British Journal of Dermatology 2000; 142: 812±851.

Correspondence

A case of paraneoplastic with antidesmoglein 1 antibodies as determined by immunoblotting

Sir, Paraneoplastic pemphigus (PNP) is a subset of pemphigus in patients with neoplasia, in which clinical and histological features of (PV) are variably associated with features of multiforme, and .1 PNP autoantibodies are directed against an antigen complex mainly composed of proteins of the plakin family: these are major components of desmosomal and hemidesmosomal plaques. We first described the presence of antidesmoglein 3 (Dsg3) antibodies in PNP sera by immuno- blotting.2 It has recently been demonstrated that pathogenic anti-Dsg3 autoantibodies can be consistently detected in PNP sera by enzyme-linked immunosorbent assay (ELISA).3 Curiously, whereas antidesmoglein 1 (Dsg1) antibodies have been recovered in more than 50% of PNP sera using ELISA, such autoantibodies have never been detected in PNP sera using immunoblotting or immunoprecipitation assays. We describe a PNP patient with an atypical clinical presentation in whom circulating anti-Dsg1 antibodies were detected by immunoblotting. A 70-year-old man with a history of chronic lymphoid leukaemia and prostate carcinoma presented with a generalized lichenoid eruption. Cutaneous lesions evolved to an exfoliative erythroderma (Fig. 1a) associated with atypical target-like lesions on the lower limbs. The patient had mucosal erosions and extensive cutaneous with a positive Nikolsky sign. He died of infection despite parenteral antibiotics and corticoid therapy. Histological examination of a cutaneous showed basilar and suprabasilar cleavage with vacuolar changes and keratinocyte necrosis. Direct and indirect immunofluorescence (IF) showed antiepidermal cell surface antibodies without antibasement membrane zone antibodies. The patient's serum stained rat bladder epithelium on indirect IF. Immunoblot analysis2 showed IgG antibodies directed against bands of 250-, 210-(doublet) and 190-kDa molecular weight, corresponding to desmoplakin I, envo- plakin and desmoplakin II, and periplakin, respectively. Additionally, the patient's serum contained IgG antibodies that recognized a 160-kDa band comigrating with the band recognized by a murine anti-Dsg1 monoclonal antibody (Clone DG3.10, Progen, Heidelberg, Germany) (Fig. 1b). It is surprising that, to date, anti-Dsg1 antibodies have never been detected in PNP sera by immunoblotting or immunoprecipitation, whereas they have recently been Figure 1. (a) Paraneoplastic pemphigus presenting as an exfoliative reported in 50% of PNP sera by an ELISA assay using 3 erythroderma, with erosions and necrolysis. (b) Immunoblot analysis baculovirus-expressed recombinant Dsg1. One possible of the patient's serum on human epidermal extract. Lane A, murine explanation is that PNP sera, like pemphigus foliaceus (PF) antidesmoglein 1 monoclonal antibody; lane B, patient's serum sera, may recognize a conformational epitope on Dsg1 which revealed with a goat antihuman IgG antibody; lane C, control serum is denatured during the immunoblotting extraction pro- from a pemphigus foliaceus patient; lane D, control serum from a cedure. The pathogenic effect of PNP anti-Dsg1 antibodies pemphigus vulgaris patient; lane E, control serum.

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remains uncertain. The exfoliative erythroderma in our 4 Hashimoto T, Amagai M, Wang N et al. Novel non-radioisotope patient is consistent with a pathogenic role for this auto- immunoprecipitation studies indicate involvement of pemphigus antibody as it can be seen in patients with PF. In contrast, it vulgaris antigen in paraneoplastic pemphigus. J Dermatol Sci 1998; has recently been demonstrated that the pathogenic effect of 17: 132±9. PNP sera containing both anti-Dsg1 and anti-Dsg3 antibodies was abolished by specific adsorption of anti-Dsg3 antibodies, suggesting that the remaining anti-Dsg1 antibodies present in the PNP sera were not pathogenic.3 The presence of mucosal A vesicular bullous pemphigoid with an autoantibody lesions in our patient and the histological suprabasilar against plectin cleavage suggested the presence of pathogenic anti-Dsg3 antibodies. Such an antibody population could not be Sir, Bullous pemphigoid (BP) is an autoimmune blistering detected in the patient's serum by immunoblotting. However, disease in which the is separated from the dermis at such anti-Dsg3 antibodies are not consistently detected in the level of the lamina lucida of the basement membrane PNP sera by immunoblotting,3,4 whereas they are con- zone. The lesions are characterized by large and tense bullae sistently detected by ELISA.3 Finally, the demonstration of up to several centimetres in diameter developing on erythe- anti-Dsg3 and/or anti-Dsg1 antibodies in sera from patients matous or apparently normal skin. Patient sera react with with PNP, PV and PF suggests a common mechanism of two major components, 230- and 180-kDa BP antigens breakdown of immunological tolerance against desmogleins (BPAg1 and BPAg2) at the dermoepidermal junction.1 Several in these types of pemphigus, and confirms the role of anti- atypical variants of BP have been reported. These include Dsg3 and possibly of anti-Dsg1 antibodies in the pathogenesis polymorphic, localized, cicatricial and vesicular2 pemphigoid. of PNP. The lesions of vesicular pemphigoid are characterized by multiple small tense vesicles with a symmetrical distribution. Clinique dermatologique, P. M ARTEL In some cases of vesicular pemphigoid, heterogeneous HoÃpital Charles Nicolle, D.GILBERT* autoantibodies against 205- and 105-kDa polypeptides in 3 1 rue de Germont, B.LABEILLE² addition to the 180-kDa BP antigen have been reported. A 76031 Rouen cedex, J.KANITAKIS³ unique subepidermal blistering disease that resembles BP France P. J OLY both clinically and immunohistopathologically has been *Laboratoire d'immunopathologie clinique et reported. Immunoblot analysis revealed that the patient expeÂrimentale, serum did not react with the 230- or 180-kDa BP antigen INSERM U519, but recognized exclusively a 450-kDa epidermal polypeptide. 22 boulevard Gambetta, This antigen has been cloned and identified as plectin by the 76183 Rouen cedex, deduced amino acid sequences.4±6 We report a patient with France atypical BP whose sera reacted with 450-kDa plectin as well ²Service de Dermatologie, as the 230- and 180-kDa BP antigens. Centre Hospitalier de Valence, A 62-year-old Japanese woman presented with a vesicular 179 boulevard du MareÂchal Juin, eruption on the trunk and extremities. She had noticed itchy 26000 Valence, lesions on the breast for 1 month, which extended to the France trunk and extremities. The lesions were characterized by ³Service de Dermatologie VeÂneÂrologie, multiple small and tense vesicles surrounded by patchy HoÃpital Edouard Herriot, erythema (Fig. 1a). She also had small erosions on the 5 place Arsonval, mucous membranes. Nikolsky's sign was absent. A skin 69003 Lyon, biopsy from the vesicles revealed a subepidermal blister with France eosinophil infiltration (Fig. 2a). Laboratory examination E-mail: [email protected] revealed leucocytosis (11´0 109 L21) and eosinophilia  (30%). These clinical and immunohistochemical features suggested a diagnosis of BP with vesicular lesions. She References received treatment with systemic prednisolone 60 mg daily for 10 days, which cleared the vesicular lesions and 1 Anhalt GJ, Kim S, Stanley JR et al. Paraneoplastic pemphigus. erythema. The prednisolone dose was gradually reduced to An autoimmune mucocutaneous disease associated with neoplasia. 15 mg daily. Five months later, she revisited our hospital for N Engl J Med 1990; 323: 1729±35. recurrent skin lesions. The new skin lesions were large, tense 2 Joly P, Thomine E, Gilbert D et al. Overlapping distribution of bullae on the trunk and extremities (Fig. 1b). Increasing autoantibodies specificities in paraneoplastic pemphigus and pemphigus vulgaris. J Invest Dermatol 1994; 103: 65±72. prednisolone to 40 mg daily resulted in improvement of the 3 Amagai M, Nishikawa T, Nousari HC et al. Antibodies against skin lesions, which enabled reduction of prednisolone to desmoglein 3 (pemphigus vulgaris antigen) are present in sera 20 mg daily. Despite extensive examination including blood from patients with paraneoplastic pemphigus and cause analyses and computed tomographic scans, a malignant acantholysis in vivo in neonatal mice. J Clin Invest 1998; 102: neoplasm or lymphoproliferative disorder was not found. 775±82. Direct immunofluorescence microscopy clearly showed linear q 2000 British Association of Dermatologists, British Journal of Dermatology, 142, 812±851 814 CORRESPONDENCE

Figure 3. Western blots of epidermal cell extracts. Epidermal extracts were reacted with serum from a typical bullous pemphigoid patient (lane 1), antiplectin antiserum (lane 2) and the serum of the present patient obtained before treatment (lane 3) and at the recurrent stage (lane 4). Figure 1. Clinical appearance of the lesions. (a) Small and tense vesicles on the breast prior to treatment, and (b) large bullae on the arm after recurrence.

