Diagnostic Dilemmas (CME and CPME accredited) Department Editor Tania Phillips, MD, FRCPC Overall Learning Objective: The physician or podiatrist participant will develop a rational approach to the evaluation and treatment of a variety of uncommon wounds and will have an increased awareness of the differential diagnosis of cutaneous wounds and the systemic diseases associated with these wounds. Submissions: To submit a case for consideration in Diagnostic Dilemmas, e-mail or write to: Executive Editor, WOUNDS, 83 General Warren Blvd., Suite 100, Malvern, PA 19355, firstname.lastname@example.org Completion Time: The estimated time to completion for this activity is 1 hour. Target Audience: This CME/CPME activity is intended for dermatologists, surgeons, podiatrists, internists, and other physicians who treat wounds. At the conclusion of this activity, the participant should be able to: 1. Describe and discuss the differences in pathophysiology of dystrophic, metastatic, and ectopic calcification 2. Discuss treatment of chronic venous ulcers in renal failure patients, including the use of living skin equivalents 3. Apply the relative points of this case presentation to his or her own patient population. Disclosure: All faculty participating in Continuing Medical Education programs sponsored by HMP Communications, LLC, are expected to disclose to the program audience any real or apparent conflict(s) of interest related to the content of their presentation. Drs. Smith and Yamada disclose no financial conflicts. Accreditation: HMP Communications, LLC, is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. HMP Communications, LLC, is approved by the Council on Podiatric Medical Education as a sponsor of continuing education in podiatric medicine. Designation: HMP Communications, LLC, designates this continuing medical education activity for 1 credit hour in Category 1 of the Physician’s Recognition Award of the American Medical Association. Each physician should claim only those hours he/she spent in the educational activity. HMP Communications designates this continuing medical activity for .1 CEUs available to participating podiatrists. Method of Participation: Read the article, take, submit, and pass post-test by April 1, 2003. This activity has been planned and produced in accordance with the ACCME Essential Areas and Policies. Release date: April 1, 2002 Expiration date: April 1, 2003 Diagnostic Dilemmas: Venous Stasus Ulcer Complicated by Calcinosis Cutis Presentation A 61-year-old Native American woman presented with a painful, full-thickness, infected, mixed fibrin and eschar, venous stasis ulcer of the left lower lateral leg approximately six weeks in duration (Figure 1). Symptoms began after she collided with a wooden bench. In an attempt to treat her wound, she preformed self care that included daily soap and water cleansing, wet-to-dry dressings, and compressive therapy. The wound progressively enlarged becoming more painful and unresponsive to self care. During deep debridement, two flat irregularly shaped foreign bodies were discovered and removed from the subcutaneous tissue. Specimens were sent to pathology for gross and microscopic examination (Figure 2). The patient’s medical history consisted of obesity, hypertension, type II diabetes mellitus, diabetic neuropathy, and chronic renal failure with hemodialysis three times a week. Her surgical history included forearm shunt placement for dialysis and bilateral forefoot pan-transmetatarsal amputations. She had no known drug allergies. Her medications included human insulin twice a day, nifedipine daily, calcium carbonate, sodium bicarbonate, and a multivitamin supplementation daily. Physical Examination Physical examination revealed a solitary, circular, full-thickness wound with eschar, fibrin, induration, crimson borders with malodor, and purulent exudate. The wound measured 2.9cm x 3.5cm x 0.3cm at the lower lateral aspect of her left leg. Her lower extremities presented with atrophic and hemosiderin pigmentation changes consistent with lipodermatosclerosis. Vascular examination revealed palpable bilateral dorsal pedis and posterior tibial pedal pulses. Bilateral audible Doppler findings revealed moderate biphasic dorsal pedis pulse and strong monophasic posterior tibial pulses. Capillary refill of bilateral forefoot stumps were within normal limits of less than five seconds. Lower-extremity brawny edema was present bilaterally. Neurological findings revealed diminished symmetrical deep tendon reflexes and bilaterally absent