Ulcerated lesions on shins - Clinical Advisor

Ulcerated lesions on shins


  • September 2014 Dermatology CME/CE

  • September 2014 Dermatology CME/CE


A man, aged 68 years, presented with ulcers on his shins of about 2 months. They began as retiform-appearing purple patches that would ulcerate and form hemorrhagic or necrotic crusts. The lesions were excruciatingly painful and tender. He had type 2 diabetes and ESRD, and had been on hemodialysis for 10-plus years. He had a history of low parathyroid hormone and a calcium-phosphate product greater than 70 mg2/dL2. Exam revealed very tender ulcers with violaceous, serpiginous borders and hemorrhagic crusts on the bilateral distal lower extremities.


A 55-year-old man presented with ulcers on his shins of 6 weeks’ duration. He said they began as small pustules after he hit his shins against a table. He had ulcerative colitis, and during a recent hospitalization for a flare, the lesions enlarged and developed into ulcers with a necrotic center and a peripheral violaceous halo. They were sensitive and tender upon palpation, but not significantly painful. Examination revealed multiple, discrete necrotic ulcers with violaceous rims over the lateral and medial aspects of the bilateral distal lower extremities.

This Clinical Advisor CME activity consists of 3 articles. To obtain credit, you must also read Red-brown lesions on the upper body and Multiple facial papules on a young girl. Then take the post-test here.

Case #1Calciphylaxis is a metastatic calcifying disorder that affects the skin and is characterized by the formation of painful, necrotic ulcers. It is most commonly associated with chronic renal failure.1The lesions of calciphylaxis initially appear as violaceous patches in a...

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Case #1

Calciphylaxis is a metastatic calcifying disorder that affects the skin and is characterized by the formation of painful, necrotic ulcers. It is most commonly associated with chronic renal failure.1

The lesions of calciphylaxis initially appear as violaceous patches in a serpiginous, reticular pattern that progress to areas of black central ischemic necrosis. The presence of bullae or gray color signifies the transition from violaceous patches to necrotic ulcer.1

The lesions seem to have a predilection for areas with high adipose content, such as the abdomen, thighs, and buttocks.2 In all of the stages of progression, a hallmark symptom of these lesions is extreme pain. Subcutaneous calcium deposits and thickened blood vessels may also be palpable.3

The lesions are classified as proximal (above the knee or elbow) or distal (below the knee or elbow). The proximal type has been reported to occur more frequently than the distal type, but distal lesions seem to have a better survival rate.3 Although damage to subcutaneous tissues is the most common manifestation, the involvement of internal organs, termed “visceral calciphylaxis,” has been reported.4

Calciphylaxis is more common in patients with end-stage renal disease (ESRD) who are on chronic hemodialysis, with a prevalence ranging from 1% to 5%.4 Longer duration of hemodialysis is associated with an increased risk of calciphylaxis.5

Other known risk factors include female gender, diabetes mellitus, obesity, secondary hyperparathyroidism, liver disease, hypoalbuminemia, and the use of systemic corticosteroids or warfarin.5,6 In the presence of normal renal function, primary hyperparathyroidism is most commonly associated with calciphylaxis.7

Metastatic calcification of small- to medium-size vessels results in local tissue ischemia and injury. While the exact cause of metastatic calcification is not entirely understood, the conversion of vascular smooth muscle cells into osteoblast-like cells is necessary for vascular calcification.1

This conversion may involve a variety of mediators, including inorganic phosphates, bone morphogenic protein (BMP)-2, and inflammatory molecules in vessel walls.1 The exposure of vascular smooth muscle cells in vitro to elevated inorganic phosphate levels has been shown to promote osteoblastic differentiation.8

In patients with chronic renal failure, hyperphosphatemia may result from impaired clearance of phosphate and impaired production of 1,25-dihydroxyvitamin D3. Insufficient 1,25-dihydroxyvitamin D3 leads to elevated levels of parathyroid hormone, mobilizing calcium and phosphate.

The differential diagnosis of cutaneous calciphylaxis includes vasculitis, purpura fulminans, diabetic gangrene, panniculitis, cryoglobulinemia, antiphospholipid antibody syndrome, warfarin skin necrosis, and pyoderma gangrenosum.

Assessing clinical presentation and risk factors can be helpful in eliminating other diagnoses and directing a workup. Often the presence of these lesions in the setting of ESRD is sufficient to make the diagnosis.

Several laboratory findings have been associated with calciphylaxis, including a calcium-phosphate product of at least 70 mg2/dL2, hyperphosphatemia, hypoalbuminemia, elevated erythrocyte sedimentation rate, and elevated alkaline phosphatase.6

There is no specific laboratory test for calciphylaxis. With a supporting history, skin examination, and laboratory findings, a skin biopsy can help confirm the diagnosis. Punch biopsy of a calciphylactic lesion down to the level of subcutaneous fat classically demonstrates calcification of the tunica media and internal elastic membrane of arteries and arterioles.