Figure 2. (a) Histology of a vesicle on the breast (haematoxylin and eosin; original magnification 160). (b) Salt-split skin test  on lesional skin with the patient's serum obtained prior to treatment (original magnification 160). Â

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deposition of IgG and C3 at the dermoepidermal junction because of the shared epitope between plectin and other zone in lesional skin (not shown). Indirect immunofluor- members of the plakin family. In our patient, immuno- escence showed circulating IgG autoantibodies against the reactivity of her serum to 450-kDa plectin was detected before dermoepidermal junction at a titre of 1 : 160 (not shown). treatment but rapidly became undetectable at the recurrent These autoantibodies bound to the epidermal side of skin split stage, and never reappeared. It is not clear whether antibodies by 1 mol L21 NaCl (Fig. 2b). against plectin had a primary role in inducing blisters in this Cultured human keratinocytes were purchased from case of atypical BP, or whether detection of the autoantibodies Sankojunyaku (Tokyo, Japan) and cultured in serum-free, might have been a secondary, albeit early, phenomenon low-calcium (0´1 mmol L21), modified MCDB 153 keratino- following initial disruption of hemidesmosomes by antibodies cyte basal media supplemented with growth factors (epi- to the 230- or 180-kDa BP antigens. dermal growth factor, insulin, hydrocortisone and bovine pituitary extract). Proteins were extracted from cells with Department of Dermatology, Y.O HNISHI 21 50 mmol L Tris±HCl pH 7´0 containing 2% sodium National Defense Medical College, S.TAJIMA² 21 dodecyl sulphate (SDS), 1 mmol L N-ethylmaleimide, 3-2 Namiki, Tokorozawa, A.ISHIBASHI 21 21 1 mmol L ethylenediamine tetraacetic acid, 1 mmol L Saitama 359-8513, Japan S.FUJIWARA* phenylmethylsulphonyl fluoride and 10 mgmL21 pepstatin *Department of Dermatology, A, as previously described.7 The proteins in the resultant Medical College of Oita, supernatant were resolved by 2±15% gradient SDS±poly- 1-1 Idaigaoka, acrylamide gel electrophoresis, then electrophoretically trans- Hasamacho, ferred on to nitrocellulose membranes. The membranes were Oita-Gun, incubated overnight at 4 8C with patient sera (diluted 1 : 50) Oita 879-55, Japan with 3% milk powder. Bound antibody was detected using ²Correspondence: Shingo Tajima ECL Western blotting detection reagents (Amersham, Little Chalfont, U.K.) using peroxidase-conjugated antihuman IgG References (1 : 100) as a secondary antibody. Patient sera were obtained at two different periods: the pretreatment stage (vesicular 1 Giudice GJ, Emery DJ, Diaz LA. Cloning and primary structural lesion) and the recurrent stage (bullous lesion). Patient serum analysis of the bullous pemphigoid autoantigen BP 180. JInvest prior to treatment reacted with three major polypeptides with Dermatol 1992; 99: 243±50. molecular weights of 450, 230 and 180 kDa (Fig. 3, lane 3). 2 Gruber GG, Owen LG, Callen JP. Vesicular pemphigoid. J Am Acad The 450-kDa polypeptide showed a similar migration position Dermatol 1980; 3: 619±22. 3 Satoh S, Seishima M, Izumi T et al. A vesicular variant of bullous to that of the polypeptide reacting with an antiplectin pemphigoid with autoantibodies against unidentified 205- and antibody prepared from recombinant plectin (Fig. 3, lane 6 105-kDa proteins at the basement membrane zone. Br J Dermatol 2). The polypeptides of 230 and 180 kDa had the same 1997; 137: 768±73. migration position as those recognized by serum from a 4 Fujiwara S, Shinkai H, Takayasu S et al. A case of subepidermal typical BP patient (Fig. 3, lane 1). Patient serum obtained at blister disease associated with autoantibody against 450 kD the recurrent stage did not react with the 450-kDa poly- protein. J Dermatol (Tokyo) 1992; 19: 610±13. peptide and reacted only with the 230- and 180-kDa 5 Fujiwara S, Kohno K, Iwamatsu A, Shinkai H. A new bullous polypeptides (Fig. 3, lane 4). pemphigoid antigen. Dermatology 1994; 189 (Suppl. 1): 120±2. Histological and immunofluorescence examination of our 6 Fujiwara S, Kohno K, Iwamatsu A et al. Identification of a patient's skin suggested a diagnosis of BP. Our patient, 450-kDa human epidermal autoantigen as a new member of the however, had unusual clinical features: initial skin lesions plectin family. J Invest Dermatol 1996; 106: 1125±30. 7 Labib RS, Anhalt GJ, Patel HP et al. Molecular heterogeneity of the were small, intense vesicles with a diameter of 2±3 mm bullous pemphigoid antigens as detected by immunoblotting. rather than large bullae, and oral mucosal involvement was J Immunol 1986; 136: 1231±5. seen. The detection of the autoantibody to 450-kDa plectin as 8 Wiche G. Role of plectin in cytoskeleton organization and well as to 230- and 180-kDa BP antigens on immunoblot dynamics. J Cell Sci 1998; 111: 2477±86. assay was also unusual. An atypical form of BP with clinical 9 Proby C, Fujii Y, Owaribe K et al. Human autoantibodies against and histological similarities to BP but with an autoantibody HD1/plectin in paraneoplastic pemphigus. J Invest Dermatol 1999; directed exclusively to plectin has been reported.4,5 This 112: 153±6. unusual case showed small tense vesicles like ours. Our case 10 Aho S, Mahoney My G, Uitto J. Plectin serves as an autoantigen in may represent an intermediate form between a typical BP and paraneoplastic pemphigus. J Invest Dermatol 1999; 113: 422±3. an unusual BP recognizing plectin alone. The pathogenetic role of plectin antibody in our patient is unclear. Plectin is a member of the plakin family and localizes An inflammatory desquamative dermatosis of the ear in the hemidesmosome, stabilizing it by connecting the with anti-180 kDa antibodies: localized cicatricial cytokeratin filament with the plasma membrane-associated pemphigoid? 8 plaque (integrin receptor a6b4). Plectin and other members of the plakin family have recently been shown to be Sir, Cicatricial pemphigoid (CP) is a rare, scarring, auto- recognized by paraneoplastic pemphigus sera,9,10 possibly immune blistering disorder. 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membranes and less frequently the skin.1 It is a disease of late also explain the different clinical features, especially the middle to old age and is more common in women. We report a tendency to scarring seen in CP compared with BP. However, case of an unusual inflammatory, scarring disease localized to the exact role of IgA autoantibodies in this disease remains the middle and outer ear. The clinical features and immuno- unclear. blotting results best fit a diagnosis of CP. CP has been previously described by our department as A 50-year-old woman with long standing chronic otitis causing deafness in a patient who presented with more media presented with a 3-year history of progressive deafness extensive mucous membrane involvement and skin bullae.2 and discharging ears. On examination there was a left attic Our patient had inflammation and scarring of the tympanic cholesteatoma and both ears showed marked inflammation of membranes and middle ears resulting in loss of hearing but the external auditory canal and middle ear mucosa. There appeared to have no evidence of disease elsewhere. These was complete loss of the squamous epithelium from both clinical features, along with the immunoblotting results, tympanic membranes and the medial part of the external make CP the most likely diagnosis and highlights the need to auditory canal. Her condition persisted despite intermittent consider this diagnosis in cases of middle and outer ear aural toileting and application of many different topical disease which persists despite conventional treatment. steroid and antibiotic drops and ointments. Surgical inter- vention included right atticoantrostomy and left suction Departments of Dermatology and A.DRUMMOND clearance in 1994, left atticotomy, meatoplasty of external *ENT Surgery, G.GUPTA auditory canal and mastoid exploration and obliteration in Glasgow Royal Infirmary, I.R.C.SWA N * 1996, right meatoplasty of external auditory canal and 84 Castle Street, J.THOMSON revision of mastoidectomy with obliteration in 1997 and Glasgow G4 OSF, U.K. right revision of mastoidectomy in 1999, all of which resulted E-mail: [email protected] in no benefit. She was extensively patch-tested in the Investigation Unit, Glasgow, with negative results. References When reviewed in the dermatology department, a diagnosis of CP was suspected due to the clinical features and the 1 Ahmed AR, Hombal SM. Cicatricial pemphigoid. Int J Dermatol observation of a similar case in the past.2 1986; 25:90±6. Routine investigations including full blood count, biochem- 2 Thomson J, Lang W, Craig J. Deafness complicating mucous istry, erythrocyte sedimentation rate and connective tissue membrane pemphigoid: a case report. Br J Dermatol 1975; 93: screen were normal. A biopsy from non-photo-exposed 337±9. 3 Venning VA, Whitehead PH, Leigh IM et al. The clinical expression buttock skin showed weak linear staining of the basement of bullous pemphigoid is not determined by the specificity of the membrane zone for C3 on direct immunofluorescence. target antigen. Br J Dermatol 1991; 125: 561±5. Indirect immunofluorescence was negative. Immunoblotting 4 Fine JD, Neises GR, Katz SI. Immunofluorescence and immuno- was performed by Dr F.Wojnarowska using previously electron microscopic studies in cicatricial pemphigoid. JInvest 3 described methodology. Immunoblotting of the patient's Dermatol 1984; 82: 39±43. serum showed IgG and IgA autoantibodies reacting with a 5 Bernard P, Prost C, Lecerf V et al. Studies of cicatricial pemphigoid 180-kDa protein in epidermal and dermal extracts. Dapsone autoantibodies using direct immunoelectron microscopy and 50 mg daily was started without complication. However, no immunoblot analysis. J Invest Dermatol 1990; 94: 630±5. clinical improvement has been noted at 4 months' follow up. 6 Bernard P, Prost C, Durepaire N et al. The major cicatricial The immunofluorescence and immunoblotting results of pemphigoid antigen is a 180-kD protein that shows immunological cross-reactivities with the bullous pemphigoid antigen. JInvest our patient would suggest a diagnosis of either CP or bullous 4 Dermatol 1992; 99: 174±9. pemphigoid (BP). Linear IgA disease and pemphigoid 7 Nie Z, Hashimoto T. IgA antibodies of cicatricial pemphigoid sera gestationis were excluded on clinical features, and bullous specifically react with C-terminus of BP180. Br J Dermatol 1999; erythematosus by a negative connective tissue screen. 112: 254±5. Epidermolysis bullosa acquisita was excluded on both clinical 8 Balding SD, Prost C, Diaz LA et al. Cicatricial pemphigoid and immunological features. Previous immunoblotting studies autoantibodies react with multiple sites on the BP180 extracellular on CP patients have shown autoantibodies directed against the domain. J Invest Dermatol 1996; 106: 141±6. 180 kDa ^ 230 kDa proteins, which are also found in BP.5,6 9 Bedane C, McMillan JR, Balding SD et al. Bullous pemphigoid and CP is usually the result of IgG autoantibodies directed against cicatricial pemphigoid autoantibodies react with ultrastructurally components of the basement membrane zone (BMZ). IgA separable epitopes on the BP180 ectodomain: evidence that BP180 autoantibodies are more unusual in patients with this disease spans the lamina lucida. J Invest Dermatol 1997; 108: 901±7. and their significance is unknown. A recent study detected (by direct immunofluorescence) IgG and IgA autoantibodies deposited along the BMZ in their CP patients. On immuno- blotting, IgA autoantibodies in 40% of the CP sera reacted Pemphigus foliaceus and figurate erythema in a patient with the C-terminal portion of the 180 kDa antigen.7 This with prostate cancer portion extends to the lamina densa8,9 and may explain why immunoblotting performed on our patient's serum was Sir, (EGR), a figurate erythema positive in both the dermal and epidermal extracts. It may associated with neoplasm,1 appears in patients with

