Incidence of pheochromocytoma and paraganglioma varies according to altitude: meta-regression analysis

in European Journal of Endocrinology
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  • 1 Division of Endocrinology and Metabolism, Department of Medicine
  • 2 Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada
  • 3 Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada
  • 4 Alberta Precision Laboratories, Alberta Health Services, Calgary, Alberta, Canada
  • 5 Department of Surgery, University of Calgary, Calgary, Alberta, Canada

Correspondence should be addressed to A A Leung; Email: aacleung@ucalgary.ca

We thank Drs Patel and Mihai for their interest in our article where we described the incidence of pheochromocytoma and paraganglioma in Alberta, Canada (1). In their letter (2), they raised important points related to the role of hypoxia in tumorigenesis, highlighting the supporting evidence to date.

Exposure to high altitude may indeed be a modifiable risk factor for pheochromocytoma and paraganglioma. However, it is admittedly difficult to examine the epidemiology of this association on a large population scale because of the inherent challenges in accurately quantifying the cumulative risk and the intensity of exposure over the period of a person’s lifetime (e.g. for those who live at different altitudes throughout their lives) (3). Accordingly, as Drs Patel and Mihai point out, the best available evidence may be derived from comparisons of existing studies that were conducted in populations of different altitudes.

Addressing this, we examined the global incidence of pheochromocytoma and paraganglioma across available studies, accounting for differences in altitude and barometric pressure (Table 1). To facilitate comparisons, the annual incidence proportions per 100 000 people along with corresponding 95% CIs were extracted, if possible (or otherwise manually calculated) (4). The altitude of the population was based on the average elevation of the geographic location of the study (https://en-ca.topographic-map.com; accessed March 2, 2021) and the corresponding barometric pressure (PB) in Torr estimated using the Model Atmosphere equation (5): PB = e(6.63268 − 0.1112 × (altitude in km) − 0.00149 × (altitude in km) × (altitude in km)). We then conducted a meta-analysis using restricted maximum likelihood estimates with a random-effects model. Statistical heterogeneity was assessed and quantified using the Cochran Q test and I2 statistic, respectively (6). We explored potential explanations for between-study heterogeneity using meta-regression.

Table 1

Summary of studies reporting incidence of pheochromocytoma and paraganglioma.

ReferenceYears of observationLocationData sourcesPopulation base, n*Tumor typeAltitude, m (barometric pressure, Torr)Incidence, cases per 100 000 people per year (95% CI)
(7)1977–1981DenmarkHospital discharge records, anatomic pathology, biochemistry, and diagnostic imaging5 000 000PH64 (754)0.19 (0.14, 0.25)
(8)1950–1979Rochester, MN, USALinked health records45 800PH+PGL355 (730)0.95 (0.43, 1.46)
(9)1995–2015NetherlandsPathology registry16 367 158PH+PGL134 (748)0.57 (0.49, 0.66)
(10)1980–1992South Galicia, SpainMedical registry523 934PH297 (735)0.21 (0.10, 0.31)
(11)2003–2014South KoreaAdministrative health data50 000 000PH+PGL72 (753)0.18 (0.14, 0.22)
(1)2012–2019Alberta, CanadaAdministrative health data, chart review, diagnostic imaging, anatomical pathology, autopsy records5 196 368PH+PGL773 (696)0.66 (0.57, 0.74)
(12)1958–1981SwedenCancer registry7 947 000PH+PGL120 (749)0.21 (0.11, 0.31)

*When available, as reported in the original study (1, 7, 8, 10, 12), otherwise estimated based on population size (https://worldpopulationreview.com/countries/) closest to the mid-year of study as possible (9, 11); When available, as reported in the original study ((1, 7, 12 and in Table 1 of (10)); otherwise, incidence proportion (IP) calculated from the number of reported cases, number at risk (n), and observation time where variance = (IP (1 − IP)) ÷ n (i.e. (8, 11) (for last year of study)); or, calculated based on age-standardised incidence rates (IR) and follow-up time (t) where incidence proportion, IP = 1 − e(−IR× t) with the assumption that age-standardised rates were similar to crude rates (9).

CI, confidence intervals; PGL, paraganglioma; PH, pheochromocytoma.

