Skip to main content
SpringerLink
Log in

Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia with a Central and Peripheral Carcinoid and Multiple Tumorlets: A Case Report Emphasizing the Role of Neuropeptide Hormones and Human Gonadotropin-Alpha

  • Published:
Endocrine Pathology Aims and scope Submit manuscript

Abstract

We report a case of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH). We performed immunohistochemical analysis of 17 neuropeptides and human gonadotropin-alpha (hCGα), a trophoblastic peptide that promotes the proliferation of neuroendocrine cells. A 51-year-old woman with no history of smoking was found to have a nodule in the right middle lobe. Upon examination, the nodule was found to comprise diffuse linear and nodular neuroendocrine cell hyperplasia (NECH), numerous pulmonary tumorlets merging with one peripheral carcinoid, and an additional central carcinoid. Immunohistochemical analysis revealed diffuse but intense expression of the general neuroendocrine markers CD56, synaptophysin, and chromogranin A, together with gastrin-releasing peptide (GRP), calcitonin, and hCGα throughout the carcinoids, tumorlets, and NECH. Positive staining was also noted for adrenocorticotropic hormone, corticotropin-releasing hormone, met-enkephalin, vasoactive intestinal polypeptide, neurotensin, and growth hormone-releasing hormone in a few isolated cells of the carcinoids and the tumorlets, but staining for these proteins was entirely negative in the NECH lesions. The presence of these neuropeptides in neuroendocrine tumors might explain the presence of neuropeptide-producing tumors of the lungs, cases of which have been reported over the last 30 years. The preoperative serum proGRP level was high but returned to normal after surgical intervention, indicating that GRP was produced and secreted by carcinoids, tumorlets, and/or NECH lesions. It is also probable that neuroendocrine cells secreted GRP into the interstitium in a paracrine manner, leading to the development of dense fibrosis around the tumorlets. During the preoperative and postoperative periods, no evidence of bronchiolitis obliterans was noted, in contrast to some previously reported cases of DIPNECH.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

References

  1. Gosney JR, Travis WD. Diffuse pulmonary neuroendocrine cell hyperplasia. In: Travis WD, Brambilla E, Mueller-Hermelink HK, Harris CC, eds. Pathology and genetics of tumours of the lung, pleura, thymus and heart. Lyon: IARC Press; 76, 2004.

    Google Scholar 

  2. Gosney JR. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia as a precursor to pulmonary neuroendocrine tumors. Chest 125: 108S, 2004.

    Article  PubMed  Google Scholar 

  3. Tsutsumi Y. Immunohistochemical analysis of neuroendocrine substances in nonneoplastic lung and in neuroendocrine lung tumors. In: Lechago J, Kameya T, eds. Endocrine pathology update. New York: Field and Wood; 189–213, 1990.

    Google Scholar 

  4. Gosney JR, Williams IJ, Dodson AR, Foster CS. Morphology and antigen expression profile of pulmonary neuroendocrine cells in reactive proliferations and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH). Histopathology 59: 751–762, 2011.

    Article  PubMed  Google Scholar 

  5. Sunday ME. Pulmonary neuroendocrine cells and lung development. Endocr Pathol 7: 173–201, 1996.

    Article  PubMed  Google Scholar 

  6. Tamai S, Kameya T, Yamaguchi K, Yanai N, Abe K, Yanaihara N, Yamazaki H, Kageyama K. Peripheral lung carcinoid tumor producing predominantly gastrin-releasing peptide (GRP). Morphologic and hormonal studies. Cancer 52: 273–281, 1983.

    Article  PubMed  CAS  Google Scholar 

  7. Miyake Y, Kodama T, Yamaguchi K. Pro-gastrin-releasing peptide(31-98) is a specific tumor marker in patients with small cell lung carcinoma. Cancer Res 54: 2136–2140, 1994.

    PubMed  CAS  Google Scholar 

  8. Arioglu E, Doppman J, Gomes M, Kleiner D, Mauro D, Barlow C, Papanicolaou DA. Cushing's syndrome caused by corticotropin secretion by pulmonary tumorlets. N Engl J Med 339: 883–886, 1998.

