Skip to main content
SpringerLink
Log in

Correlation of 68Ga-DOTATATE uptake on PET/CT with pathologic features of cellular proliferation in neuroendocrine neoplasms

  • Original Article
  • Published:
Annals of Nuclear Medicine Aims and scope Submit manuscript

Abstract

Objective

68Ga-DOTATATE positron emission tomography/computed tomography (PET/CT) is a useful tool for diagnosing and staging neuroendocrine neoplasms (NEN). Unlike other PET tracers like FDG, the meaningfulness and use of standardized uptake values (SUVs) of 68Ga-DOTATATE is not well-established. This study aimed to determine if a correlation exists between intensity of 68Ga-DOTATATE uptake and markers of cellular proliferation.

Methods

This retrospective study included 79 patients with positive 68Ga-DOTATATE PET/CT and Ki-67 and/or mitotic index (MI) available on pathology report. SUVmax of the most intense lesion and the most intense organ-matched lesion were determined. Demographics and pathology results for Ki-67 and MI were collected from the electronic medical record. Correlations and trends for correlations of SUVmax to Ki-67 and MI were performed using Kruskal–Wallis and Cuzick trend tests.

Results

A trend for an association between SUVmax and Ki-67 grade was found; median SUVmax of Ki-67 < 3%, 3–20%, and > 20% was 35.2, 31.8, and 12.8 (p = 0.077), respectively. There was also a trend between SUVmax and Ki-67 categories in organ-matched lesions (p = 0.08). The median organ-matched SUVmax of MI < 2, 2–20, and > 20 lesions was 34.2, 18, and 21.7, respectively, (Cuzick trend test p = 0.066). The median SUVmax for small bowel, pancreatic, and other primary locations was 27.6, 46.9, and 9.3 (p < 0.01), respectively.

Conclusions

The association between 68Ga-DOTATATE SUVmax, histologic grade, and primary site of NEN demonstrates its potential use for prognostication, or potentially as a surrogate for histologic grading when biopsy is not possible.

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

Similar content being viewed by others

References

  1. Taal BG, Visser O. Epidemiology of neuroendocrine tumours. Neuroendocrinology. 2004;80(Suppl 1):3–7.

    Article  CAS  Google Scholar 

  2. Dasari A, Shen C, Halperin D, Zhao B, Zhou S, Xu Y, et al. Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol. 2017;3(10):1335–42.

    Article  Google Scholar 

  3. Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, 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(18):3063–72.

    Article  Google Scholar 

  4. Ozaslan E, Bayram F, Karaca H, Gursoy S, Ozturk F, Sozuer E, et al. Best prognostic factor of neuroendocrine tumors: grade or stage? A multidisciplinary single-center study. Turk J Gastroenterol. 2016;27(6):509–14.

    Article  Google Scholar 

  5. Nagtegaal ID, Odze RD, Klimstra D, Paradis V, Rugge M, Schirmacher P, et al. The 2019 WHO classification of tumours of the digestive system. Histopathology. 2020;76(2):182–8.

    Article  Google Scholar 

  6. Rindi G, Klimstra DS, Abedi-Ardekani B, Asa SL, Bosman FT, Brambilla E, et al. A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal. Mod Pathol. 2018;31(12):1770–86.

    Article  Google Scholar 

  7. Halfdanarson TR, Strosberg JR, Tang L, Bellizzi AM, Bergsland EK, O’Dorisio TM, et al. The North American neuroendocrine tumor society consensus guidelines for surveillance and medical management of pancreatic neuroendocrine tumors. Pancreas. 2020;49(7):863–81.

    Article  Google Scholar 

  8. Strosberg JR, Halfdanarson TR, Bellizzi AM, Chan JA, Dillon JS, Heaney AP, et al. The North American neuroendocrine tumor society consensus guidelines for surveillance and medical management of midgut neuroendocrine tumors. Pancreas. 2017;46(6):707–14.

