Neuroendocrine neoplasms – think about it and choose the most appropriate diagnostic and therapeutic steps

  • Christian A. KochEmail author
  • S. Petersenn

We are pleased to present the second issue on neuroendocrine neoplasms (NEN). Often, NEN are also referred to as “zebras” because of their rarity, and we would like to expand this thought into “black swans,” a term that is based on an ancient perception that presumed black swans did not exist, but had to be changed once they were discovered in nature. This should teach us that any system of thought should constantly be re-evaluated. It is understandable that humans usually harbor some anxiety towards the unknown and that this angst is more pronounced in more conservative communities than in progressive ones. Discoveries are usually made by thinking “outside of the box.” For instance, excessively high serum calcitonin levels could be alarming for an existing NEN. The odds of a possible NEN would call for a neck examination to search for medullary thyroid carcinoma and in some cases thyroidectomy would be performed without identifying any tumor [1], because calcitonin secretion occurs ectopically from an unsuspected NEN [2, 3, 4, 5, 6, 7, 8]. More recently, the presence of macrocalcitonin as a pitfall in the endocrine laboratory assessment has been discovered [9]. Similar to other macrohormones such as macroprolactin, a macro-thyroid stimulating hormone, macrocalcitonin has neglectable biological activity [9, 10, 11].

The first article is a report on rare locations of NEN including kidney, lung, and heart/ileum [12]. Solitary fibrous tumors of the pleura can demonstrate increased tracer uptake at 68Ga-DOTATOC positron emission tomography imaging [13]. In addition, we present a 17-year-old young man with multifocal pheochromocytoma/paraganglioma syndrome in von Hippel Lindau (VHL) disease who during a 9 year follow-up remained in remission. According to a recent study of 272 patients with malignant pheochromocytoma/paraganglioma over 55 years, the clinical course of these patients is very variable [14]. Predictors of rapid progression in that study included males, older age at diagnosis, larger tumor size, synchronous metastases, and not undergoing resection of primary tumor. For unresectable pheochromocytomas/paragangliomas associated with uncontrolled endocrine hypertension, peptide receptor radionuclide therapy with 177Lu-DOTA-octreotate can lead to worthwhile clinical and biochemical responses in selected patients [15]. Treating patients with VHL disease and growing and/or unresectable lesions with pazopanib may reduce tumor size [16, 17]. It is both challenging and yet necessary to make NEN visible. Functional imaging modalities have resolution limits and usually cannot depict lesions smaller than 4 mm in size. In addition, uptake in areas that are not typically NEN can occur and are often referred to as “false positive uptake.” This problem will be discussed in the article concerning nuclear medicine by Professor Vani Vijayakumar and colleagues [18]. Typically, functional imaging technologies in NEN should be used in combination with conventional imaging modalities, if resolution limits permit. Often this task is directed by skilled radiologists. However, for small, pancreatic NEN, an endocrinologist or gastroenterologist, highly skilled in conducting endosonography, may localize NEN better than magnetic resonance imaging, as demonstrated in the article by Professor Kann [19].

Once a NEN is discovered, the question arises of what the next steps should be in its management. This is especially important in family members of hereditary tumor syndromes [17]. For instance, Pieterman and colleagues [20] in a retrospective longitudinal observational cohort study of patients with small (<2 cm) nonfunctional pancreatic NEN from the Dutch national multiple endocrine neoplasia type 1 database, found that the growth rate of 115 NEN from 99 patients was 0.4 mm per year, irrespective of the underlying MEN1 genotype [20]. Moreover, Ariotti and colleagues [21] provide a review on how incidentally discovered gastrointestinal and pancreatic NEN should be followed. If the decision is made to perform surgery on a patient with NEN, a multidisciplinary team should discuss the perioperative proceedings including an effective prophylaxis against an intraoperative carcinoid crisis, supportive therapy, and nutrition [7, 8, 22]. Psychosocial support, expert nursing, nutritional support and management of cancer related pain will be reviewed by the groups, Auernhammer and Spitzweg, as well as the group, Faggiano, Colao, Muscogiuri and colleagues [23, 24].

