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Cyclosporine-induced folliculodystrophy
CASE
REPORTS
Cyclosporine-induced folliculodystrophy Michael R. Heaphy, Jr, MD,a H. Nicholas Shamma, MD,b Martha Hickmann, MD,c and Michael J. White, MDa Dayton, Ohio We describe a 34-year-old kidney transplant patient who developed a distinct cutaneous side-effect to cyclosporine manifested as an infiltrated appearance to the skin with abundant flesh-colored, follicular papules predominantly affecting the ears, nose, and surrounding areas of the face, but also the trunk and extremities. The clinical and histologic findings in this case closely match those presented in 2 previous case reports, in which immunosuppressive doses of cyclosporine appeared to be causative. We present a detailed report of the clinical and histologic findings that are unique to these 3 cases and we introduce a theory, based on the recent in vitro studies involving cyclosporine, to help explain the pathogenic events induced by cyclosporine in these patients. We propose the term “cyclosporine induced folliculodystrophy” or CIF as an appropriate name for this distinct clinicohistopathologic entity. Finally, we set forth 3 clinical and 4 histopathologic criteria upon which the diagnosis of CIF can be made. (J Am Acad Dermatol 2004; 50:310-5.)
CASE REPORT A 34-year-old African American woman with an 11-year history of systemic lupus erythematosus presented with a papular eruption of the face of 8 months duration. The eruption featured slowly enlarging follicular prominences of all hair-bearing areas. She had mild pruritus of the most affected areas, particularly those involving the nose and ears. She had undergone renal transplantation secondary to systemic lupus erythematosus–induced renal failure 3 years earlier. The kidney was ultimately rejected despite immunosuppressive therapy for more than 2 years. During this time she had been treated with various immunosuppressive and antihypertensive agents including cyclosporine (Neoral, 175 mg twice daily), mycophenolate mofetil (Cellcept, 1000 mg twice daily), prednisone (10 mg/d), tacrolimus (Prograft), amlodipine (Norvasc, 10 mg twice daily), famotidine (Pepcid, 20 mg/d), chlorpheniramine/ pseudoephidrine, (Deconamine SR)(prn), bumetanide (Bumex, 2 mg/d as required), doxazosin (Cardura, 6 mg twice daily), clonidine (CatapresFrom the Division of Dermatology, Wright State University School of Medicine,a Dermatopathology Laboratory of Central States, Division of Dermatology, Wright State University School of Medicine,b and Advanced Dermatology.c Funding sources: None. Conflicts of interest: None identified. Accepted for publication September 21, 2002. Reprint requests: Michael R. Heaphy, Jr, MD, 124 Jackson St, Dayton, OH 45402. E-mail: [email protected]. 0190-9622/$30.00 Copyright © 2004 by the American Academy of Dermatology, Inc. doi:10.1016/S0190-9622(03)00774-6
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TTS, 2 patches/wk), and sertraline (Zoloft, 50 mg/d). She began to notice changes of the skin of her face in February 2001 and in May 2001 all immunosuppressives, with the exception of prednisone and Cellcept, were discontinued. In August, Cellcept was discontinued and she started back on hemodialysis. The lesions began as papules of the alar rims that quickly spread to involve the entire nose, eyebrows, chin, and ears. At the same time, she began losing her eyelashes and eyebrows. Soon after, the growths extended to involve the entire face and, to a lesser extent, all follicle-bearing areas of skin with exception of the scalp. The patient also developed gingival hyperplasia, which normalized within 2 weeks of stopping cyclosporine. With monthly follow-up examinations, it was not until Februrary 2002 that a reduction in the size of the alar and centrofacial papules, and regrowth of eyelashes and eyebrows, could begin to be noticed. On physical examination, the skin of the face had an infiltrated appearance with numerous hypertrophic, flesh-colored, follicular papules located predominantly on the nose, ears, and surrounding areas of the face, but also on the extremities, chest, and upper back. On the nose, upper lip, and central face, there were dystrophic hairs and hairlike structures with characteristic features including various degrees of vellus hair formation and the presence of nonpigmented, coarse, keratinous, hairlike spicules of varying diameter. In addition, there was diffuse thinning of the hair of the eyebrows and eyelashes (Figs 1 and 2). There was no alopecia or alteration of the skin of the scalp. Other than obesity, there were
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Fig 3. Note aberrant follicular structure with wide follicular lumen replete with hyperkeratotic and dystrophic keratinous structures. (Hematoxylin-eosin stain; original magnification ⫻200.)
Fig 1. Flesh-colored, follicular papules located predominantly on the nose and surrounding areas of the face.
Fig 4. Supramatrical cells of the follicular bulb are disorganized and lack polarization. Some of these cells contain prominent eosinophilic, perinuclear globules. (Hematoxylin-eosin stain; original magnification ⫻200.)
Fig 2. As in Fig 1, numerous flesh-colored follicular papules are prominent on the ears.
no other abnormalities on physical examination. Social, family, and medical history were noncontributory. Histologic examination of skin from the nose and upper aspect of lip revealed aberrant follicular proliferation evidenced by a high density of anagen-
type follicular units, sometimes bifid in structure, which were abnormally large for an anatomic area such as the nose or the ear (Fig 3). At higher magnification, follicular lumina appeared dilated and lined by variably hyperplastic squamous epithelium. The majority of the follicles displayed disordered maturation. Cornification of the hair shafts was incomplete and the affected follicles contained disorganized, hyperkeratotic masses of parakeratotic cells and eosinophilic debris rather than well-defined hair shafts. The follicular bulbs appeared abnormally large and the supramatrical cells were disorganized and lacked polarization. Some of these cells appeared vacuolated whereas others contained prominent perinuclear eosinophilic globules (Fig 4). The nature of these eosinophilic globules has not been ascertained but they may represent keratinous material. Treatment, which was unsuccessful, included topical desoximetasone (Topicort), topical antibiotics, minocycline, tacrolimus (Protopic), and tretinoin 0.05% cream (Retin-A).