vibratory sensation and protective threshold. Orthopedic examination revealed adequate range of motion at all remaining major joints of feet and legs with adequate muscle strength. The patient was afebrile without distress, and vital signs were unremarkable. Her white blood cell count was reported to be 4.87 x 103mm3 (normal, 4.5–11 x 103mm3) with a neutrophil count of 42.1 percent (normal, 35–66%) and lymphocyte count of 50 percent (normal, 24–44%). Her compressive metabolic profile was unremarkable with the following exceptions: elevated serum creatinine of 4.6mg/dL (normal, 0.5–1.4mg/dL), elevated urea nitrogen of 23mg/dL (normal, 7–20mg/dL), and an elevated fasting blood glucose of 149mg/dL (normal, 60–110mg/dL). Both her serum calcium and alkaline phosphatase were within normal limits (9.5mg/dL [normal, 8.6–10.3mg/dL] and 94IU/L [normal, 40–150IU/L]), respectfully. Radiographs of her lower extremities showed diffuse vascular calcification of medium-sized blood vessels as well as evidence of global osteopenia of the remaining feet. Pathology There was focal necrosis at the premier of the ulcer, full thickness in nature with fibrin deposits, calor, rubor, and malodor measuring 2.9cm x 3.5cm x 0.3cm. During debridement, the subcutaneous tissue presented two flat, irregularly shaped tissue fragments grossly described as moderately firm and ranging in size from 1.5cm x 1.4cm x 0.2cm up to 1.7cm x 1.5cm x 0.2cm. The fragments were grayish tan in appearance. Microscopic and pathologic findings revealed ossified tissue consistent with dystrophic calcification and necrosis along one margin. Culture of the purulent wound exudate revealed both Staphylococcus aureus and Pseudomonas aeruginosa organisms both sensitive to levofloxacin. Diagnosis The patient was diagnosed with a venous stasis ulcer with aberrant cutaneous calcification secondary to metastatic calcification and lipodermatosclerosis. Discussion Calcification is the deposition of insoluble calcium salt. When it occurs in cutaneous tissues, it is known as calcinosis cutis. Dystrophic calcification is the most common type of calcinosis cutis.1 Specifically, calcinosis cutis has been reported as a result of scars from trauma, burns, and surgery.2–4 Although calcium and phosphate metabolism and serum levels are normal, local tissue abnormalities, such as alternations in collagen, elastin, or subcutaneous fat, may precipitate calcification. Metastatic calcification is the precipitation of calcium salts in normal tissue as a result of an underlying defect in calcium and/or phosphate metabolism. Cutaneous metastatic calcification commonly occurs in chronic renal failure and takes the form of either benign nodular calcification4 or calciphylaxis.1 In chronic renal failure, there is decreased clearance of phosphate resulting in hyperphosphatemia. In addition, there is impaired production of vitamin D [1,25 (OH)2D3] resulting in a decrease in calcium absorption from the intestine and decrease in calcium levels. Elevated parathyroid hormones cause bone resorption and mobilization of calcium and phosphate into the serum. Classic metastatic calcinosis due to chronic renal failure occurs with secondary hyperparathyroidism when the Ca x P product is much higher than 70mg/100mL.5–7 The calcium deposits occur most frequently in the abdominal mucosa, the lungs, the kidney, or the heart and much more rarely in the skin.8 Within the cell it is the mitochondria that serves as the nidus for metastatic calcification. Since there is a high affinity for both calcium and phosphate, the mitochondria concentrates these elements allowing for high enough levels to concentrate calcium causing it to crystalize. High levels of intracellular calcium may result from membrane damage, leading to a large influx of calcium. Cellular necrosis creates a more acidic environment that lacks certain calcium inhibitors contributing to more crystallization.1 The association of soft-tissue calcification and renal failure has been recognized for more than 100 years, first noted by Virchow in 1855.9,10 The pathogenesis of skin lesions in uremic patients remains unclear. A combination of multiple local (dystrophic) and systemic (metastatic) factors, such as vascular calcification, serum protein C activity, and hemodialysis, should be considered in the pathogenesis of metastatic calcification and skin necrosis in uremic and hemodialysis patients.5,8,11 Dialysis itself may make the skeleton more responsive to parathyroid hormone.5 Ectopic calcification is a common response to soft-tissue injury