Relative hypoxia at high altitudes increases the incidence of phaeochromocytomas

in European Journal of Endocrinology
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  • 1 Department of Endocrine Surgery, Churchill Cancer Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, Oxfordshire, UK

Correspondence should be addressed to R Mihai; Email: radumihai@doctors.org.uk

We read with great interest the recent paper reporting a high incidence of phaeochromocytomas and paragangliomas in an unselected population from the western region of Canada (1). All cases were identified based on clinical data available over a 7 years period. Interestingly, Alberta has a higher altitude (3678 ft, https://en-gb.topographic-map.com/maps/lrg4/Alberta/) compared with other geographical areas from where a lower incidence was reported in previous papers (Table 1). Similarly, detailed epidemiological data from multiple geographical area are not easily available. Previous reports involving the entire USA population cannot be scrutinised as they lack ‘granular details’ regarding states with different altitudes. There is, however, a convincing trend that suggests that high altitude (as in Alberta) and its associated relative hypoxia modulate the risk of development of phaeochromocytomas.

Table 1

Regional variability in incidence of phaeochromocytoma.

RefData sourceCountryAverage altitudeAge-standardized incidence rates (per 100 000 person-years)
2Dutch pathology registry

Netherlands

(1995–2015)
98 ft (30 m)Phaeo: 0.29 (95% CI: 0.24–0.33) to 0.46 (95% CI: 0.39–0.53)

PGL 0.08 (95% CI: 0.06–0.10) and 0.11 (95% CI: 0.09–0.13)
3National Health Insurance Service Database

South Korea

(2003–2014)
925 ft (282 m)0.18
4 National cancer registry

Sweden

(1958–1981)
1050 ft (320 m)0.21
5Epidemiology studyRochester, Minnesota

(1950–1979)
1100 ft (314 m)0.8
6Population studySouth Galicia, Spain

(1980–1992)
1296 ft0.2 (range 0.0–0.39) per million.

In support of this hypothesis, in an analysis of 58 subjects from 23 families with SDHD mutations, subjects with phaeochromocytomas lived at higher altitudes and were exposed to higher altitude-years than those without them. Furthermore, those who were diagnosed with single tumours at their first clinical evaluation lived at lower average altitudes and were exposed to lower altitude-years than those with multiple tumours (7). Population-weighted elevations were approximately 260 m for the United States and 2 m for the central-Western Netherlands (P~0), suggesting that low altitudes in The Netherlands reduce penetrance and relax the natural selection on SDHD mutations (7).

Previous basic research data provide a mechanism that could explain this relation through the pseudohypoxia model. Hypoxia-induced factor (HIF2α) is more intensely expressed in both noradrenergic sporadic and hereditary von–Hippel Lindau (VHL)-related tumours than in sporadic and familial adrenergic tumours . HIF-2α is also expressed in developing sympathetic neurones, where it regulates the expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine synthesis (8). Such expression might confer onto these cells a susceptibility to VHL-associated tumorigenesis, thereby explaining both the development of such tumours and their associated noradrenergic phenotype (9).

Robust data is available on the ability of hypoxia to modulate enzymatic activity needed for catecholamine production. Long-term hypoxia in ewes maintained at high altitude (3820 m) results in a selective reduction in plasma adrenaline following acute stress, due to a reduction in tyrosine hydroxylase (TH), dopamine beta-hydroxylase (DBH) and phenylethanolamine N-methyltransferase (PNMT) expression (10). In animals conceived, born and raised at high altitude (3800 m, 13% PO2), the activities of the synthesizing enzymes, TH, DDC and PNMT, were variably affected at some time during the perinatal period. The activities of the catabolizing enzymes, MAO and COMT, at high altitude were increased on the last days of gestation but depressed after birth (11).

In laboratory settings, mouse pheochromocytoma cells (MP712 cells) showed a two-fold increase in PNMT mRNA after incubation in 5%O2, with an inverse relationship between PNMT gene reporter gene expression and O2 concentration between 10 and 1%. Anoxia evokes the most pronounced response, detectable within 15 min, becoming maximal at 45 min then subsiding to normoxic levels by 120 min (12).

Traditionally it is considered that noradrenaline (NA) and adrenaline (Adr) are stored in different types of intracellular granules. In a previous study using electron microscopy we found no correlation between the proportion of adrenergic granules (range 7–89%) and the output of catecholamines as assessed by 24-h urine catecholamine levels (13). If the morphology of tumour granules is not directly correlated with its biochemical profile, it remains likely that intra-tumoural functional changes modulate the catecholamine output. When the histology reports from 92 phaeochromocytomas were scrutinised, we found that patients whose tumours contained areas of necrosis/haemorrhage (i.e. assumed to be ischaemic tumours) had a tendency for higher adrenaline secretion as reflected by higher metanephrine/normetanephrine ratio (median: 0.432 (0.005–3.0820) vs 0.334 (0.004–16.073) (Fig. 1). It remains to be confirmed whether changes in hypoxia-induced PNMT activity modulate the pattern of catecholamine secretion from individual tumours.

Figure 1
Figure 1

Metanephrine/normetanephrine ratios in 92 patients with phaeochromocytomas. Filled circles: with necrosis or haemorrhage; open circle: no necrosis and no haemorrhage.

