Many exogenous or “foreign” substances resulting from intentional, traumatic or iatrogenic inoculation can be identified in cutaneous histopathology. Examples of such substances include tattoo pigment, intradermal fillers, plant material, metal debris, and other organic and inorganic products.1,2 Dermatopathologists play a key role in recognizing characteristic features of foreign materials, as precise identification can aid clinicians in their approach to diagnosis and treatment.1
In the current opioid abuse epidemic, dermatologists and dermatopathologists have an important responsibility to recognize cutaneous signs of drug abuse. Some drug users crush pharmaceutical tablets, including prescription opiates, and perform intradermal injection of an aqueous solution in a technique known as “skin popping.”3–5 This can result in a variety of cutaneous complications, including infection, scarring, and foreign body reaction.3,4 In this study, we describe 2 cases of necrotic skin lesions that histologically revealed the presence of crospovidone, an inert ingredient in pharmaceutical tablets. We also outline the key histologic features that can help dermatopathologists to identify this unusual foreign material.
A 36-year-old woman with history of intravenous drug abuse (on buprenorphine–naloxone program for 5 years) and hepatitis C presented with a 4-year history of recurrent sores on her hands and legs. She stated that the lesions would become sore and ulcerated, then slowly heal leaving permanent scars. She also reported puffy swollen hands. She endorsed a history of intravenous drug abuse. On further questioning, she admitted to subcutaneous injection of crushed buprenorphine–naloxone tablets into her skin on multiple occasions. Physical examination revealed moderate pitting edema of dorsal hands with scattered thin pink papules, along with a 1.5-cm crusted pink nodule on the left shin (Figs. 1A, B). The clinical differential diagnosis for the legs was broad and included vasculitis, vasculopathy, foreign body granuloma, or infection (eg, fungal or atypical mycobacterial). The differential diagnosis for the papules on the hands included lichen planus, eczematous dermatitis, or sequelae related to her history of drug abuse.
Punch biopsies were performed of a papule on the right hand and the nodule on the left shin. Both biopsies demonstrated suppurative and granulomatous inflammation and polarizable material consistent with talc. In addition, there was an irregularly shaped, nonpolarizable, coral-shaped, deeply basophilic foreign material (Figs. 1C, D). Although the histologic appearance was reminiscent of calcium, the von Kossa stain did not highlight the foreign substance (Fig. 1E). The material stained dark red by mucicarmine, dark blue by periodic acid–Schiff with diastase (PAS/D), dark red by trichrome, and bright red by Alcian blue (Figs. 1F, H). The histologic appearance and staining pattern were consistent with crospovidone.
A 30-year-old woman with a history of opiate abuse and hepatitis C presented to dermatology clinic with a 6 × 5.5-cm necrotic plaque with surrounding erythema, located in her popliteal fossa (Fig. 2A). Initially, the lesion presented as a large painful bruise and was diagnosed as a possible Baker's cyst. Subsequently, the area grew, drained bloody fluid, and became an ulcerated eschar. The patient was treated with antibiotics, but the lesion continued to progress. Clinically, the differential diagnoses included vasculitis, including levamisole-induced skin necrosis, although the patient denied recent drug use. A punch biopsy was performed.
Histopathologic examination revealed a dermal and subcutaneous granulomatous tissue reaction. Deposits of basophilic material with an irregular, jagged surface were observed in the dermis and phagocytized within multinucleate giant cells (Fig. 2B). The phagocytosed foreign material stained blue with Alcian blue, and red with mucicarmine and Congo red. This material was not birefringent, and von Kossa stain failed to highlight the basophilic material (Fig. 2C). The morphology and staining pattern of this material were consistent with crospovidone.
In addition to the presence of crospovidone, there was birefringent foreign material on polariscopic examination. The birefringent material displayed a Maltese cross pattern, as seen with talc or starch (Fig. 2D). Our patient has not been seen within our system since 2015, and her current status is unknown.
Crospovidone (poly[N-vinyl-2-pyrrolidone], polyvinylpyrrolidone, PVP), a highly cross-linked polymer of polyvinylpyrrolidone, is an inert insoluble polymer used as a disintegrant in pharmaceutical tablets. Disintegrants are agents that cause tablets to release their active ingredient(s) on contact with moisture. Crospovidone is synthesized by polymerization of vinyl pyrrolidone.6 It has been described in the lungs of intravenous drug users and embolized with other tablet components such as talc and microcrystalline cellulose.6 It has also been identified in the lungs of patients with history of aspiration.7 In addition, crospovidone was recently reported in gastrointestinal specimens.8
Deposition of crospovidone and other pharmaceutical components can result in significant pathology. When embolized to the lungs, these materials can be associated with pulmonary angiothrombosis, foreign body granuloma, bronchiolitis obliterans–organizing pneumonia, and granulomatous angiitis.6,7 In the gastrointestinal tract lumen, crospovidone is typically an incidental finding without associated pathology; however, extraluminal presence of crospovidone can indicate perforation of the gastrointestinal tract.8,9
Between 1970 and 1984, there were several reports of skin complications from injection of polyvinyl pyrrolidone, resulting in pseudotumors, pseudosarcomatous granuloma, pseudoxanthomatous papules, or “povidone panniculitis.”10–13 The substance referred to in these articles is described as a hydrophilic basophilic globular material with foamy appearance resembling mucin that was found within histiocytes and the surrounding dermis.10–13 Based on the descriptions of this material and review of the associated photomicrographs, we believe that this substance has a different composition and histologic appearance when compared with crospovidone.
On histologic sections, crospovidone appears as basophilic, dense, irregular, nonbirefringent, sponge or coral-shaped material.6,8 Crospovidone stains violet-blue with hematoxylin and eosin (H&E). It does not stain with von Kossa stain, whereas it is red with mucicarmine, Fontana Masson, Prussian blue, and Congo red (Table 1). Staining with Alcian blue and Movat pentachrome is variable, depending on whether the crospovidone is phagocytized or not.6,14
On H&E-stained sections, crospovidone can closely resemble calcification; however, it does not stain with von Kossa or alizarin red.6 The morphology and staining pattern of crospovidone are distinct from other foreign materials (eg, talc, cellulose, and starch), which are generally colorless with H&E and show birefringence with polarized microscopy.6 In both of our cases, crospovidone was accompanied by polarizable tablet components.
Some drug users crush tablets and inhale or inject them for an enhanced euphoric effect.3 Previous reports have described the clinical complications from such injections, including infection, venous thrombosis, edema, livedoid, and necrotic skin ulcers.3,15,16 The skin manifestations associated with our cases of crospovidone deposition were variable and included papules, nodules, and ulcers with eschar. Both patients complained of pain associated with their skin lesions. One of the patients also had prominent edema of the hands, consistent with what has previously been described as “puffy hand syndrome.”17
Crospovidone is present in a variety of pharmaceutical preparations that can be crushed and injected, including oxycodone–acetaminophen (Percocet) and hydrocodone–acetaminophen (Vicodin).8 Both of our patients were enrolled in a buprenorphine–naloxone program. A review of the package insert reveals that the sublingual tablets of buprenorphine–naloxone contain povidone K30.18 Further studies would be required to determine whether this material has the same histologic appearance as crospovidone.
To the best of our knowledge, these are the first reported cases of crospovidone deposition in the skin. Crospovidone is an inert, inorganic disintegrant that can be found in the skin after injection of crushed pharmaceutical tablets. In this setting, it can be associated with tender nodules or necrotic skin lesions. Recognition of this distinct foreign body and its associated clinical manifestations can aid physicians in making a timely and accurate diagnosis.
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