Nonhyperparathyroid Wound Calcifications: Two Case Presentations and Literature Review

Introduction Subcutaneous calcification has been well described in the medical literature as a complication of chronic venous insufficiency.1 Other occurrences of such calcifications have been noted due to causes that are not well understood. Regardless of the etiology, the presence of calcium deposits in soft tissues may lead to chronic wounds that do not respond to conservative local wound care.2 For healing to occur it is well established that the solid calcific deposits and surrounding devitalized tissue must be removed from the wound sites.3 The mechanism for nonhealing is thought to be similar to that of a foreign body reaction caused by calcified tissue leading to chronic inflammation that does not allow granulation tissue to form.4 The following cases represent different etiologies contributing to subcutaneous wound calcifications. One patient represents a case in which chronic insufficiency and/or trauma may have been the cause of calcifications. The other case involves a patient who has wound calcifications that are idiopathic in nature. Regardless of the etiology, the mechanism of dystrophic calcifications is not well understood. Both cases represent patients who underwent surgical removal of these calcific deposits to allow proper wound healing, albeit incomplete in the second case presented. Case Report One A 75-year-old Caucasian woman was seen at the Wound Healing Institute on July 10, 1998, with a nonhealing wound on the right leg present for greater than one month duration. The patient previously was admitted for cellulitis of the right leg in June at another hospital. She underwent an incision and drainage of an abscess on her right leg, which was performed at bedside by another surgeon and resulted in a dehisced wound with serous drainage measuring 9mm W x 23mm L x 21mm D with 24mm of undermining at 12:00. The patient denied nausea, vomiting, or shortness of breath. She had a 10-year history of diabetes, 28-year history of hypertension, and suffered an automobile accident 13 years prior to presentation, which resulted in chronic pain and complicated ambulation. The automobile accident resulted in multiple surgeries to both lower extremities, including closed reduction of a fibular fracture and a skin graft to the left heel. There is a history of venous stasis disease for an unknown length of time. The patient denied any numbness or tingling in either lower extremity. This patient was taking chlorpropamide 1.25mg daily for her diabetes and amlodipine besylate 7.5mg and doxazosin mesylate 4mg for her hypertension. Other medications included oxaprozin, gabapentin, hydrocodone bitartrate with acetaminophen, and dipyridamole. The patient denied tobacco, alcohol, or street drug use, but related drinking seven cups of coffee per week for the past 50 years. Physical examination revealed an alert, morbidly obese woman in no acute respiratory distress. The patient complained of diffuse pain throughout the body, including headache, back pain, abdominal pain, and leg cramps. The lungs were clear bilaterally and there was regular rate and rhythm on cardiac examination. Vital signs were stable with temperature at 96.7 degrees F, pulse at 74, respiration at 20, and blood pressure at 160/62. An extremity exam revealed +3 edema of the right lower extremity with mild hair growth and warm temperature. The right lateral leg wound measured 9mm x 23mm x 21mm with 24mm of undermining at 12:00. A vascular exam of the right leg revealed +2 popliteal, dorsalis pedis, and posterior tibial pulses. Capillary refill was immediate. Reflexes were intact without decease in proprioceptive or vibratory sensation. Treatment on the initial visit consisted of debridement of the wound dimensions. A culture was obtained from the depth of the wound. The wound was packed with .25-inch plain gauze packing (Nu-Gauze, Johnson & Johnson Wound Management, Somerville, New Jersey) saturated with normal saline wet to moist twice daily. An elastic wrap was applied from her foot to below the knee. She was advised to elevate the extremity as much as possible and return in one week. Wound cultures revealed few gram-positive cocci. Radiographic evaluation of the right leg revealed multiple soft-tissue calcifications with soft tissue swelling (Figure 1). There was evidence of a healed, fibular, mid-shaft fracture. A blood count show mild anemia with a red blood cell count of 3.98, hemoglobin of 11.6, and hematocrit of 35.4. Sedimentation rate was 77mm. On her second visit, she was placed on trimethoprim sulfamethoxazole 160/800 twice daily. After continuous use of saline wet-to-moist dressings and oral antibiotics, no improvement was noted and the patient was taken to the operating room for irrigation and drainage of the right leg wound. In the operating room, large individual calcific deposits at the proximal protion of the wound were noted. At least eight separate islands of calcific deposits were removed from the wound