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underlying visceral malignancy, and usually disappears after the bullae spread over his entire body. On 11 August, when treatment of the malignancy.2 We describe a patient with he visited a dermatology clinic, his trunk and extremities pemphigus foliaceus (PF) accompanied by EGR-like figurate were covered with erythema intermingled with flaccid bullae erythema associated with prostate cancer. and erosions. Oral mucous membranes were not involved. A 65-year-old Japanese man consulted a urologist on 9 July Laboratory studies showed no abnormalities. Skin biopsy 1998 after 1 month of dysuria. The serum prostate-specific revealed a subcorneal cleft with acantholytic cells and antigen (PSA) was 30´7 mgL21 (normal range , 3´6). deposition of IgG and C4 in the intercellular spaces Prostate biopsy revealed adenocarcinoma and computed throughout the epidermis without any deposition at the tomography proved its invasion to the seminal vesicles; the basement membrane zone (BMZ). Circulating antibodies stage was C (T3, N0, M0). On 22 July he noticed flaccid against intercellular substances of keratinocytes were bullae on his arms. From 27 July, the prostate cancer was shown by indirect immunofluorescence (IIF) at a titre of treated with monthly luteinizing hormone-releasing hormone 1 : 320. The IIF for circulating anti-BMZ antibodies was (LH-RH) agonist injection. After the second injection, he negative even when rat oesophagus was used as substrate. stopped the treatment voluntarily because he thought the The serum reacted strongly with recombinant desmoglein 1 injection might have caused the flaccid bullae. However, (Dsg1), index 119´65 (3 SD of normal range , 9´78); but not

Figure 1. (a,b) Figurate erythema on the left shoulder appeared after 2 months' suspension of luteinizing hormone-releasing hormone agonist treatment for prostate cancer. (c) Skin biopsy from early lesion of figurate erythema on the shoulder showed non-specific perivascular mononuclear cell infiltration. q 2000 British Association of Dermatologists, British Journal of Dermatology, 142, 812±851 818 CORRESPONDENCE

with desmoglein 3 (Dsg3), index 7´98 (3 SD of normal range against skin BMZ were not demonstrated by IIF in our case, , 9´79) by enzyme-linked immunosorbent assays (Dsg1 and the second hypothesis is more reasonable in explaining the Dsg3 ELISA Kit, Medical and Biological Laboratories, Nagoya, features in our patient. Japan). Thus, the diagnosis of PF was made. His PF was treated initially with oral prednisolone 40 mg Department of Dermatology, M.OTA daily (0´8 mg kg21 daily) and azathioprine 100 mg daily Hokkaido University K.C.SATO-MATSUMURA (2 mg kg21 daily) from 28 September, but did not respond to School of Medicine, T.M ATSUMURA therapy for 3 weeks. During the next 2 weeks, the exfoliative Kita 15 Nishi 7, Y.T SUJI erythema changed into figurate erythema which resembled Kita-ku, A.OHKAWARA EGR (Fig. 1a,b), although lesions did not move centrifugally Sapporo, 060-8638, Japan as quickly as in classical EGR.2 Skin biopsy showed super- ficial perivascular non-specific mononuclear cell infiltration (Fig. 1c). On 20 October, therapy for prostate cancer with References LH-RH agonist was resumed after a suspension of 2 months, 1 Summerly R. The figurate and neoplasia. Br J Dermatol followed by significant improvement of not only the prostate 1964; 76: 370±3. cancer but also the figurate erythema. By 18 December, 2 Boyd AS, Neldner KH, Menter A. Erythema gyratum repens: a 2 months after resumption of LH-RH agonist treatment, the paraneoplastic eruption. J Am Acad Dermatol 1992; 26: 757±62. figurate erythema had totally disappeared. The prostate 3 Younus J, Ahmed AR. The relationship of pemphigus to cancer reduced, with regression of invasion to the seminal neoplasia. J Am Acad Dermatol 1990; 23: 498±502. 2 vesicles and serum PSA below 0´1 mgL 1. Currently his PF 4 Thomson J, Stankler L. Erythema gyratum repens. Reports of two and prostate cancer are controlled with oral prednisolone further cases associated with carcinoma. Br J Dermatol 1970; 82: 25 mg daily and continuing hormone therapy with LH-RH 406±11. agonist. The most recent titre of circulating antibodies against 5 Holt PJ, Davies MG. Erythema gyratum repensÐan immuno- intercellular substances were at a titre of 1 : 160; the size of logically mediated dermatosis? Br J Dermatol 1977; 96: 343±7. the prostate cancer has diminished with no signs of 6 Caux F, Lebbe C, Thomine E et al. Erythema gyratum repens. A case studied with immunofluorescence, immunoelectron microscopy recurrence, and the figurate erythema has not recurred. and immunohistochemistry. Br J Dermatol 1994; 131: 102±7. There are two interesting features in the present case. First, 7 Graham-Brown RA. Bullous pemphigoid with figurate erythema PF did not respond to the initial therapy until the therapy for associated with carcinoma of the bronchus. Br J Dermatol 1987; prostate cancer was resumed. Therefore, the PF in this case 117: 385±8. could have been triggered by prostate cancer, although pemphigus is rarely associated with prostate cancer; in 42 cases of pemphigus associated with non-thymic malignancy, 3 Multiple myeloma and Kaposi's sarcoma: none was prostate cancer. Secondly, figurate erythema what is the association? developed when the therapy for prostate cancer was suspended, and disappeared after resumption of the therapy Sir, Kaposi's sarcoma (KS) is a vascular tumour which may be for the cancer. In the previous report of EGR associated with sporadic (classical), endemic (African), associated with human prostate cancer, the cancer was found 6 years after EGR immunodeficiency virus (HIV) infection or associated with started.4 In the present case, the cancer was diagnosed immunosuppression from other causes (such as following solid 3 months previously. organ transplantation or after chemotherapy). KS secondary to Incomplete therapy for the cancer or prednisolone treat- immunosuppression has an aggressive course. We report such a ment for PF could have caused immunological alterations case occurring in association with multiple myeloma. leading to development of figurate erythema in the present An 81-year-old man presented with a 6-month history of case. Immunological mechanisms are important in the lower back pain. Investigations revealed destruction of L1 on aetiology of EGR. Antibody deposition at the BMZ was lumbar spine radiograph, a raised erythrocyte sedimentation shown in some previously reported EGR cases: coarse rate at 136 mm in the first hour, rouleaux on the blood film, granular deposits of IgG and C3 at the BMZ in both involved anaemia (haemoglobin 9´9 g dL21), IgG paraprotein on 5 and uninvolved skin, mottled granular deposits of IgG and serum electrophoresis (IgG 65´0 g L21, normal 6´8±15´5) C3 in the upper dermis just beneath the dermal aspect of and positive urinary Bence±Jones protein. The diagnosis of 6 the lamina densa, and deposition of IgG C3, C4 in EGR multiple myeloma was confirmed on bone marrow biopsy, 7 coexisting with pemphigoid. Two immunological patho- and cyclophosphamide 450 mg once weekly was commenced genic mechanisms of EGR were proposed on the basis of with localized radiotherapy to the lumbar spine. After one these findings. (i) Antibodies against tumour antigens may dose of cyclophosphamide the patient developed sepsis, and cross-react with similar antigenic determinants in the further treatment was delayed for 6 weeks. Three months patient's skin, and (ii) the tumour produces molecules which later, he had developed purple nodules on the chin, neck and alter components of the BMZ, with subsequent induction of arms (Fig. 1a) which 3 weeks later had spread to the lower antibodies and their local deposition, which could cross-react legs (Fig. 1b). These lesions were suggestive of KS, which with the BMZ of the patient's skin. As circulating antibodies was confirmed histologically. A Warthin±Starry stain was

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negative, excluding bacillary angiomatosis, and vascular be the result of acquiring a new infection with KSHV.19 markers CD31 and CD34 were positive. Immunosuppression is common in patients with multiple S-100 and SMA were negative. Further investigations at myeloma, and susceptibility to infection is a major cause of this time revealed a CD4 lymphopenia: normal total white morbidity and mortality. B- as well as T-cell abnormalities, cell count (3´7 109 L21), total lymphocytes low at both qualitative and quantitative, have been demonstrated.20 9 21  9 21 0´7 10 L , low CD4 (0´19 10 L , normal 0´6± CD4 lymphopenia with normal or increased CD4 subsets  9  9 21 1´4 10 ), and CD8 0´44 10 L (normal 0´2± (mainly suppressor rather than cytotoxic cells) leading to a  9  0´6 10 ). HIV testing was negative. KS-associated herpes-  virus (KSHV) DNA was detected on polymerase chain reaction analysis of blood and tumour tissue (0´1 copy of KHSV DNA per cell). Despite continuing cyclophosphamide, the myeloma and KS progressed with the development of aggressive ulcerating lesions on both feet. The chemotherapy regimen was therefore changed to lomustine, idarubicin and dexa- methasone, and he received localized radiotherapy to both soles with good response. Eighteen months after diagnosis, the patient died from bronchopneumonia, having required no further chemotherapy. KS is due to infection with KSHV, also known as human herpesvirus 8, which is found in 90% of all cases. KSHV is unique in that it contains genes encoding cytokines, including interleukin (IL)-6. Human IL-6 is a known potent growth and survival factor in multiple myeloma. This was first identified by Kawano et al.1 in 1988, who showed that myeloma cells secreted IL-6 and possessed the IL-6 receptor on their surface. They also demonstrated exogenous IL-6- induced DNA synthesis in myeloma cells. Viral IL-6 produced by KSHV shares 25% homology with human IL-6. It also retains biological activity, as demonstrated by its ability to support murine plasmacytoma cells.2 Viral IL-6 can therefore act as a growth factor in a similar, albeit weaker, manner to human IL-6 in patients with multiple myeloma. An association between multiple myeloma and KS was first noted in 1965,3 and several case reports and reviews have subsequently appeared discussing the possible pathogenesis for such an association.4±7 More recently, Rettig and coworkers8 found KSHV DNA in cultured bone marrow dendritic cells using polymerase chain reaction and in situ hybridization from 20 patients with multiple myeloma, a finding confirmed later by French workers.9 A paracrine model was therefore suggested in which KSHV infection causes increased IL-6 concentration within the bone marrow stroma, leading to transformation of a benign monoclonal plasma cell proliferation to a malignant one, i.e. myeloma. A similar paracrine model has been suggested for KS in HIV infection. However, other authors have not been able to confirm the findings of Rettig et al., and have failed to detect KSHV DNA in myeloma patients10±12 or to show a positive serology for KSHV antibodies in these patients.13±16 Further- more, the incidence of the two conditions does not correlate: in areas where the incidence of KS is high, there is no corresponding increase in the incidence of multiple myeloma, which therefore argues against a common viral aetiology. It has recently been shown that following solid organ trans- plantation, the risk of KS is related to the severity of immunosuppression.17 In renal transplant recipients, KS may either be due to reactivation of the virus during Figure 1. (a) Purple plaques of Kaposi's sarcoma (KS) are evident on immunosuppression18 (in areas where KSHV is endemic) or the neck. (b) Aggressive KS lesions may be seen on the lower legs. q 2000 British Association of Dermatologists, British Journal of Dermatology, 142, 812±851 820 CORRESPONDENCE

