Incidence of PPGL according to altitude – Calendar time is of the essence

in European Journal of Endocrinology
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  • 1 Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
  • | 2 Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
  • | 3 Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark

Correspondence should be addressed to E Søndergaard Email esben.sondergaard@clin.au.dk
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We recently read the article by Leung et al. (1) on the incidence of pheochromocytoma and paraganglioma (PPGL) with great enthusiasm. However, we have some concerns regarding the recent speculations on the relationship between the incidence of PPGL and the ‘modifiable’ risk factor of altitude in the correspondence between Patel and Mihai (2) and Leung et al. (3). In the first letter, Patel and Mihai laid out the evidence for the pseudo-hypoxia model as a cause of PPGL (4) and speculate on a possible association between altitude, hypoxia, and PPGL. In their reply, Leung et al. report the results of a meta-regression analysis to support the theory.

Unfortunately, Leung et al. do not provide any detail on how papers in their meta-regression were selected, while a number of other studies were not included (5, 6, 7, 8, 9, 10, 11). We therefore searched for all papers presenting the incidence of PPGL in a defined geographic location. We screened the identified references and included 14 relevant papers. Taking all these studies into account and collecting annual incidence rates rather than study averages, we redid the meta-regression analysis on the incidence of PPGL and altitude. The search strategy, study data, and code are available on https://github.com/andreasebbehoj/2021-EJE-letter-PPGL-altitude-and-time. In our analysis, altitude was still a predictor of PPGL incidence (Fig. 1A). However, the regression line fits the data poorly (R2 = 23.0%), and there is considerable heterogeneity between estimates (I2 = 93.8%). Therefore, a meta-regression of these heterogenous studies should be interpreted with caution.

Figure 1
Figure 1

Meta-regression for (A) altitude and (B) calendar year using annual incidence rates. s.e. was calculated for all papers with Poisson based on the number of patients and the population at risk in each year. This was done to present data in a unified way, since CIs were not available in all papers.

Citation: European Journal of Endocrinology 186, 1; 10.1530/EJE-21-0680

It is surprising that Leung et al. do not find an association between time and incidence rate. This is in contrast with a combined systematic review and nationwide study by Berends et al. (12), who showed an increasing incidence of PPGL in both previously published studies and in the Netherlands. We find it worth noting that the study by Kim et al. (13) is the largest study in Leung et al.’s meta-analysis but seems to be an outlier compared to other recent studies (Fig. 1B). Kim et al.(13) base their incidence rates on an unvalidated registry-based algorithm, which combine diagnosis codes, surgery codes, and biochemical tests. Having previously validated another PPGL algorithm, we have no doubt that the combination of PPGL-related surgery and diagnosis codes will have a positive predictive value close to 100% but will also likely lead to an underreporting of PPGL patients by 20–40% (14). Underreporting does not invalidate Kim et al.’s clinical findings per se, but it is far from an ideal study design to determine the incidence of PPGL. Having said that, Kim et al.’s data do actually also show an increase in the incidence of PPGL over time.

Based on the included studies, we find it evident that the incidence of diagnosed PPGL is indeed increasing over time. The fact that Leung et al.’s meta-regression analysis does not find any association between incidence and year of publication raises the question if the year of publication is a good measure when studies often cover one or several decades. Indeed, if redoing the meta-regression with annual incidence rates, the time trend is clear, though estimates vary considerably (R2 = 47.0% and I2= 90.9%, Fig. 1B). If excluding Kim 2020, the association with time becomes even clearer (R2 = 70.3% and I2 = 81.5%), while the association with altitude remains poor (R2 = 21.6% and I2 = 92.3%).

In conclusion, while the potential role of altitude as a modifier for the pseudohypoxia-driven PPGL development is an intriguing connection, the selective reporting of incidence data of PPGL and failure to recognize the increase in incidence over time severely limits the value of the performed meta-regression analysis. While our re-analysis does not rebuff the altitude theory, we hope it may provide data for a more critical discussion of the theory.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this letter.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

References

  • 1

    Leung AA, Pasieka JL, Hyrcza MD, Pacaud D, Dong Y, Boyd JM, Sadrzadeh H, Kline GA. Epidemiology of pheochromocytoma and paraganglioma: population-based cohort study. European Journal of Endocrinology 2021 184 1928. (https://doi.org/10.1530/EJE-20-0628)

    • Search Google Scholar
    • Export Citation
  • 2

    Patel N, Mihai R. Relative hypoxia at high altitudes increases the incidence of phaeochromocytomas. European Journal of Endocrinology 2021 184 L17L19. (https://doi.org/10.1530/EJE-21-0063)

    • Search Google Scholar
    • Export Citation
  • 3

    Leung AA, Hyrcza MD, Pasieka JL, Kline GA. Incidence of pheochromocytoma and paraganglioma varies according to altitude: meta-regression analysis. European Journal of Endocrinology 2021 184 L21L23. (https://doi.org/10.1530/EJE-21-0258)