    Article  PubMed  CAS  Google Scholar 

  9. Fukayama M, Hayashi Y, Koike M, Hajikano H, Endo S, Okumura H. Human chorionic gonadotropin in lung and lung tumors. Immunohistochemical study on unbalanced distribution of subunits. Lab Invest 55: 433–443, 1986.

    PubMed  CAS  Google Scholar 

  10. Dirnhofer S, Freund M, Rogatsch H, Krabichler S, Berger P. Selective expression of trophoblastic hormones by lung carcinoma: neurendocrine tumors exclusively produce human chorionic gonadotropin alpha-subunit (hCGalpha). Hum Pathol 31: 966–972, 2000.

    Article  PubMed  CAS  Google Scholar 

  11. Carey RM, Varma SK, Drake CR, Jr., Thorner MO, Kovacs K, Rivier J, Vale W. Ectopic secretion of corticotropin-releasing factor as a cause of Cushing's syndrome. A clinical, morphologic, and biochemical study. N Engl J Med 311: 13–20, 1984.

    Article  PubMed  CAS  Google Scholar 

  12. Tsuchihashi T, Yamaguchi K, Abe K, Yanaihara N, Saito S. Production of immunoreactive corticotropin-releasing hormone in various neuroendocrine tumors. Jpn J Clin Oncol 22: 232–237, 1992.

    PubMed  CAS  Google Scholar 

  13. Kameya T. Spectrum of neuroendocrine marker substance production in carcinoid tumors revealed by immunohistochemistry. In: Lechgo J, Kameya T, eds. Endocrine pathology update. New York: Field and Wood; 151–169, 1990.

    Google Scholar 

  14. Pratz KW, Ma C, Aubry MC, Vrtiska TJ, Erlichman C. Large cell carcinoma with calcitonin and vasoactive intestinal polypeptide-associated Verner-Morrison syndrome. Mayo Clin Proc 80: 116–120, 2005.

    PubMed  Google Scholar 

  15. Fessler MB, Cool CD, Miller YE, Schwarz MI, Brown KK. Idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells in a patient with acromegaly. Respirology 9: 274–277, 2004.

    Article  PubMed  Google Scholar 

  16. Hitomi J, Adachi I, Yamaguchi K. Production of neurotensin in multiple peptide hormone-producing tumors. Nihon Rinshou Suppl 1993: 265–270, 1993.

    Google Scholar 

  17. Aguayo SM, Miller YE, Waldron JA, Jr., Bogin RM, Sunday ME, Staton GW, Jr., Beam WR, King TE, Jr. Brief report: idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells and airways disease. N Engl J Med 327: 1285–1288, 1992.

    Article  PubMed  CAS  Google Scholar 

  18. Sheerin N, Harrison NK, Sheppard MN, Hansell DM, Yacoub M, Clark TJ. Obliterative bronchiolitis caused by multiple tumourlets and microcarcinoids successfully treated by single lung transplantation. Thorax 50: 207–209, 1995.

    Article  PubMed  CAS  Google Scholar 

  19. Miller RR, Muller NL. Neuroendocrine cell hyperplasia and obliterative bronchiolitis in patients with peripheral carcinoid tumors. Am J Surg Pathol 19: 653–658, 1995.

    Article  PubMed  CAS  Google Scholar 

  20. Armas OA, White DA, Erlandson RA, Rosai J. Diffuse idiopathic pulmonary neuroendocrine cell proliferation presenting as interstitial lung disease. Am J Surg Pathol 19: 963–970, 1995.

    Article  PubMed  CAS  Google Scholar 

  21. Canessa PA, Santini D, Zanelli M, Capecchi V. Pulmonary tumourlets and microcarcinoids in bronchiectasis. Monaldi Arch Chest Dis 52: 138–139, 1997.

    PubMed  CAS  Google Scholar 

  22. Brown MJ, English J, Muller NL. Bronchiolitis obliterans due to neuroendocrine hyperplasia: high-resolution CT–pathologic correlation. AJR Am J Roentgenol 168: 1561–1562, 1997.

    Article  PubMed  CAS  Google Scholar 

  23. Cohen AJ, King TE, Jr., Gilman LB, Magill-Solc C, Miller YE. High expression of neutral endopeptidase in idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells. Am J Respir Crit Care Med 158: 1593–1599, 1998.

