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Microstructural comparative analysis of calcification patterns in calciphylaxis versus arteriolosclerotic ulcer of Martorell

  • Investigative Report
  • Published:
European Journal of Dermatology

Abstract

Background

Calciphylaxis and the arteriolosclerotic ulcer of Martorell (ASUM) represent two entities of cutaneous calcific arteriolopathies. Their differential diagnosis can be challenging, given similarities in their clinical and histological presentation. Calcification patterns have been proposed as a possible discriminative histological criterion, however, a systematic microstructural comparative analysis is lacking.

Objectives

The study aimed at a systematic comparative microstructural analysis of the calcification patterns in calciphylaxis versus ASUM.

Materials & Methods

Skin biopsies of patients with leg ulcers due to calciphylaxis (20) and ASUM (69) diagnosed at three European wound care centres (Vienna, Bern, Zurich) were included. The extent of calcification, arteriolar calcification pattern and presence of extra-arteriolar calcification were assessed.

Results

All calciphylaxis and most ASUM patients (77%) presented with arteriolar calcification. Although the mean number of calcified vessels and the proportion of calcified area were significantly higher in calciphylaxis specimens (p = 0.003 and p = 0.0171), there was no significant difference in the pattern of arteriolar calcification (p = 0.177). Interestingly, extra-arteriolar calcification was detected in the majority of both calciphylaxis (93.3%) and ASUM samples (85.2%, p = 0.639). Notably, Alizarin Red S staining was superior to H&E for the detection of calcifications of both entities (p = 0.014 and p < 0.0001), and to von Kossa staining for ASUM samples (p = 0.0001). However, no differences could be observed between cases with uraemic and non-uraemic calciphylaxis or ulcerations located on the upper and lower leg.

Conclusion

Our results indicate that extra-arteriolar calcification is not only present in calciphylaxis, but can also be detected in ASUM suggesting a lack of specificity for this finding. However, more specific calcification stains, such as Alizarin Red S, should be used in suspected cases, as calcifications may be overlooked using conventional H&E staining.

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References

  1. Hafner J. Calciphylaxis and Martorell hypertensive ischemic leg ulcer: same pattern — One pathophysiology. Dermatology 2016; 232: 523–33.

    Article  CAS  Google Scholar 

  2. Olaoye OA, Koratala A. Calcific uremic arteriolopathy. Oxf Med Case Rep 2017; 2017: omx055.

    Article  Google Scholar 

  3. Yerram P, Chaudhary K. Calcific uremic arteriolopathy in end stage renal disease: pathophysiology and management. Ochsner J 2014; 14: 380–5.

    PubMed  PubMed Central  Google Scholar 

  4. Riemer CA, El-Azhary RA, Wu KL, Strand JJ, Lehman JS. Underreported use of palliative care and patient-reported outcome measures to address reduced quality of life in patients with calciphylaxis: a systematic review. Br J Dermatol 2017; 177: 1510–8.

    Article  CAS  Google Scholar 

  5. Ghosh T, Winchester DS, Davis MDP, El-Azhary R, Comfere NI. Early clinical presentations and progression of calciphylaxis. Int J Dermatol 2017; 56: 856–61.

    Article  Google Scholar 

  6. Dauden E, Onate MJ. Calciphylaxis. Dermatol Clin 2008; 26: 557–68.

    Article  Google Scholar 

  7. Hafner J, Nobbe S, Partsch H, et al. Martorell hypertensive ischemic leg ulcer: a model of ischemic subcutaneous arteriolosclerosis. Arch Dermatol 2010; 146: 961–8.

    Article  Google Scholar 

  8. Lima Pinto AP, Silva NA Jr., Osorio CT, et al. Martorell’s ulcer: diagnostic and therapeutic challenge. Case Rep Dermatol 2015; 7: 199–206.

    Article  Google Scholar 

  9. Giot JP, Paris I, Levillain P, et al. Involvement of IL-1 and oncostatin M in acanthosis associated with hypertensive leg ulcer. Am J Pathol 2013; 182: 806–18.

    Article  CAS  Google Scholar 

  10. Dagregorio G, Guillet G. A retrospective review of 20 hypertensive leg ulcers treated with mesh skin grafts. J Eur Acad Dermatol Venereol 2006; 20: 166–9.

    Article  CAS  Google Scholar 

  11. Henderson CA, Highet AS, Lane SA, Hall R. Arterial hypertension causing leg ulcers. Clin Exp Dermatol 1995; 20: 107–14.

    Article  CAS  Google Scholar 

  12. Duncan HJ, Faris IB. Martorell’s hypertensive ischemic leg ulcers are secondary to an increase in the local vascular resistance. J Vasc Surg 1985; 2: 581–4.

    Article  CAS  Google Scholar 

  13. Martorell F. Ulcus cruris hypertonicum. Med Klin 1957; 52: 1945–6.

    CAS  PubMed  Google Scholar 

  14. Colboc H, Moguelet P, Bazin D, et al. Localization, morphologic features, and chemical composition of calciphylaxis-related skin deposits in patients with calcific uremic arteriolopathy. JAMA Dermatol 2019; 155: 789–96.