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Fig 5. Histopathologic features of follicular structure from original case report by Izakovic J, Buchner SA, Duggelin M, Guggenheim R, Itin PH. [Hair-like hyperkeratoses in patients with kidney transplants. A new cyclosporin side effect]. (Hautarzt 1995;46:841-6. Reprinted with permission. ©Springer-Verlag.)
DISCUSSION We believe that sufficient evidence exists pointing to cyclosporine as the cause of the follicular anomaly reported herein. There is no clinical or histologic evidence implicating infection or neoplasia. Furthermore, such overt follicular malformation has never been described for patients with lupus erythematosus or renal failure, or in any other patient treated with any of the other medications taken. However, in 1995, Izakovic et al1 described for the first time a similar case of a 31-year-old patient undergoing renal transplant and treated with cyclosporine (Sandimmune) for 8 months who developed skin-colored follicular papules in a distribution similar to that found in our patient including the centrofacial predominance. In that case, the only other immunosuppressive agent used was prednisone. These authors described hyperplastic follicles with widened lumina replete with distinctive amorphous keratin masses and occasional hairlike structures (Fig 5). The features illustrated in the photomicrograph included in their report–which shows sections of the follicular bulb, stem, and infundibulum–are structurally similar to corresponding sections of the follicular apparatus shown in Fig 3. The authors commented that within 2 months of lowering the dose of cyclosporine from 400 to 175 mg twice a day, the follicular disturbance cleared. Chastain and Millikan2 recently described a case of a 13-year-old girl with severe cystic fibrosis for whom bilateral lung transplantation had been performed and various immunosuppressives, antibiotics, and antihypertensives prescribed. After 3 years of continuous immunosuppression, the patient presented with dystrophic facies characterized by “many hypertrophic, flesh-colored, follicular papules and plaques located predominantly on the ears,
Fig 6. Ear of patient presented by Chastain MA, Millikan LE. Pilomatrix dysplasia in an immunosuppressed patient (J Am Acad Dermatol 2000;43:118-22). Note clinical similarity to features shown in Fig 2.
nose, and surrounding areas of the face, but also the proximal extremities” (Fig 6).2 On histology, their findings consisted of “dilated, irregularly outlined follicles with anagen characteristics that contained disorganized, hyperkeratotic, and parakeratotic debris rather than well developed hair shafts.”2 They also described “follicular structures that were lined by hyperplastic squamous epithelium and a variably thickened inner root sheath containing many cells with pale, vacuolated cytoplasm” (Fig 7). 2 Their clinical and histopathologic findings were essentially identical to ours. In these 2 case reports, which seem to be the first and second, respectively, to describe the clinical and histologic changes found in our patient, the authors present compelling evidence that cyclosporine was the causative agent. Pathophysiology Cyclosporine is an immunosuppressive agent known to cause hirsutism and induction of follicular keritinization.3 The promotion of the anagen phase
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Fig 7. Histopathologic features of follicular structure from same case shown in Fig 6. Note similarity to features shown in Fig 3.
of the hair follicle by cyclosporine has been demonstrated in both mouse4 and human5 studies. Other side effects of a hyperproliferative nature are also known to occur with use of cyclosporine. Some of these include excessive granulation tissue formation6,7 hyperplastic pseudofolliculitis barbae,8 and gingival hyperplasia.9-11 In a study of 67 patients undergoing renal transplant, 80.6% developed cyclosporine-induced cutaneous lesions,12 including hypertrichosis, folliculitis, epidermal (follicular infundibular) cysts, pilar keratosis, and sebaceous gland hyperplasia. Among the findings known to occur with use of cyclosporine, our patient experienced only gingival hyperplasia. Substantial changes in facial appearance have been reported in a group of children treated with prednisone and cyclosporine for immunosuppression after renal transplantation. In these cases, there was thickening of the nares, lips, and ears; puffiness of the cheeks; prominence of the supraorbital ridges; and mandibular prognathism.13 In these cases, no histologic studies were reported. It has been observed that the calcium channel blocker, nifedipine, increases the risk of gingival hyperplasia in some patients treated with cyclosporine.14 It has also been found that nifedipine itself can result in gingival hyperplasia.15 As our patient was treated with amlodipine, for which there have been no reports of similar hyperproliferative reactions, it is unlikely that this particular calcium channel blocker has played any role in the pathology at hand. Like the patient reported by Chastain and Millikan,2 our patient had also been treated with mycophenolate mofetil and prednisone but, to our knowledge, there are no reports in the literature of these drugs causing follicular abnormalities. Furthermore, mycophenolate mofetil was not used in the case presented by Izacovich et al. Increased hair growth of the bearded area, and on the arms and back, is a
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known side effect of systemic corticosteroids.16 There are, however, no associations between corticosteroids and any kind of follicular dystrophy. Because the 3 patients mentioned in this report were all treated with prednisone in addition to cyclosporine, it is possible that the pathologic skin changes noted are a result of a combined effect of these 2 medications. Our patient was also receiving systemic tacrolimus. Of interest is the finding that topical application of tacrolimus to skins of mice, rats, and hamsters markedly stimulates hair growth. However, this hair growth-stimulating effect of tacrolimus is not seen after oral administration, even with a dose that causes marked immunosuppression.17,18 Takahashi and Kamimura19 recently demonstrated that cyclosporine can stimulate both hair and keratinocyte proliferation in murine epidermal cell culture systems.19 They observed a growth-promoting action on hair epithelial cells by cyclosporine of about 150% to 160% relative to controls at an optimum dose range of 1 to 1000 ng/mL, whereas growth-promoting action on epidermal keratinocytes (approximately 140% relative to controls) was observed at a dose range of 1 to 100 ng/mL, although the effect was relatively weaker than that on the hair epithelial cell. In both cases, a growthinhibiting effect was observed at higher dosages (⬎3 g/mL).19 They observed