and systemic imbalance.5 These clinical consequences are devastating when present in either the heart valves or blood vessels. Alterations in the balance between procalcific and anticalcific regulatory proteins in mesenchymal and inflammatory cells induced by injury or disease are postulated to induce ectopic apatite deposition.13 Arterial vessel walls are the predominant site for ectopic calcification. Regulation of vascular calcification is an actively regulated process similar to osteogenesis and is distinct from a metastatic passive mineralization. Parhami, et al.,14 have described four important mediators of vascular calcification as being calcifying vascular cells, oxidized lipids, cytokines, and leptin. Giachelli13 described both in-vitro and in-vivo models of ectopic calcification and found that elevated extracellular phosphate levels induce smooth muscle culture mineralization morphologically similar to that observed in calcified human valves and atherosclerotic plaques. Giachelli13 also found that osteopontin, a secreted phosphoprotein abundant in macrophages found in human calcified atherosclerotic and valvular lesions, is a potent inhibitor of ectopic calcification. Sodium-dependent phosphate cotransporter function is required for smooth muscle cell culture mineralization. Finally, smooth muscle cell culture mineralization is associated with dramatic loss of smooth muscle-specific gene expression and the gain of osteoblast-like properties, including expression of osteoblast differentiation factor, Cbfa-1, suggesting inhibitory molecules that control ectopic calcification are produced by both mesenchymal and inflammatory cells. Literature sources have reported that both calcium and vitamin D [1,25(OH)2D3] have profound effects on keratinocyte proliferation, differentiation, and cell-cell adhesion.1,15–19 The mechanism by which vitamin D [1,25(OH)2D3] may induce differentiation of epidermal cells may be via calcium because calcium is required for terminal differentiation of keratinocytes. Venous ulcers of the lower extremity are often regarded as treatable conditions. Trauma6 plays an important role in the initiation of venous ulcers, particularly in patients with extensive lipodermatosclerosis.20 Dystrophic calcium deposits develop in about 10 percent of all cases of lipodermatosclerosis.21 Compression therapy is the gold standard for the treatment of venous stasis ulcers.22 Patient Management This patient’s treatment over time consisted of both systemic and topical antibiotics, cadexomer iodine, becaplermin, daily wound care, and various modalities of compressive therapy. Despite these aggressive treatment modalities, this patient’s ulcer remained open for 10 months. The wound’s size ranged from 5.4cm x 3.5cm x 0.5cm to 1.9cm x 1.5cm x 0.3cm. At this point, an allogenic, cultured, human skin equivalent* was selected to be used with compressive therapy. The human skin equivalent was sterilely placed over the wound and secured with 1/8-inch steri-strips. Zinc oxide was applied to the surrounding wound borders, and a nonadhesive, silicone dressing was placed over the human skin equivalent. A layered compression dressing was applied over the entire left lower extremity. This compression dressing remained in place for one week at a time and was changed when the patient returned for her weekly follow-up appointment. The wound’s size progressively decreased with a favorable outcome of total wound closure achieved within four weeks. The patient’s wound remains closed without recurrence 18 months after application (Figure 3). We would like to offer some speculation on the considerable advantages human skin equivalents have when treating chronic venous ulcers in renal failure patients with calciphylaxis. Its contact with the wound seems sufficient to stimulate reepithelialization. It promotes healthy granulation tissue formation within the wound bed, as well as acting as an occlusive dressing, which prevents wound dehydration and maintains a moist environment. This may be due to the release of growth factors as reported in the literature.24 Perhaps this environment prevents the continuation of an acidic pH and a decrease in the body’s inflammatory response. Human skin equivalents do not trigger an immunological response because they do not contain Langerhans cells, dermal dendritic cells, endothelial cells, or passenger leucocytes. Also, type 1 collagen from bovine origin does not seem to trigger an immunological adverse response. Its fibroblasts in the dermal layer are mitotically active and are readily available to secrete collagen and other matrix components enhancing cell proliferation and angiogenesis. This abundance of fibroblasts also promotes accelerated wound contraction, whether it is from cellular contraction or cellular traction.25,26 Conclusion The mechanism of action of human skin equivalent is not known.23 Based on a review of the literature, the following can be supported regarding this case study: 1. The etiology of our patient’s aberrant dystrophic cutaneous calcification was possibly related to trauma, lipodermatosclerosis, and metastatic calcification as a result of an underlying defect in both calcium and phosphate metabolism. 