    Article  Google Scholar 

  15. Hines EA Jr., Farber EM. Ulcer of the leg due to arteriolosclerosis and ischemia, occurring in the presence of hypertensive disease (hypertensive-ischemic ulcers). Proc Staff Meet Mayo Clin 1946; 21: 337–46.

    PubMed  Google Scholar 

  16. Weenig RH, Sewell LD, Davis MD, McCarthy JT, Pittelkow MR. Calciphylaxis: natural history, risk factor analysis, and outcome. J Am Acad Dermatol 2007; 56: 569–79.

    Article  Google Scholar 

  17. Nigwekar SU, Thadhani R, Brandenburg VM. Calciphylaxis. N Engl J Med 2018; 378: 1704–14.

    Article  CAS  Google Scholar 

  18. Angelis M, Wong LL, Myers SA, Wong LM. Calciphylaxis in patients on hemodialysis: a prevalence study. Surgery 1997; 122: 1083–9 (discussion 9–90).

    Article  CAS  Google Scholar 

  19. Nigwekar SU, Wolf M, Sterns RH, Hix JK. Calciphylaxis from nonuremic causes: a systematic review. Clin J Am Soc Nephrol 2008; 3: 1139–43.

    Article  Google Scholar 

  20. Hafner J, Keusch G, Wahl C, et al. Uremic small-artery disease with medial calcification and intimal hyperplasia (so-called calciphylaxis): a complication of chronic renal failure and benefit from parathyroidectomy. J Am Acad Dermatol 1995; 33: 954–62.

    Article  CAS  Google Scholar 

  21. Rezaie W, Overtoom HA, Flens M, Klaassen RJ. Calciphylaxis in chronic renal failure: an approach to risk factors. Indian J Nephrol 2009; 19: 115–8.

    Article  CAS  Google Scholar 

  22. Nigwekar SU, Kroshinsky D, Nazarian RM, et al. Calciphylaxis: risk factors, diagnosis, and treatment. Am J Kidney Dis 2015; 66: 133–46.

    Article  Google Scholar 

  23. Fuchs F, Franke I, Tüting T, Gaffal E. Successful treatment of non-uremic calciphylaxis with bisphosphonate. J Dtsch Dermatol Ges 2020; 18: 1498–500.

    PubMed  Google Scholar 

  24. Vuerstaek JD, Reeder SW, Henquet CJ, Neumann HA. Arteriolosclerotic ulcer of Martorell. J Eur Acad Dermatol Venereol 2010; 24: 867–74.

    Article  CAS  Google Scholar 

  25. Mochel MC, Arakaki RY, Wang G, Kroshinsky D, Hoang MP. Cutaneous calciphylaxis: a retrospective histopathologic evaluation. Am J Dermatopathol 2013; 35: 582–6.

    Article  Google Scholar 

  26. Chen TY, Lehman JS, Gibson LE, Lohse CM, El-Azhary RA. Histopathology of calciphylaxis: cohort study with clinical correlations. Am J Dermatopathol 2017; 39: 795–802.

    Article  CAS  Google Scholar 

  27. World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA 2013;310: 2191–4.

    Article  Google Scholar 

  28. Graves JW, Morris JC, Sheps SG. Martorell’s hypertensive leg ulcer: case report and concise review of the literature. J Hum Hypertens 2001; 15: 279–83.

    Article  CAS  Google Scholar 

  29. McCarthy JT, El-Azhary RA, Patzelt MT, et al. Survival, risk factors, and effect of treatment in 101 patients with calciphylaxis. Mayo Clin Proc 2016; 91: 1384–94.

    Article  Google Scholar 

  30. Schindelin J, Arganda-Carreras I, Frise E, et al. Fiji: an open-source platform for biological-image analysis. Nat Methods 2012; 9: 676–82.

    Article  CAS  Google Scholar 

  31. Gomes F, La Feria P, Costa C, Santos R. Non-uremic calciphylaxis: a rare diagnosis with limited therapeutic strategies. Eur J Case Rep Intern Med 2018; 5: 000986.

    PubMed  PubMed Central  Google Scholar 

  32. Baby D, Upadhyay M, Joseph MD, et al. Calciphylaxis and its diagnosis: a review. J Family Med Prim Care 2019; 8: 2763–7.

    Article  Google Scholar 

Download references

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Correspondence to Benedikt Weber.

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Disclosure

Financial support: We would like to thank the following funding institutions for their support: Austrian Science Fund (FWF; P-30615), Medical Scientific Fund of the Mayor of the City of Vienna (MA-GMWF-501912-2019), Vienna Science and Technology Fund (WWTF; LS18-080), and institutional funding of the Medical University of Vienna, Austria. Conflicts of interest: none.

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Deinsberger, J., Sirovina, S., Bromberger, S. et al. Microstructural comparative analysis of calcification patterns in calciphylaxis versus arteriolosclerotic ulcer of Martorell. Eur J Dermatol 31, 705–711 (2021). https://doi.org/10.1684/ejd.2021.4182

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  • DOI: https://doi.org/10.1684/ejd.2021.4182

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