A Case of Calciphylaxis and Chronic Myelomonocytic Leukemia Heather W. Goff, MD; Ronald E. Grimwood, MD A 70-year-old woman presented for evaluation of trauma as physiologic challengers in calciphylaxis in symmetric necrotic ulcers of the lower extremities. humans as well.5-7 Biopsy results revealed changes consistent with calciphylaxis. The predisposing factors in this Case Report patient included calcium supplementation, obe- A woman came to our hospital for a second opinion sity, female gender, viscous blood, renal failure, regarding symmetric necrotic ulcers with central and diabetes mellitus. To our knowledge, this is leathery eschar and surrounding violaceous erythema the first report of calciphylaxis occurring in the and bullae on the inferior and posterior aspects of setting of chronic myelomonocytic leukemia. We both lower extremities; these lesions had begun discuss the history, clinical presentation, diagno- developing 3 weeks earlier (Figure 1). According to sis, and treatment of calciphylaxis. the patient’s history, the lesions were initially Cutis. 2005;75:325-328. painful, hard, lumpy areas, which eventually pro- ceeded to break down into small individual viola- ceous papules with central ischemic ulceration; the alciphylaxis involves a pathologic calcifica- papules gradually eroded from about 1 cm to larger tion of nonosseous tissue for which neither than 10 cm in diameter. C hypercalcemia nor hyperphosphatemia is The patient also had risk factors for calciphy- necessary. The condition results in calcification of laxis, including calcium supplementation, obesity, subcutaneous arterioles and infarctions of subcuta- female gender, viscous blood, renal failure, and neous adipose tissue. Although the etiology of cal- diabetes mellitus. In addition, the patient had a ciphylaxis is unclear, many predisposing factors history of chronic myelomonocytic leukemia, hypo- have been identified.1-3 thyroidism, and recent colon cancer resection. The Selye4 reproduced metastatic calcification in rat cancer surgery included administration of blood models in 1962. His model included 2 stages. In the products followed by diuresis. The diuretics were first stage, a sustained absolute or relative hypercal- administered during an earlier hospital stay and cemia acted as a sensitizer. This stage was followed continued on an outpatient basis, leading to a rela- by exposure to a challenger substance, such as an tively protracted period of impaired renal function. injection of metallic salts, steroids, or albumin, Initial laboratory values included low plasma which induced pathophysiologic derangements.4 In potassium levels (2.2 mEq/L; reference range, humans, sensitizers that have been identified 3.5–5 mEq/L), increased serum creatinine levels include hyperparathyroidism, high serum levels of (2.6 mg/dL; reference range, 0.7–1.4 mg/dL), vitamin D, calcium supplementation, and metastatic increased serum blood urea nitrogen levels breast cancer.5 Several reports have implicated sys- (31 mg/dL; reference range, 6–23 mg/dL), and temic administration of steroids, intravenous injec- low serum calcium levels (6.9 mg/dL; reference tion of albumin, iron supplementation, and tissue range, 8.6–10.3 mg/dL). The serum phosphorus level was slightly elevated at 6.1 mg/dL (ref- erence range, 2.2–4.3 mg/dL), and the level of thyroid-stimulating hormone was elevated to Accepted for publication May 26, 2004. 39.13 mIU/mL (reference range, 0.35–5.50 mIU/mL). From the Division of Dermatology, University of Texas Health Results of a complete blood count demonstrated a Science Center at San Antonio. leukocyte count of 49.4ϫ109/L (reference range, The authors report no conflict of interest. ϫ 9 Reprints: Ronald E. Grimwood, MD, University of Texas Health 4.8–10.8 10 /L) with 32% neutrophils, 8% bands, Science Center, 7703 Floyd Curl Dr, MC 7876, San Antonio, TX 5% atypical lymphocytes, 1% metamyelocytes, and 78229-3900 (e-mail: [email protected]). 1% myelocytes. The hematocrit value was 33.1% VOLUME 75, JUNE 2005 325 Calciphylaxis and Leukemia Figure 1. Necrotic ulceration with surrounding violaceous erythema and bulla formation on the distal lateral aspect of left lower extremity. (reference range, 36%–46%), mean corpuscular The role of “challengers” as classically described volume was 99.7 fL (reference range, 80–98 fL), by Selye4 (ie, insults that occur in a patient predis- and the red cell distribution width was 8.1% (refer- posed to the development of calciphylaxis) is ence range, 12.6%–15.7%). The platelet count was equally important. Results of a study by Wilmer et 300ϫ109/L (reference range, 130–400ϫ109/L), and al12 revealed a positive correlation between serum levels of 25-hydroxyvitamin D and 1,25- decreased percutaneous oxygen tension