We identified a total of seven studies that reported on the incidence of pheochromocytoma and paraganglioma over the last seven decades (Table 1) (1, 7, 8, 9, 10, 11, 12). There were large differences between the studies as related to the geographic locations, data sources, and the types of tumours ascertained. The pooled annual incidence proportion was 0.38 cases per 100 000 people (95% CI: 0.20 to 0.57 cases per 100 000 people) and this was associated with large statistical heterogeneity (P < 0.01; I2 = 97.5%) (13). Meta-regression confirmed that altitude was significantly associated with the occurrence of pheochromocytoma and paraganglioma (Fig. 1), revealing that for every 500-m increase in elevation (i.e. roughly corresponding to the difference between Milan, Italy and Madrid, Spain, situated at 122 m and 667 m above sea level, respectively), the annual incidence proportion was estimated to increase by 0.31 cases per 100 000 people (95% CI: 0.01–0.61 cases per 100 000 people; P = 0.046). Meta-regression analysis revealed an inverse association between incidence and barometric pressure. However, inclusion of altitude (or barometric pressure) only reduced the I2 value to 95.8% (meaning, there was still large amounts of residual between-study variance). Moreover, there were no statistically significant differences in incidence when examined according to publication year (P = 0.53), or whether pheochromocytoma alone vs a combination of pheochromocytoma and paraganglioma were considered (P = 0.19).

Figure 1
Figure 1

Meta-regression line for annual incidence proportion and altitude. Circles are the observed estimates; size is based on the inverse of the s.e. of each study; the grey area represents the bounds of the 95% CIs.

Citation: European Journal of Endocrinology 184, 5; 10.1530/EJE-21-0258

The findings of the meta-regression analysis indicate that the incidence of pheochromocytoma and paraganglioma varies according to altitude, as is consistent with previous studies suggesting that hypoxia mediates tumorigenesis (3, 14). Here, however, variations between studies were only partially explained by altitude; other important factors that likely impacted study estimates were differences in study quality as well as the presence of true clinical and genetic heterogeneity. As such, while the elevation of Alberta, Canada may be part of the reason that there was a high incidence of tumors in our study compared to others (1), it is also likely our use of comprehensive data sources and inclusion of head-and-neck paragangliomas (which have generally been undercounted and underrepresented in previous studies) were considerable contributing factors as well. Future high-quality, comprehensive, and comparable studies in other jurisdictions of differing altitudes would be ideal for examining this association further.

Declaration of interest

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

Funding

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

Author contribution statement

All authors contributed to the writing of this letter. All authors read and approved the final manuscript for publication.

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

    Astrom K, Cohen JE, Willett-Brozick JE, Aston CE & Baysal BE Altitude is a phenotypic modifier in hereditary paraganglioma type 1: evidence for an oxygen-sensing defect. Human Genetics 2003 113 228237. (https://doi.org/10.1007/s00439-003-0969-6)

    • Search Google Scholar
    • Export Citation
  • 4

    Greenland S & Rothman KJ Measures of occurrence. In Modern Epidemiology, pp. 3250. Eds Rothman KJ, Greenland S, Lash TLPhiladelphia: Lippincott Williams & Wilkins, 2008.

    • Search Google Scholar
    • Export Citation
  • 5

    West JB Prediction of barometric pressures at high altitude with the use of model atmospheres. Journal of Applied Physiology 1996 81 18501854. (https://doi.org/10.1152/jappl.1996.81.4.1850)

    • Search Google Scholar
    • Export Citation
  • 6

    Thompson SG & Higgins JP How should meta-regression analyses be undertaken and interpreted? Statistics in Medicine 2002 21 15591573. (https://doi.org/10.1002/sim.1187)

    • Search Google Scholar
    • Export Citation
  • 7

    Andersen GS, Toftdahl DB, Lund JO, Strandgaard S & Nielsen PE The incidence rate of phaeochromocytoma and Conn’s syndrome in Denmark, 1977–1981. Journal of Human Hypertension 1988 2 187189.

    • Search Google Scholar
    • Export Citation
  • 8

    Beard CM, Sheps SG, Kurland LT, Carney JA & Lie JT Occurrence of pheochromocytoma in Rochester, Minnesota, 1950 through 1979. Mayo Clinic Proceedings 1983 58 802804.

