Neuroendocrine Cancer
Neuroendocrine cancer, also known as neuroendocrine neoplasms (NENs), comprises a heterogeneous group of malignancies arising from cells of the neuroendocrine system, which are distributed widely throughout the body. These cells possess characteristics of both nerve cells and hormone-producing endocrine cells, enabling them to secrete peptides and neuroamines that can cause distinct clinical syndromes. The pathogenesis of neuroendocrine cancers involves genetic and epigenetic alterations leading to uncontrolled cellular proliferation, resistance to apoptosis, and, in many cases, hormone hypersecretion. Tumorigenesis may be driven by mutations in genes such as MEN1, DAXX, ATRX, and mTOR pathway components, with environmental and hereditary factors also contributing. Health impacts range from asymptomatic indolent tumors to aggressive metastatic disease, with symptoms often related to hormone overproduction (e.g., flushing, diarrhea, hypoglycemia) or mass effect. The disease can significantly impair quality of life and, when advanced, may result in substantial morbidity and mortality.
GEP-NETs are the most prevalent neuroendocrine tumors and arise from neuroendocrine cells scattered throughout the gastrointestinal tract and pancreas. These tumors are further categorized by their site of origin, including pancreatic, small intestinal, rectal, and gastric neuroendocrine tumors. They may be functional, secreting hormones such as insulin, gastrin, or serotonin, or nonfunctional, presenting due to tumor mass effects or metastatic spread. GEP-NETs are graded based on mitotic count and Ki-67 index, which correlate with their biological behavior and prognosis.
Pulmonary neuroendocrine tumors originate from neuroendocrine cells in the respiratory epithelium and encompass a spectrum from typical carcinoids (low-grade) and atypical carcinoids (intermediate-grade) to high-grade neoplasms such as large cell neuroendocrine carcinoma and small cell lung carcinoma. These tumors may present with cough, hemoptysis, or paraneoplastic syndromes and show variable aggressiveness and metastatic potential.
Merkel cell carcinoma is a rare, aggressive cutaneous neuroendocrine malignancy arising from mechanoreceptor Merkel cells in the skin. It typically presents as a rapidly growing, painless, firm nodule on sun-exposed areas in elderly or immunocompromised individuals. The tumor is characterized by a high propensity for local recurrence and early metastasis, contributing to its poor prognosis.
Pheochromocytomas are neuroendocrine tumors arising from chromaffin cells of the adrenal medulla, whereas paragangliomas originate from extra-adrenal paraganglionic tissue. These tumors often secrete catecholamines, leading to episodic hypertension, palpitations, and diaphoresis. They may be sporadic or associated with hereditary syndromes such as MEN2, VHL, or SDH mutations.
Medullary thyroid carcinoma develops from parafollicular C cells of the thyroid gland, producing calcitonin and other peptides. It can occur sporadically or as part of familial syndromes such as multiple endocrine neoplasia type 2. The tumor may present as a thyroid nodule, cervical lymphadenopathy, or with symptoms related to hormone secretion.
Neuroendocrine cancers are relatively rare, comprising approximately 0.5% of all newly diagnosed malignancies. The overall annual incidence has been steadily increasing, with recent population-based studies reporting rates of 6–7 cases per 100,000 individuals. Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) represent the most common subtype, accounting for about two-thirds of cases, followed by pulmonary neuroendocrine tumors. The median age at diagnosis is typically between 50 and 60 years, though certain subtypes such as Merkel cell carcinoma may present at older ages. There is a slight male predominance in some subtypes, while others, like medullary thyroid carcinoma, show no significant gender bias. Many neuroendocrine tumors are diagnosed at an advanced stage due to their indolent growth and nonspecific symptoms. Survival rates vary widely depending on tumor grade, stage, and primary site, with low-grade localized NETs exhibiting 5-year survival rates exceeding 80%, while high-grade or metastatic disease carries a much poorer prognosis.