    • Search Google Scholar
    • Export Citation
  • 4

    Jochmanová I, Zhuang Z, Pacak K. Pheochromocytoma: gasping for air. Hormones and Cancer 2015 6 191205. (https://doi.org/10.1007/s12672-015-0231-4)

    • Search Google Scholar
    • Export Citation
  • 5

    De Graeff J, Horak BJV. The incidence of phaeochromocytoma in the Netherlands. Acta Medica Scandinavica 1964 176 583593. (https://doi.org/10.1111/j.0954-6820.1964.tb00661.x)

    • Search Google Scholar
    • Export Citation
  • 6

    Hartley L, Perry‐Keene D. Phaeochromocytoma in Queensland – 1970–1983. Australian and New Zealand Journal of Surgery 1985 55 471475. (https://doi.org/10.1111/j.1445-2197.1985.tb00925.x)

    • Search Google Scholar
    • Export Citation
  • 7

    Takayanagi R, Miura K, Nakagawa H, Nawata H. Epidemiologic study of adrenal gland disorders in Japan. Biomedicine and Pharmacotherapy 2000 54 (Supplement 1) 164s168s. (https://doi.org/10.1016/s0753-3322(0080036-0)

    • Search Google Scholar
    • Export Citation
  • 8

    Holland J, Chandurkar V. A retrospective study of surgically excised phaeochromocytomas in Newfoundland, Canada. Indian Journal of Endocrinology and Metabolism 2014 18 542–545. (https://doi.org/10.4103/2230-8210.137514)

    • Search Google Scholar
    • Export Citation
  • 9

    Cvasciuc IT, Gull S, Oprean R, Lim KH, Eatock F. Changing pattern of pheochromocytoma and paraganglioma in a stable UK population. Acta Endocrinologica 2020 16 7885. (https://doi.org/10.4183/aeb.2020.78)

    • Search Google Scholar
    • Export Citation
  • 10

    Ebbehoj A, Li D, Kaur RJ, Zhang C, Singh S, Li T, Atkinson E, Achenbach S, Khosla S & Arlt W et al.Epidemiology of adrenal tumours in Olmsted County, Minnesota, USA: a population-based cohort study. Lancet: Diabetes and Endocrinology 2020 8 894902. (https://doi.org/10.1016/S2213-8587(2030314-4)

    • Search Google Scholar
    • Export Citation
  • 11

    Ebbehoj A, Stochholm K, Jacobsen SF, Trolle C, Jepsen P, Robaczyk MG, Rasmussen ÅK, Feldt-Rasmussen U, Thomsen RW & Søndergaard E et al.Incidence and clinical presentation of pheochromocytoma and sympathetic paraganglioma: a population-based study. Journal of Clinical Endocrinology and Metabolism 2021 106 e2251e2261. (https://doi.org/10.1210/clinem/dgaa965)

    • Search Google Scholar
    • Export Citation
  • 12

    Berends AMA, Buitenwerf E, de Krijger RR, Veeger NJGM, van der Horst-Schrivers ANA, Links TP, Kerstens MN. Incidence of pheochromocytoma and sympathetic paraganglioma in the Netherlands: a nationwide study and systematic review. European Journal of Internal Medicine 2018 51 6873. (https://doi.org/10.1016/j.ejim.2018.01.015)

    • Search Google Scholar
    • Export Citation
  • 13

    Kim JH, Moon H, Noh J, Lee J & Kim SG Epidemiology and prognosis of pheochromocytoma/paraganglioma in Korea: a nationwide study based on the National Health Insurance Service. Endocrinology and Metabolism 2020 35 157164. (https://doi.org/10.3803/EnM.2020.35.1.157)

    • Search Google Scholar
    • Export Citation
  • 14

    Ebbehoj A, Jacobsen SF, Trolle C, Robaczyk MG, Rasmussen ÅK, Feldt-Rasmussen U, Thomsen RW, Poulsen PL, Stochholm K, Søndergaard E. Pheochromocytoma in Denmark during 1977–2016: validating diagnosis codes and creating a national cohort using patterns of health registrations. Clinical Epidemiology 2018 10 683695. (https://doi.org/10.2147/CLEP.S163065)

    • Search Google Scholar
    • Export Citation

 

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    Meta-regression for (A) altitude and (B) calendar year using annual incidence rates. s.e. was calculated for all papers with Poisson based on the number of patients and the population at risk in each year. This was done to present data in a unified way, since CIs were not available in all papers.