reversed CD4/CD8 ratio is the most important abnormality herpesvirus infection and multiple myeloma. (Letter.) Science and can play a major part in the immune deficiency 1997; 278: 1969±70. associated with multiple myeloma. Chemotherapy exacer- 11 Masood R, Zheng T, Tupule A et al. Kaposi's sarcoma-associated bates this immune suppression and may even be responsible herpesvirus infection and multiple myeloma. (Letter.) Science for the reactivation of KSHV and the appearance of KS.21 1997; 278: 1970±1. 12 Tarte K, Olsen SJ, Lu ZY et al. Clinical grade functional dendritic The development of KS appears to be related both to the cells from patients with multiple myeloma are not infected with duration of therapy and to the cumulative dose received. As Kaposi's sarcoma-associated herpesvirus. Blood 1998; 6: 1851±7. our patient had only received a total cumulative dose of 2´5 g 13 Whitby D, Boshoff C, Luppi M, Torelli G. Kaposi's sarcoma- of cyclophosphamide and developed KS lesions only 6 weeks associated herpesvirus infection and multiple myeloma. (Letter.) later, we think it unlikely that the chemotherapy played an Science 1997; 278: 1971±2. important part. 14 Cottoni F, Uccini S. Kaposi's sarcoma-associated herpesvirus infection and multiple myeloma. (Letter.) Science 1997; 278: 1972. Departments of Medicine & Elderly Care, A.J.J.ABDULLA 15 Marcelin AG, Dupin N, Bouscary D et al. HHV-8 and multiple ²Dermatology, S.E.MUNN* myeloma in France. (Letter.) Lancet 1997; 350: 1144. 16 MacKenzie J, Sheldon J, Morgan G et al. HHV-8 and multiple ³Histopathology and N.HARDWICK² myeloma in the UK. (Letter.) Lancet 1997; 350: 1144±5. ¶Haematology, S.HARRIS³ 17 Penn I. Cancer in cyclosporine treated vs azathioprine treated Mid-Staffordshire General Hospitals, M.HOWARD§ patients. Transplant Proc 1996; 28: 876±8. Cannock Chase Hospital, P. R EVELL¶ 18 Parravicini C, Olsen SJ, Capra M et al. Risk of Kaposi's sarcoma Brunswick Road, associated herpes virus transmission from donor allografts among Cannock WS11 2XY, U.K. Italian posttransplant Kaposi's sarcoma patients. Blood 1997; 90: *Department of Dermatology, 2826±9. King's College Hospital, 19 Regamey N, Tamim M, Wernli M et al. Transmission of human London, U.K. herpesvirus 8 infection from renal transplant donors to recipients. §Department of Virology, N Engl J Med 1988; 339: 1358±63. University College London, 20 Foerster J, Paraskevas F. Multiple myeloma. In: Wintrobe's Clinical London, U.K. Hematology (Lee, Foerster, Lukas et al. eds), 10th edn. 1998; 231±80. 21 Kapadia SB, Krause JR. Kaposi's sarcoma after long-term alkylating agent therapy for multiple myeloma. South Med J References 1977; 70: 1011±13.

1 Kawano M, Hirano T, Matsuda T, Taga T. Autocrine generation and essential requirements of BSF-2/IL-6 for human multiple myeloma. Nature 1988; 332:83±5. Metastatic calcinosis cutis in multiple myeloma 2 Nicholas J, Ruvulo VR, Zong J et al. A single 13-kilobase divergent Sir, Calcinosis cutis is a process that is characterized by the locus in the Kaposi sarcoma-associated herpesvirus (human herpesvirus-8) genome contains nine open reading frames that precipitation and deposition of calcium and phosphate salts in are homologous to or related to cellular proteins. J Virol 1997; the dermis and subcutaneous tissues. It may be divided into 71: 1963±74. four main groups: dystrophic, idiopathic, metastatic and 3 Reynolds AW, Winkelmann KR, Soule HE. Kaposi sarcoma: a iatrogenic calcification, depending on previous tissue damage 1 clinicopathologic study with particular reference to its relation- and/or abnormal calcium and phosphorus metabolism. ship to the reticuloendothelial system. Medicine 1965; 44: Metastatic calcification (MC) results from an increased 413±19. calcium phosphate product in the serum, leading to  2 4 Mazzferri LE, Penn MG. Kaposi's sarcoma associated with hypercalcaemia or hyperphosphataemia. It has rarely been multiple myeloma. Arch Intern Med 1968; 122: 521±5. associated with diseases involving bone destruction (e.g. 5 Law PI. Kaposi's sarcoma and plasma cell dyscrasia. JAMA 1974; Paget's disease, metastatic carcinoma) and is exceptional in 229: 1329±31. cases of multiple myeloma. 6 Mandel ME, Lask D, Gafter U et al. Multiple myeloma associated A 54-year-old woman was admitted in April 1997 with with Kaposi's sarcoma. Acta Hematol 1977; 58: 120±8. fever, breathing symptoms, disseminated bone pain and 7 Summerfield GP, Bellingham AJ, Barnes RMR, Stewart TW. slightly itchy pigmented cutaneous lesions of 2±3 months Kaposi's sarcoma in patient with multiple myeloma, sideroblastic duration. The patient blamed the skin lesions on the anaemia and T-lymphocyte abnormalities. Lancet 1983; 8329: 871±2. continuous use of an electric blanket. Examination showed 8 Rettig MB, Ma HJ, Vescio RA et al. Kaposi's sarcoma-associated pigmented macules and that formed extensive herpesvirus infection of bone marrow dendritic cells from irregular and reticulated plaques, located on the back, multiple myeloma patients. Science 1997; 276: 1851±4. lumbar region and the backs of both thighs (Fig. 1a). These 9 Brousset P, Meggetto F, Attal M, Delsol G. Kaposi's sarcoma- plaques had a stony consistency and in some areas small associated herpesvirus infection and multiple myeloma. (Letter.) whitish particles were observed. Science 1997; 278: 1972. Laboratory tests showed red blood cell count 2´55 12 21 2Â1 10 Parravicini C, Lauri E, Baldini L et al. Kaposi's sarcoma-associated 10 L , haematocrit 23´1%, haemoglobin 7´9 g dL ,

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white cell count 14´1 109 L21 (neutrophils 85%, lympho- granulocyte-macrophage colony-stimulating factor, with an  8,9 cytes 8%, monocytes 6%, eosinophils 1%), platelets 195 increase in the serum levels of calcium and phosphate. 9 21 21 21  10 L , urea 185 mg dL , creatinine 4´9 mg dL , alkaline However, MC is uncommon in multiple myeloma; indeed, phosphatase 824 U L21, lactate dehydrogenase 1981 mg only one case report exists, describing widespread arterial dL21, uric acid 11´3 mg dL21, calcium 16´4 mg dL21 (normal 8´5±10´5), ionized calcium 1´98 mmol L21 (normal 1´15±1´35), phosphate 7´7 mg dL21 (normal 2´4±4´5), parathyroid hormone 15 pg mL21 (normal 15±75), total proteins 5´7 g dL21, albumin 3 g dL21. Proteinogram and immunoglobulin assays showed albumin 48´8%, a1-globulin 12´7%, a2-globulin 15´1%, b-globulin 17´7%, g-globulin 5´8% (normal 15±22), IgG 403 mg dL21 (normal 800± 1800), IgA 97 mg dL21 (normal 90±450), IgM 29 mg dL21 (normal 60±250), IgD 12 U mL21, IgE 30 U mL21 (normal 0±100), C3 98 mg dL21, C453mgdL21. There was no evidence of immunoglobulins in urine. X-ray of the thorax showed a focus of alveolar consolidation in the left inferior pulmonary lobe, pathological costal fracture and osteolytic changes in both clavicles; X-ray of the skull showed intense osteolysis with a `moth-eaten' appearance. Bone marrow examination demonstrated an increase in plasma cells (70% of total nucleated cell population). Histology showed irregular acanthosis with orthohyperkeratosis, focal deposits of irregular basophilic material at the dermoepidermal junction, and scanty pigmentation of the basal layer (Fig. 1b). A von Kossa stain confirmed the presence of calcium. The diagnosis was non-secretor multiple myeloma in stage IIIB (British Medical Research Council), pneumonia, renal failure and metastatic calcinosis cutis. Treatment was carried out with intermittent courses of vincristine, adriamycin and dexamethasone; this improved the renal failure, and the cutaneous lesions disappeared in 2±3 months, leaving only residual . Nevertheless, some months later, a progressive general deterioration occurred and the patient died in February 1998. MC is the result of the precipitation of calcium salts in normal tissues as a consequence of an increased calcium 1,2  phosphate product in the serum (70 or higher). MC can appear in disorders with hyperphosphataemia and normo- calcaemia such as chronic renal failure and pseudohypopara- thyroidism,3,4 or secondary to processes with hypercalcaemia such as primary hyperparathyroidism, hypervitaminosis D, milk±alkali syndrome, or sarcoidosis. It occurs less frequently in diseases with bony destruction such as Paget's disease, metastatic carcinoma, osteomyelitis, lymphoma or leukaemia, and more rarely in multiple myeloma.5±7 MC of the skin presents as indurated papules, nodules or plaques of different sizes, often itching and painful; they may become fluctuant, ulcerate and extrude their chalky contents. The lesions are located symmetrically, mainly on the extremities and also on the trunk. Histology shows a deposit of amorphous and irregular basophilic material in the dermis or hypodermis. The deposit stains black with von Kossa stain. One of the main characteristics of plasma cells is their Figure 1. (a) Pigmented and reticulated plaques are evident on the capacity to induce bone destruction due to an increase in back, lumbar region and right buttock. (b) A skin biopsy from the osteoclastic activity and inhibition of osteoformation, by back showed irregular acanthosis with orthohyperkeratosis and focal secretion of osteoclastic activator factors such as interleukin deposits of basophilic material along the dermoepidermal junction (IL)-6, IL-1b, tumour necrosis factor (TNF)-a, TNF-b and (haematoxylin and eosin; original magnification 200).  q 2000 British Association of Dermatologists, British Journal of Dermatology, 142, 812±851 822 CORRESPONDENCE

