Skip to main content

Advertisement

SpringerLink
Log in

Increased Prevalence of Malignancies in Fibrous Dysplasia/McCune-Albright Syndrome (FD/MAS): Data from a National Referral Center and the Dutch National Pathology Registry (PALGA)

  • Original Research
  • Published:
Calcified Tissue International Aims and scope Submit manuscript

Abstract

Malignant transformation of fibrous dysplasia lesions has been reported in patients with fibrous dysplasia/McCune-Albright syndrome (FD/MAS). Recently, we have observed an increased risk for breast cancer. In this study, the prevalence of skeletal and extraskeletal malignancies in patients with FD/MAS in the Netherlands was assessed by analyzing data from our cohort of FD/MAS patients, the Dutch Pathology Registry (PALGA), and the Netherlands Cancer Registry (NCR). We extracted data on sex, age at diagnosis of FD/MAS, type of FD/MAS, type of malignancy, and age at diagnosis of malignancy and histology of bone and malignant tissue when available, including GNAS-mutation analysis from patients’ medical records. Standardized Morbidity Ratios (SMRs) with 95% confidence intervals were calculated. Twelve malignancies were identified in the LUMC FD/MAS cohort and 100 in the PALGA cohort. In this cohort, SMR was increased for osteosarcoma (19.7, 95% CI 3.5–48.9), cervical cancer (4.93, 95%CI 1.7–8.2), thyroid cancer (3.71, 95% CI 1.1–7.8), prostate cancer (3.08, 95% CI 1.8–4.6), and melanoma (2.01, 95%CI 1.2–3.1). SMRs for pancreatic cancer or hepatocellular carcinoma could not be calculated due to low numbers. The small number of malignancies identified in our FD/MAS cohort precluded the calculation of SMRs for our cohort specifically. Our findings show that patients with FD/MAS appear to have an increased risk for osteosarcoma, cervical, thyroid, and prostate cancer and melanoma. However, these data should be interpreted with caution, as true incidence rates of the identified malignancies may be influenced by the inclusion of only patients with histologically confirmed FD/MAS. The etiology of this increased risk for malignancies still needs to be elucidated.

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

Similar content being viewed by others

References

  1. Weinstein LSLJ, Sakamoto A, Xie T, Chen M (2004) Minireview: GNAS: normal and abnormal functions. Endocrinology 145(12):5459–5464

    CAS  PubMed  Google Scholar 

  2. O’Hayre M, Vazquez-Prado J, Kufareva I, Stawiski EW, Handel TM, Seshagiri S, Gutkind JS (2013) The emerging mutational landscape of G-proteins and G-protein coupled receptors in cancer. Nat Rev Cancer 13(6):412–424

    PubMed  PubMed Central  Google Scholar 

  3. Boyce AMCW, Shawker TH, Pinto PA, Linehan WM, Bhattacharryya N, Merino MJ, Singer FR, Collins MT (2012) Characterization and management of testicular pathology in McCune-albright syndrome. J Clin Endocrinol Metab 97(9):E1782–E1790

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Penn DL, Tartarini RJ, Glass CH, De Girolami U, Zamani AA, Dunn IF (2017) Natural history of cranial fibrous dysplasia revealed during long-term follow-up: case report and literature review. Surg Neurol Int 8:209

    PubMed  PubMed Central  Google Scholar 

  5. DiCaprio MREW (2005) Fibrous dysplasia. Pathophysiology, evaluation and treatment. J Bone Joint Surg Am 87(8):1848–1864

    PubMed  Google Scholar 

  6. Riddle NDBM (2013) Fibrous dysplasia. Arch Pathol Lab Med 137(1):134–138

    CAS  PubMed  Google Scholar 

  7. Majoor BCJ, van de Sande MAJ, Appelman-Dijkstra NM, Leithner A, Jutte PC, Velez R et al (2019) Prevalence and clinical features of mazabraud syndrome: a multicenter European study. J Bone Joint Surg Am 101(2):160–168