that the growth curves of keratinocytes and hair epithelial cells differed when responding to the same dose of cyclosporine. Furthermore, they observed morphologic changes in epidermal keratinocytes and hair epithelial cells incubated with 3 g/mL of cyclosporine such as enlargement and vacuolization. Photomicrographs, included in their report, comparing hair epithelial cells cultured in the presence and the absence of cyclosporine, demonstrate that the cells cultured with cyclosporine are relatively enlarged and vacuolated. They also observed that at a level of 10 g/mL both epidermal keratinocytes and hair epithelial cells died. In patients treated with psoriatic doses of cyclosporine, concentration of this drug in wet epidermis was calculated by Fisher et al20 to be 1 to 3 g/mL. We are not aware of any studies that show the epidermal cyclosporine concentration in patients treated with transplant level doses (which can be up to 3-5 times higher), but it is reasonable to conclude that the epidermal cyclosporine concentration in these cases would be substantially greater. Epidermal cyclosporine concentrations above some as-yet-undefined threshold may, in some cases, cause severe morphologic changes in follicular epithelium consistent with those observed in the 3
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patients described in this report and in the in vitro study presented by Takahashi and Kamimura.19 The mechanism by which cyclosporine most likely induced the morphologic changes observed in our patient may relate to its effects on the interaction of protein kinase C (PKC) with epithelial cells. PKC is a soluble cytosolic protein that plays a key role in many aspects of growth and metabolism in cells. It is possible that selective PKC isoenzyme expression is involved in the regulation of hair epithelial cell proliferation, differentiation, and hair cycle regulation. To elucidate the mechanism of cyclosporine in regard to keratinocyte and hair epithelial growth and differentiation, Takahashi and Kamimura19 examined the effect of cyclosporin-A on PKC expression and translocation in murine hair epithelial cells. Their results indicated that cyclosporine inhibits the overall expression of PKC–␣, PKC-I, and PKC-II, and that cyclosporine increases the overall expression of PKC– in cultured murine hair epithelial cells. The authors concluded that cyclosporine likely affects intracellular localization of PKC isoenzymes (␣, I, II, and ) and their interaction with membranes, the cytoskeleton, and distinct subcellular compartments. These events would then trigger specific gene expression and changes in the secretion of growth factors, cytokines, or other cellular factors responsible for the unusual growth characteristics observed in their cyclosporine-treated follicular cell cultures. CONCLUSION In summary, our case, in addition to the cases independently reported by Izakovic et al1 and Chastain and Millikan,2 and the in vitro work by Takahashi and Kamimura,19 supports the conclusion that these characteristic follicular alterations should be classified as a side effect of high-dose cyclosporine. We conclude with the proposal that this specific constellation of clinical and histopathologic findings, in association with the use of cyclosporine, be referred to as cyclosporine-induced folliculodystrophy. “Folliculo” was selected in preference to “tricho” or “pilo” because the pathologic processes herein described involves the entire epithelial structure that produces the hair. “Dys,” a prefix derived from the Greek, means bad or disordered and “trophic,” also of Greek origin, refers to the concept of nourishing or stimulating. This name emphasizes that the entire follicle is aberrant in structure and function as a result of the deleterious stimulation of cyclosporine. We propose 3 clinical and 4 histologic criteria that, when present in the context of prolonged use
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of cyclosporine, can be used to diagnose cyclosporine-induced folliculodystrophy. The clinical criteria are: (1) an infiltrated appearance to the skin with abundant flesh-colored, follicular papules predominantly affecting the ears, nose, and surrounding areas of the face, but also the trunk and extremities; (2) dystrophic hairs and hairlike structures located on the nose, central aspect of face, and ears with characteristic features including various degrees of vellus hair formation and the presence of nonpigmented, coarse, keratinous hairlike spicules; and (3) partial loss of hair of the eyebrows and eyelashes. The histologic criteria are: (1) aberrant follicular proliferation evidenced by a density of anagen-type follicular units, sometimes bifid in structure, which are abnormally large for an anatomic area such as the nose or ear; (2) dilated follicular lumina lined by variably hyperplastic squamous epithelium; (3) disorganized, hyperkeratotic masses of parakeratotic cells and eosinophilic debris in many follicles rather than well-defined hair shafts; and (4) enlarged follicular bulbs with abnormally large, supramatrical cells that are disorganized and lack polarization– some of these cells appear vacuolated whereas others contain prominent eosinophilic perinuclear globules. Translation of the German article by Izakovic et al was kindly provided by Maggie S. Ryan. We thank Dr Jan Izakovic of the Department of Dermatology, University Hospital of Basel, for providing the photomicrograph shown in Fig 1 of this report. REFERENCES 1. Izakovic J, Buchner SA, Duggelin M, Guggenheim R, Itin PH. Hairlike hyperkeratoses in patients with kidney transplants: a new cyclosporin side-effect. Hautarzt 1995;46:841-6. 2. Chastain MA, Millikan LE, Pilomatrix dysplasia in an immunosuppressed patient. J Am Acad Dermatol 2000;43:118-22. 3. Seibel W, Sundberg JP, Lesko LJ, Sauk JJ, McCleary LB, Hassell TM. Cutaneous papillomatous hyperplasia in cyclosporine-A treated beagles. J Invest Dermatol 1989;93:224-30. 4. Paus R, Stenn KS, Link RE. The induction of anagen hair growth in telogen mouse skin by cyclosporine A administration. Lab Invest 1989;60:365-9. 5. Taylor M, Ashcroft ATT, Messenger AG. Cyclosporin A prolongs human hair growth in vitro. J Invest Dermatol 1993;100:237-9. 6. Wakelin SH, Emmerson RW. Excess granulation tissue development during treatment with cyclosporin. Br J Dermatol 1994; 131:147-8. 7. Higgins EM, Hughes JR, Snowden S, Pembroke AC. Cyclosporininduced periungual granulation tissue. Br J Dermatol 1995;132: 829-30. 8. Lear J, Bourke JF, Burns DA. Hyperplastic pseudofolliculitis barbae associated with cyclosporin. Br J Dermatol 1997;136:132-3. 9. Adams D, Davies G. Gingival hyperplasia associated with cyclosporin A: a report of two cases. Br Dent J 1984;157:89-90. 10. Wysocki GP, Gretzinger HA, Laupacis A, Ulan RA, Stiller CR. Fi-
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11.
