Calcinosis Cutis Presenting in the Context of Long-Term Therapy for Chronic Myeloid Leukemia: A Case Report and Review of the Literature

Calcinosis cutis is a poorly understood process in which calcium salts deposit in the skin and subcutaneous tissues. Due to its multifactorial pathogenesis, several subtypes and potential etiologies have been described.   Presented here is a case of bilateral pretibial calcinosis cutis in a patient on long-term tyrosine kinase inhibitor therapy for chronic myeloid leukemia. The patient initially presented with a right tibial ulceration treated with multiple surgical debridements, antibiotics, and negative pressure wound therapy. The wound was ultimately closed with a split-thickness skin graft. Relevant literature is examined and several possible mechanisms are discussed.

  Calcinosis cutis results from calcium salt deposition in the skin. Four subtypes have been described—dystrophic, metastatic, iatrogenic, and idiopathic,^1,2—with the dystrophic subtype being the most common. These subtypes vary with regard to etiology and associated symptoms.^2,3 Potential pathophysiologic mechanisms include calcium deposition at the sites of chronic actinic damage with injured elastic fibers, abnormal calcium and/or phosphate metabolism, genetic predisposition, or injury secondary to infiltration of a chemotherapeutic agent into the cutaneous or subcutaneous tissues.^1,4 Calcinosis cutis results in significant morbidity from local skin irritation, inflammation, ulceration, infection, intramuscular calcification, muscle atrophy, and joint contracture.⁵ Associated disorders include, but are not limited to, autoimmune and connective tissue diseases, infections, panniculitis, and neoplasms.^5,6

  A 49-year-old white male was seen during his inpatient stay at the University of Illinois Hospital and Health Sciences System (Chicago, IL). A wound care consult was initiated to evaluate the patient’s wound located on the right anterior tibial region. The patient reported the wound started 3 years prior as a dry spot. Before that, he had similar lesions on the left leg that healed after daily treatment with an over-the-counter antibiotic ointment and dry dressing application.

  The patient reported no pain, drainage, bleeding, or odor from the presenting wound. Past medical history was significant for hypertension, diabetes mellitus, obesity, obstructive sleep apnea, and chronic myeloid leukemia (CML). His allergies included penicillin, shellfish, sulfa drugs, and iodinated contrast. He denied tobacco, alcohol, or illicit drug use, and his family history was considered noncontributory to the wound-related issues.

  Chronic myeloid leukemia: history and treatment. The patient was diagnosed with CML in 2000 and treated with hydroxyurea, followed by imatinib. Due to a relapse in 2003, the dosage of this medication was increased. The patient experienced a second relapse in 2007, during which the imatinib was stopped and he was started on nilotinib. Subsequently, due to pancreatitis in 2007, the dose of the nilotinib had to be reduced. In 2009, the patient received hyperfractionated chemotherapy (both courses) and achieved remission before undergoing an allogenic stem cell transplant the following year.

  After the transplant, the patient developed acute graft-versus-host disease (GVHD) of the colon and conjunctiva, which was treated with high-dose steroids. In July 2010, he was started on a low dose of dasatinib, which was stopped in May 2011 due to hypoxia and worsening pulmonary function. From then on, he was treated with prednisone, mycophenolic acid, and biweekly extracorporeal photopheresis.

  On physical exam, the patient was afebrile with normal vital signs. The exam of the head, eyes, ears, nose, throat, heart, lungs, and abdomen was unremarkable. The skin examination of the right anterior mid-shaft tibial region revealed a dry, punched out eschar-like 2 cm x 1 cm lesion surrounded by atrophie blanche. No drainage, bleeding, odor, or signs of infections were present. Dorsalis pedis and posterior tibial pulses were readily palpable with biphasic signals noted on the qualitative bedside Doppler assessment.

  Lab values at presentation included normal electrolytes, including calcium (9.2 mg/dl) and phosphorus (4.5 mg/dl), with HgA1C of 13%. A bilateral tibial/fibular x-ray showed diffuse soft tissue calcifications, and the MRI of the right lower extremity (RLE) was negative for osteomyelitis.