calcification of the subcutaneous cellular tissue and leuco- A case of angiosarcoma of the face successfully treated cytoclastic .7 We believe that in the present case, the with combined chemotherapy and radiotherapy multiple myeloma and the renal failure produced an increase Sir, Cutaneous angiosarcoma is a rare, aggressive vascular in serum calcium levels which, coupled with the increase of tumour occurring more frequently in the elderly; it is temperature produced by the electric blanket, represented extremely rare in children and shows no gender prevalence.1 decisive factors in the appearance of the calcification of the It represents 2% of all soft tissue sarcomas. Sixty per cent of skin by precipitation of calcium salts. Local factors such as angiosarcomas arise in the skin or superficial soft tissue, and repeated trauma, needle stick injuries, burn scars and medical 50% of cutaneous angiosarcomas affect the head and neck.2 studies with saturated calcium chloride electrode paste10±12 The prognosis is generally poor, with reported 5-year survival have been incriminated in the genesis of dystrophic calcinosis, rates of 10±35%.3,4 Diagnosis is frequently delayed and and justify our thinking that local heat could possibly have patients often present when the primary tumour is large and favoured cutaneous calcinosis in this patient with metastatic, extends into the cutaneous tissue, and often has already but not dystrophic calcinosis (by previous hypercalcaemia). metastatized.3±5 We describe treatment of a 66-year-old man This could also explain the exceptional fact that the calcifi- with angiosarcoma of the face. cation was located at the dermoepidermal junction and An otherwise healthy 66-year-old man presented in remitted in a few months, after normalization of calcaemia. September 1998 with an irregular triangular-shaped brown±red lesion with frayed margins on his right cheek, Department of Dermatology, A.J.CHAVES ALVAREZ with extensive adjacent telangiectases. The lesion had Hospital Universitario Virgen Macarena, A.HERRERA SAVAL previously been interpreted as a bruise and had been treated Avda Dr Fedriani s/n, J.MARQUEZ ENRIQUEZ with vasoprotective ointment. The lesion had occurred about Seville 41009, Spain F. C AMACHO MARTINEZ 10±12 months before, and had progressively enlarged and involved the right cheek, assuming an oval shape, 3 2cm in size (Fig. 1a). The lesion was firm to the touch but asymptomatic. References Routine blood tests, ultrasonography of the neck, axillae, 1 Walsh JS, Fairley JA. Calcifying disorders of the skin. J Am Acad abdomen and chest, and X-rays of the chest and skull Dermatol 1995; 33: 693±706. were normal, as were tumour markers (CA125, CA19.9, 2 Raimer SS, Archer ME, Jorizzo JM. Metastatic calcinosis cutis. carcinoembryonic antigen, alpha-fetoprotein, total prostate- Cutis 1983; 32: 463±5. specific antigen, CA15.3). A computed tomographic scan of 3 Kolton B, Pedersen J. Calcinosis cutis and renal failure. Arch the head with contrast medium revealed no alteration in the Dermatol 1974; 110: 256±7. brain and bone structures, but showed abnormal small blood 4 Prendiville JS, Lucky AW, Mallory SB et al. Osteoma cutis as a vessels in the subcutaneous tissue of the right cheek, at the presenting sign of pseudohypoparathyroidism. Pediatr Dermatol site of the clinical lesion (reported as being consistent with an 1992; 9: 11±18. angiomatous lesion). 5 Panicek DM, Harty MP, Scicutella CJ et al. Calcification in Histopathological examination showed a normal epidermis untreated mediastinal lymphoma. Radiology 1988; 166: and a vascular proliferation with irregular architecture 735±6. involving the deep and superficial dermis, dissecting the 6 Abe M, Segami H, Wakasa H. Hypercalcemia and metastasic collagen bundles and invading cutaneous appendages and calcification in adult T-cell leukemia: pathogenesis of hyper- calcemia. Fukushima J Med Sci 1985; 31:85±7. nerve fibres. Neoplastic blood vessels were lined by atypical 7 Raper RF, Ibels LS. Osteosclerotic myeloma complicated by diffuse endothelial cells with eosinophilic cytoplasm and large nuclei. arteritis, vascular calcification and extensive cutaneous necrosis. Proliferating endothelial cells overlapped and protruded into Nephron 1985; 39: 389±92. the vascular lumen. No mitosis was observed. Immuno- 8 Bataille R, Jourdan M, Zhang XG, Klein B. Serum levels of staining with an anti-CD31 monoclonal antibody (clone interleukin-6, a potent myeloma cell growth factor, as a reflection JC70, Dako, Glostrup, Denmark) demonstrated intense diffuse of disease severity in plasma cell dycrasias. J Clin Invest 1989; 84: staining of tumour cells and normal dermal vascular 2008±11. structures, confirming the endothelial nature of the neoplasia 9 Sati HI, Apperley JF, Greaves M et al. Interleukin-6 is expressed by (Fig. 1b). On the basis of the clinical and histopathological plasma cells from patients with multiple myeloma and mono- findings, a diagnosis of a well-differentiated angiosarcoma of clonal gammopathy of undetermined significance. Br J Haematol the face was made. 1998; 101: 287±95. No surgical treatment was carried out due to the extent 10 Skidmore RA, Davis DA, Woosley JT, McCauliffe DP. Massive and localization of the neoplasm, so the patient was treated dystrophic calcinosis cutis secondary to chronic needle trauma. first with radiotherapy at a single dose of 25 Gy administered Cutis 1997; 60: 259±62. overa8 4 cm field size including the right cheek close to 11 Johnson RC, Fitzpatrick JE, Hahn DE. Calcinosis cutis following  electromyographic examination. Cutis 1993; 52: 161±4. the nose and the right side of the nose, then with five chemotherapy cycles using ifosfamide 1300 mg m22 (days 12 Puig L, Rocamora V, Romani J et al. Calcinosis cutis following 22 calcium chloride electrode paste application for auditory-brain- 1±3) and epirubicin 50 mg m (day 1) every 3 weeks. After stem evoked potentials recording. Pediatr Dermatol 1998; 15: the therapy, a reduced firmness and discoloration (towards a 27±30. bluish pattern) was observed in the site of the cutaneous

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lesion. Twelve months after the initial diagnosis, no local or distant relapse has been observed. Types of cutaneous angiosarcoma include: (i) angio- sarcoma of the face and scalp (usually described in elderly patients); (ii) angiosarcoma associated with chronic lympho- edema (Stewart±Treves syndrome); and (iii) postirradiation angiosarcoma (observed after high-dose radiation for cuta- neous visceral tumours). Epithelioid angiosarcoma is a rare variant of cutaneous angiosarcoma which has been described recently; clinically, it is distinct from conventional angio- sarcoma due to the location of the lesions on the lower extremities.6±8 Angiosarcoma of the face and scalp was first described by Caro and Stubenrauch in 1945,9 while Wilson-Jones described the clinical and histological variants of cutaneous angiosarcoma in 1964.10 The lesion initially occurs as an erythematous±oedematous patch with subsequent evolution to a flat plaque, then as a nodular and occasionally ulcerated lesion with possible satellite lesions.3,9 Such lesions initially appear as an ill-defined bruise-like area simulating a haematoma, as in our case; this spreads gradually over a relatively short period. A recent study has suggested that tumour grade may have an impact on prognosis. Low-grade angiosarcomas seem to have a more favourable clinical behaviour: in a series of 67 patients with angiosarcoma, with a follow-up ranging from 1 to 173 months (median 30), 67% of patients with low-grade tumour were disease-free, compared with only 19% of patients with high-grade histology. However, no multivariate Figure 1. (a) An irregular triangular-shaped red±brown lesion with statistical analysis was performed to assess this,11 and other frayed margins is evident on the cheek. (b) Immunostaining with an authors do not all support this view.12 In our case, well- anti-CD31 monoclonal antibody showing diffuse staining of tumour differentiated features were observed in all sections of the cells and a normal dermal vascular structure. neoplasm. However, site and size of the tumour are generally considered prognostic.11 It is uncertain whether the apparently good course Early diagnosis is very important to avoid metastasis and observed in our patient after combined treatment with local relapse caused by tumour multifocality and by the radiotherapy and subsequent chemotherapy may be related aggressive behaviour of the tumour. Treatment options to the early diagnosis (that led to early local and systemic include wide surgical excision with histological control of therapy) or to the well-differentiated nature of the neoplasm the border (due to difficulty in macroscopically defining the in this case. extent of the neoplasm), radiotherapy alone or in combi- nation with surgery, and chemotherapy plus radiotherapy Second Dermatology Clinic, L.AMATO without surgery.4,5,13 Morrison et al. in a study of 14 patients Department of Dermatological Science and S.MORETTI with angiosarcoma of the face and neck treated with *Institute of Anatomic Pathology, G.M.PALLESCHI radiotherapy after surgery, reported a 5-year survival rate of University of Florence, I.GALLERANI 50%, while in patients treated with radiotherapy alone, or Italy A.FRANCHI* with radiotherapy and chemotherapy without surgery, the P. F ABBRI survival rate was only 13%.13 Although an association between angiosarcoma and previous radiotherapy has been reported in the literature,4±14 the risk of radiotherapy- induced sarcoma is small, with published prevalence figures References ranging from 0´03 to 0´08%.15 1 Wick MR. Vascular sarcomas of the skin. In: Pathology of Unusual Prognosis is poor, with a 5-year survival rate of 10±35%. Malignant Cutaneous Tumours. New York: Marcel Dekker, Inc., Maddox and Evans, in a series of patients with angiosarcoma, 1985: 181±209. observed that 16 of 17 patients developed local recurrence 2 Yang JC, Rosenberg SA, Glatstein EJ. Sarcomas of soft tissue. In: after treatment, and only one patient had long-term Cancer: Principles and Practice of Oncology (De Vita VT, Hellman S, 5 survival. Holden et al. reported a 5-year survival in 12% of Rosenberg SA, eds), 4th edn. Philadelphia: J.B.Lippincott, 1993: 3 72 patients with angiosarcoma at all sites. 1436±55. q 2000 British Association of Dermatologists, British Journal of Dermatology, 142, 812±851 824 CORRESPONDENCE

