DR [Dermatology Reports 2018; 10:7445] [page 1] A case of chronic ulcer due to subcutaneous arteriolosclerosis in an obese patient mimicking pyoderma gangrenosum Sezin Fıçıcıoğlu,1 Nuray Can,2 Busem Tutuğ2 1Department of Dermatology; and 2Department of Pathology, Trakya University Faculty of Medicine, Edirne, Turkey Abstract The differential diagnosis of chronic ulcers covers a wide range of diseases and poses a diagnostic challenge. Subcutaneous ischemic arteriolosclerosis can lead to local ischaemia and ulceration as a result of arte- riolar narrowing and reduction of tissue per- fusion. This pathophysiological feature can be seen in eutrophication (nonuremic cal- ciphylaxis) in morbid obesity, hypertensive ischemic leg ulcer (Martorell ulcer) and cal- ciphylaxis in chronic renal insufficiency. All of the ulcers happened in this way can be wrongly diagnosed as pyoderma gangre- nosum because of clinical similarity and inadequate biopsies. We report a case of chronic ulcer due to subcutaneous arterio- losclerosis in morbid obesity, wrongly diag- nosed as pyoderma gangrenosum. It can be detrimental to misdiagnose the ulcers due to subcutaneous arteriolosclerosis as pyoder- ma gangrenosum since they need a diamet- rically different approach. Introduction The differential diagnosis of chronic ulcers covers a wide range of diseases and poses a diagnostic challenge.1,2 The clinical presentations, underlying etiology, and pat- hological manifestations of the ulcers are major clues to make the diagnosis. Hafner reviewed four diseases: i) cal- ciphylaxis (distal patern); ii) calciphylaxis (proximal patern); iii) Martorell hypertensi- ve ischemic leg ulcer; iv) calciphylaxis with normal renal and parathyroid function (eut- rophication) all having the same clinical features as necrotizing livedo, skin infarcti- ons and ulcerations at typical locations. Hafner stated that these four diseases lar- gely share the same risk factors including arterial hypertension, diabetes mellitus (types 1 and 2), secondary or tertiary hyper- parathyroidism (in end-stage kidney disea- se) and oral anticoagulation with vitamin K antagonists.3 Also a shared histopathology has been stated in these diseases: subcuta- neous ischemic arteriolosclerosis characte- rized by a medial calcinosis and stenosis due to thickening of the vessel wall (hyperplasia of the smooth muscle layer) and/or intimal hyperplasia.2-4 Hafner et al.5 suggested the term uremic small artery disease with medial calcification and inti- mal hyperplasia instead of the customary denomination calciphylaxis. In 1992 Ramsey-Stewart reported a case of progres- sive dermatoliponecrosis in a morbidly obese patient and suggested the term eut- rophication for. Even though he did not investigate the existance of subcutaneous arteriolosclerosis he claimed that in obese people inadequate peripheral tissue perfusi- on affects the apex of grossly dependent adipose folds and leads patchy gangrenous changes and skin infartions.6 Case Report A 44-year-old man who had Nissen fun- doplication and incisional hernia repair operation one year and three months ago respectively, referred to our hospital for a linear necrotic ulcer 15 cm in length 5 cm in width at the anterior abdomen, on incision line. He had type 2 diabetes mellitus for five years, no hypertension or renal insuffici- ency and he was obese as his body mass index was 31.1 kg/m². The ulcer first appea- red after removing the sutures of incisional hernia repair and rapidly enlarged. After surgical debridement of necrotic tissues and three sessions of negative pressure wound therapy with vacuum dressings, a prominent effect was not observed. The ulcer kept on growing, reached 15×10 cm dimensions with raised and rolled undermining margins (Figure 1A). By the way the incisional biopsy taken from the edge of the ulcer con- cluded as pyoderma gangrenosum. After taking 80 mg/day methylprednisolone for one week the ulcer got worse, enlarged and deepened (Figure 1B). Systemic steroid tre- atment stopped and a second biopsy was taken in a large elliptical shape starting from healthy skin at the ulcer edge exten- ding into the fascia. Histological examinati- on revealed subcutaneous arteriolosclerosis with thickened arteriole walls and narrowed lumens and Von Kossa staining also displa- yed the calcification in the vessel walls (Figure 2). Serum concentration of urea was 14 mg/dL [normal range (nr): 19-50], crea- tinine was 0.73 mg/dL (nr: 0.72-1.25), parathyroid hormone was 32.5 pg/mL (nr: 11-88), calcium was 10.1 mg/mL (nr: 8.8- 