    PubMed  Google Scholar 

  8. Wood LD, Noe M, Hackeng W, Brosens LA, Bhaijee F, Debeljak M et al (2017) Patients with McCune-Albright syndrome have a broad spectrum of abnormalities in the gastrointestinal tract and pancreas. Virchows Arch 470(4):391–400

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Parvanescu ACJ, Ronot M, Hentic O, Grybek V, Couvelard A, Levy P, Chanson P, Ruszniewski P, Sauvanet A, Gaujoux S (2014) Lessons from McCune-albright syndrome-associated intraductal papillary mucinous neoplasms—GNAS-activating mutations in pancreatic carcinogenesis. JAMA Surg 149(8):858–862

    PubMed  Google Scholar 

  10. Gaujoux SSS, Ronot M, Rangheard AS, Cros J, Belghiti J, Sauvanet A, Ruszniewski P, Chanson P (2014) Hepatobiliary and Pancreatic neoplasms in patients with McCune-Albright syndrome. J Clin Endocrinol Metab 99(1):E97-101

    PubMed  Google Scholar 

  11. Collins MTSN, Merino MJ, Monroe J, Crawford SE, Krakoff JA, Guthrie LC, Bonat S, Robey PG, Shenker A (2003) Thyroid carcinoma in the McCune-Albright syndrome: contributory role of activating Gs alpha mutations. J Clin Endocrinol Metab 88(9):4413–4417

    CAS  PubMed  Google Scholar 

  12. Chevalier NPF, Fontana S, Delotte J, Gaspari L, Ferrari P, Sultan C, Fénichel P (2015) Postpubertal persistent hyperestrogenemia in McCune-albright syndrome: unilateral oophorectomy improved fertility but detected an unexpected borderline epithelial ovarian tumor. J Periatr Adolesc Gynecol 28(6):e169–e172

    Google Scholar 

  13. Huston TLSR (2004) Ductal carcinoma in situ in a 27-year-old woman with McCune-albright syndrome. Breast J 10(5):440–442

    PubMed  Google Scholar 

  14. Nault JC, Fabre M, Couchy G, Pilati C, Jeannot E, Van Nhieu JT, Saint-Paul MC, De Muret A, Redon MJ, Buffet C, Salenave S, Balabaud C, Prevot S, Labrune P, Bioulac-Sage P, Scoazec JY, Chanson P, Zucman-Rossi J (2012) GNAS-activating mutations define a rare subgroup of inflammatory liver tumors characterized by STAT3 activation. J Hepatol 56(1):184–191

    CAS  PubMed  Google Scholar 

  15. Majoor BC, Boyce AM, Bovee JV, Smit VT, Collins MT, Cleton-Jansen AM et al (2018) Increased risk of breast cancer at a young age in women with fibrous dysplasia. J Bone Miner Res 33(1):84–90

    CAS  PubMed  Google Scholar 

  16. Matsubara A, Sekine S, Kushima R, Ogawa R, Taniguchi H, Tsuda H et al (2013) Frequent GNAS and KRAS mutations in pyloric gland adenoma of the stomach and duodenum. J Pathol 229(4):579–587

    CAS  PubMed  Google Scholar 

  17. van den Hurk K, Balint B, Toomey S, O’Leary PC, Unwin L, Sheahan K et al (2015) High-throughput oncogene mutation profiling shows demographic differences in BRAF mutation rates among melanoma patients. Melanoma Res 25(3):189–199

    PubMed  Google Scholar 

  18. Frey UH, Eisenhardt A, Lummen G, Rubben H, Jockel KH, Schmid KW et al (2005) The T393C polymorphism of the G alpha s gene (GNAS1) is a novel prognostic marker in bladder cancer. Cancer Epidemiol Biomarkers Prev 14(4):871–877