2. Pathology studies are very important when assessing patients with cutaneous metastatic calcification. 3. Although dystrophic calcium deposits develop in only 10 percent of all cases of lipodermatosclerosis, it still represents significant morbidity as a health risk. 4. Healthcare providers should have an understanding of the pathology surrounding metastatic soft tissue calcification as it relates to dialysis patients to lessen its long-term morbidity on this particular population. *Apligraf® (Novartis Pharmaceutical Inc., East Hanover, New Jersey) References 1. Walsh JS, Fairley JA. Calcifying disorders of the skin. J Am Acad Dermatol 1995;33:693–709. 2. Coskey RJ, Mehregan AH. Calcinosis cutis in a burn scar [Letter]. J Am Acad Dermatol 1984;11:666–8. 3. Ellis IO, Foster MC, Womack C. Plumber’s knee: Calcinosis cutis after repeated trauma in a plumber. Br Med J 1984;288:1723. 4. Katz I, LeVine M. Bone formation in laparotomy scars: Roentgen findings. Am J Radiol 1960;84:248–61. 5. Metastatic calcification and dialysis. Br Med J 1972;1:762–3. 6. Poesen N, Heidbuchel M, Van den Oord JJ, et al. Chronic renal failure and skin calcifications. Dermatol 1995;190:321–3. 7. Kolton B, Pedersen J. Calcinosis cutis and renal failure. Arch Dermatol 1974;110:256–7. 8. Kuzela DC, Huffer WE, Conger JD, et al. Soft tissue calcification in chronic dialysis patients. Am J Pathol 1977;86:403–24. 9. Virchow R. Kalk metastasen. Virchows Arch Pathol Anat 1855;8:103–13. 10. Parfitt AM. Soft-tissue calcification in uremia. Arch Intern Med 1969;124:544–53. 11. Tada J, Torigoe R, Shimoe K, et al. Calcium deposition in the skin of a hemodialysis patient with widespread skin necrosis. Am J Dermatopathol 1991;13:605–10. 12. Dahl PR, Winkelmann RK, Connolly SM. The vascular calcification-cutaneous necrosis syndrome. J Am Acad Dermatol 1995;33:53–8. 13. Giachelli CM. Ectopic calcification: New concepts in cellular regulation. Z Kardiol 2001;90(Suppl 3):31–7. 14. Parhami F, Tintut Y, Patel JK, et al. Regulation of vascular calcification in arthrosclerosis. Z Kardiol 2001;90(Suppl 3):27–30. 15. Hennings H, Michael D, Cheng C, et al. Calcium regulation on growth and differentiation of mouse epidermal cells in culture. Cell 1980;19:245–54. 16. Yuspa SH. Methods for the use of epidermal cell culture to study chemical carcinogenesis. In: Skerrow D, Skerrow C (eds). Methods of Skin Research. Sussex, England: John Wiley, 1985;213–49. 17. Yuspa SH, Kilkenny AE, Steinert PM, et al. Expression of murine epidermal differentiation markers is tightly regulated by restricted extracellular calcium concentrations in vitro. J Cell Biol 1989;109:1207–17. 18. Milstone LM. Calcium modulates the growth of human keratinocytes in confluent culture. Epithelia 1987;1:129–40. 19. Pillai S, Bikle DD, Elias PM. Vitamin D and epidermal differentiation: Evidence for a role of endogenously produced vitamin D metabolites in keratinocyte differentiation. Skin Pharmacol 1988;1:149–60. 20. Falanga V. Venous ulceration. WOUNDS 1996;8:102–8. 21. Burton CS. Management of chronic and problem lower-extremity wounds. Dermatol Clin 1993:11:767–73. 22. Phillips TJ, Dover JS. Leg ulcers. J Am Acad Dermatol 1991;25:965–89. 23. Phillips TJ. New skin for old: Developments in biological skin substitutes. Arch Dermatol 1998;134:344–9. 24. Falanga V, Margolis D, Alvarez O, et al. Rapid healing of venous ulcers and lack of clinical rejection with an allogenic cultured human skin equivalent. Arch Dermatol 1998;134:293–300. 25. Gabbiani G, Ryan GB, Majno G. Presence of modified fibroblasts in granulation tissue and their possible role in wound contraction. Experientia 1971;27:549–51. 26. Ehrlich HP, Rajaratiiam JBM. Cell locomotion forces versus cell contraction forces for collagen lattice contraction: An in-vitro model of wound contraction. Tissue Cell 1990;22:407–17.
Venous Stasis Ulcer Complicated by Calcinosis Cutis