  Wound history. The patient’s right tibial lesion started in 2009. At the initial inpatient consultation in March 2012, the wound was treated with hydrogel and managed similarly on an outpatient basis after he was discharged from the hospital. The patient was readmitted to the hospital in May 2012 after presenting to the authors’ wound care clinic with a satellite lesion and cellulitic changes on his RLE. Both wounds demonstrated purulent drainage (Figure 1). Sharp, full-thickness excisional debridement was performed, which exposed necrotic tissue and suppurative inflammation. The superior wound measured 2.2 cm x 1.3 cm x 1.0 cm and the inferior wound measured 4 cm x 3 cm x 0.7 cm (Figure 2). The patient was placed on clindamycin for 14 days and discharged home. A postsurgical pathology report did not reveal GVHD and showed no soft tissues calcifications. Subsequently, due to issues with transportation, the patient was seen and hospitalized several times at another institution for intravenous antibiotic wound treatments.

  The patient presented to the authors’ clinic in August 2012 with a wound measuring 9.5 cm x 3.2 cm x 0.7 cm that was diffusely covered with yellow adherent slough and had mild to moderate serous drainage, rolled-in edges, and some undermining (Figure 3). He was admitted to the hospital for another excisional debridement and biopsy. At that time, histological examination revealed dense dermal fibrosis and organizing fat necrosis with abundant calcification. Negative pressure wound therapy (NPWT) was started and the patient was discharged to a skilled nursing facility (SNF).

  Negative pressure wound therapy was discontinued in September 2012 due to a significant biobioburden; the patient was started on oral doxycycline and iodoflex. When the wound was optimized and measured 12.5 cm x 5.4 cm x 0.2 cm (Figure 4), a split-thickness skin graft closure was completed with approximately 97% skin engraftment by November 2012 (Figure 5). The superior portion remained open with palpable calcified material.

  The following month, the superior pole of the wound exhibited purulent drainage. After sharp excisional debridement and copious tissue irrigation, a wound culture was obtained and revealed the presence of E.coli. Appropriate antibiotics were used and the wound was dressed with calcium alginate (Restore Calcium Alginate Dressing, Hollister Wound Care, Libertyville, IL). The wound was completely healed by February 2013 (Figure 6).

  Calcification of the skin and subcutaneous tissue, otherwise called calcinosis cutis, occurs in various disease states and is divided into dystrophic, metastatic, idiopathic, or iatrogenic etiology, with the dystrophic subtype being the most common.¹ Dystrophic calcification occurs in pancreatic panniculitis, also known as enzymatic panniculitis, associated with pancreatitis. Characteristic histologic findings include multiple foci of fat necrosis and ghost adipocytes with cytoplasmic calcifications.⁷ This results from saponification by the hydrolytic action of pancreatic enzymes on adipose tissue.⁷ One case study revealed panniculitis in the pretibial regions bilaterally as an early sign of acute alcohol-induced pancreatitis.⁸ Medical records and personal patient accounts do not indicate the evidence of any pretibial panniculitis or nonhealing skin lesions at or around the time of this patient’s acute pancreatitis in 2007, arguing against cutaneous calcification subsequent to pancreatitis-related panniculitis.

  Calciphylaxis is defined as calcification of small vessels, mainly in the dermis or subcutaneous fat, resulting in ischemia and infarction of skin tissue.⁵ Calcium and phosphate metabolism is abnormal, and hyperparathyroidism is commonly present. This type of calcinosis occurs almost exclusively in patients with end-stage renal disease (ESRD), although cases associated with other factors, including chemotherapy⁹ and metastatic cancer,¹⁰ have been reported.

  The patient did not have ESRD, nor was he diagnosed with hyperparathyroism. Even though he received hyperfractionated chemotherapy for lymphoblastic crisis in 2009, his skin lesions did not resemble the violaceous mottled to reticulated, livedo reticularis-like lesions seen in cutaneous calciphylaxis. Histopathologic findings of calciphylaxis include calcific deposition in the medial layer of small to medium diameter blood vessels of the reticular dermis and subcutaneous fat. Tissue biopsies obtained in May and August 2012 showed no evidence of calcification within the vessel walls, making the diagnosis of calciphylaxis in this patient unlikely.

  Metastatic calcinosis cutis is characterized by abnormal calcium and/or phosphate metabolism that results in precipitation of calcium in cutaneous and/or subcutaneous tissue, most commonly in periarticular regions. Size and number of calcifications appear to correlate with the degree of hypercalcemia and hyperphosphatemia, and this type of calcinosis regresses as calcium and phosphate serum levels normalize.¹ There is a paucity of evidence in the literature for calcinosis cutis in patients with CML. A single case report describes periarticular calcinosis cutis in untreated CML with hypercalcemia and hyperphosphatemia,¹¹ consistent with typical metastatic calcinosis cutis. While the authors’ patient had CML with an episode of lymphoblastic crisis, metastatic calcinosis cutis does not seem likely.