    Article  Google Scholar 

  9. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. In: Travis WD, Brambilla E, Burke AP, et al., editors. 4 ed. Lyon: IARC; 2015.

  10. Antunes P, Ginj M, Zhang H, Waser B, Baum RP, Reubi JC, et al. Are radiogallium-labelled DOTA-conjugated somatostatin analogues superior to those labelled with other radiometals? Eur J Nucl Med Mol Imaging. 2007;34(7):982–93.

    Article  CAS  Google Scholar 

  11. Khan MU, Khan S, El-Refaie S, Win Z, Rubello D, Al-Nahhas A. Clinical indications for Gallium-68 positron emission tomography imaging. Eur J Surg Oncol. 2009;35(6):561–7.

    Article  CAS  Google Scholar 

  12. Reubi JC, Schär JC, Waser B, Wenger S, Heppeler A, Schmitt JS, et al. Affinity profiles for human somatostatin receptor subtypes SST1-SST5 of somatostatin radiotracers selected for scintigraphic and radiotherapeutic use. Eur J Nucl Med. 2000;27(3):273–82.

    Article  CAS  Google Scholar 

  13. Deppen SA, Blume J, Bobbey AJ, Shah C, Graham MM, Lee P, et al. 68Ga-DOTATATE compared with 111In-DTPA-octreotide and conventional imaging for pulmonary and gastroenteropancreatic neuroendocrine tumors: a systematic review and meta-analysis. J Nucl Med. 2016;57(6):872–8.

    Article  CAS  Google Scholar 

  14. Deppen SA, Liu E, Blume JD, Clanton J, Shi C, Jones-Jackson LB, et al. Safety and efficacy of 68Ga-DOTATATE PET/CT for diagnosis, staging, and treatment management of neuroendocrine tumors. J Nucl Med. 2016;57(5):708–14.

    Article  CAS  Google Scholar 

  15. Geijer H, Breimer LH. Somatostatin receptor PET/CT in neuroendocrine tumours: update on systematic review and meta-analysis. Eur J Nucl Med Mol Imaging. 2013;40(11):1770–80.

    Article  CAS  Google Scholar 

  16. Hofman MS, Kong G, Neels OC, Eu P, Hong E, Hicks RJ. High management impact of 68Ga-DOTATATE (GaTate) PET/CT for imaging neuroendocrine and other somatostatin expressing tumours. J Med Imaging Radiat Oncol. 2012;56(1):40–7.

    Article  Google Scholar 

  17. Krenning EP, Valkema R, Kooij PP, Breeman WA, Bakker WH, deHerder WW, et al. Scintigraphy and radionuclide therapy with [indium-111-labelled-diethyl triamine penta-acetic acid-D-Phe1]-octreotide. Ital J Gastroenterol Hepatol. 1999;31(Suppl 2):S219–23.

    PubMed  Google Scholar 

  18. Cherk MH, Kong G, Hicks RJ, Hofman MS. Changes in biodistribution on (68)Ga-DOTA-Octreotate PET/CT after long acting somatostatin analogue therapy in neuroendocrine tumour patients may result in pseudoprogression. Cancer Imaging. 2018;18(1):3.

    Article  Google Scholar 

  19. Binderup T, Knigge U, Loft A, Federspiel B, Kjaer A. 18F-fluorodeoxyglucose positron emission tomography predicts survival of patients with neuroendocrine tumors. Clin Cancer Res. 2010;16(3):978–85.

    Article  CAS  Google Scholar 

  20. Binderup T, Knigge U, Loft A, Mortensen J, Pfeifer A, Federspiel B, et al. Functional imaging of neuroendocrine tumors: a head-to-head comparison of somatostatin receptor scintigraphy, 123I-MIBG scintigraphy, and 18F-FDG PET. J Nucl Med. 2010;51(5):704–12.

    Article  Google Scholar 

  21. Bucau M, Laurent-Bellue A, Poté N, Hentic O, Cros J, Mikail N, et al. 18F-FDG uptake in well-differentiated neuroendocrine tumors correlates with both Ki-67 and VHL pathway inactivation. Neuroendocrinology. 2018;106(3):274–82.