  • 1

    Leung AA, Pasieka JL, Hyrcza MD, Pacaud D, Dong Y, Boyd JM, Sadrzadeh H, Kline GA. Epidemiology of pheochromocytoma and paraganglioma: population-based cohort study. European Journal of Endocrinology 2021 184 1928. (https://doi.org/10.1530/EJE-20-0628)

    • Search Google Scholar
    • Export Citation
  • 2

    Patel N, Mihai R. Relative hypoxia at high altitudes increases the incidence of phaeochromocytomas. European Journal of Endocrinology 2021 184 L17L19. (https://doi.org/10.1530/EJE-21-0063)

    • Search Google Scholar
    • Export Citation
  • 3

    Leung AA, Hyrcza MD, Pasieka JL, Kline GA. Incidence of pheochromocytoma and paraganglioma varies according to altitude: meta-regression analysis. European Journal of Endocrinology 2021 184 L21L23. (https://doi.org/10.1530/EJE-21-0258)

    • Search Google Scholar
    • Export Citation
  • 4

    Jochmanová I, Zhuang Z, Pacak K. Pheochromocytoma: gasping for air. Hormones and Cancer 2015 6 191205. (https://doi.org/10.1007/s12672-015-0231-4)

    • Search Google Scholar
    • Export Citation
  • 5

    De Graeff J, Horak BJV. The incidence of phaeochromocytoma in the Netherlands. Acta Medica Scandinavica 1964 176 583593. (https://doi.org/10.1111/j.0954-6820.1964.tb00661.x)

    • Search Google Scholar
    • Export Citation
  • 6

    Hartley L, Perry‐Keene D. Phaeochromocytoma in Queensland – 1970–1983. Australian and New Zealand Journal of Surgery 1985 55 471475. (https://doi.org/10.1111/j.1445-2197.1985.tb00925.x)

    • Search Google Scholar
    • Export Citation
  • 7

    Takayanagi R, Miura K, Nakagawa H, Nawata H. Epidemiologic study of adrenal gland disorders in Japan. Biomedicine and Pharmacotherapy 2000 54 (Supplement 1) 164s168s. (https://doi.org/10.1016/s0753-3322(0080036-0)

    • Search Google Scholar
    • Export Citation
  • 8

    Holland J, Chandurkar V. A retrospective study of surgically excised phaeochromocytomas in Newfoundland, Canada. Indian Journal of Endocrinology and Metabolism 2014 18 542–545. (https://doi.org/10.4103/2230-8210.137514)

    • Search Google Scholar
    • Export Citation
  • 9

    Cvasciuc IT, Gull S, Oprean R, Lim KH, Eatock F. Changing pattern of pheochromocytoma and paraganglioma in a stable UK population. Acta Endocrinologica 2020 16 7885. (https://doi.org/10.4183/aeb.2020.78)

    • Search Google Scholar
    • Export Citation
  • 10

    Ebbehoj A, Li D, Kaur RJ, Zhang C, Singh S, Li T, Atkinson E, Achenbach S, Khosla S & Arlt W et al.Epidemiology of adrenal tumours in Olmsted County, Minnesota, USA: a population-based cohort study. Lancet: Diabetes and Endocrinology 2020 8 894902. (https://doi.org/10.1016/S2213-8587(2030314-4)

    • Search Google Scholar
    • Export Citation
  • 11

    Ebbehoj A, Stochholm K, Jacobsen SF, Trolle C, Jepsen P, Robaczyk MG, Rasmussen ÅK, Feldt-Rasmussen U, Thomsen RW & Søndergaard E et al.Incidence and clinical presentation of pheochromocytoma and sympathetic paraganglioma: a population-based study. Journal of Clinical Endocrinology and Metabolism 2021 106 e2251e2261. (https://doi.org/10.1210/clinem/dgaa965)

    • Search Google Scholar
    • Export Citation
  • 12

    Berends AMA, Buitenwerf E, de Krijger RR, Veeger NJGM, van der Horst-Schrivers ANA, Links TP, Kerstens MN. Incidence of pheochromocytoma and sympathetic paraganglioma in the Netherlands: a nationwide study and systematic review. European Journal of Internal Medicine 2018 51 6873. (https://doi.org/10.1016/j.ejim.2018.01.015)

    • Search Google Scholar
    • Export Citation
  • 13

    Kim JH, Moon H, Noh J, Lee J & Kim SG Epidemiology and prognosis of pheochromocytoma/paraganglioma in Korea: a nationwide study based on the National Health Insurance Service. Endocrinology and Metabolism 2020 35 157164. (https://doi.org/10.3803/EnM.2020.35.1.157)

    • Search Google Scholar
    • Export Citation
  • 14

    Ebbehoj A, Jacobsen SF, Trolle C, Robaczyk MG, Rasmussen ÅK, Feldt-Rasmussen U, Thomsen RW, Poulsen PL, Stochholm K, Søndergaard E. Pheochromocytoma in Denmark during 1977–2016: validating diagnosis codes and creating a national cohort using patterns of health registrations. Clinical Epidemiology 2018 10 683695. (https://doi.org/10.2147/CLEP.S163065)

    • Search Google Scholar
    • Export Citation