  Despite short-term elevations in phosphate, the patinet’s calcium level had never been above normal limits. Phosphate levels rose as high as 5.7 mg/dl and 5.3 mg/dl in February 2010 and June 2011, respectively, but were recorded to be within normal limits between September 2011 and August 2012. X-rays showed calcifications in the calf region bilaterally in March 2012, and subsequent pretibial tissue biopsies demonstrated abundant calcification. However, the pretibial location of calcifications seen in this patient is not characteristic of the periarticular lesions seen in metastatic calcinosis. Taken together, the lack of temporal correlation with phosphate levels and calcification, as well as the pretibial location, do not indicate a metastatic type of calcinosis cutis.

  Two cases of biopsy-confirmed panniculitis secondary to dasatinib therapy for chronic phase CML have been reported.¹² In both patients, the skin lesions were discovered 1-3 months after dasatinib therapy was initiated, resolved when dasatinib was withheld, and returned upon rechallenge. Adding a steroid to the regimen controlled the panniculitis in 1 patient, but not in the other. Both patients had previously been treated with imatinib without any adverse cutaneous effects.

  The authors’ patient was treated with prednisone 100 mg orally twice daily for GVHD of the colon and conjunctiva until October 7, 2012. Dasatinib 20 mg by mouth daily was started on July 8, 2010, but discontinued in May 2011 due to hypoxia and worsening pulmonary function tests. Since the patient’s lesion started in 2009, it is possible that the pretibial panniculitis and calcifications occurred subsequent to the administration of nilotinib and were exacerbated later by treatment with dasatinib.

  This case study could represent a newly recognized form of iatrogenic dystrophic calcinosis cutis. Nilotinib and dasatinib are both second-generation tyrosine kinase inhibitors created to treat CML after failed or poorly tolerated imatinib therapy.¹³ Nilotinib possesses an in vitro breakpoint cluster region (BCR)-Abl1 gene binding potency 30 times greater than imatinib in imatinib-resistant cells, and 5-7 times greater than imatinib in imatinib-susceptible leukemic cells.^14,15 Dasatinib has greater specificity in that it has demonstrated in vitro a 325-fold greater potency than imatinib against cells expressing unmutated BCR-Abl1, is effective against most imatinib-resistant kinase domain mutation, and has a lower affinity for off-targets such as mast/stem cell growth factor receptor and platelet-derived growth factor receptor.^14,15 Neutropenia, myelosuppression, and pulmonary hypertension are common side effects seen with tirosine kinase inhibitors. In fact, due to new onset of pulmonary hypertension in the authors’ patient, the treatment with dasatinib had to be stopped. Overall, cutaneous side effects including panniculits are the most common nonhematological side effects seen in the second-generation tyrosine kinase inhibitors.¹⁶

  Of interest, there is evidence that imatinib and dasatinib dysregulate bone remodeling by, at least in part, inhibition of osteoclasts through suppression of the macrophage-colony-stimulating factor 1 receptor.¹⁴ While this does not provide direct evidence for a mechanism, one might consider that these drugs could dysregulate cutaneous calcium metabolism as well.

  Calcinosis cutis is a condition where calcification of the skin and subcutaneous tissue occurs secondary to various disease states. The patient with CML in the current case review presented with pretibial calcinosis cutis in the context of a nonhealing wound with numerous comorbidities including hypertension, obesity, uncontrolled diabetes mellitus, and an immunosuppressed state following an allogeneic stem cell transplant.

  Skin biopsies from May and August 2012 were negative for GVHD, but showed dense dermal fibrosis and organizing fat necrosis with abundant calcification. Transdermal elimination of calcified material was consistent with histopathologic findings of typical dystrophic calcinosis cutis. Despite the presence of the wound in the setting of multiple disease states, there was no temporal evidence of pretibial calcinosis cutis or panniculitis prior to therapy with nilotinib and dasatinib. Therefore, the authors posit that this patient may represent a new type of iatrogenic dystrophic calcinosis cutis due to the second-generation of tyrosine kinase inhibitors.

  The authors are from Department of Surgery, Division of Vascular Surgery, Section of Wound Healing and Tissue Repair, College of Medicine, University of Illinois Hospital and Health Sciences System, Chicago, IL.

Address correspondence to:
Igor Altman, DO, MBA
ialtman@uic.edu

Disclosure: The authors disclose no financial or other conflicts of interest.