12.
13.
14.
15.
brous hyperplasia of the gingiva: a side effect of cyclosporin A therapy. Oral Surg Oral Med Oral Pathol 1983;55:274-8. Ashrafi SH, Slaski K, Thu K, Neiman ES, Cunningham MP. Scanning electron microscopy of cyclosporine-induced gingival overgrowth. Scanning Microsc 1996;10:219-25. Bencini PL, Montagnino G, Sala F, De Vecchi A, Crosti C, Tarantino A. Cutaneous lesions in 67 cyclosporin-treated renal transplant recipients. Dermatologica 1986;172:24-30. Reznik VM, Durham BL, Jones KL, Mendoza SA. Changes in facial appearance during cyclosporin treatment. Lancet 1987;1:1405-7. Busque S, Demers P, St-Louis G, Boily J-G, Tousignant J, Lemieux F, et al. Conversion from Neoral (cyclosporine) to tacrolimus of kidney transplant recipients for gingival hyperplasia or hypertrichosis. Transplant Proc 1998;30:1247-8. Hancock RH, Swan RH. Nifedipine-induced gingival overgrowth. J Clin Periodontol 1992;19:12-4.
16. Frauman AG. An overview of the adverse reactions to adrenal corticosteroids. Adverse Drug React Toxicol Rev 1996;15:203-6. 17. Jiang H, Yamamoto S, Kato R. Induction of anagen in telogen mouse skin by topical application of FK506, a potent immunosuppressant. J Invest Dermatol 1995;104:523-5. 18. Yamamoto S, Jiang H, Kato R. Stimulation of hair growth by topical application of FK506, a potent immunosuppressive agent. J Invest Dermatol 1994;102:160-4. 19. Takahashi T, Kamimura A. Cyclosporin A promotes hair epithelial cell proliferation and modulates protein kinase C expression and translocation in hair epithelial cells. J Invest Dermatol 2001; 117:605-11. 20. Fisher GJ, Duell EA, Nickoloff BJ, Annesley TM, Kowalke JK, Ellis CN, et al. Levels of cyclosporin in epidermis of treated psoriasis patients differentially inhibit growth of keratinocytes cultured in serum free versus serum containing media. J Invest Dermatol 1988;91:142-6.
Infectious eccrine hidradenitis caused by Nocardia Diana D. Antonovich, MD, Adrienne Berke, MD, Jane M. Grant-Kels, MD, and Maxwell Fung, MD Farmington, Connecticut Neutrophilic eccrine hidradenitis is a nonspecific clinical reaction pattern classified as a neutrophilic dermatosis that typically occurs in the setting of chemotherapy for hematologic malignant disease. Neutrophilic eccrine hidradenitis more rarely has been reported in association with infectious agents, including Serratia, Enterobacter, Staphylococcus, and HIV. We describe the first case of infectious eccrine hidradenitis occurring in a patient with cutaneous Nocardia infection. (J Am Acad Dermatol 2004;50:315-8.)
N
eutrophilic eccrine hidradenitis (NEH) is a rare neutrophilic dermatosis that most commonly occurs after administration of chemotherapy. The disorder was first reported, by Harris et al,1 with use of cytarabine to treat a patient with acute myelogenous leukemia. NEH has since been associated with diverse clinical conditions, occurring during use of both chemotherapeutic and nonchemotherapeutic agents,2-4 in immunocompromised and healthy persons,5-8 and infrequently in infection. Infectious NEH is rare, only 4 published reports documenting the presence of an infectious pathoFrom the Department of Dermatology, University of Connecticut Health Center. Funding sources: None. Conflict of interest: None identified. Reprint requests: Adrienne Berke, MD, University of Connecticut Health Center, 263 Farmington Ave, Farmington, CT 06030. Email: [email protected]. 0190-9622/$30.00 Copyright © 2004 by the American Academy of Dermatology, Inc. doi:10.1016/S0190-9622(03)02163-7
gen at the cutaneous eruption site.5,9-11 Five reports of NEH describing the ailment in HIV-infected patients have been published in the English literature.3,12-14 We describe the clinical and histopathologic findings of the first reported case of infectious eccrine hidradenitis (IEH) associated with Nocardia infection.