    Article  PubMed  CAS  Google Scholar 

  24. Lee JS, Brown KK, Cool C, Lynch DA. Diffuse pulmonary neuroendocrine cell hyperplasia: radiologic and clinical features. J Comput Assist Tomogr 26: 180–184, 2002.

    Article  PubMed  Google Scholar 

  25. Papla B, Zielinski M, Kuzdzal J, Harazda M. Hyperplasia of endocrine cells, tumorlets and atypical carcinoid of the lung–a case report. Pol J Pathol 55: 31–33, 2004.

    PubMed  Google Scholar 

  26. Swigris J, Ghamande S, Rice TW, Farver C. Diffuse idiopathic neuroendocrine cell hyperplasia; an interesting lung disease with airway obstruction. J Bronchology 12: 62–65, 2005.

    Article  Google Scholar 

  27. Adams H, Brack T, Kestenholz P, Vogt P, Steinert HC, Russi EW. Diffuse idiopathic neuroendocrine cell hyperplasia causing severe airway obstruction in a patient with a carcinoid tumor. Respiration 73: 690–693, 2006.

    Article  PubMed  Google Scholar 

  28. Kuhnen C, Winter BU. EGFR-expression in pulmonary neuroendocrine cell hyperplasia. Pathologe 27: 147–151, 2006.

    Article  PubMed  CAS  Google Scholar 

  29. Johney EC, Pfannschmidt J, Rieker RJ, Schnabel PA, Mechtersheimer G, Dienemann H. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia and a typical carcinoid tumor. J Thorac Cardiovasc Surg 131: 1207–1208, 2006.

    Article  PubMed  Google Scholar 

  30. Ge Y, Eltorky MA, Ernst RD, Castro CY. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. Ann Diagn Pathol 11: 122–126, 2007.

    Article  PubMed  Google Scholar 

  31. Reyes LJ, Majo J, Perich D, Morell F. Neuroendocrine cell hyperplasia as an unusual form of interstitial lung disease. Respir Med 101: 1840–1843, 2007.

    Article  PubMed  CAS  Google Scholar 

  32. Aubry MC, Thomas CF, Jr., Jett JR, Swensen SJ, Myers JL. Significance of multiple carcinoid tumors and tumorlets in surgical lung specimens: analysis of 28 patients. Chest 131: 1635–1643, 2007.

    Article  PubMed  Google Scholar 

  33. Davies SJ, Gosney JR, Hansell DM, Wells AU, du Bois RM, Burke MM, Sheppard MN, Nicholson AG. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: an under-recognised spectrum of disease. Thorax 62: 248–252, 2007.

    Article  PubMed  Google Scholar 

  34. Lebras L, Arpin D, Collardeau-Frachon S, Isaac S, Guerin JC, Perol M. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: a rare preneoplastic condition. Rev Mal Respir 25: 1131–1135, 2008.

    Article  PubMed  CAS  Google Scholar 

  35. Rizvi SM, Goodwill J, Lim E, Yap YK, Wells AU, Hansell DM, Davis P, Abdel-Ghani S, Goldstraw P, Nicholson AG. The frequency of neuroendocrine cell hyperplasia in patients with pulmonary neuroendocrine tumours and non-neuroendocrine cell carcinomas. Histopathology 55: 332–337, 2009.

    Article  PubMed  Google Scholar 

  36. Coletta EN, Voss LR, Lima MS, Arakaki JS, Camara J, D'Andretta Neto C, Pereira CA. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia accompanied by airflow obstruction. J Bras Pneumol 35: 489–494, 2009.

    Article  PubMed  Google Scholar 

  37. Lim C, Stanford D, Young I, McCaughan B, Cooper W. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: a report of two cases. Pathol Int 60: 538–541, 2010.

    Article  PubMed  Google Scholar 

  38. Stenzinger A, Weichert W, Hensel M, Bruns H, Dietel M, Erbersdobler A. Incidental postmortem diagnosis of DIPNECH in a patient with previously unexplained ‘asthma bronchiale’. Pathol Res Pract 206: 785–787, 2010.