with some purulence expressed as well. The deposition of the calcium deposits appeared random. The calcific deposits were sent to pathology for further evaluation and cultures were taken of the purulent material. The distal portion of the wound was closed and the proximal wound was left open and packed with the .25-inch saline-saturated gauze. The pathology report revealed dense fibrosis, acute inflammation, focal necrosis, and calcification. Wound cultures returned as Staphylococcus epidermidis resistant to oxacillin. The patient was placed on rifampin 300mg twice a day. The patient was continually followed and treated with saline wet-to-dry dressings and compression stockings for her venous stasis disease. During treatment at the Wound Healing Institute, more calcific material was removed from the wound on several occasions and sent to pathology. The pathology reports returned with a diagnosis of focally calcified, dense, amorphous material (Figure 2). The patient was taken back to surgery in December for primary closure of the wound with excellent results (Figures 3A-C). Case Report Two An 84-year-old Caucasian woman presented to the Wound Healing Institute from her nursing home residence with a nonhealing wound on her left medial lower leg. The wound measured 8mm x 10mm x 3mm with extensive subepidermal calcification and calcium deposits extruding from the wound. The calcific deposits appeared as individual “islands” of calcium. The wound had been present for four or five years with no history of trauma. The patient denied nausea, vomiting, or shortness of breath. The patient had a history of hypertension and urinary tract infections with no history of diabetes or tuberculosis. The patient was taking multivitamins, Zinc sulfate 220mg (qd), hydrochlorothiazide, metoprolol, docusate sodium, vitamin C, lactase enzyme, famotidine, diphenhydramine, and acetaminophen. The patient denied any use of alcohol or tobacco, but related drinking coffee occasionally. The patient had a history of anemia. Physical examination revealed an alert patient. Lungs were clear to auscultation and percussion bilaterally. Cardiac exam revealed regular rhythm with a grade 3/6 systolic murmur. A lower-extremity vascular examination revealed palpable popliteal, dorsalis pedis, and posterior tibial pulses with immediate capillary refill. Skin examination showed minimal hair growth with mild lymphedema and multiple varicosities noted. The wound site measure 8mm x 10mm x 3mm in dimension with extensive subepidermal calcification radiating from the wound site. Wound cultures showed rare Pseudomonas aeruginosa and Staphylococcus aureus. X-ray of the left leg revealed extensive soft tissue calcifications or ossification overlying the distal tibia and fibula as well as posterior to the distal femur with no fracture or focal bone destruction noted (Figure 4). Biopsy of the wound showed granulation tissue with areas of necrosis, severe acute inflammation, and focal calcium deposition (Figure 5). PT and PTT were within normal limits. The patient was slightly anemic with hemoglobin levels of 9.5 and MCV at 99. The SMA-7 was within normal limits. The patient underwent local wound care consisting of saline wet-to-moist dressings with antibiotic therapy and was taken to surgery for resection of the calcific deposits to allow granulation tissue to form. In the operating room, segments of calcific deposits were removed from the wound bed down to the fascial level. Pathologic examination of the deposits revealed fragments of necrotic bone and soft tissue. Wound cultures were also taken at this time and showed moderate white blood cells with few gram positive cocci with culture results returning Staphylococcus aureus. The wound, appearing free of any calcifications, was covered with a cadaveric allograft. Upon the first postoperative visit, the graft site had a green exudate and appeared infected. At that time the allograft and exudate were removed from the wound and the wound was allowed to granulate. The proximal portion of the wound again showed a significant amount of subcutaneous calcific deposits that were removed at the Wound Healing Institute. Local wound care consisting of saline wet-to-moist dressings significantly decreased the size of the initial wound but new periwound excoriations were noted with the etiology being unknown. These wounds eventually formed a solitary wound measuring 20mm x 24mm x 1mm with a clean granulatory base. Over the next few months, more subcutaneous calcifications were noted with multiple areas of chronic hypertrophic granulation tissue and nonhealing wounds about the area (Figures 6A–C). The patient refused additional surgery and continued to be seen until she was lost to further follow up. Discussion A review of the literature suggests that dystrophic wound calcification is a topic that is currently not well understood. Dystrophic calcifications have been seen in a variety of clinical settings, including chronic venous insufficiency, areas of trauma, osteomyelitis, and areas