3 Holden CA, Spittle MF, Jones EW. Angiosarcoma of the face and to excess sunlight, and she had not avoided sun-exposure scalp, prognosis and treatment. Cancer 1987; 59: 1046±57. intentionally nor used sun-screens after the development of 4 Mark RJ, Tran LM, Sercart J. Angiosarcoma of the head and neck. . She had not received psoralen plus UVA (PUVA) Arch Otolaryngol Head Neck Surg 1993; 119: 973±8. therapy for her vitiligo and had taken no regular medication. 5 Maddox JC, Evans HL. Angiosarcoma of skin and soft tissue: a Physical examination revealed extensive depigmented lesions study of 44 cases. Cancer 1981; 48: 1907±21. on her scalp, trunk and limbs. Many erythematous scaly 6 Fletcher CDM, Beham A, Becker S. Angiosarcoma of deep soft tissue: a distinctive tumour in reality mistaken for an epithelial patches were present on the vitiligo lesions which were in neoplasm. Am J Surg Pathol 1991; 15: 915±24. sun-exposed areas (Fig. 1). In contrast, there were few AKs 7 Marrogi AJ, Hunt SJ, Santa Cruz DJ. Cutaneous epithelioid on her face which was normally pigmented and devoid of angiosarcoma. Am J Dermatopathol 1990; 12: 350±6. vitiligo. Ulcerated nodules were present on her scalp and left 8 Maiorana A, Fante R, Fano RA, Collina G. Epithelioid angiosar- forearm measuring 7´0 10´0 cm and 3´6 2´6 cm, Â Â coma of the buttock: case report with immunohistochemical respectively. Histological examination of both nodules con- study on the expression of keratin polypeptides. Surg Pathol 1991; firmed a diagnosis of invasive SCC. The epidermis adjacent to 4: 325±32. these showed hyperkeratosis, parakeratosis and dysplasia of 9 Caro MR, Stubenrauch CH Jr. Hemangioendothelioma of the skin. keratinocytes, compatible with AK. Marked solar elastosis Arch Dermatol Syphilol 1945; 51: 295±304. was observed in the upper dermis. Soon after the diagnosis 10 Wilson-Jones E. Malignant haemangioendothelioma of the skin. Br J Dermatol 1964; 76: 21±39. was established, she died of injuries from a traumatic 11 Mark RJ, Poen JC, Tran LM et al. Angiosarcoma. A report of accident. 67 patients and a review of the literature. Cancer 1996; 77: Our patient was very elderly and had long-lasting 2400±6. vitiligo for more than 50 years affecting both sun-exposed 12 Requena L, Sangueza OP. Cutaneous vascular proliferations. Part and sun-protected areas except her face. The number of AKs III. Malignant neoplasms, other cutaneous neoplasms with on sun-exposed vitiligo lesions was obviously much greater significant vascular component, and disorders erroneously than on her face; there were no AKs on sun-protected vitiligo considered as vascular neoplasms. J Am Acad Dermatol 1998; lesions such as on her trunk, and SCCs on her scalp and 38: 143±75. 13 Morrison WH, Byers RM, Garden AS. Cutaneous angiosarcoma of the head and neck. A therapeutic dilemma. Cancer 1995; 76: 319±27. 14 Sordillo PP, Chapman R, Hajdiu SI. Lymphangiosarcoma. Cancer 1981; 48: 1674±9. 15 Mark RJ, Tran LM, Selch MT. Post-irradiation sarcomas: a single institution study and review of the literature. Cancer 1994; 73: 2653±62.

Multiple actinic keratoses and squamous cell carcinomas on the sun-exposed areas of widespread vitiligo

Sir, Epidemiological and experimental studies have shown that solar ultraviolet (UV) radiation primarily induces non- skin cancers.1 Melanin is widely believed to protect keratinocytes from DNA damage by UV light.2 One would therefore expect that the complete lack of melanin pigmentation, as in vitiligo, might increase the risk of (AK) and skin cancer. However, the incidence of skin cancer on long-term vitiligo patches is very rare,3 and only three such cases have been reported.4,5 We describe an elderly Japanese woman with multiple AKs and squamous cell carcinomas (SCCs) that developed on the sun-exposed areas of vitiligo. A 98-year-old Japanese woman visited our department with a 2-year history of growing tumours on her scalp and left forearm. There was no history of exposure to arsenic or ionizing radiation. She had had widespread vitiligo from the age of 40 years. She spent the majority of her life as a housewife at 36850 north in Japan. She had not been exposed Figure 1. Actinic keratoses on a vitiligo lesion of the right forearm.

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forearm developed only 2 years before she came to us. These Erythroplasia of Queyrat treated by topical clinical findings support the concept of the gradual induction aminolaevulinic acid photodynamic therapy: of AK/SCC by solar UV radiation and photoprotection by a cautionary tale melanin pigment. The incidence of SCC is high even on normally pigmented Sir, Stables et al. raise some important issues in their skin in fair-skinned races, which may explain the paucity of interesting article on photodynamic therapy (PDT) for reports showing the association of the development of SCC erythroplasia of Queyrat (EOQ).1 To add to their discussion, and sun-exposed vitiligo lesion. Although the Japanese have we present a man who developed a squamous cell carcinoma darker skin-colour than Caucasian people, we often observe (SCC) after topical 5-aminolaevulinic acid PDT for EOQ. SCC/AK in elderly Japanese.6 However, the numerous AKs A 38-year-old uncircumcised Caucasian presented with a concomitant with SCC in this case is exceptional. Considering 12-month history of inflammation on the glans penis and that she had not had undue exposure to sunlight, as an symptoms of dysuria, soreness and oozing from the glans and indoor habitant, we believe her peculiar features may be prepuce. Examination revealed an erythematous plaque on explained by the lack of melanin pigment. the glans, prepuce and coronal sulcus with cornification A long-term study on side-effects of psoralen light therapy around the urethral meatus. A biopsy showed features of in India demonstrated that the vitiliginous skin appeared to EOQ. He was treated with PDT by application of 20% be more prone to actinic damage than normally pigmented 5-aminolaevulinic acid in Unguentum Merckw under occlu- 7 8 skin. Buckley and Rogers reported multiple AKs and SCCs in sion for 4 h, followed by irradiation with 105 J cm22 of a patient who received PUVA treatment for widely distributed incoherent red light from the Waldmann PDT 1200 vitiligo. On clinical examination of our patient, we could not (wavelength range 600±730 nm) (Waldmann Medizin- differentiate her skin lesion from leucoderma; we could only technik GmbH, Villingen-Schwenningen, Germany). Ametho- describe it as widely distributed vitiligo. We believe that her caine 4% gel local anaesthetic was applied 1 h before skin changes may represent the increased susceptibility of irradiation (4´5 g). During the procedure, the patient vitiligo to UV-induced AK and SCC. experienced discomfort which was tolerable. Post-procedure, Our life span is getting longer, and recent ozone depletion the patient took dextropropoxyphene and paracetamol as has increased the solar UV radiation reaching the earth's analgesics and used polymixin B sulphate and bacitracin zinc surface, thus we should not dismiss the risks of SCC in vitiligo. twice daily and petroleum jelly topically. He experienced discomfort and some weeping from the treatment site for The Department of Dermatology, S.AKIMOTO 3 days but no difficulties with micturition. This regimen was Gunma University School of Medicine, Y.S UZUKI repeated at monthly intervals for 3 months and was better 3-39-22 Schowamachi, O.ISHIKAWA tolerated on each occasion. Although punch biopsies Maebashi, Gunma 371-8511, performed from three representative sites at the end of Japan treatment failed to show any residual dysplasia, some clinical E-mail: [email protected] doubt existed regarding the completeness of regression due to remaining erythema and our lack of experience in the clinical References appearance of EOQ after PDT. Therefore, he was commenced on twice weekly applications of 5-fluorouracil. Four months 1 Vitasa BC, Taylor HR, Strickland PT et al. Association of later, he developed a nodule on the penis. A biopsy revealed nonmelanoma skin cancer and actinic keratosis with cumulative solar ultraviolet exposure in Maryland watermen. Cancer 1990; 65: an invasive well-differentiated SSC which was successfully 2811±17. treated with a partial penectomy. 2 Kaidbey KH, Agin PP, Sayre RM, Kingman AM. Photoprotection by Although initial results with PDT have been encouraging, melaninÐa comparison of black and Caucasian skin. J Am Acad caution needs to be exercised before it becomes established Dermatol 1979; 1: 249±60. therapy. Treatment of SCC with PDT has been reported with 3 OettleÁ AG. Skin cancer in Africa. Natl Cancer Inst Monogr 1963; 10: widely varying success rates.2±4 In our case, an SCC develop- 197±214. ing 4 months after PDT may raise questions regarding the 4 Ortonne JP, Pelletier N, Chabanon M, Thivolet J. Vitiligo et carcinogenic potential of PDT. We cannot say whether PDT eÂpitheÂliomas cutaneÂs. Ann Dermatol Venereol (Paris) 1978; 105: caused progression of EOQ to SCC as the risk of transforma- 1063±4. tion of EOQ to invasive SCC is 10±33% per year.5,6 Thus, one 5 Lisi P. Vitiligine e cancro cutaneo. Minerva Dermatol 1972; 47: outcome could be incomplete clearance with subsequent 427±9. progression to SCC. However, long-term follow-up is manda- 6 Naruse K, Ueda M, Nagano T et al. Prevalence of actinic keratosis in tory (after treatment with PDT and other modalities) until Japan. J Dermatol Sci 1997; 15: 183±7. further experience is gained. Wolf et al. have reported 7 Pathak MA, Mosher DB, Fitzpatrick TB. Safety and therapeutic melanoma development at a site treated seven times by PDT effectiveness of 8-methoxypsoralen, 4, 50, 8-trimethylpsoralen, and 7 psoralen in vitiligo. Natl Cancer Inst Monogr 1984; 66: 165±73. for solar keratoses and superficial SCC. 8 Buckley DA, Rogers S. Multiple keratoses and squamous carcinoma Treatment of EOQ is difficult and recurrences are not after PUVA treatment of vitiligo. Clin Exp Dermatol 1996; 21: infrequent; thus PDT would appear a logical and attractive 43±5. therapy either alone or in combination with other treatments. q 2000 British Association of Dermatologists, British Journal of Dermatology, 142, 812±851 826 CORRESPONDENCE