    Article  CAS  Google Scholar 

  22. Ambrosini V, Campana D, Polverari G, Peterle C, Diodato S, Ricci C, et al. Prognostic value of 68Ga-DOTANOC PET/CT SUVmax in patients with neuroendocrine tumors of the pancreas. J Nucl Med. 2015;56(12):1843–8.

    Article  CAS  Google Scholar 

  23. Campana D, Ambrosini V, Pezzilli R, Fanti S, Labate AM, Santini D, et al. Standardized uptake values of (68)Ga-DOTANOC PET: a promising prognostic tool in neuroendocrine tumors. J Nucl Med. 2010;51(3):353–9.

    Article  Google Scholar 

  24. Kaewput C, Suppiah S, Vinjamuri S. Correlation between standardized uptake value of (68)Ga-DOTA-NOC positron emission tomography/computed tomography and pathological classification of neuroendocrine tumors. World J Nucl Med. 2018;17(1):34–40.

    Article  Google Scholar 

  25. Partelli S, Rinzivillo M, Maurizi A, Panzuto F, Salgarello M, Polenta V, et al. The role of combined Ga-DOTANOC and (18)FDG PET/CT in the management of patients with pancreatic neuroendocrine tumors. Neuroendocrinology. 2014;100(4):293–9.

    Article  CAS  Google Scholar 

  26. Boy C, Heusner TA, Poeppel TD, Redmann-Bischofs A, Unger N, Jentzen W, et al. 68Ga-DOTATOC PET/CT and somatostatin receptor (sst1-sst5) expression in normal human tissue: correlation of sst2 mRNA and SUVmax. Eur J Nucl Med Mol Imaging. 2011;38(7):1224–36.

    Article  CAS  Google Scholar 

  27. Chan H, Moseley C, Zhang L, Bergsland EK, Pampaloni MH, Van Loon K, et al. Correlation of DOTATOC uptake and pathologic grade in neuroendocrine tumors. Pancreas. 2019;48(7):948–52.

    Article  CAS  Google Scholar 

  28. Miederer M, Seidl S, Buck A, Scheidhauer K, Wester HJ, Schwaiger M, et al. Correlation of immunohistopathological expression of somatostatin receptor 2 with standardised uptake values in 68Ga-DOTATOC PET/CT. Eur J Nucl Med Mol Imaging. 2009;36(1):48–52.

    Article  CAS  Google Scholar 

  29. Kayani I, Bomanji JB, Groves A, Conway G, Gacinovic S, Win T, et al. Functional imaging of neuroendocrine tumors with combined PET/CT using 68Ga-DOTATATE (DOTA-DPhe1, Tyr3-octreotate) and 18F-FDG. Cancer. 2008;112(11):2447–55.

    Article  Google Scholar 

  30. Yu J, Li N, Li J, Lu M, Leal JP, Tan H, et al. The correlation between [(68)Ga]DOTATATE PET/CT and cell proliferation in patients with GEP-NENs. Mol Imaging Biol. 2019;21(5):984–90.

    Article  CAS  Google Scholar 

  31. Panagiotidis E, Alshammari A, Michopoulou S, Skoura E, Naik K, Maragkoudakis E, et al. Comparison of the impact of 68Ga-DOTATATE and 18F-FDG PET/CT on clinical management in patients with neuroendocrine tumors. J Nucl Med. 2017;58(1):91–6.

    Article  Google Scholar 

  32. Strosberg J, Nasir A, Coppola D, Wick M, Kvols L. Correlation between grade and prognosis in metastatic gastroenteropancreatic neuroendocrine tumors. Hum Pathol. 2009;40(9):1262–8.

    Article  Google Scholar 

  33. Khan MS, Luong TV, Watkins J, Toumpanakis C, Caplin ME, Meyer T. A comparison of Ki-67 and mitotic count as prognostic markers for metastatic pancreatic and midgut neuroendocrine neoplasms. Br J Cancer. 2013;108(9):1838–45.