The deposited calcium is in the form of calcium hydroxyapatite.4 Edematous intimal thickening leads to concentric stenosis of these vessels.5 In the absence of medial calcification, the presence of perieccrine calcification has been shown to be highly specific for calciphylaxis.9

A skin biopsy should only be performed if the history and clinical features do not provide a certain diagnosis, as the lesion may expand in response.5 However, to prevent secondary infection, the lesions may require debridement, which would yield tissue for histopathologic evaluation.

Differentiating calciphylaxis from warfarin skin necrosis and diabetic gangrene can be particularly difficult as both diabetes and warfarin use are risk factors. In these cases, a skin biopsy is particularly helpful in achieving a correct diagnosis.

The components of initial care of calciphylaxis, which are essential in preventing sepsis, include wound debridement and care, antibiotics, and correction of metabolic derangement.3 Mortality from superimposed sepsis has been reported to be as high as 80%.3

Recent evidence supports intravenous (IV) infusion or intralesional injections of sodium thiosulfate as a treatment for calciphylaxis. Sodium thiosulfate dissolves calcium deposits via chelation, yielding a more soluble calcium thiosulfate.10,11

Within a period of days to weeks, the use of sodium thiosulfate can achieve rapid relief of ischemic pain.4 If IV infusion is used, it is important to be aware that a high anion gap metabolic acidosis may occur due to accumulation of thiosulfuric acid.4

Minor side effects from sodium thiosulfate infusion include nausea, vomiting, and headaches.4 Intralesional sodium thiosulfate injections may be safer than IV infusion by avoiding systemic distribution and has been shown to be effective in a recent case series.11

In those with chronic renal failure, treatment strategies include reducing the calcium-phosphate product by using calcium-free phosphate binders and normocalcic dialysate.10 Parathyroidectomy may promote rapid wound healing in patients with hyperparathyroidism who are eligible for surgery.12

Our patient received intralesional injections of sodium thiosulfate with good results.

Case #2

Pyoderma gangrenosum (PG) is a neutrophilic dermatosis characterized by recurrent cutaneous ulcers that are frequently associated with a systemic disease.1 PG often begins as a pustule on an erythematous or violaceous base, an erythematous nodule, or a bulla on a violaceous base that undergoes necrosis leading to an ulcer. 

Classic findings of a developing ulcer include a purulent base with undermined irregular borders that are gunmetal or violaceous in color.1 The developing ulcer has the propensity to expand rapidly and can be painful. While there is a predilection for the lower extremities, lesions can form anywhere, including mucous membranes and peristomal sites.1

These lesions often exhibit pathergy, which is defined as non-healing ulcers that result from minor trauma. Pathergy is the likely explanation for peristomal involvement and can occur any time between 2 months and 25 years after stomal placement.13,14 A history of trauma, as conveyed by the patient in this case, is a characteristic feature of PG. 

There are multiple clinical variants of PG. Vesiculobullous PG has vesicles or bullae that evolve into shallow erosions rather than necrotic ulcers.14 This variant tends to spread rapidly and may be painful. Pustular PG has multiple small, sterile pustules with an erythematous halo that usually regress but can evolve into necrotic ulcers;1 it is most likely that our patient had this variant.

Pyostomatitis vegetans has pustular or ulcerative lesions that involve the buccal or labial mucosa.14 Superficial PG is a localized, superficial ulcerative lesion without undermined borders or a purulent base that typically follows surgery.1,14 While superficial PG can occur anywhere, it most commonly affects the head and neck.14

Between 44% and 78% of patients with PG have an underlying condition such as inflammatory bowel disease (IBD) or myeloproliferative or rheumatologic disorders.14 Cases without an associated condition are considered idiopathic. PG is most commonly seen with IBD, representing up to 20% to 30% of all cases.13

Among patients with IBD and PG, a greater percentage have ulcerative colitis than Crohn disease. The variants of PG that are most commonly associated with IBD include pustular PG and pyostomatitis vegetans.14

Bullous PG is associated with various hematological malignancies but can occur alone.14 Available data on recurrence rates are inconsistent, depending on treatment modality and PG subtypes, and require further follow-up studies.

The pathogenesis of PG is poorly understood, but it seems to involve the loss of innate immune regulation and altered neutrophil chemotaxis.15 Tumor necrosis factor (TNF) and various interleukins (ILs) have been implicated in the development of PG.

A rare familial form of PG characterized by pyogenic sterile arthritis, PG, and acne (PAPA syndrome) has shed some light on an IL that is potentially responsible for PG. PAPA syndrome is an autosomal-dominant disorder with a mutation in a gene encoding proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1).15

Mutated PSTPIP1 results in increased IL-1β production and inflammation. Anakinra, an IL-1β inhibitor, has been shown to improve PG lesions in those with PAPA syndrome.16 Clinical improvement in PG lesions with biologic TNF inhibitors indicates that TNF likely plays a key role. Other studies have suggested that overexpression of IL-8 and IL-16 may be associated with PG.15

Differential diagnosis of PG depends on the stage of lesion development. If the dermatosis is in an early stage, which may include papules, pustules, or nodules, the differential diagnosis includes follicular infections, reactions to insect bites, cellulitis, panniculitis, or Behçet disease. In a later, more ulcerated stage, the differential diagnosis includes infections, vasculitis, vascular disease, and malignancy.1