Furthermore, Professor Goretzki and colleagues, review curative and palliative surgery in patients with neuroendocrine tumors of the gastro-entero-pancreatic (GEP) tract with excellent case illustrations [25]. Lastly, this issue is concluded with an article by Professor Castaño and his group demonstrating once more the heterogeneity of NEN and underscoring the critical importance for all health care providers involved in the care of NEN patients to have an interest in and understanding of the pathogenesis of these rare, but not so uncommon tumor entities [26].


Compliance with ethical standards

Conflict of interest

Prof. Christian Koch declares no direct conflict with this article. He has served on the Advisory Board of Novartis on the topic acromegaly and has participated in educational conferences on the topics neuroendocrine tumors and acromegaly sponsored by Novartis and Ipsen.

Prof. Stephan Petersenn declares no direct conflict with this article. He has served on the Advisory Board of Ipsen on the topics of acromegaly and NEN.


  1. 1.
    Johannessen JV, Gould VE. Neuroendocrine skin carcinoma associated with calcitonin production: a Merkel cell carcinoma? Hum Pathol. 1980;11(5 Suppl):586–8.PubMedGoogle Scholar
  2. 2.
    Uccella S, Blank A, Maragliano R, Sessa F, Perren A, La Rosa S. Calcitonin-producing neuroendocrine neoplasms of the pancreas: Clinicopathological study of 25 cases and review of the literature. Endocr Pathol. 2017;28(4):351–61.CrossRefGoogle Scholar
  3. 3.
    Fertig RM, Alperstein A, Diaz C, Klingbeil KD, Vangara SS, Misawa R, et al. Metastatic neuroendocrine tumor of the esophagus with features of medullary thyroid carcinoma. Intractable Rare Dis Res. 2017;6(3):224–9.CrossRefGoogle Scholar
  4. 4.
    Cvijovic G, Micic D, Kendereski A, Zoric S, Sumarac-Dumanovic M, Tatic S, et al. Ectopic calcitonin secretion in a woman with large cell neuroendocrine lung carcinoma. Hormones (Athens). 2013;12(4):584–90.CrossRefGoogle Scholar
  5. 5.
    Kameya T, Shimosato Y, Adachi I, Abe K, Ebihara S, Ono I. Neuroendocrine carcinoma of the paranasal sinus: a morphological and endocrinological study. Cancer. 1980;45(2):330–9.CrossRefGoogle Scholar
  6. 6.
    Heath H 3rd, Edis AJ. Pheochromocytoma associated with hypercalcemia and ectopic secretion of calcitonin. Ann Intern Med. 1979;91(2):208–10.CrossRefGoogle Scholar
  7. 7.
    Vinik A, Perry RR, Casellini C, Hughes MS, Feliberti E. Pathophysiology and Treatment of Pancreatic Neuroendocrine Tumors (PNETs): New Developments. In: De Groot LJ, Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, Koch C, Korbonits M, McLachlan R, New M, Purnell J, Rebar R, Singer F, Vinik A, editors. Endotext [Internet]. South Dartmouth (MA):, Inc.; 2000-2018.
  8. 8.
    Vinik A, Hughes MS, Feliberti E, Perry RR, Casellini C, Sinesi M, Vingan H, Johnson L. Carcinoid tumors. In: De Groot LJ, Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, Koch C, Korbonits M, McLachlan R, New M, Purnell J, Rebar R, Singer F, Vinik A, editors. Endotext [internet]. South Dartmouth (MA):, Inc.; 2000–2018.
  9. 9.
    Alves TG, Kasamatsu TS, Yang JH, Meneghetti MC, Mendes A, Kunii IS, et al. Macrocalcitonin is a novel pitfall in the routine of serum calcitonin immunoassay. J Clin Endocrinol Metab. 2016;101(2):653–8.CrossRefGoogle Scholar
  10. 10.
    Giusti M, Conte L, Repetto AM, Gay S, Marroni P, Mittica M, et al. Detection of polyethylene glycol thyrotropin (TSH) Precipitable percentage (macro-TSH) in patients with a history of thyroid Cancer. Endocrinol Metab (Seoul). 2017;32(4):460–5.CrossRefGoogle Scholar
  11. 11.