We endorse the view held by Stables et al. that PDT currently The use of TL-01 in EPP was reported in an open study of does not seem to be as effective on penile intraepidermal six patients.2 All patients noted an increase in their tolerance carcinoma in situ as cutaneous lesions.1 Thus, although the to sunlight but one patient felt that treatment was not use of PDT in the treatment of cutaneous lesions has been met worthwhile. The use of cysteine was reported in a double- with almost universal optimism, caution should be exercised blind, cross-over study of 16 patients.3 Cysteine ingestion in its use in the treatment of penile lesions. significantly prolonged the time it took to develop erythema by phototesting and significantly increased the patients' Department of Dermatology, S.VARMA tolerance to sunlight. University Hospital of Wales, P. J. A . H OLT The use of b-carotene in EPP was first reported in 1970, 4 Heath Park, A.V.ANSTEY* and in 1977 Mathews-Roth et al. reported the results of a Cardiff CF14 4XW, U.K. collaborative U.S. study of 133 EPP patients treated with *Department of Dermatology, b-carotene. Tolerance to sunlight was increased by a factor of Royal Gwent Hospital, 3 or more in 84% of the patients. A review of publications up Newport, to 1982, excluding those by Mathews-Roth et al., confirmed a Gwent NP9 2UB, U.K. beneficial effect in over 84% of almost 200 patients with EPP treated with b-carotene.5 However, the only controlled trial of b-carotene in EPP showed no significant improvement over placebo in 14 patients, although a lower dose was used in the References trial than is now recommended and some patients from the 1 Stables GI, Stringer MR, Robinson DJ, Ash DV. Erythroplasia of unsuccessfully treated group later responded to a higher dose.6,7 Queyrat treated by topical aminolaevulinic acid photodynamic More robust data on the effectiveness of b-carotene in EPP therapy. Br J Dermatol 1999; 140: 514±17. are unlikely to appear because of the difficulties of study 2 Kennedy JC, Pottier RH, Pross DC. Photodynamic therapy with design related to the long periods needed to achieve adequate endogenous protoporphyrin IX. basic principles and present clinical serum concentration and for the concentration to return to experience. J Photochem Photobiol B 1990; 6: 143±8. baseline.8 Until more effective treatment becomes available, 3 Calzavara-Pinton PG. Repetitive photodynamic therapy with topical delta-aminolaevulinic acid as an appropriate approach to the b-carotene is likely to remain the first choice for symptomatic routine treatment of superficial non-melanoma skin tumours. treatment of EPP because of its ease of administration, with J Photochem Photobiol B 1995; 29:53±7. TL-01 phototherapy a useful innovative alternative. 4 Fink-Puches R, Soyer HP, Hofer A et al. Long-term follow-up and histological changes of superficial nonmelanoma skin cancers Department of Dermatology, D.J.TODD treated with topical delta-aminolevulinic acid photodynamic Faculty of Medicine, therapy. Arch Dermatol 1998; 134: 821±6. Jordan University of Science & Technology, 5 Graham JG, Helwig EB. Erythroplasia of Queyrat. A clinicopatho- Irbid, PO Box 3030, logic and histochemical study. Cancer 1973; 32: 1396±414. Jordan 6 Mikhail GR. Cancers, precancers, and pseudocancers on the male E-mail: [email protected] genitalia. A review of clinical appearances, histopathology, and management. J Dermatol Surg Oncol 1980; 6: 1027±35. 7 Wolf P, Fink-Puches R, Reimann-Weber A, Kerl H. Development of References malignant melanoma after repeated topical photodynamic therapy with 5-aminolevulinic acid at the exposed site. Dermatology 1997; 1 Murphy GM. for the British Photodermatology Group. The cutane- 194:53±4. ous porphyrias: a review. Br J Dermatol 1999; 140: 573±81. 2 Collins P, Ferguson J. Narrow band UVB (TL-01) phototherapy: an effective preventative treatment for the photodermatoses. Br J Dermatol 1995; 132: 956±63. 3 Mathews-Roth MM, Rosner B, Benfell K et al. A double-blind study Therapeutic options for erythropoietic protoporphyria of cysteine photoprotection in erythropoietic protoporphyria. Sir, In the excellent review article on the cutaneous Photodermatol Photoimmunol Photomed 1994; 10: 244±8. porphyrias by Murphy for the British Photodermatology 4 Mathews-Roth MM, Pathak MA, Fitzpatrick TB et al. Beta carotene Group,1 the table of therapeutic protocols lists b-carotene and therapy for erythropoietic protoporphyria and other photosensitive diseases. Arch Dermatol 1977; 113: 1229±32. cysteine as having possible efficacy for treating the photo- 5 Krook G, Haeger-Aronsen B. b-Carotene in the treatment of sensitivity of erythropoietic protoporphyria (EPP), and erythropoietic protoporphyria. Acta Derm Venereol (Suppl.) (Stockh) narrow-band ultraviolet B TL-01 phototherapy as giving a 1982; 100: 125±9. protection factor of 8. Readers may assume from this that 6 Corbett MF, Herxheimer A, Magnus IA et al. The longterm TL-01 phototherapy is now the first-line treatment to relieve treatment with beta-carotene in erythropoietic protoporphyria: a the symptoms of EPP. The accompanying comment reinforces controlled trial. Br J Dermatol 1977; 97: 655±62. this by stating that TL-01 is perhaps the most innovative of 7 Shafrir A. Comments on a case of erythropoietic protoporphyria the therapeutic options and that robust data on the efficacy of with onycholysis. Proc R Soc Med 1977; 70: 574. b-carotene are lacking. While these statements may be true, I 8 Mathews-Roth MM. Erythropoietic protoporphyria. (Letter.) Br J think they need further clarification. Dermatol 1996; 134: 977.

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Reply 5´3 mg kg21 daily, due to a slight relapse when tapering the drug. No associated diseases were discovered during a Sir, In the absence of adequate controlled trials, argument 21-month follow-up. seems destined to continue as to the efficacy or otherwise of The widespread extent of PG in this patient was due to the b-carotene in erythropoietic protoporphyria (EPP). A drug failure of recognition of the disease at the outset by non- which changes the colour of the skin has a very powerful dermatologists, and the numerous traumatic excisions with placebo effect and affects the judgement of both patient and worsening of the disease represented the `pathergic phenom- clinician alike. Standard practice, nevertheless, is to give a enon' known in PG.1 Surgeons should therefore be aware of trial of b-carotene to a patient who has symptomatic EPP. The this disease to avoid a dramatic increase in ulceration due to point of my comments in the review was to make clinicians repeated excision. The age of the patient, the axillary aware of the lack of solid data behind claims for the efficacy of localization and the development during pregnancy are b-carotene and, if the drug is not effective, to consider the use noteworthy. Five other reports of PG during pregnancy have of TL-01 depending on local circumstances. been published to date,2±6 associated with leukaemia, lupus erythematosus and antiphospholipid syndrome, and idio- Photobiology Unit, G.M.MURPHY pathic (in two cases, as in our report). We carefully excluded Beaumont and Mater Misericordiae Hospitals, associated autoimmune disease which could have favoured Dublin 7, both PG and premature delivery. However, pregnancy by itself Ireland induces an immunocompromised state. In our opinion, E-mail: [email protected] pregnancy may be added to the list of possible aetiologies of PG.

Pyoderma gangrenosum with pathergic phenomenon in pregnancy Sir, Pyoderma gangrenosum (PG) is a painful chronic ulcerative disorder often occurring in association with systemic disease.1 It typically affects the lower limbs, and sometimes develops after trauma or surgical procedures. The occurrence of PG during pregnancy is uncommon, with only five reports in the literature since 1969, and prompts our report. During the third month of pregnancy, a 29-year-old woman presented to the surgical emergency room with an inflammatory pseudocystic lesion in the left axilla. Her past medical history was unremarkable except for a miscarriage and two premature deliveries. Several surgical incisions were unproductive and the lesion evolved to an extensive inflammatory ulceration. As she was suspected of having bacterial necrotizing , several surgical excisions were performed, leading to a wide painful ulcerative inflammatory thoracic lesion with undermined borders (Fig. 1). When we first saw the patient, the diagnosis of PG was strongly suspected on the basis of the clinical history and the presentation: a 15 20 cm extensive painful ulceration with  inflammatory borders involved the upper part of the left breast. This diagnosis was supported by negative results of multiple bacterial swabs, and the histopathological data which showed massive dermal neutrophilic infiltration with no vasculitis. We decided to start systemic corticosteroids 1mgkg21 daily, which stopped progression of the disease. This therapy was progressively reduced and replaced by cyclosporin (Neoralw, 3 mg kg21 daily), with the aim of sparing steroids during pregnancy. Besides its benefits on the evolution of PG, cyclosporin had a striking effect on the pain. Three months later, our patient delivered by Caesarian section Figure 1. Clinical presentation after multiple surgical excisions: a healthy premature (29 weeks gestation) boy weighing widespread thoracic ulceration with limited inflammatory evolving 1500 g. After delivery, the dosage of cyclosporin was raised to border, close to the nipple. q 2000 British Association of Dermatologists, British Journal of Dermatology, 142, 812±851 828 CORRESPONDENCE