    Article  PubMed  Google Scholar 

  39. Irshad S, McLean E, Rankin S, Barrington S, Santis G, Spicer J, Lang-Lazdunski L. Unilateral diffuse idiopathic pulmonary neuroendocrine cell hyperplasia and multiple carcinoids treated with surgical resection. J Thorac Oncol 5: 921–923, 2010.

    Article  PubMed  Google Scholar 

  40. Falkenstern-Ge RF, Kimmich M, Friedel G, Tannapfel A, Neumann V, Kohlhaeufl M. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: 7-year follow-up of a rare clinicopathologic syndrome. J Cancer Res Clin Oncol 137: 1495–1498, 2011.

    Article  PubMed  CAS  Google Scholar 

  41. Nassar AA, Jaroszewski DE, Helmers RA, Colby TV, Patel BM, Mookadam F. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: a systematic overview. Am J Respir Crit Care Med 184: 8–16, 2011.

    Article  PubMed  Google Scholar 

  42. Cameron CM, Roberts F, Connell J, Sproule MW. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: an unusual cause of cyclical ectopic adrenocorticotrophic syndrome. Br J Radiol 84: e14–e17, 2011.

    Article  PubMed  CAS  Google Scholar 

  43. Gorshtein A, Gross DJ, Barak D, Strenov Y, Refaeli Y, Shimon I, Grozinsky-Glasberg S. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia and the associated lung neuroendocrine tumors: clinical experience with a rare entity. Cancer 118: 612–619, 2012.

    Article  PubMed  Google Scholar 

  44. Schedelbeck U, Held M, Geissinger E, Marten K. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: a rare differential diagnosis in patients with multiple pulmonary circular foci. Fortschr Roentgenstr 180: 257–263, 2008.

    Article  CAS  Google Scholar 

  45. Watanabe H, Kobayashi H, Honma K, Ohnishi Y, Iwafuchi M. Diffuse panbronchiolitis with multiple tumorlets. A quantitative study of the Kultschitzky cells and the clusters. Acta Pathol Jpn 35: 1221–1231, 1985.

    PubMed  CAS  Google Scholar 

  46. Aguayo SM, King TE, Jr., Waldron JA, Jr., Sherritt KM, Kane MA, Miller YE. Increased pulmonary neuroendocrine cells with bombesin-like immunoreactivity in adult patients with eosinophilic granuloma. J Clin Invest 86: 838–844, 1990.

    Article  PubMed  CAS  Google Scholar 

  47. Rossi G, Cavazza A, Graziano P, Papotti M. mTOR/p70S6K in diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. Am J Respir Crit Care Med 185: 341, 2012.

    Article  PubMed  Google Scholar 

  48. Du EZ, Goldstraw P, Zacharias J, Tiffet O, Craig PJ, Nicholson AG, Weidner N, Yi ES. TTF-1 expression is specific for lung primary in typical and atypical carcinoids: TTF-1-positive carcinoids are predominantly in peripheral location. Hum Pathol 35: 825–831, 2004.

    Article  PubMed  CAS  Google Scholar 

Download references

Disclosure

The authors declare no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Pathology, Saitama Cancer Center, 818, Komuro, Ina, Kita-adachi, Saitama, 362-0806, Japan

    Hanako Oba, Kazunori Nishida & Masafumi Kurosumi

  2. Division of Thoracic Surgery, Department of Surgery, Nippon Medical School, Tokyo, Japan

    Shingo Takeuchi

  3. Department of Thoracic Surgery, Saitama Cancer Center, Saitama, Japan

    Hirohiko Akiyama

  4. Pathology Division, Shizuoka Cancer Center Hospital and Research Institute, Shizuoka, Japan

    Koji Muramatsu & Toru Kameya

Authors
  1. Hanako Oba
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kazunori Nishida
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shingo Takeuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hirohiko Akiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Koji Muramatsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Masafumi Kurosumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Toru Kameya
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hanako Oba.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Oba, H., Nishida, K., Takeuchi, S. et al. Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia with a Central and Peripheral Carcinoid and Multiple Tumorlets: A Case Report Emphasizing the Role of Neuropeptide Hormones and Human Gonadotropin-Alpha. Endocr Pathol 24, 220–228 (2013). https://doi.org/10.1007/s12022-013-9265-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12022-013-9265-8

Keywords

Search

Navigation