Neuroendocrine neoplasms of unknown primary site
- John D Hainsworth, MD
John D Hainsworth, MD
- Chief Scientific Officer
- Sarah Cannon Research Institute
- F Anthony Greco, MD
F Anthony Greco, MD
- Medical Director
- Sarah Cannon Cancer Center
- Jonathan R Strosberg, MD
Jonathan R Strosberg, MD
- Associate Professor
- Department of Gastrointestinal Oncology
- H. Lee Moffitt Cancer Center
- Section Editors
- James R Jett, MD
James R Jett, MD
- Section Editor — Lung Cancer
- Professor of Medicine Emeritus
- National Jewish Health
- Richard M Goldberg, MD
Richard M Goldberg, MD
- Section Editor — Gastrointestinal Cancer
- Director of the West Virginia University Cancer Institute and the Mary Babb Randolph Cancer Center
- Professor of Medicine
- Laurence S. & Jean J. DeLynn Chair of Oncology
Cancer of unknown primary site (CUP) is a relatively common clinical entity, accounting for 4 to 5 percent of all invasive cancers . Within this category, tumors from many primary sites with varying biology are represented. Neuroendocrine neoplasms constitute less than 5 percent of all CUPs . (See "Overview of the classification and management of cancers of unknown primary site".)
Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms that differ in biologic behavior, histologic appearance, and response to treatment (table 1). Several types of these neoplasms (eg, well-differentiated NET of the tubular gastrointestinal tract [carcinoid tumors] and pancreas [pancreatic NETs or PNET], medullary thyroid cancers, pheochromocytomas) are characterized by slow growth and frequent secretion of hormones or vasoactive substances [3-5]. In most cases, these tumors also have typical histologic appearance and are accurately diagnosed with standard pathologic methods (light microscopy and immunohistochemical staining). Others, as typified by small cell carcinoma of the lung, are highly aggressive neoplasms, classified as neuroendocrine carcinomas, and are usually advanced when diagnosed. (See "Pathology, classification, and grading of neuroendocrine tumors arising in the digestive system".)
This review will cover the evaluation and treatment of patients with biopsy-proven metastatic NETs of unknown primary. The diagnostic workup of rare patients who present with symptoms suggestive of an underlying neuroendocrine hormonal syndrome (eg flushing, diarrhea, hypoglycemia, hyperglycemia) is discussed elsewhere. (See "Diagnosis of the carcinoid syndrome and tumor localization" and "Classification, epidemiology, clinical presentation, localization, and staging of pancreatic neuroendocrine tumors (islet-cell tumors)", section on 'Functionality and nomenclature'.)
Neuroendocrine tumors (NETs) of unknown primary site are relatively uncommon, accounting for 10 to 14 percent of all NETs:
●In a review of over 35,000 patients diagnosed with NETs over a 31-year period (most had well-differentiated tumors arising from the gastrointestinal tract), a primary site could not be found or classified in only 13 percent .To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Greco FA, Hainsworth JD. Cancer of unknown primary site. In: Cancer: Principles and Practice of Oncology, DeVita VT Jr, Hellman S, Rosenberg SA (Eds), JB Lippincott, Philadelphia 2011. p.2033.
- Spigel DR, Hainsworth JD, Greco FA. Neuroendocrine carcinoma of unknown primary site. Semin Oncol 2009; 36:52.
- Moertel CG. Karnofsky memorial lecture. An odyssey in the land of small tumors. J Clin Oncol 1987; 5:1502.
- Kaltsas GA, Besser GM, Grossman AB. The diagnosis and medical management of advanced neuroendocrine tumors. Endocr Rev 2004; 25:458.
- Strosberg JR, Nasir A, Hodul P, Kvols L. Biology and treatment of metastatic gastrointestinal neuroendocrine tumors. Gastrointest Cancer Res 2008; 2:113.
- Yao JC, Hassan M, Phan A, et al. One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 2008; 26:3063.
- Catena L, Bichisao E, Milione M, et al. Neuroendocrine tumors of unknown primary site: gold dust or misdiagnosed neoplasms? Tumori 2011; 97:564.
- Scoazec JY, Couvelard A, Monges G, et al. Professional Practices and Diagnostic Issues in Neuroendocrine Tumour Pathology: Results of a Prospective One-Year Survey Among French Pathologists (the PRONET Study). Neuroendocrinology 2016.
- Klimstra DS, Modlin IR, Coppola D, et al. The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading, and staging systems. Pancreas 2010; 39:707.
- Rindi G, Arnold R, Bosman FT, et al. Nomenclature and classification of neuroendocrine neoplasms of the digestive system. In: WHO Classification of Tumours of the Digestive System, 4th ed, Bosman TF, Carneiro F, Hruban RH, Theise ND (Eds), International Agency for Research on cancer (IARC), Lyon 2010. p.13.
- Hainsworth JD, Johnson DH, Greco FA. Poorly differentiated neuroendocrine carcinoma of unknown primary site. A newly recognized clinicopathologic entity. Ann Intern Med 1988; 109:364.
- Riihimäki M, Hemminki A, Sundquist K, et al. The epidemiology of metastases in neuroendocrine tumors. Int J Cancer 2016; 139:2679.