Diagnosis of PG is one of exclusion. Because of the broad differential diagnosis, the patient’s medical history is of utmost importance. A thorough evaluation should be performed for other causes of skin ulceration and associated diseases. The preferred skin biopsy is a deep elliptical incisional biopsy that includes a portion of the lesion’s edge.15

Diagnostic criteria, which require the fulfillment of two major and two minor criteria, have been proposed for PG. Major criteria are (1) rapidly progressing necrotic ulcer(s) with irregular, violaceous undermined borders and (2) exclusion of other causes of cutaneous ulceration. Minor criteria include (1) a history of pathergy or cribriform scarring, (2) associated systemic disease, (3) histopathologic findings (sterile dermal neutrophilia, with or without mixed inflammation and/or lymphocytic vasculitis), and (4) rapid response to systemic corticosteroids.1,15

Treatment of PG depends on the size, number, location, and type of lesions.15 It also depends on whether an underlying disease, such as IBD, is present. As with calciphylaxis, initial treatment should focus on wound care and infection prevention. Standard treatment is local or combined local and systemic corticosteroid therapy.1

Adjunct treatments include intralesional corticosteroids, cyclosporine, anti-neutrophilic therapies (such as colchicine, tetracyclines, and dapsone), and biologic therapies.15 Biologic therapies have become a more common treatment modality and have been shown to be efficacious.15

However, because of the potential for adverse effects, biologics should be used cautiously. Measuring the size and depth of the lesion at each visit is an important way to assess the response to treatment. 

Our patient responded well to treatment with topical clobetasol ointment. Had there been no improvement, the plan was to try topical dapsone gel before considering systemic medications.

John Muzic, MD, is a research fellow at Mayo Clinic in Rochester, Minn., and recently graduated from the University of Minnesota in Minneapolis, where Tiffany Shih, MD, is a resident physician.

This Clinical Advisor CME activity consists of 3 articles. To obtain credit, you must also read Red-brown lesions on the upper body and Multiple facial papules on a young girl. Then take the post-test here.


  1. Bolognia JL, Jorizzo JL, Schaffer JV, eds. Dermatology. 3rd ed. Philadelphia, Pa.: Elsevier Saunders; 2012:427-431, 729-736.

  2. Ng AT, Peng DH. Calciphylaxis. Dermatol Ther. 2011;24(2):256-262.

  3. Rogers NM, Coates PT. Calcific uraemic arteriolopathy: an update. Curr Opin Nephrol Hypertens. 2008;17(6):629-634.

  4. Hayashi M. Calciphylaxis: Diagnosis and clinical features. Clin Exp Nephrol. 2013;17(4):498-503.

  5. Angelis M, Wong LL, Myers SA, Wong LM. Calciphylaxis in patients on hemodialysis: a prevalence study. Surgery. 1997;122(6):1083-1089.

  6. Girotto JA, Harmon JW, Ratner LE, et al. Parathyroidectomy promotes wound healing and prolongs survival in patients with calciphylaxis from secondary hyperparathyroidism. Surgery. 2001;130(4):645-650.

  7. Nigwekar SU, Wolf M, Sterns RH, Hix JK. Calciphylaxis from nonuremic causes: a systematic review. Clin J Am Soc Nephrol. 2008;3(4):1139-1143. 

  8. Jono S, McKee MD, Murry CE, et al. Phosphate regulation of vascular smooth muscle cell calcification. Circ Res. 2000;87(7):e10-e17. 

  9. Mochel MC, Arakaki RY, Wang G, et al. Cutaneous calciphylaxis: a retrospective histopathologic evaluation. Am J Dermatopathol. 2013;35(5):582-586.

  10. Vedvyas C, Winterfield LS, Vleugels RA. Calciphylaxis: a systematic review of existing and emerging therapies. J Am Acad Dermatol. 2012;67(6):e253-e260.

  11. Strazzula L, Nigwekar SU, Steele D, et al. Intralesional sodium thiosulfate for the treatment of calciphylaxis. JAMA Dermatol. 2013;149(8):946-949.

  12. 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(6):954-962.

  13. Thrash B, Patel M, Shah KR, et al. Cutaneous manifestations 
of ­gastrointestinal disease: part II. J Am Acad Dermatol. 

  14. Marzano AV, Ishak RS, Saibeni S, et al. Autoinflammatory skin disorders in inflammatory bowel diseases, pyoderma gangrenosum and Sweet’s syndrome: a comprehensive review and disease classification criteria. Clin Rev Allergy Immunol. 2013;45(2):202-210.

  15. Ahronowitz I, Harp J, Shinkai K. Etiology and management of pyoderma gangrenosum: a comprehensive review. Am J Clin Dermatol. 2012;13(3):191-211.

  16. Brenner M, Ruzicka T, Plewig G, et al. Targeted treatment of pyoderma gangrenosum in PAPA (pyogenic arthritis, pyoderma gangrenosum and acne) syndrome with the recombinant human interleukin-1 receptor antagonist anakinra. Br J Dermatol. 2009;161(5):1199-1201. 

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