CASE REPORT An 83-year-old woman had a 2-day history of diffuse pain, tenderness, edema, and erythema of the right leg. The clinical impression was cellulitis. The patient was admitted to the hospital, and treatment with cefazolin was initiated. The medical history was significant for chronic obstructive pulmonary disease, mitral valve prolapse, and breast and endometrial cancer. She had undergone right lumpectomy with axillary node dissection 5 years earlier and total abdominal hysterectomy 15 years earlier. The patient’s current medications included tamoxifen, prednisone 12.5 mg orally once a day, and pulmonary inhalers as needed. With the excep-
REPORTS
Cyclosporine-induced folliculodystrophy Michael R. Heaphy, Jr, MD,a H. Nicholas Shamma, MD,b Martha Hickmann, MD,c and Michael J. White, MDa Dayton, Ohio We describe a 34-year-old kidney transplant patient who developed a distinct cutaneous side-effect to cyclosporine manifested as an infiltrated appearance to the skin with abundant flesh-colored, follicular papules predominantly affecting the ears, nose, and surrounding areas of the face, but also the trunk and extremities. The clinical and histologic findings in this case closely match those presented in 2 previous case reports, in which immunosuppressive doses of cyclosporine appeared to be causative. We present a detailed report of the clinical and histologic findings that are unique to these 3 cases and we introduce a theory, based on the recent in vitro studies involving cyclosporine, to help explain the pathogenic events induced by cyclosporine in these patients. We propose the term “cyclosporine induced folliculodystrophy” or CIF as an appropriate name for this distinct clinicohistopathologic entity. Finally, we set forth 3 clinical and 4 histopathologic criteria upon which the diagnosis of CIF can be made. (J Am Acad Dermatol 2004; 50:310-5.)
CASE REPORT A 34-year-old African American woman with an 11-year history of systemic lupus erythematosus presented with a papular eruption of the face of 8 months duration. The eruption featured slowly enlarging follicular prominences of all hair-bearing areas. She had mild pruritus of the most affected areas, particularly those involving the nose and ears. She had undergone renal transplantation secondary to systemic lupus erythematosus–induced renal failure 3 years earlier. The kidney was ultimately rejected despite immunosuppressive therapy for more than 2 years. During this time she had been treated with various immunosuppressive and antihypertensive agents including cyclosporine (Neoral, 175 mg twice daily), mycophenolate mofetil (Cellcept, 1000 mg twice daily), prednisone (10 mg/d), tacrolimus (Prograft), amlodipine (Norvasc, 10 mg twice daily), famotidine (Pepcid, 20 mg/d), chlorpheniramine/ pseudoephidrine, (Deconamine SR)(prn), bumetanide (Bumex, 2 mg/d as required), doxazosin (Cardura, 6 mg twice daily), clonidine (CatapresFrom the Division of Dermatology, Wright State University School of Medicine,a Dermatopathology Laboratory of Central States, Division of Dermatology, Wright State University School of Medicine,b and Advanced Dermatology.c Funding sources: None. Conflicts of interest: None identified. Accepted for publication September 21, 2002. Reprint requests: Michael R. Heaphy, Jr, MD, 124 Jackson St, Dayton, OH 45402. E-mail: [email protected]. 0190-9622/$30.00 Copyright © 2004 by the American Academy of Dermatology, Inc. doi:10.1016/S0190-9622(03)00774-6
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TTS, 2 patches/wk), and sertraline (Zoloft, 50 mg/d). She began to notice changes of the skin of her face in February 2001 and in May 2001 all immunosuppressives, with the exception of prednisone and Cellcept, were discontinued. In August, Cellcept was discontinued and she started back on hemodialysis. The lesions began as papules of the alar rims that quickly spread to involve the entire nose, eyebrows, chin, and ears. At the same time, she began losing her eyelashes and eyebrows. Soon after, the growths extended to involve the entire face and, to a lesser extent, all follicle-bearing areas of skin with exception of the scalp. The patient also developed gingival hyperplasia, which normalized within 2 weeks of stopping cyclosporine. With monthly follow-up examinations, it was not until Februrary 2002 that a reduction in the size of the alar and centrofacial papules, and regrowth of eyelashes and eyebrows, could begin to be noticed. On physical examination, the skin of the face had an infiltrated appearance with numerous hypertrophic, flesh-colored, follicular papules located predominantly on the nose, ears, and surrounding areas of the face, but also on the extremities, chest, and upper back. On the nose, upper lip, and central face, there were dystrophic hairs and hairlike structures with characteristic features including various degrees of vellus hair formation and the presence of nonpigmented, coarse, keratinous, hairlike spicules of varying diameter. In addition, there was diffuse thinning of the hair of the eyebrows and eyelashes (Figs 1 and 2). There was no alopecia or alteration of the skin of the scalp. Other than obesity, there were
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Fig 3. Note aberrant follicular structure with wide follicular lumen replete with hyperkeratotic and dystrophic keratinous structures. (Hematoxylin-eosin stain; original magnification ⫻200.)
Fig 1. Flesh-colored, follicular papules located predominantly on the nose and surrounding areas of the face.
Fig 4. Supramatrical cells of the follicular bulb are disorganized and lack polarization. Some of these cells contain prominent eosinophilic, perinuclear globules. (Hematoxylin-eosin stain; original magnification ⫻200.)
Fig 2. As in Fig 1, numerous flesh-colored follicular papules are prominent on the ears.
no other abnormalities on physical examination. Social, family, and medical history were noncontributory. Histologic examination of skin from the nose and upper aspect of lip revealed aberrant follicular proliferation evidenced by a high density of anagen-
type follicular units, sometimes bifid in structure, which were abnormally large for an anatomic area such as the nose or the ear (Fig 3). At higher magnification, follicular lumina appeared dilated and lined by variably hyperplastic squamous epithelium. The majority of the follicles displayed disordered maturation. Cornification of the hair shafts was incomplete and the affected follicles contained disorganized, hyperkeratotic masses of parakeratotic cells and eosinophilic debris rather than well-defined hair shafts. The follicular bulbs appeared abnormally large and the supramatrical cells were disorganized and lacked polarization. Some of these cells appeared vacuolated whereas others contained prominent perinuclear eosinophilic globules (Fig 4). The nature of these eosinophilic globules has not been ascertained but they may represent keratinous material. Treatment, which was unsuccessful, included topical desoximetasone (Topicort), topical antibiotics, minocycline, tacrolimus (Protopic), and tretinoin 0.05% cream (Retin-A).