of infarcts.4 Calcium is a divalent cation that, in humans, presents in many forms with a variety of physiologic functions. Only 10 percent of total body calcium is soluble and present in extra and intracellular fluid, with the remaining 90 percent present as crystalline substances, such as hydroxyapatite. Of the body’s 10-percent soluble calcium, 50 percent is biologically active with the remaining 50 percent being bound to albumin or complexed with other anions.4,6 The parathyroid hormone and 1, 25 (OH) 2D3 tightly regulate serum calcium. Parathyroid hormone is a single chain polypeptide synthesized in the parathyroid glands. It is secreted in an active form and is inactivated in peripheral circulation. An inverse relation exists between extracellular calcium concentration and parathyroid hormone secretion. Increased calcium plasma concentration is caused by increased parathyroid hormone concentration by its direct effects on bone and kidneys and by its indirect effects on the intestine. Conversely, an increase in the serum concentration of ionized calcium results in a decrease in parathyroid hormone production. 1, 25(OH) 2D3, or the active form of Vitamin D3, is produced in the liver and kidney from inactive Vitamin D3. 1, 25(OH) 2D3, like parathyroid hormone, increases plasma calcium levels. Unlike parathyroid hormone, its primary action is to stimulate active calcium transport across the small intestine via an electrochemical gradient. The exact mechanism in which 1, 25(OH) 2D3 stimulates the accumulation of calcium in the intestinal cell is unknown.4,6 Despite tight regulation of serum calcium, subcutaneous or cutaneous tissue calcification may occur. Cutaneous tissue calcification (or calcinosis cutis) is a common occurrence associated with chronic venous stasis but can be caused by several mechanisms.1 The causes of cutaneous calcifications are generally divided into categories based on etiology. These include dystrophic, metastatic, idiopathic, and iatrogenic causes.8 Subcutaneous tissue calcifications may present as dystrophic calcification in the form of venous stasis disease, collagen vascular diseases, neoplasms, panniculitis, certain inherited disorders, trauma, and some infections. Metastatic tissue calcification is seen in cases where there is an underlying defect in calcium and/or phosphate metabolism. The most well published form of metastatic tissue calcification would be that seen in chronic renal failure.4 Chronic renal failure may deposit calcium in tissues as benign nodular calcifications or in the form of calciphylaxis. Calciphylaxis is characterized by progressive vascular calcification, soft tissue necrosis, and ischemic necrosis of the skin.7 Some other causes of metastatic tissue calcification are milk alkali syndrome, hypervitaminosis D, and Albright hereditary osteodystrophy.8 Idiopathic calcification occurs without abnormal calcium and/or phosphate metabolism or obvious underlying tissue abnormalities.4 Cutaneous ossification involves membranous and enchondral bone formation in the skin. This condition may be seen in areas surrounding neoplasms, in calcified tissue, in inflammatory and metabolic diseases, and infrequently in normal tissue. In all cases, the pathogenesis of cutaneous ossification remains unknown.5 The first case presented is an example of subcutaneous wound calcification in a patient with a history of trauma as well as chronic venous insufficiency. In this patient, mineral deposition was limited to the subcutaneous tissues with sparing of the skin, fascial, and muscle layers. The second case is a scenario in which calcium was frankly extruded from the wound. The pathology report stated that there were some areas of bone formation with the calcific deposits. Heterotropic bone formation may be seen in hypertrophic scars; however, in this wound, hypertrophic scarring was not noted.5 This case represents the idiopathic nature in which some wound calcifications form. Calcification may potentially occur in all chronic wounds but is rarely seen as such large deposits or as being frankly extruded from wounds. These presentations are unusual but reiterate the importance of looking for such areas, despite normal calcium levels. Differentiating subcutaneous calcification from subcutaneous ossification cannot be made by gross visualization of the wound or wound deposits. Use of radiographs is only somewhat helpful in making the distinction. Histopathologic evaluation of the deposits is the only way to differentiate the two types of wound deposits. Calcified tissue may be seen with osseous deposits at the time of biopsy. It is believed that calcification is a precursor to ossification.5 It is a common occurrence to see calcium deposits in conjunction with osseous tissue. The mechanism of formation of such material is not well understood but involves deposition of collagen type I matrix by osteoblasts. It is interesting to note that virtually any process that calcifies may secondarily ossify, but primary ossification is a rare occurrence.5