    CAS  PubMed  Google Scholar 

  19. Casparie M, Tiebosch AT, Burger G, Blauwgeers H, van de Pol A, van Krieken JH et al (2007) Pathology databanking and biobanking in The Netherlands, a central role for PALGA, the nationwide histopathology and cytopathology data network and archive. Cell Oncol 29(1):19–24

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Nomura R, Saito T, Mitomi H, Hidaka Y, Lee SY, Watanabe S et al (2014) GNAS mutation as an alternative mechanism of activation of the Wnt/beta-catenin signaling pathway in gastric adenocarcinoma of the fundic gland type. Hum Pathol 45(12):2488–2496

    CAS  PubMed  Google Scholar 

  21. Matsubara A, Sekine S, Ogawa R, Yoshida M, Kasamatsu T, Tsuda H et al (2014) Lobular endocervical glandular hyperplasia is a neoplastic entity with frequent activating GNAS mutations. Am J Surg Pathol 38(3):370–376

    PubMed  Google Scholar 

  22. IKNL. Nederlandse Kankerregistratie. 2017.

  23. Thorvaldsdottir H, Robinson JT, Mesirov JP (2013) Integrative genomics viewer (IGV): high-performance genomics data visualization and exploration. Brief Bioinform 14(2):178–192

    CAS  PubMed  Google Scholar 

  24. Lopez-Ben R, Pitt MJ, Jaffe KA, Siegal GP (1999) Osteosarcoma in a patient with McCune-Albright syndrome and Mazabraud’s syndrome. Skeletal Radiol 28:522–526

    CAS  PubMed  Google Scholar 

  25. Qu N, Yao W, Cui X, Zhang H (2015) Malignant transformation in monostotic fibrous dysplasia: clinical features, imaging features, outcomes in 10 patients, and review. Medicine (Baltimore) 94(3):e369

    Google Scholar 

  26. Schwartz DTAM (1964) The malignant transformation of fibrous dysplasia. Am J Med Si 247:1–20

    CAS  Google Scholar 

  27. Ruggieri PSF, Bond JR, Unni KK (1994) Malignancies in fibrous dysplasia. Cancer 73(5):1411–1423

    CAS  PubMed  Google Scholar 

  28. Dumitrescu CE, Collins MT (2008) McCune-Albright syndrome Orphanet. J Rare Dis 3:12

    Google Scholar 

  29. Jhala DNEI, Carroll AJ, Lopez-Ben R, Lopez-Terrada D, Rao PH, Pettenati MJ, Siegal GP (2003) Osteosarcoma in a patient with McCune-Albright syndrome and Mazabraud’s syndrome: a case report emphasizing the cytological and cytogenetic findings. Hum Pathol 34(12):1354–1357

    PubMed  Google Scholar 

  30. Collins MT, Bianco P et al (2013) Primer on the metabolic bone diseases and disorders of mineral metabolism. Wiley, Hoboken

    Google Scholar 

  31. Collins MT, Singer FR, Eugster E (2012) McCune-Albright syndrome and the extraskeletal manifestations of fibrous dysplasia. Orphanet J Rare Dis. 7(Suppl 1):4

    Google Scholar 

  32. Lopez-Ben RPM, Jaffe KA, Siegal GP (1999) Osteosarcoma in a patient with McCune-Albright syndrome and Mazabraud’s syndrome. Skelet Radiol 28(9):522–526

    CAS  Google Scholar 

  33. Liu FLW, Yao Y, Li G, Yang Y, Dou W, Zhong D, Wang L, Zhu X, Hu H, Zhang J, Wang R, Chen G (2011) A case of McCune-Albright syndrome associated with pituitary GH adenoma: therapeutic process and autopsy. J Periatr Endocrinol Metab 24(5–6):283–287

    Google Scholar 

  34. Ruchala M, Wolinski K (2019) Health-related complications of acromegaly-risk of malignant neoplasms. Front Endocrinol 10:268