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Fig 5. Histopathologic features of follicular structure from original case report by Izakovic J, Buchner SA, Duggelin M, Guggenheim R, Itin PH. [Hair-like hyperkeratoses in patients with kidney transplants. A new cyclosporin side effect]. (Hautarzt 1995;46:841-6. Reprinted with permission. ©Springer-Verlag.)
DISCUSSION We believe that sufficient evidence exists pointing to cyclosporine as the cause of the follicular anomaly reported herein. There is no clinical or histologic evidence implicating infection or neoplasia. Furthermore, such overt follicular malformation has never been described for patients with lupus erythematosus or renal failure, or in any other patient treated with any of the other medications taken. However, in 1995, Izakovic et al1 described for the first time a similar case of a 31-year-old patient undergoing renal transplant and treated with cyclosporine (Sandimmune) for 8 months who developed skin-colored follicular papules in a distribution similar to that found in our patient including the centrofacial predominance. In that case, the only other immunosuppressive agent used was prednisone. These authors described hyperplastic follicles with widened lumina replete with distinctive amorphous keratin masses and occasional hairlike structures (Fig 5). The features illustrated in the photomicrograph included in their report–which shows sections of the follicular bulb, stem, and infundibulum–are structurally similar to corresponding sections of the follicular apparatus shown in Fig 3. The authors commented that within 2 months of lowering the dose of cyclosporine from 400 to 175 mg twice a day, the follicular disturbance cleared. Chastain and Millikan2 recently described a case of a 13-year-old girl with severe cystic fibrosis for whom bilateral lung transplantation had been performed and various immunosuppressives, antibiotics, and antihypertensives prescribed. After 3 years of continuous immunosuppression, the patient presented with dystrophic facies characterized by “many hypertrophic, flesh-colored, follicular papules and plaques located predominantly on the ears,
Fig 6. Ear of patient presented by Chastain MA, Millikan LE. Pilomatrix dysplasia in an immunosuppressed patient (J Am Acad Dermatol 2000;43:118-22). Note clinical similarity to features shown in Fig 2.
nose, and surrounding areas of the face, but also the proximal extremities” (Fig 6).2 On histology, their findings consisted of “dilated, irregularly outlined follicles with anagen characteristics that contained disorganized, hyperkeratotic, and parakeratotic debris rather than well developed hair shafts.”2 They also described “follicular structures that were lined by hyperplastic squamous epithelium and a variably thickened inner root sheath containing many cells with pale, vacuolated cytoplasm” (Fig 7). 2 Their clinical and histopathologic findings were essentially identical to ours. In these 2 case reports, which seem to be the first and second, respectively, to describe the clinical and histologic changes found in our patient, the authors present compelling evidence that cyclosporine was the causative agent. Pathophysiology Cyclosporine is an immunosuppressive agent known to cause hirsutism and induction of follicular keritinization.3 The promotion of the anagen phase
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Fig 7. Histopathologic features of follicular structure from same case shown in Fig 6. Note similarity to features shown in Fig 3.
of the hair follicle by cyclosporine has been demonstrated in both mouse4 and human5 studies. Other side effects of a hyperproliferative nature are also known to occur with use of cyclosporine. Some of these include excessive granulation tissue formation6,7 hyperplastic pseudofolliculitis barbae,8 and gingival hyperplasia.9-11 In a study of 67 patients undergoing renal transplant, 80.6% developed cyclosporine-induced cutaneous lesions,12 including hypertrichosis, folliculitis, epidermal (follicular infundibular) cysts, pilar keratosis, and sebaceous gland hyperplasia. Among the findings known to occur with use of cyclosporine, our patient experienced only gingival hyperplasia. Substantial changes in facial appearance have been reported in a group of children treated with prednisone and cyclosporine for immunosuppression after renal transplantation. In these cases, there was thickening of the nares, lips, and ears; puffiness of the cheeks; prominence of the supraorbital ridges; and mandibular prognathism.13 In these cases, no histologic studies were reported. It has been observed that the calcium channel blocker, nifedipine, increases the risk of gingival hyperplasia in some patients treated with cyclosporine.14 It has also been found that nifedipine itself can result in gingival hyperplasia.15 As our patient was treated with amlodipine, for which there have been no reports of similar hyperproliferative reactions, it is unlikely that this particular calcium channel blocker has played any role in the pathology at hand. Like the patient reported by Chastain and Millikan,2 our patient had also been treated with mycophenolate mofetil and prednisone but, to our knowledge, there are no reports in the literature of these drugs causing follicular abnormalities. Furthermore, mycophenolate mofetil was not used in the case presented by Izacovich et al. Increased hair growth of the bearded area, and on the arms and back, is a