and the dihydroxyvitamin D were low. development of calciphylaxis. Decreased percuta- The patient’s primary care physician provided neous oxygen tension also was seen more com- the results of laboratory studies conducted just monly in patients with obesity; this correlation prior the development of skin lesions according to may help explain why obese body habitus is a risk the history given by the patient. These results showed factor for calciphylaxis.12 a serum calcium level of 8.8 mg/dL and a serum One study focused on the role of matrix protein creatinine level of 2.1 mg/dL; serum phosphate expression by vascular smooth muscle cells in tissue levels had not been determined at that time. Results calcification.11 It has been demonstrated that of biopsies performed prior to the time of presenta- smooth muscle cells in vitro can dedifferentiate tion were interpreted by our hospital’s dermato- into osteoblastlike cells and produce bone matrix pathology service as consistent with a diagnosis of proteins such as osteopontin, which has been found calciphylaxis (Figure 2). at the base of calcium aggregates in calcified vessels of patients with calciphylaxis. It is postulated that Comment mechanisms of cellular injury, such as ischemia, Most cases of calciphylaxis described in the litera- may be causative factors leading to vascular smooth ture are associated with chronic renal failure muscle cell dedifferentiation and calcification.11 In requiring dialysis.3,6-9 However, cases of calciphy- the case of our patient, diabetes and obesity were laxis during episodes of acute renal failure in likely contributing factors to a physiologic milieu patients with normal serum calcium levels have that led to poor tissue perfusion and vascular been reported.2,10 Most patients with this condition endothelial damage. In addition, chronic are women, and there is a significant association myelomonocytic leukemia may have enhanced her with hypercalcemic states such as secondary hyper- risk of developing calciphylaxis by furthering parathyroidism, autonomous hyperparathyroidism, ischemia in small vessels. This supposition is based and metastatic breast cancer.5,6 In addition, obesity on the demonstration that larger, more rigid blast and diabetes mellitus are commonly seen in cells occurring in leukemias can impede the flow of patients in whom this condition develops.11-12 erythrocytes in the microcirculation.13 Other studies show that serum levels of parathyroid Histologic features of calciphylaxis include hormone, calcium, and phosphate are not statisti- microcalcifications of small and medium vessels in cally higher in patients with calciphylaxis and the dermis and subcutaneous fat.14 In addition to chronic renal failure than they are in control sub- microvascular calcifications, one of the most con- jects with chronic renal failure alone.12 sistent histologic features of calciphylaxis is acute 326 CUTIS® Calciphylaxis and Leukemia Figure 2. Subcuta- neous fat with calcifica- tions of the small to medium vessels in a biopsy sample taken from left lower extrem- ity (H&E, original mag- nification ϫ20). and chronic panniculitis with a predominant sep- single, clear, pathophysiologic milieu that leads to tal pattern.15 A case study indicates that these calciphylaxis, but the reports reinforce the concept microscopic findings develop slowly and silently that development of this condition is a compli- over a period of months to years prior to the onset cated physiologic process that can result from mul- of clinical manifestations.16 For this reason, some tiple, concomitant physical states and insults. authors feel the lesions associated with calciphy- Further research may help identify additional fac- laxis in humans represent 2 stages: primary lesions tors associated with calciphylaxis prior to its devel- that involve microvascular calcifications and sec- opment in at-risk patients, thereby targeting ondary lesions that include the gross manifesta- aspects amenable to intervention to prevent the tions of this disease, including infarcts of the occurrence of secondary skin lesions. superficial fascia and skin that often follow a livedo reticularis pattern.1,6,14,15 REFERENCES The treatment of calciphylaxis focuses on 1. Janigan DT, Hirsch DJ, Klassen GA, et al. Calcified subcu- removing the inciting factors. Because the results taneous arterioles with infarcts of the subcutis and skin of parathyroidectomy have been mixed, its use should (“calciphylaxis”) in chronic renal failure. Am J Kidney Dis. be reserved for cases in which elevated parathyroid 2000;35:588-597. hormone level is believed to be a causative 2. Richens G, Piepkorn MW, Krueger GG. Calcifying pan- agent.7,17,18 Patients taking calcium carbonate niculitis associated with renal