    Google Scholar 

  35. Shanmugalingam T, Bosco C, Ridley AJ, Van Hemelrijck M (2016) Is there a role for IGF-1 in the development of second primary cancers? Cancer Med 5(11):3353–3367

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Allen NE, Key TJ, Appleby PN, Travis RC, Roddam AW, Rinaldi S et al (2007) Serum insulin-like growth factor (IGF)-I and IGF-binding protein-3 concentrations and prostate cancer risk: results from the European prospective investigation into cancer and nutrition. Cancer Epidemiol Biomarkers Prev 16(6):1121–1127

    CAS  PubMed  Google Scholar 

  37. Finne P, Auvinen A, Koistinen H, Zhang WM, Maattanen L, Rannikko S et al (2000) Insulin-like growth factor I is not a useful marker of prostate cancer in men with elevated levels of prostate-specific antigen. J Clin Endocrinol Metab 85(8):2744–2747

    CAS  PubMed  Google Scholar 

  38. Lukanova A, Zeleniuch-Jacquotte A, Lundin E, Micheli A, Arslan AA, Rinaldi S et al (2004) Prediagnostic levels of C-peptide, IGF-I, IGFBP -1, -2 and -3 and risk of endometrial cancer. Int J Cancer 108(2):262–268

    CAS  PubMed  Google Scholar 

  39. Mikami K, Ozasa K, Nakao M, Miki T, Hayashi K, Watanabe Y et al (2009) Prostate cancer risk in relation to insulin-like growth factor (IGF)-I and IGF-binding protein-3: a nested case-control study in large scale cohort study in Japan. Asian Pac J Cancer Prev 10(Suppl):57–61

    PubMed  Google Scholar 

  40. Pham TM, Fujino Y, Kikuchi S, Tamakoshi A, Yatsuya H, Matsuda S et al (2007) A nested case-control study of stomach cancer and serum insulin-like growth factor (IGF)-1, IGF-2 and IGF-binding protein (IGFBP)-3. Eur J Cancer 43(10):1611–1616

    CAS  PubMed  Google Scholar 

  41. Sakauchi F, Nojima M, Mori M, Wakai K, Suzuki S, Tamakoshi A et al (2009) Serum insulin-like growth factors I and II, insulin-like growth factor binding protein-3 and risk of breast cancer in the Japan Collaborative Cohort study. Asian Pac J Cancer Prev 10(Suppl):51–55

    PubMed  Google Scholar 

  42. Spitz MR, Barnett MJ, Goodman GE, Thornquist MD, Wu X, Pollak M (2002) Serum insulin-like growth factor (IGF) and IGF-binding protein levels and risk of lung cancer: a case-control study nested in the beta-carotene and retinol efficacy trial cohort. Cancer Epidemiol Biomarkers Prev 11(11):1413–1418

    CAS  PubMed  Google Scholar 

  43. Suzuki S, Kojima M, Tokudome S, Suzuki K, Ozasa K, Ito Y et al (2009) Insulin-like growth factor (IGF)-I, IGF-II, IGF binding protein-3, and risk of colorectal cancer: a nested case-control study in the Japan collaborative cohort study. Asian Pac J Cancer Prev 10(Suppl):45–49

    PubMed  Google Scholar 

  44. Weinstein LSSA, Gejman PV, Merino MJ, Friedman E, Spiegel AM (1991) Activating mutations of the stimulatory G protein in the McCune–albright syndrome. N Engl J Med 325(24):1688–1695

    CAS  PubMed  Google Scholar 

  45. Szuhai K, Cleton-Jansen AM, Hogendoorn PC, Bovee JV (2012) Molecular pathology and its diagnostic use in bone tumors. Cancer Genet 205(5):193–204

    CAS  PubMed  Google Scholar 

  46. Fukumoto S, Martin TJ (2009) Bone as an endocrine organ. Trends Endocrinol Metab 20(5):230–236

    CAS  PubMed  Google Scholar 

  47. Boyce AM, Florenzano P, de Castro LF, Collins MT (1993) Fibrous dysplasia/McCune-albright syndrome. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K et al (eds) GeneReviews . University of washington, Seattle WA