10.6) and phosphate was 3.3 mg/mL (nr: 2.5-4.5), alanine aminotransferase was 5 U/L (nr: 0-50), aspartate aminotransferase was 15 U/L (nr: 0-50), gamma-glutamyl transferase was 27 U/L (nr: 0-55), total bili- rubin was 0.2 mg/dL (nr: 0.3-1.2), direct bilirubin was 0.1 mg/dL (nr: 0-0.2). His other liver function parameters including prothrombin time test, serum protein elect- rophoresis and abdominal ultrasonography were in normal limits. Also he had no his- tory of weight loss, pain, fever, fatique, per- sistent cough or hoarseness, no change in bowel habits and no finding of lymphade- nopathy in physical examination. With these clinical and laboratory findings we ruled out uremic calciphylaxis, liver failure, neoplasia and made the diagnosis of eutrop- hication (nonuremic calciphylaxis). After six more sessions of negative pressure wound therapy with vacuum dressings, split thickness skin grafting was done success- fully. Discussion Eutrophication or nonuremic calciphy- laxis or calciphylaxis in normal renal func- tion affects morbidly obese people who has also arterial hypertension and type 2 diabe- Dermatology Reports 2018; volume 10:7445 Correspondence: Sezin Fıçıcıoğlu, Trakya Üniversitesi Tıp Fakültesi, Dermatoloji Anabilim Dalı, Balkan Yerleşkesi, 22030 Edirne, Turkey. Tel.: +90.284.2357641 - extension: 1282. E-mail: sezinkuru@hotmail.com Key words: Arteriolosclerosis; eutrophication; pyoderma gangrenosum; calciphylaxis. Authors’ contributions: SF had participated in the study, in conception and design, analysis and interpretation of data, drafting the article and final approval of the version. NC and BT had participated in the study in analysis and interpretation of data, revising it critically for important intellectual content and final approval of the version. Conflict of interest: the authors declare no potential conflict of interest. Received for publication: 13 October 2017. Accepted for publication: 16 March 2018. This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0). ©Copyright S. Fıçıcıoğlu et al., 2018 Licensee PAGEPress, Italy Dermatology Reports 2018; 10:7445 doi:10.4081/dr.2018.7445 No n- co mm er cia l u se on ly tes mellitus. It is characterized by rapid appearance of progressive skin infarctions in places where fatty tissue is particularly thick such as inner thigh, fatty abdominal apron, breasts or outer upper arms.3,4 The skin infarction begins with a painful livedo- id area and becomes necrotic with progres- sive livid margins. Histologically arterioles show massive thickening of the vessel wall (hyperplasia of the smooth muscle layer) leaving a narrow lumen which is often thrombosed. This subcutaneous ischemic arteriolosclerosis is a common pathophysio- logical feature also in Martorell hypertensi- ve ischemic leg ulcer, calciphylaxis in chro- nic renal insufficiency. All of them can lead to local ischaemia and ulceration as a result of arteriolar narrowing and reduction of tis- sue perfusion.2,3,7 On the other hand, pyoderma gangreno- sum (PG) is a rare neutrophilic inflamma- tory skin disease presenting with painful sterile ulcerations. Its etiology remains unk- nown however it is commonly associated with inflammatory bowel disease, rheuma- toid arthritis, hematologic malignancies and disorders.8,9 Also it may occur in areas of trauma or surgery; a phenomenon called pathergy.10 Jockenhöfer et al.11 also sugges- ted an association of obesity and PG. Our patient was a confusing case as he did not have a disorder like inflammatory bowel disease, rheumatoid artritis or hema- tologic malignancy but he was obese, had a surgery before the ulceration, his ulcer with livid margins and undermining edges enlar- ged progressively directing us to the diag- nosis of PG. After the pathological confir- mation of pyoderma gangrenosum we deci- ded to start systemic steroids which are often the first choice drugs for PG along with other immunosuppressive treatments. But he did not benefit from steroid treat- ment and even it aggravated the ulcer. The ulcers mentioned above whose sha- red histopathology was subcutaneous ische- mic arteriolosclerosis can be wrongly diag- nosed as pyoderma gangrenosum because of clinical similarity and inadequate biopsi- es.3,4,12 Moreover, superficial biopsy sam- ples taken from many types of chronic wound base can be misdiagnosed as pyoder- ma gangrenosum because necrotic dermis with sheets of neutrophil granulocytes can be found. In a study by Hafner et al.4 50% of 31 cases of Martorell ulcers were misdi- agnosed as pyoderma gangrenosum and 20% as