    Favresse J, Burlacu MC, Maiter D, Gruson D. Interferences with thyroid function immunoassays: clinical implications and detection algorithm. Endocr Rev. 2018;39:830–50. Scholar
  12. 12.
    Koch CA, Petersenn S. Black swans – neuroendocrine neoplasms of rare locations. Rev Endocr Metab Disord. 2018.
  13. 13.
    Lococo F, Rapicetta C, Casali M, Bellafiore S, Rossi G, Treglia G, et al. 68Ga-DOTATOC PET/CT imaging in solitary fibrous tumor of the pleura. Clin Nucl Med. 2017;42(6):e294–6.CrossRefGoogle Scholar
  14. 14.
    Hamidi O, Young WF Jr, Iñiguez-Ariza NM, Kittah NE, Gruber L, Bancos C, et al. Malignant Pheochromocytoma and Paraganglioma: 272 patients over 55 years. J Clin Endocrinol Metab. 2017;102(9):3296–305.CrossRefGoogle Scholar
  15. 15.
    Kong G, Grozinsky-Glasberg S, Hofman MS, Callahan J, Meirovitz A, Maimon O, et al. Efficacy of peptide receptor radionuclide therapy for functional metastatic Paraganglioma and Pheochromocytoma. J Clin Endocrinol Metab. 2017;102(9):3278–87.CrossRefGoogle Scholar
  16. 16.
    Giles RH, Glasker S. The first prospective trial for von Hippel-Lindau disease: pazopanib. Lancet Oncol. 2018. Scholar
  17. 17.
    Gläsker S, Neumann HPH, Koch CA, Vortmeyer A. Von Hippel-Lindau Disease. In: De Groot LJ, Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, Koch C, Korbonits M, McLachlan R, New M, Purnell J, Rebar R, Singer F, Vinik A, editors. Endotext [internet]. South Dartmouth (MA):, Inc.; 2000–2018.
  18. 18.
    Bhanat E, Koch CA, Parmar R, Garla V, Vijayakumar V. Somatostatin receptor expression in non-classical localizations - clinical relevance? Rev Endocr Metab Disord 2018.
  19. 19.
    Kann P. Is endoscopic ultrasonography more sensitive than magnetic resonance imaging in detecting and localizing pancreatic neuroendocrine tumors? Rev Endocr Metab Disord.
  20. 20.
    Pieterman CRC, de Laat JM, Twisk JWR, van Leeuwaarde RS, de Herder WW, Dreijerink KMA, et al. Long-term natural course of small nonfunctional pancreatic neuroendocrine tumors in MEN1-results from the Dutch MEN1 study group. J Clin Endocrinol Metab. 2017;102(10):3795–805.CrossRefGoogle Scholar
  21. 21.
    Ariotti R, Partelli S, Muffatti F, Andreasi V, Sala FD, Falconi M How should incidental NEN of the pancreas and gastrointestinal tract be followed? Rev Endocr Metab Disord 2018.
  22. 22.
    Woltering EA, Wright AE, Stevens MA, Wang YZ, Boudreaux JP, Mamikunian G, et al. Development of effective prophylaxis against intraoperative carcinoid crisis. J Clin Anesth. 2016;32:189–93.CrossRefGoogle Scholar
  23. 23.
    Jin XF, Spampatti MP, Spitzweg C, Auernhammer CJ. Supportive therapy in gastroenteropancreatic neuroendocrine tumors: often forgotten but important. Rev Endocr Metab Disord 2018.
  24. 24.
    Altieri B, Barrea L, Modica R, Muscogiuiri G, Savastano S, Colao A, Faggiano A. Nutrition and neuroendocrine tumors: an update of the literature. Rev Endocr Metab Disord 2018.
  25. 25.
    Goretzki PE, Mogl M, Akca A, Pratschke J. Curative and palliative surgery in patients with neuroendocrine tumors of the gastro-entero-pancreatic (GEP) tract. Rev Endocr Metab Disord 2018.
  26. 26.
    Pedraza-Arevalo S, Gahete MD, Alors-Perez E, Luque RM, Castano JP. Mutilayered heterogeneity as an intrinsic hallmark of neuroendocrine tumors. Rev Endocr Metab Disord 2018.

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Medicover GmbH GermanyBerlin / HannoverGermany
  2. 2.Carl von Ossietzky University of OldenburgOldenburgGermany
  3. 3.Technical University of DresdenDresdenGermany
  4. 4.University of LouisvilleLouisvilleUSA
  5. 5.ENDOC Center for Endocrine TumorsHamburgGermany
  6. 6.University of Duisburg-EssenDuisburgGermany

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