    Article  CAS  Google Scholar 

  34. McCall CM, Shi C, Cornish TC, Klimstra DS, Tang LH, Basturk O, et al. Grading of well-differentiated pancreatic neuroendocrine tumors is improved by the inclusion of both Ki67 proliferative index and mitotic rate. Am J Surg Pathol. 2013;37(11):1671–7.

    Article  Google Scholar 

  35. Klimstra DSKG, La Rosa S, Rindi G. Classification of neuroendocrine neoplasms of the digestive system. In: Board W, editor. WHO classification of tumours: digestive system tumors. 5th ed. Lyon: International Agency for Research on Cancer; 2019. p. 16.

    Google Scholar 

  36. O’Toole D, Saveanu A, Couvelard A, Gunz G, Enjalbert A, Jaquet P, et al. The analysis of quantitative expression of somatostatin and dopamine receptors in gastro-entero-pancreatic tumours opens new therapeutic strategies. Eur J Endocrinol. 2006;155(6):849–57.

    Article  CAS  Google Scholar 

  37. Adams MC, Turkington TG, Wilson JM, Wong TZ. A systematic review of the factors affecting accuracy of SUV measurements. Am J Roentgenol. 2010;195(2):310–20.

    Article  Google Scholar 

  38. Focke CM, Bürger H, van Diest PJ, Finsterbusch K, Gläser D, Korsching E, et al. Interlaboratory variability of Ki67 staining in breast cancer. Eur J Cancer. 2017;84:219–27.

    Article  CAS  Google Scholar 

  39. Alkhasawneh A, Reith JD, Toro TZ, Ayed AO, Lu X, George TJ, et al. Interobserver variability of mitotic index and utility of PHH3 for risk stratification in gastrointestinal stromal tumors. Am J Clin Pathol. 2015;143(3):385–92.

    Article  CAS  Google Scholar 

  40. Qian ZR, Li T, Ter-Minassian M, Yang J, Chan JA, Brais LK, et al. Association between somatostatin receptor expression and clinical outcomes in neuroendocrine tumors. Pancreas. 2016;45(10):1386–93.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Imaging, Dana-Farber Cancer Institute, 450 Brookline Avenue, DL203, Boston, MA, 02215, USA

    Shawn Karls & Heather Jacene

  2. Department of Radiology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    Shawn Karls & Heather Jacene

  3. St. Georges University, School of Medicine, St. George, Grenada

    Richard Gold

  4. Division of Biostatistics, Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA

    Sasha Kravets, Yating Wang & SuChun Cheng

  5. Program in Neuroendocrine and Carcinoid Tumors, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    Kimberly Perez & Jennifer Chan

Authors
  1. Shawn Karls
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Richard Gold
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sasha Kravets
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yating Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. SuChun Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kimberly Perez
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jennifer Chan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Heather Jacene
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Heather Jacene.

Ethics declarations

Conflict of interest

Dr. Heather Jacene discloses Advanced Accelerator Applications—consulting fees, American Roentgen Ray Society—stipend, Australian and New Zealand Urogenital and Prostate Cancer Clinical Trial Group—honoraria, Cambridge University Press—royalties, Janssen—honoraria, Siemens Healthcare, GTx, Inc, Blue Earth Diagnostics, Inc—research support to institution. Dr. Jennifer Chan discloses—consulting for Advanced Accelerator Applications, Lexicon, Ipsen and Stock Ownership: Merck. The rest of the authors have no conflicts of interest to disclose.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Karls, S., Gold, R., Kravets, S. et al. Correlation of 68Ga-DOTATATE uptake on PET/CT with pathologic features of cellular proliferation in neuroendocrine neoplasms. Ann Nucl Med 35, 1066–1077 (2021). https://doi.org/10.1007/s12149-021-01642-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12149-021-01642-3

Keywords

Search

Navigation