Citation: European Journal of Endocrinology 184, 5; 10.1530/EJE-21-0063

In summary, the recent publication by Leung et al. in a recent issue of the European Journal of Endocrinology reinforces the concept that variability of phaechromocytoma incidence in different parts of the world is, at least partially, due to the impact of physical factors represented by variable partial pressure of oxygen at different altitudes. This would be a translation to population level of the accepted hypoxic signature on cellular and tumoural secretion of catecholamines from phaeochromocytomas.

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
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  • 2

    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
  • 3

    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
  • 4

    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
  • 5

    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
  • 6

    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
  • 7

    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
  • 8

    Favier J, Kempf H, Corvol P & Gasc JM Cloning and expression pattern of EPAS1 in the chicken embryo. Colocalization with tyrosine hydroxylase. FEBS Letters 1999 462 1924. (https://doi.org/10.1016/s0014-5793(9901476-3)

    • Search Google Scholar
    • Export Citation
  • 9

    Eisenhofer G, Huynh TT, Pacak K, Brouwers FM, Walther MM, Linehan WM, Munson PJ, Mannelli M, Goldstein DS & Elkahloun AG Distinct gene expression profiles in norepinephrine- and epinephrine-producing hereditary and sporadic pheochromocytomas: activation of hypoxia-driven angiogenic pathways in von Hippel-Lindau syndrome. Endocrine-Related Cancer 2004 11 897911. (https://doi.org/10.1677/erc.1.00838)

    • Search Google Scholar
    • Export Citation
  • 10

    Ducsay CA, Hyatt K, Mlynarczyk M, Root BK, Kaushal KM & Myers DA Long-term hypoxia modulates expression of key genes regulating adrenomedullary function in the late gestation ovine fetus. American Journal of Physiology: Regulatory, Integrative and Comparative Physiology 2007 293 R1997R2005. (https://doi.org/10.1152/ajpregu.00313.2007)

    • Search Google Scholar
    • Export Citation
  • 11

    Garvey DJ, Vaccari A & Timiras PS Developmental profiles of catecholaminergic enzymes in adrenals of perinatal rats: effect of a hypoxic environment. Hormone and Metabolic Research 1980 12 318322. (https://doi.org/10.1055/s-2007-996279)

    • Search Google Scholar
    • Export Citation
  • 12

    Evinger MJ, Cikos S, Nwafor-Anene V, Powers JF & Tischler AS Hypoxia activates multiple transcriptional pathways in mouse pheochromocytoma cells. Annals of the New York Academy of Sciences 2002 971 6165. (https://doi.org/10.1111/j.1749-6632.2002.tb04434.x)

    • Search Google Scholar
    • Export Citation
  • 13

    Mihai R, Wong NA, Luckett M, Sheffield E & Farndon JR No correlation between phaeochromocytoma catecholamine secretion and granule ultrastructure. British Journal of Surgery 1998 85 16811685. (https://doi.org/10.1046/j.1365-2168.1998.00965.x)

    • Search Google Scholar
    • Export Citation

 

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    Metanephrine/normetanephrine ratios in 92 patients with phaeochromocytomas. Filled circles: with necrosis or haemorrhage; open circle: no necrosis and no haemorrhage.

  • 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

    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
  • 3

    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
  • 4

    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
  • 5

    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
  • 6

    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
  • 7

    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
  • 8

    Favier J, Kempf H, Corvol P & Gasc JM Cloning and expression pattern of EPAS1 in the chicken embryo. Colocalization with tyrosine hydroxylase. FEBS Letters 1999 462 1924. (https://doi.org/10.1016/s0014-5793(9901476-3)

    • Search Google Scholar
    • Export Citation
  • 9

    Eisenhofer G, Huynh TT, Pacak K, Brouwers FM, Walther MM, Linehan WM, Munson PJ, Mannelli M, Goldstein DS & Elkahloun AG Distinct gene expression profiles in norepinephrine- and epinephrine-producing hereditary and sporadic pheochromocytomas: activation of hypoxia-driven angiogenic pathways in von Hippel-Lindau syndrome. Endocrine-Related Cancer 2004 11 897911. (https://doi.org/10.1677/erc.1.00838)

    • Search Google Scholar
    • Export Citation
  • 10

    Ducsay CA, Hyatt K, Mlynarczyk M, Root BK, Kaushal KM & Myers DA Long-term hypoxia modulates expression of key genes regulating adrenomedullary function in the late gestation ovine fetus. American Journal of Physiology: Regulatory, Integrative and Comparative Physiology 2007 293 R1997R2005. (https://doi.org/10.1152/ajpregu.00313.2007)

    • Search Google Scholar
    • Export Citation
  • 11

    Garvey DJ, Vaccari A & Timiras PS Developmental profiles of catecholaminergic enzymes in adrenals of perinatal rats: effect of a hypoxic environment. Hormone and Metabolic Research 1980 12 318322. (https://doi.org/10.1055/s-2007-996279)

    • Search Google Scholar
    • Export Citation
  • 12

    Evinger MJ, Cikos S, Nwafor-Anene V, Powers JF & Tischler AS Hypoxia activates multiple transcriptional pathways in mouse pheochromocytoma cells. Annals of the New York Academy of Sciences 2002 971 6165. (https://doi.org/10.1111/j.1749-6632.2002.tb04434.x)

    • Search Google Scholar
    • Export Citation
  • 13

    Mihai R, Wong NA, Luckett M, Sheffield E & Farndon JR No correlation between phaeochromocytoma catecholamine secretion and granule ultrastructure. British Journal of Surgery 1998 85 16811685. (https://doi.org/10.1046/j.1365-2168.1998.00965.x)

    • Search Google Scholar
    • Export Citation