    Google Scholar 

  48. Lee NK, Sowa H, Hinoi E, Ferron M, Ahn JD, Confavreux C et al (2007) Endocrine regulation of energy metabolism by the skeleton. Cell 130(3):456–469

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Croucher PI, McDonald MM, Martin TJ (2016) Bone metastasis: the importance of the neighbourhood. Nat Rev Cancer 16(6):373–386

    CAS  PubMed  Google Scholar 

  50. Feng S, Wang J, Zhang Y, Creighton CJ, Ittmann M (2015) FGF23 promotes prostate cancer progression. Oncotarget 6(19):17291–17301

    PubMed  PubMed Central  Google Scholar 

  51. de Groot AF, Appelman-Dijkstra NM, van der Burg SH, Kroep JR (2018) The anti-tumor effect of RANKL inhibition in malignant solid tumors—a systematic review. Cancer Treat Rev 62:18–28

    PubMed  Google Scholar 

Download references

Funding

This work was funded by a grant regarding research into fibrous dysplasia from the Bontius Foundation of the Leiden University Medical Center. Marlous Hagelstein-Rotman and Bas C.J. Majoor were supported by grants from Leiden University’s Bontius Foundation during the conduct of the study.

Author information

Authors and Affiliations

  1. Department of Medicine, Division Endocrinology, Center for Bone Quality, Leiden University Medical Center, Leiden, The Netherlands

    M. Hagelstein-Rotman, N. A. T. Hamdy, O. M. Dekkers & N. M. Appelman-Dijkstra

  2. Department of Orthopaedic Surgery, Center for Bone Quality, Leiden University Medical Center, Leiden, The Netherlands

    M. E. Meier, B. C. J. Majoor, P. D. S. Dijkstra & M. A. J. van de Sande

  3. Department of Pathology, Center for Bone Quality, Leiden University Medical Center, Leiden, The Netherlands

    A. H. G. Cleven

  4. Department of Epidemiology, Center for Bone Quality, Leiden University Medical Center, Leiden, The Netherlands

    O. M. Dekkers

  5. Department of Epidemiology, Aarhus University Hospital, Aarhus, Denmark

    O. M. Dekkers

Authors
  1. M. Hagelstein-Rotman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. E. Meier
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. B. C. J. Majoor
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. H. G. Cleven
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. P. D. S. Dijkstra
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. N. A. T. Hamdy
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M. A. J. van de Sande
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. O. M. Dekkers
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. N. M. Appelman-Dijkstra
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The study was designed by MH-R, PDSD, NATH, OMD, and NMA‐D. Acquisition of the data was performed by MH-R, MEM, and NMA‐D. Analysis and interpretation of the data were performed by MH-R, MEM, BCJM, AGHC, PDSD, NATH, MAJS, OMD, and NMA‐D. Drafting of the manuscript, including critical revision, was performed by all authors. All authors accept responsibility for the integrity of the data analysis.

Corresponding author

Correspondence to M. Hagelstein-Rotman.

Ethics declarations

Conflict of interest

M. Hagelstein-Rotman, M.E. Meier, B.C.J. Majoor, A.H.G. Cleven, P.D.S. Dijkstra, N.A.T. Hamdy, M.A.J. van de Sande, O.M. Dekkers, and N.M. Appelman-Dijkstra declare that they have no conflicts of interest.

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

Hagelstein-Rotman, M., Meier, M.E., Majoor, B.C.J. et al. Increased Prevalence of Malignancies in Fibrous Dysplasia/McCune-Albright Syndrome (FD/MAS): Data from a National Referral Center and the Dutch National Pathology Registry (PALGA). Calcif Tissue Int 108, 346–353 (2021). https://doi.org/10.1007/s00223-020-00780-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00223-020-00780-6

Keywords

Search

Navigation