The diagnosis of neuroendocrine cancer is multifaceted and relies on a combination of clinical evaluation, biochemical testing, imaging studies, and histopathological confirmation. Initial assessment includes a thorough history and physical examination, with attention to symptoms suggestive of hormone hypersecretion. Biochemical evaluation may involve measurement of specific tumor markers such as chromogranin A, neuron-specific enolase, and, in functional tumors, hormone levels like serotonin (5-HIAA in urine), insulin, or catecholamines. Imaging modalities play a pivotal role in localization and staging; contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI) are standard for anatomical delineation, while functional imaging with radiolabeled somatostatin analogs, such as [111In]pentetreotide scintigraphy or positron emission tomography (PET) with copper Cu 64 dotatate, enables detection of somatostatin receptor-expressing lesions. Histopathological examination of biopsy or resected tissue confirms the diagnosis, with immunohistochemical staining for neuroendocrine markers (chromogranin, synaptophysin, CD56) and assessment of proliferative index (Ki-67 labeling) to determine tumor grade. Staging is based on the primary site, size, lymph node involvement, and presence of distant metastases, following site-specific TNM classification systems. Additional genetic testing may be indicated in cases with suspected hereditary syndromes.
A range of pharmacological agents are available for the management of neuroendocrine cancer. Belzutifan is utilized as a therapeutic option targeting pathways involved in tumor growth and angiogenesis. Sulfatinib, also known as surufatinib, is employed for its inhibitory effects on multiple tyrosine kinase receptors implicated in neuroendocrine tumor progression. Copper Cu 64 dotatate serves as a radiopharmaceutical for positron emission tomography (PET) imaging, enabling visualization of somatostatin receptor-positive neuroendocrine tumors. Lutetium Lu 177 dotatate, also referred to as 177Lu-oxodotreotide, is administered as a peptide receptor radionuclide therapy, delivering targeted radiation to somatostatin receptor-expressing tumor cells. Cabozantinib S-malate is used for its activity as a multi-kinase inhibitor, interfering with oncogenic signaling pathways relevant to neuroendocrine malignancies. Everolimus is prescribed as an mTOR pathway inhibitor, exerting antiproliferative effects in advanced neuroendocrine tumors. [111In]pentetreotide, or indium In 111 pentetreotide, is a radiolabeled somatostatin analog utilized for scintigraphic imaging to localize neuroendocrine lesions. Iobenguane I 131 is employed therapeutically, particularly in tumors such as pheochromocytoma and paraganglioma, leveraging its targeted radiotherapeutic properties. Metirosine, also known as metyrosine, is administered to reduce catecholamine synthesis in hormone-secreting tumors, aiding in symptom control. Vincristine sulfate is used as a cytotoxic chemotherapeutic agent in certain neuroendocrine cancer regimens, contributing to tumor cell death through inhibition of microtubule formation.
| Structure | Generic Name | CAS Registry Number | Molecular Formula | Molecular Weight |
|---|---|---|---|---|
 | belzutifan (Rec INN; USAN) | 1672668-24-4 | C17 H12 F3 N O4 S | 383.342 |
 | sulfatinib; surufatinib (Rec INN; USAN) | 1308672-74-3 | C24 H28 N6 O3 S | 480.583 |
 | copper Cu 64 dotatate (USAN) | 1426155-87-4 | C65 H88 N14 O19 S2 . Cu | 1497.607 |
 | 177Lu-oxodotreotide (Rec INN); lutetium Lu 177 dotatate (USAN) | C65 H87 N14 O19 S2 . Lu | 1609.599 | |
 | cabozantinib S-malate (Prop INNM; USAN) | 1140909-48-3; 849217-68-1 (free base) | C28 H24 F N3 O5 . C4 H6 O5 | 635.593 |
 | everolimus (Rec INN; USAN) | 159351-69-6 | C53 H83 N O14 | 958.224 |
 | [111In]pentetreotide (Rec INNM; BANM); indium In 111 pentetreotide (USAN) | 139096-04-1 | C63 H84 N13 O19 S2 . In | 1502.547 |
 | iobenguane I 131 (USAN); iobenguane[131I] (Rec INN) | 77679-27-7 | C8 H10 I N3 | 279.185 |
 | metirosine (Rec INN; BAN); metyrosine (USAN) | 672-87-7 | C10 H13 N O3 | 195.215 |
 | vincristine sulfate (Rec INNM; USAN; BANM) | 2068-78-2 | C46 H56 N4 O10 . H2 O4 S | 923.036 |
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Neuroendocrine Cancer
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