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known side effect of systemic corticosteroids.16 There are, however, no associations between corticosteroids and any kind of follicular dystrophy. Because the 3 patients mentioned in this report were all treated with prednisone in addition to cyclosporine, it is possible that the pathologic skin changes noted are a result of a combined effect of these 2 medications. Our patient was also receiving systemic tacrolimus. Of interest is the finding that topical application of tacrolimus to skins of mice, rats, and hamsters markedly stimulates hair growth. However, this hair growth-stimulating effect of tacrolimus is not seen after oral administration, even with a dose that causes marked immunosuppression.17,18 Takahashi and Kamimura19 recently demonstrated that cyclosporine can stimulate both hair and keratinocyte proliferation in murine epidermal cell culture systems.19 They observed a growth-promoting action on hair epithelial cells by cyclosporine of about 150% to 160% relative to controls at an optimum dose range of 1 to 1000 ng/mL, whereas growth-promoting action on epidermal keratinocytes (approximately 140% relative to controls) was observed at a dose range of 1 to 100 ng/mL, although the effect was relatively weaker than that on the hair epithelial cell. In both cases, a growthinhibiting effect was observed at higher dosages (⬎3 g/mL).19 They observed that the growth curves of keratinocytes and hair epithelial cells differed when responding to the same dose of cyclosporine. Furthermore, they observed morphologic changes in epidermal keratinocytes and hair epithelial cells incubated with 3 g/mL of cyclosporine such as enlargement and vacuolization. Photomicrographs, included in their report, comparing hair epithelial cells cultured in the presence and the absence of cyclosporine, demonstrate that the cells cultured with cyclosporine are relatively enlarged and vacuolated. They also observed that at a level of 10 g/mL both epidermal keratinocytes and hair epithelial cells died. In patients treated with psoriatic doses of cyclosporine, concentration of this drug in wet epidermis was calculated by Fisher et al20 to be 1 to 3 g/mL. We are not aware of any studies that show the epidermal cyclosporine concentration in patients treated with transplant level doses (which can be up to 3-5 times higher), but it is reasonable to conclude that the epidermal cyclosporine concentration in these cases would be substantially greater. Epidermal cyclosporine concentrations above some as-yet-undefined threshold may, in some cases, cause severe morphologic changes in follicular epithelium consistent with those observed in the 3
314 Case reports
patients described in this report and in the in vitro study presented by Takahashi and Kamimura.19 The mechanism by which cyclosporine most likely induced the morphologic changes observed in our patient may relate to its effects on the interaction of protein kinase C (PKC) with epithelial cells. PKC is a soluble cytosolic protein that plays a key role in many aspects of growth and metabolism in cells. It is possible that selective PKC isoenzyme expression is involved in the regulation of hair epithelial cell proliferation, differentiation, and hair cycle regulation. To elucidate the mechanism of cyclosporine in regard to keratinocyte and hair epithelial growth and differentiation, Takahashi and Kamimura19 examined the effect of cyclosporin-A on PKC expression and translocation in murine hair epithelial cells. Their results indicated that cyclosporine inhibits the overall expression of PKC–␣, PKC-I, and PKC-II, and that cyclosporine increases the overall expression of PKC– in cultured murine hair epithelial cells. The authors concluded that cyclosporine likely affects intracellular localization of PKC isoenzymes (␣, I, II, and ) and their interaction with membranes, the cytoskeleton, and distinct subcellular compartments. These events would then trigger specific gene expression and changes in the secretion of growth factors, cytokines, or other cellular factors responsible for the unusual growth characteristics observed in their cyclosporine-treated follicular cell cultures. CONCLUSION In summary, our case, in addition to the cases independently reported by Izakovic et al1 and Chastain and Millikan,2 and the in vitro work by Takahashi and Kamimura,19 supports the conclusion that these characteristic follicular alterations should be classified as a side effect of high-dose cyclosporine. We conclude with the proposal that this specific constellation of clinical and histopathologic findings, in association with the use of cyclosporine, be referred to as cyclosporine-induced folliculodystrophy. “Folliculo” was selected in preference to “tricho” or “pilo” because the pathologic processes herein described involves the entire epithelial structure that produces the hair. “Dys,” a prefix derived from the Greek, means bad or disordered and “trophic,” also of Greek origin, refers to the concept of nourishing or stimulating. This name emphasizes that the entire follicle is aberrant in structure and function as a result of the deleterious stimulation of cyclosporine. We propose 3 clinical and 4 histologic criteria that, when present in the context of prolonged use
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of cyclosporine, can be used to diagnose cyclosporine-induced folliculodystrophy. The clinical criteria are: (1) an infiltrated appearance to the skin with abundant flesh-colored, follicular papules predominantly affecting the ears, nose, and surrounding areas of the face, but also the trunk and extremities; (2) dystrophic hairs and hairlike structures located on the nose, central aspect of face, and ears with characteristic features including various degrees of vellus hair formation and the presence of nonpigmented, coarse, keratinous hairlike spicules; and (3) partial loss of hair of the eyebrows and eyelashes. The histologic criteria are: (1) aberrant follicular proliferation evidenced by a density of anagen-type follicular units, sometimes bifid in structure, which are abnormally large for an anatomic area such as the nose or ear; (2) dilated follicular lumina lined by variably hyperplastic squamous epithelium; (3) disorganized, hyperkeratotic masses of parakeratotic cells and eosinophilic debris in many follicles rather than well-defined hair shafts; and (4) enlarged follicular bulbs with abnormally large, supramatrical cells that are disorganized and lack polarization– some of these cells appear vacuolated whereas others contain prominent eosinophilic perinuclear globules. Translation of the German article by Izakovic et al was kindly provided by Maggie S. Ryan. We thank Dr Jan Izakovic of the Department of Dermatology, University Hospital of Basel, for providing the photomicrograph shown in Fig 1 of this report. REFERENCES 1. Izakovic J, Buchner SA, Duggelin M, Guggenheim R, Itin PH. Hairlike hyperkeratoses in patients with kidney transplants: a new cyclosporin side-effect. Hautarzt 1995;46:841-6. 