- La Rosa S, Chiaravalli AM, Placidi C, et al. TTF1 expression in normal lung neuroendocrine cells and related tumors: immunohistochemical study comparing two different monoclonal antibodies. Virchows Arch 2010; 457:497.
- Oien KA. Pathologic evaluation of unknown primary cancer. Semin Oncol 2009; 36:8.
- La Rosa S, Rigoli E, Uccella S, et al. CDX2 as a marker of intestinal EC-cells and related well-differentiated endocrine tumors. Virchows Arch 2004; 445:248.
- Wang SC, Parekh JR, Zuraek MB, et al. Identification of unknown primary tumors in patients with neuroendocrine liver metastases. Arch Surg 2010; 145:276.
- Sadowski SM, Neychev V, Millo C, et al. Prospective Study of 68Ga-DOTATATE Positron Emission Tomography/Computed Tomography for Detecting Gastro-Entero-Pancreatic Neuroendocrine Tumors and Unknown Primary Sites. J Clin Oncol 2016; 34:588.
- http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm504524.htm (Accessed on June 07, 2016).
- Strosberg JR, Shibata D, Kvols LK. Intermittent bowel obstruction due to a retained wireless capsule endoscope in a patient with a small bowel carcinoid tumour. Can J Gastroenterol 2007; 21:113.
- Khashab MA, Yong E, Lennon AM, et al. EUS is still superior to multidetector computerized tomography for detection of pancreatic neuroendocrine tumors. Gastrointest Endosc 2011; 73:691.
- Rösch T, Lightdale CJ, Botet JF, et al. Localization of pancreatic endocrine tumors by endoscopic ultrasonography. N Engl J Med 1992; 326:1721.
- Anderson MA, Carpenter S, Thompson NW, et al. Endoscopic ultrasound is highly accurate and directs management in patients with neuroendocrine tumors of the pancreas. Am J Gastroenterol 2000; 95:2271.
- Bellizzi AM. Assigning site of origin in metastatic neuroendocrine neoplasms: a clinically significant application of diagnostic immunohistochemistry. Adv Anat Pathol 2013; 20:285.
- Heverhagen AE, Geis C, Fendrich V, et al. Embryonic transcription factors CDX2 and Oct4 are overexpressed in neuroendocrine tumors of the ileum: a pilot study. Eur Surg Res 2013; 51:14.
- Sangoi AR, Ohgami RS, Pai RK, et al. PAX8 expression reliably distinguishes pancreatic well-differentiated neuroendocrine tumors from ileal and pulmonary well-differentiated neuroendocrine tumors and pancreatic acinar cell carcinoma. Mod Pathol 2011; 24:412.
- Maxwell JE, Sherman SK, Stashek KM, et al. A practical method to determine the site of unknown primary in metastatic neuroendocrine tumors. Surgery 2014; 156:1359.
- Bergsland EK, Nakakura EK. Neuroendocrine tumors of unknown primary: is the primary site really not known? JAMA Surg 2014; 149:889.
- Yao JC, Buzzoni R, Carnaghi C, et al. Baseline demographics of the randomized, placebo-controlled, double-blind, phase III RADIANT-4 study of everolimus in nonfunctional gastrointestinal (GI) or lung neuroendocrine tumors (NET) (abstr) J Clin oncol 33, 2015 (suppl 3; abstr 276). Abstract available online at http://meetinglibrary.asco.org/content/140092-158 (Accessed on September 04, 2015).
- Yao JC, et al. Everolimus in advanced nonfunctional neuroendocrine tumors of lung or gastrointestinal origin: efficacy and safety results from the placebo-controlled double-blinded multicenter, phase III RADIANT-4 study. Data presented at 2015 European Cancer Congress, Vienna Austria (LBA 5) September 27. 2015. Abstract available online at http://www.europeancancercongress.org/Scientific-Programme/Searchable-Programme#anchorScpr (Accessed on September 30, 2015).
- Strosberg JR, Wolin EM, Chasen B, et al. NETTER-1 phase III: Progression-free survival, radiographic response, and preliminary overall survival results in patients with midgut neuroendocrine tumors treated with 177-Lu-Dotatate (abstract). J Clin Oncol 34, 2016 (suppl 4S; abstr 194). http://meetinglibrary.asco.org/content/160126-173 (Accessed on February 03, 2016).
- Pavel M, Baudin E, Couvelard A, et al. ENETS Consensus Guidelines for the management of patients with liver and other distant metastases from neuroendocrine neoplasms of foregut, midgut, hindgut, and unknown primary. Neuroendocrinology 2012; 95:157.
- Hicks RJ. Use of molecular targeted agents for the diagnosis, staging and therapy of neuroendocrine malignancy. Cancer Imaging 2010; 10 Spec no A:S83.
- Strosberg JR, Coppola D, Klimstra DS, et al. The NANETS consensus guidelines for the diagnosis and management of poorly differentiated (high-grade) extrapulmonary neuroendocrine carcinomas. Pancreas 2010; 39:799.
- Hainsworth JD, Spigel DR, Litchy S, Greco FA. Phase II trial of paclitaxel, carboplatin, and etoposide in advanced poorly differentiated neuroendocrine carcinoma: a Minnie Pearl Cancer Research Network Study. J Clin Oncol 2006; 24:3548.