necrotizing vasculitis. So in the sus- picion of eutrophication and other ulcers caused by subcutaneous arteriolosclerosis, biopsies should be of sufficient depth exten- ding into the subcutis. Our case’s not the first but the second biopsy which was taken in a large elliptical shape starting from healthy skin at the ulcer edge extending into the fascia yielded the subcutaneous arterio- les with hyperplasia of the smooth muscle layer and narrowing of the lumen. Our pati- ent’s ulcer did not begin spontaneously but occured after the surgery on the incision line but it is not contradictory to the eutrop- hication (nonuremic calciphylaxis) theory as the subcutaneous arteriolosclerosis and decreased tissue perfusion did not allow the cutt to heal and enlarged the ulcer. It can be detrimental to misdiagnose eutrophication (nonuremic calciphylaxis) and other subcutaneous arteriolosclerotic ulcers as pyoderma gangrenosum since they need a diametrically different approach. Pyoderma gangrenosum needs systemic ste- roid treatment and surgical approaches are not recommended.3,4,9 However treatment of skin infarctions from subcutaneous ische- mic arteriolosclerosis includes surgical deb- ridement, negative pressure wound therapy and split thickness skin grafting and syste- mic medication for analgesia and infecti- on.1,3,7 Systemic steroids can cause exacer- bation as in our case, sepsis and even death in subcutaneous arteriolosclerosis. Conclusions According to Hafner3, eutrophication (nonuremic calciphylaxis) and other entities showing subcutaneous ischemic arteriolosc- lerosis are not known very well and familia- [page 2] [Dermatology Reports 2018; 10:7445] Case Report Figure 1. The ulcer on the incision line at the anterior abdomen had livid undermined margins resembling pyoderma gangrenosum, before steroid treatment (A) and after tak- ing 80 mg/day methylprednisolone for one week the ulser enlarged and deepened (B). Figure 2. A) Subcutaneous arteriole (black arrow) shows hyperplasia of smooth muscle layer, narrowing of the lumen and increased wall-to-lumen ratio resulting in skin infarc- tion leading to ulceration (hematoxylin-eosin, original magnification ×10). B) Von Kossa staining (×20) shows vessel calcification (yellow arrow) in addition to narrowing of the lumen. A B A B No n- co mm er cia l u se on ly [Dermatology Reports 2018; 10:7445] [page 3] rity with these disorders should be impro- ved especially because of the risk of confu- sion with pyoderma gangrenosum. And our case demonstrates that he is wright. References 1. Novinscak T, Filipovic M, Edita J, et al. Surgical approach to atypical wounds (clinical cases). Subcutaneous ischemic arteriolosclerosis (Martorell ulcer, cal- ciphylaxis, eutrophication). Acta Med Croatica 2012;66:139-45. 2. Alavi A, Hafner J, Sibbald RG. Martorell hypertensive ischemic leg ulcer: an underdiagnosed entity. Adv Skin Wound Care 2012;25:563-72. 3. Hafner J. Calciphylaxis and Martorell hypertensive ischemic leg ulcer: same pattern - one pathophysiology. Dermatology 2016;232:523-33. 4. Hafner J, Nobbe S, Partsch H, et al. Martorell hypertensive ischemic leg ulcer: a model of ischemic subcuta- neous arteriolosclerosis. Arch Dermatol 2010;146:961-8. 5. Hafner J, Keusch G, Wahl C, et al. Uremic small-artery disease with medi- al calcification and intimal hyperplasia (so-called calciphylaxis): a complica- tion of chronic renal failure and benefit from parathyroidectomy. J Am Acad Dermatol 1995;33:954-62. 6. Ramsey-Stewart G. Eutrophication: spontaneous progressive derma- toliponecrosis. A fatal complication of gross morbid obesity. Obes Surg 1992;2:263-4. 7. Vuerstaek JDD RS, Henquet CJM, Neumann HAM. Arteriolosclerotic ulcer of Martorell. JEADV 2010;24:867-74. 8. Al Ghazal P, Korber A, Klode J, Dissemond J. Investigation of new co- factors in 49 patients with pyoderma gangrenosum. J Dtsch Dermatol Ges 2012;10:251-7. 9. Vallini V, Andreini R, Bonadio A. Pyoderma gangrenosum: a current problem as much as an unknown one. Int J Low Extrem Wounds 2017; 16:191-201. 10. Urman CO, Ashby-Richardson H, Thakker PS. Pyoderma gangrenosum following gastric bypass surgery. Cutis 2014;93:261-3. 11. Jockenhofer F, Herberger K, Schaller J, et al. Tricenter analysis of cofactors and comorbidity in patients with pyoderma gangrenosum. J Dtsch Dermatol Ges 2016;14:1023-30. 12. Kolios AGA, Hafner J, Luder C, et al. Comparison of pyoderma gangrenosum and hypertensive ischemic leg ulcer Martorell in a Swiss cohort. Br J Dermatol 2017 [Epub ahead of print]. Case Report No n- co mm er cia l u se on ly