2. Chastain MA, Millikan LE, Pilomatrix dysplasia in an immunosuppressed patient. J Am Acad Dermatol 2000;43:118-22. 3. Seibel W, Sundberg JP, Lesko LJ, Sauk JJ, McCleary LB, Hassell TM. Cutaneous papillomatous hyperplasia in cyclosporine-A treated beagles. J Invest Dermatol 1989;93:224-30. 4. Paus R, Stenn KS, Link RE. The induction of anagen hair growth in telogen mouse skin by cyclosporine A administration. Lab Invest 1989;60:365-9. 5. Taylor M, Ashcroft ATT, Messenger AG. Cyclosporin A prolongs human hair growth in vitro. J Invest Dermatol 1993;100:237-9. 6. Wakelin SH, Emmerson RW. Excess granulation tissue development during treatment with cyclosporin. Br J Dermatol 1994; 131:147-8. 7. Higgins EM, Hughes JR, Snowden S, Pembroke AC. Cyclosporininduced periungual granulation tissue. Br J Dermatol 1995;132: 829-30. 8. Lear J, Bourke JF, Burns DA. Hyperplastic pseudofolliculitis barbae associated with cyclosporin. Br J Dermatol 1997;136:132-3. 9. Adams D, Davies G. Gingival hyperplasia associated with cyclosporin A: a report of two cases. Br Dent J 1984;157:89-90. 10. Wysocki GP, Gretzinger HA, Laupacis A, Ulan RA, Stiller CR. Fi-
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brous hyperplasia of the gingiva: a side effect of cyclosporin A therapy. Oral Surg Oral Med Oral Pathol 1983;55:274-8. Ashrafi SH, Slaski K, Thu K, Neiman ES, Cunningham MP. Scanning electron microscopy of cyclosporine-induced gingival overgrowth. Scanning Microsc 1996;10:219-25. Bencini PL, Montagnino G, Sala F, De Vecchi A, Crosti C, Tarantino A. Cutaneous lesions in 67 cyclosporin-treated renal transplant recipients. Dermatologica 1986;172:24-30. Reznik VM, Durham BL, Jones KL, Mendoza SA. Changes in facial appearance during cyclosporin treatment. Lancet 1987;1:1405-7. Busque S, Demers P, St-Louis G, Boily J-G, Tousignant J, Lemieux F, et al. Conversion from Neoral (cyclosporine) to tacrolimus of kidney transplant recipients for gingival hyperplasia or hypertrichosis. Transplant Proc 1998;30:1247-8. Hancock RH, Swan RH. Nifedipine-induced gingival overgrowth. J Clin Periodontol 1992;19:12-4.
16. Frauman AG. An overview of the adverse reactions to adrenal corticosteroids. Adverse Drug React Toxicol Rev 1996;15:203-6. 17. Jiang H, Yamamoto S, Kato R. Induction of anagen in telogen mouse skin by topical application of FK506, a potent immunosuppressant. J Invest Dermatol 1995;104:523-5. 18. Yamamoto S, Jiang H, Kato R. Stimulation of hair growth by topical application of FK506, a potent immunosuppressive agent. J Invest Dermatol 1994;102:160-4. 19. Takahashi T, Kamimura A. Cyclosporin A promotes hair epithelial cell proliferation and modulates protein kinase C expression and translocation in hair epithelial cells. J Invest Dermatol 2001; 117:605-11. 20. Fisher GJ, Duell EA, Nickoloff BJ, Annesley TM, Kowalke JK, Ellis CN, et al. Levels of cyclosporin in epidermis of treated psoriasis patients differentially inhibit growth of keratinocytes cultured in serum free versus serum containing media. J Invest Dermatol 1988;91:142-6.
Infectious eccrine hidradenitis caused by Nocardia Diana D. Antonovich, MD, Adrienne Berke, MD, Jane M. Grant-Kels, MD, and Maxwell Fung, MD Farmington, Connecticut Neutrophilic eccrine hidradenitis is a nonspecific clinical reaction pattern classified as a neutrophilic dermatosis that typically occurs in the setting of chemotherapy for hematologic malignant disease. Neutrophilic eccrine hidradenitis more rarely has been reported in association with infectious agents, including Serratia, Enterobacter, Staphylococcus, and HIV. We describe the first case of infectious eccrine hidradenitis occurring in a patient with cutaneous Nocardia infection. (J Am Acad Dermatol 2004;50:315-8.)
N
eutrophilic eccrine hidradenitis (NEH) is a rare neutrophilic dermatosis that most commonly occurs after administration of chemotherapy. The disorder was first reported, by Harris et al,1 with use of cytarabine to treat a patient with acute myelogenous leukemia. NEH has since been associated with diverse clinical conditions, occurring during use of both chemotherapeutic and nonchemotherapeutic agents,2-4 in immunocompromised and healthy persons,5-8 and infrequently in infection. Infectious NEH is rare, only 4 published reports documenting the presence of an infectious pathoFrom the Department of Dermatology, University of Connecticut Health Center. Funding sources: None. Conflict of interest: None identified. Reprint requests: Adrienne Berke, MD, University of Connecticut Health Center, 263 Farmington Ave, Farmington, CT 06030. Email: [email protected]. 0190-9622/$30.00 Copyright © 2004 by the American Academy of Dermatology, Inc. doi:10.1016/S0190-9622(03)02163-7
gen at the cutaneous eruption site.5,9-11 Five reports of NEH describing the ailment in HIV-infected patients have been published in the English literature.3,12-14 We describe the clinical and histopathologic findings of the first reported case of infectious eccrine hidradenitis (IEH) associated with Nocardia infection.
CASE REPORT An 83-year-old woman had a 2-day history of diffuse pain, tenderness, edema, and erythema of the right leg. The clinical impression was cellulitis. The patient was admitted to the hospital, and treatment with cefazolin was initiated. The medical history was significant for chronic obstructive pulmonary disease, mitral valve prolapse, and breast and endometrial cancer. She had undergone right lumpectomy with axillary node dissection 5 years earlier and total abdominal hysterectomy 15 years earlier. The patient’s current medications included tamoxifen, prednisone 12.5 mg orally once a day, and pulmonary inhalers as needed. With the excep-