary thyroid carcinoma
• Systemic mastocytosis
• Lung cancers

Surgical Oncology

Surgical resection is the only potentially curative treatment for localized and locally advanced NETs. Pancreaticoduodenectomy or Whipple surgery and distal pancreatectomy are procedures typically used for pNETs greater than 2 cm, symptomatic disease, and low to intermediate grade. Whereas, surgical removal of pNETs less than 2cm in size, non-functioning, and low grade remains controversial.[21] Platinum-based chemotherapy is recommended following surgery in surgically excised, poorly differentiated tumors.

When surgical removal of the tumor is not accessible due to tumor size, a debulking surgery is recommended. For midgut NETs, surgery is still the preferred management modality even in patients with small, asymptomatic tumors detected incidentally. For tumors localized in or near the ileocecal valve and small bowel tumors greater than 2 cm, right hemicolectomy and small intestinal resection are usually performed, respectively. For appendiceal tumors less than 1 cm, simple appendectomy is usually curative, but for small intestinal NETs less than 1 cm, typically small intestinal resection is required.[22] A carcinoid crisis is an intraoperative complication of carcinoid syndrome surgery. Common predisposing factors are anesthesia, epinephrine, and tumor manipulation. Any patient who will undergo surgery should receive a dose of octreotide 250 to 500 mcg subcutaneously or intravenously 1 to 2 hours before surgery.

Radiation Oncology

Due to the fact that the majority of GEP-NETs tumor cells express a large number of SSTRs on their surface, peptide receptor radiotherapy (PRRT) is a systemic radiotherapy modality that uses radionuclide complexes targeting these receptors. Such complexes are composed of a radionuclide isotope, in addition to a carrier (typically octreotide or octreotate), and a chelator. PRRT was found to be effective against GEP-NETs.[23] Side effects resulting from PRRT may include bone marrow suppression and renal insufficiency, which is improved by concomitant use of amino acids. Y-DOTATOC and Lu-DOTATATE are the most recent radionuclides targeting SSTRs and have been shown to have better results than the traditional agents. Lower rates of nephrotoxicity have been found associated with Lu-DOTATATE. Inoperable liver metastases can be treated with internal radiation therapy with yttrium-90 glass or resin microspheres.

Medical Oncology

Systemic therapy aims to control symptoms caused by hormonal secretion and decrease tumor proliferation and progression.

Somatostatin Analogs (SSAs)

Due to the short half-life of somatostatin, synthetic analogs to somatostatin with much longer half-lives have been approved for the treatment of NETs, which are octreotide (sandostatin) and lanreotide (somatuline depot). Clinical trials PROMID, using octreotide and CLARINET trial, using lanreotide, have shown improved progression-free survival in patients with metastatic small bowel NETs.[24] Therefore, octreotide and lanreotide are used as first-line therapy for low-grade NETs. The most frequent side effects are hyperglycemia and GI upset.

Interferon-alpha (IFN-a)

Combination therapy of IFN-a and SSAs has been studied against SSAs alone. Although the 5-year survival rate improved in the combination group, the difference between both groups was not statistically significant.[25] Its use is limited due to the potential side effects, including fever, myalgia, depression, and bone marrow depression.[26]

mTOR Inhibitors

Everolimus is an oral mammalian target of rapamycin (mTOR) inhibitor, which was approved for the management of non-functioning lung and gastrointestinal tumors as well as advanced pNETs based on multiple studies.[27][28] It inhibits cellular proliferation and angiogenesis. The use of everolimus might cause oral ulcers, rash, diarrhea, pneumonitis, hypophosphatemia, hyperlipidemia, and hyperglycemia. Due to its side effects, everolimus use is limited to advanced disease.

Tyrosine Kinase Inhibitors

Sunitinib acts by inhibiting angiogenesis by affecting the PDGF receptor and VEGF receptor types 1,2 and 3 expressed by the tumor cells. It is approved for the management of progressive pNETs. It improves progression-free survival compared to placebo.[29] Toxicities of sunitinib include diarrhea, nausea, vomiting, hypertension, palmar-plantar erythrodysesthesia (hand-foot syndrome), and hypothyroidism.

Monoclonal Antibodies

Bevacizumab is a monoclonal antibody targeting VEGF receptors. The potential benefit of bevacizumab was shown in a phase II clinical trial, which compared bevacizumab combined with octreotide versus octreotide plus interferon alfa-2b.[30]

Staging

The most recent TNM staging system for NETs has been proposed by the American Joint Committee on Cancer (AJCC) in 2017.[31] There are separate TNM staging systems for well-differentiated NETs of the appendix, stomach, and colorectal tumors. Furthermore, there is a specific staging system for NETs arising from the small intestine, and there is a new TNM staging system for pancreatic NETs, which is different from that for pancreatic exocrine tumors.

Prognosis

Survival rates of NETs were found to vary significantly depending on primary sites. Tumors that arise from the rectum have the best prognosis. In contrast, pNETs have the worst prognosis as pancreatic tumors have the highest proportion of metastatic lesions at the time of diagnosis.[32] Primary tumor location is one of the most useful predictors of outcome in patients with NETs.

Complications

• Carcinoid heart disease
• Mesenteric fibrosis
• Psychiatric disorders
• Carcinoid crisis
• Skin and pulmonary fibrosis and pellagra