    • Search Google Scholar
    • Export Citation
  • 9

    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
  • 10

    Fernandez-Calvet L & Garcia-Mayor RV Incidence of pheochromocytoma in South Galicia, Spain. Journal of Internal Medicine 1994 236 675677. (https://doi.org/10.1111/j.1365-2796.1994.tb00861.x)

    • Search Google Scholar
    • Export Citation
  • 11

    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
  • 12

    Stenstrom G & Svardsudd K Pheochromocytoma in Sweden 1958–1981. An analysis of the National Cancer Registry Data. Acta Medica Scandinavica 1986 220 225232.

    • Search Google Scholar
    • Export Citation
  • 13

    Higgins JP, Thompson SG, Deeks JJ & Altman DG Measuring inconsistency in meta-analyses. BMJ 2003 327 557560. (https://doi.org/10.1136/bmj.327.7414.557)

    • Search Google Scholar
    • Export Citation
  • 14

    Her YF, Nelson-Holte M & Maher 3rd LJ Oxygen concentration controls epigenetic effects in models of familial paraganglioma. PLoS ONE 2015 10 e0127471. (https://doi.org/10.1371/journal.pone.0127471)

    • Search Google Scholar
    • Export Citation

 

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    Meta-regression line for annual incidence proportion and altitude. Circles are the observed estimates; size is based on the inverse of the s.e. of each study; the grey area represents the bounds of the 95% CIs.

  • 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

    Astrom K, Cohen JE, Willett-Brozick JE, Aston CE & Baysal BE Altitude is a phenotypic modifier in hereditary paraganglioma type 1: evidence for an oxygen-sensing defect. Human Genetics 2003 113 228237. (https://doi.org/10.1007/s00439-003-0969-6)

    • Search Google Scholar
    • Export Citation
  • 4

    Greenland S & Rothman KJ Measures of occurrence. In Modern Epidemiology, pp. 3250. Eds Rothman KJ, Greenland S, Lash TLPhiladelphia: Lippincott Williams & Wilkins, 2008.

    • Search Google Scholar
    • Export Citation
  • 5

    West JB Prediction of barometric pressures at high altitude with the use of model atmospheres. Journal of Applied Physiology 1996 81 18501854. (https://doi.org/10.1152/jappl.1996.81.4.1850)

    • Search Google Scholar
    • Export Citation
  • 6

    Thompson SG & Higgins JP How should meta-regression analyses be undertaken and interpreted? Statistics in Medicine 2002 21 15591573. (https://doi.org/10.1002/sim.1187)

    • Search Google Scholar
    • Export Citation
  • 7

    Andersen GS, Toftdahl DB, Lund JO, Strandgaard S & Nielsen PE The incidence rate of phaeochromocytoma and Conn’s syndrome in Denmark, 1977–1981. Journal of Human Hypertension 1988 2 187189.

    • Search Google Scholar
    • Export Citation
  • 8

    Beard CM, Sheps SG, Kurland LT, Carney JA & Lie JT Occurrence of pheochromocytoma in Rochester, Minnesota, 1950 through 1979. Mayo Clinic Proceedings 1983 58 802804.

    • Search Google Scholar
    • Export Citation
  • 9

    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
  • 10

    Fernandez-Calvet L & Garcia-Mayor RV Incidence of pheochromocytoma in South Galicia, Spain. Journal of Internal Medicine 1994 236 675677. (https://doi.org/10.1111/j.1365-2796.1994.tb00861.x)

    • Search Google Scholar
    • Export Citation
  • 11

    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
  • 12

    Stenstrom G & Svardsudd K Pheochromocytoma in Sweden 1958–1981. An analysis of the National Cancer Registry Data. Acta Medica Scandinavica 1986 220 225232.

    • Search Google Scholar
    • Export Citation
  • 13

    Higgins JP, Thompson SG, Deeks JJ & Altman DG Measuring inconsistency in meta-analyses. BMJ 2003 327 557560. (https://doi.org/10.1136/bmj.327.7414.557)

    • Search Google Scholar
    • Export Citation
  • 14

    Her YF, Nelson-Holte M & Maher 3rd LJ Oxygen concentration controls epigenetic effects in models of familial paraganglioma. PLoS ONE 2015 10 e0127471. (https://doi.org/10.1371/journal.pone.0127471)

    • Search Google Scholar
    • Export Citation