The use of cyclosporin, which has significant benefit in the medicine and rarely in dermatology. We describe a patient management of PG,7 helped us to stop the progression of who developed MPO-ANCA-associated vasculitis with leg lesions and allowed the avoidance of steroids during erythema during propylthiouracil therapy. pregnancy, and reduced pain as a noteworthy secondary A 57-year-old woman with Graves' disease had been benefit. However, the relapse after reducing the dose of treated with propylthiouracil 300 mg daily for 4 years. In cyclosporin demonstrates the necessity of an adequate dose, January 1997, she was admitted to the department of which can be up to 10 mg kg21 daily, as stated by Chow internal medicine because of thyrotoxicosis, pericardial and Ho.7 effusion, polyarthralgia and fever. Potassium iodide 20 mg As our patient underwent a Caesarian section for delivery, daily was added, resulting in an improvement of the we were anxious regarding the possibility of the `pathergic thyrotoxicosis. However, the pericardial effusion, poly- phenomenon' in the scar, as described by Harland et al.5 but arthralgia and fever continued. In March 1997, because of this risk was presumably abolished by the systemic treatment erythema on her legs, she came to our department. Several she received. slightly indurated areas of erythema resembling were found on her legs (Fig. 1). Results of Departments of Dermatology and B.SASSOLAS laboratory studies revealed serum C-reactive protein (CRP) 21 9 21 ²Gynecology, and Y. L E RU 8´1 mg dL , white cell count 6´1 10 L , platelets 9 21  ³Hyperbaric Unit, P. P LANTIN* 505 10 L and normal urinalysis. Results of liver and  Centre Hospitalier Universitaire de Brest, G.LAIR kidney function tests were normal. Antinuclear antibodies 29609 Brest, France P-F.DUPRE² were present (1 : 80, homogeneous pattern) and a lupus *Department of Dermatology, G.COCHARD³ erythematosus test was negative. The serum p-ANCA and CHIC, G.GUILLET cytoplasmic (c)-ANCA were both positive, and the serum 29000 Quimper, France MPO-ANCA titre was 275 EU mL21. Results of echocardio- E-mail: [email protected] graphy and computed tomographic scans of the chest revealed pericardial effusion due to epicarditis. Skin biopsy revealed pustules and spongiosis in the epidermis and References leucocytoclastic vasculitis in the upper dermis. Results of 1 Powell FC, Su WPD, Perry HO. Pyoderma gangrenosum: classifica- direct immunofluorescence studies demonstrated deposition tion and management. J Am Acad Dermatol 1996; 34: 395±409. of C3 in the pustules. A renal biopsy showed normal tissue. 2 Freedman AM, Phelps RG, Lebwohl M. Pyoderma gangrenosum We diagnosed the patient as having MPO-ANCA-associated associated with anticardiolipin antibodies in a pregnant patient. Int vasculitis due to propylthiouracil, and discontinued the drug. J Dermatol 1997; 36: 205±7. After propylthiouracil was withdrawn, the fever, pericardial 3 Roger D, Aldigier JC, Peyronnet P et al. Acquired and effusion, polyarthralgia and skin eruption all began to pyoderma gangrenosum in a patient with systemic lupus erythe- matosus. Clin Exp Dermatol 1993; 18: 268±70. 4 Maier H, Diem E, Gotschim A, Ortel B. Pyoderma gangrenosum as a precursor of myeloid leukemia. Hautarzt 1995; 46: 647±50. 5 Harland CC, Jaffe W, Holden CA, Ross LD. Pyoderma gangrenosum complicating Caesarian section. J Obstet Gynaecol 1993; 13: 115±16. 6 Nurse DS. Pyoderma gangrenosum. Australas J Dermatol 1969; 10: 188±9. 7 Chow RKP, Ho VC. Treatment of pyoderma gangrenosum. JAm Acad Dermatol 1996; 34: 1047±60.

Myeloperoxidase-antineutrophil cytoplasmic antibody-associated vasculitis following propylthiouracil therapy

Sir, Antineutrophil cytoplasmic antibody (ANCA) is an important marker in systemic vasculitic disorders such as Wegener's granulomatosis, microscopic polyarteritis, poly- arteritis nodosa, Churg±Strauss syndrome and necrotizing crescentic glomerulonephritis. The target antigen of the most common perinuclear (p)-ANCA pattern is specific to myeloperoxidase (MPO).1 Unclassified vasculitis with positive MPO-ANCA has been recognized in patients treated with Figure 1. Slightly indurated brownish-red erythema on the leg, antithyroid drugs. Most cases have been reported in internal resembling erythema multiforme.

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Table 1. Case reports of myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA)-associated vasculitis with antithyroid drug treatment which include details of the skin eruption Patient Age (years)/ Duration MPO-ANCA Histological Direct no. sex Drug (mg daily) (years) (EU mL21) Clinical findings findings immunofluorescence 1 72/F Propylthiouracil (300) 3 Positive Leg , Capillary- ND purpura venular vasculitis 2 22/F Propylthiouracil (200±300) 3 107 Indurated Necrotizing ND erythema, vasculitis subcutaneous nodules 3 24/F Methimazole (10) 4 Positive Leg ulcer Leucocytoclastic Vessel vasculitis walls C3- positive 4 36/F Propylthiouracil (150) 2 239 Erythema Panniculitis ND nodosum-like 5a 57/F Propylthiouracil (300) 4 275 Erythema Leucocytoclastic Pustules C3- multiforme-like vasculitis positive a Our patient; ND, not done.

regress, and improved completely within 2 months. Arthral- Clinical improvement occurred in all cases. The prognosis of gia recurred after 2 months, and a similar skin eruption this disease is regarded as satisfactory, because by drug recurred twice, after 2 and 5 months; all of these episodes withdrawal alone, clinical improvement was found in six regressed spontaneously within a few weeks without treat- cases including our own. ment. The serum CRP level and platelet count soon began to We have documented in Table 1 the cases of this condition decrease, and fell to normal limits. The MPO-ANCA titre has in which the skin lesions are definite. Five reports,3±6 remained high for 2 years, although c-ANCA became including ours, are detailed. The cutaneous findings are negative after 3 months. The patient has had no symptoms variable, and include leg ulcer, purpura, subcutaneous during the last 2 years. nodules, and -like and erythema multi- The association of positive ANCA with antithyroid drug forme-like lesions. Histological findings are also variable, and therapy was first described by Dolman et al.2 Subsequently, 22 include capillary-venular vasculitis, necrotizing vasculitis, patients with MPO-ANCA-associated vasculitis due to anti- leucocytoclastic vasculitis and panniculitis. Direct immuno- thyroid drugs have been reported (including our patient), as far fluorescence studies were performed in patient 3, and as we can determine. Their ages range from 11 to 82 years demonstrated C3 deposits in the vessel walls. (mean 40´3). Seven men and 15 women have been reported; The mechanism of MPO-ANCA-associated vasculitis is not women are more liable to suffer from thyroid disorders such clear, but it has been suggested that antithyroid drugs or as Graves' disease than men. The primary diseases were 15 metabolites may cross-react with a neutrophilic cytoplasmic cases of Graves' disease and seven unknown causes. The antigen.7 On the other hand, propylthiouracil selectively drugs implicated were propylthiouracil 100±600 (mean 282) accumulates in neutrophils8 and binds to MPO, resulting in a mg daily (20 cases), methimazole 10 mg daily (one case) change to the heme structure of the enzyme.9 Furthermore, and carbimazole 20 mg daily (one case). The medication propylthiouracil can inactivate MPO in the presence of period ranged between 1 month and 6 years (mean hydrogen peroxide.10 It is conceivable that propylthiouracil 2´6 years). The MPO-ANCA titre ranged from 54´8 to could alter MPO by oxidation in a minority of susceptible 502 EU mL21 (mean 243´6). In our patient, the titre individuals. The altered enzymes, possibly still combined with varied from 179 to 445 EU mL21, most measurements the drug, could initiate production of anti-MPO auto- being about 250±275 EU mL21. Skin lesions were found antibodies, stimulating other neutrophils to degranulate and in 10 of the 22 patients. Fourteen patients had arthralgia, therefore cause vascular damage. However, these views are 13 had haematuria and/or proteinuria, nine had fever, hypotheses. Further clinical trials should be conducted to four had alveolar haemorrhage and two had pleural clarify the correlation between MPO-ANCA-associated effusion. Epicarditis, which our patient developed, has vasculitis and propylthiouracil therapy. not been found previously. Renal biopsy was performed in 15 cases, revealing crescentic glomerulonephritis in 13, mesangeal proliferating glomerulonephritis in one and Department of Dermatology, S.OTSUKA normal tissue in our patient. The treatment was steroid Dokkyo University School of Medicine, A.KINEBUCHI pulse therapy in nine cases, withdrawal of causative drugs in Mibu, H.TABATA six, oral prednisolone in six (mean dose 46´3 mg daily), Tochigi 321-0293, A.YAMAKAGE cyclophosphamide pulse in two and plasmapheresis in one. Japan S.YAMAZAKI q 2000 British Association of Dermatologists, British Journal of Dermatology, 142, 812±851 830 CORRESPONDENCE

References erythema had gradually extended and the thighs had become stiff. Concurrently, the stiffness had spread to his forearms. 1 Falk RJ, Jennette JC. Anti-neutrophil cytoplasmic autoantibodies with specificity for myeloperoxidase in patients with systemic He had had asthma for 30 years, but did not receive vasculitis and idiopathic necrotizing and crescentic glomerulo- l-tryptophan-containing products. He had been exposed to nephritis. N Engl J Med 1988; 318: 1651±7. trichloroethylene for 8 years, from 18 to 26 years of age. 2 Dolman KM, Gans ROB, Vervaat TJ et al. Vasculitis and Examination revealed symmetrical irregular shaped dark- antineutrophil cytoplasmic autoantibodies associated with reddish erythematous areas with oedema and sclerosis. propylthiouracil therapy. Lancet 1993; 342: 651±2. Subcutaneous stiffness of the extremities was also observed. 3 Stankus SJ, Johnson NT. Propylthiouracil-induced hyper- His face, hands, feet and trunk were spared, and his general sensitivity vasculitis presenting as respiratory failure. Chest condition was good. There was no history of Raynaud's 1992; 102: 1595±6. phenomenon and -fold capillaroscopy was normal. 4 Aoki A, Suzuki H, Ohata T et al. A case of p-ANCA positive Further examination revealed hypereosinophilia (white necrotizing vasculitis associated with Graves' disease. Rheumati blood cell count 11´1 109 L21, eosinophils 13´0%) and (Jpn) 1995; 35: 683±7. Â 21 5 Kawauchi Y, Nukaga H, Otsuka F. ANCA-associated vasculitis hypergammaglobulinaemia (IgG 21´19 g L , normal 6´14± 21 complicated with lupus-like syndrome due to methimazole. Jpn J 12´95). C-reactive protein was 1´6 mg dL , anti-ssDNA 21 Dermatol 1996; 106: 1743±5. antibody was positive (21 U mL ), antinuclear antibody was 6 Fujii A, Arimura Y, Minoshima S et al. MPO-ANCA related negative, and serum aldolase was normal (4´2 U L21). A skin vasculitis with pulmonary hemorrhage during propylthiouracil biopsy from his thigh demonstrated dermal fibrosis, thickened (PTU) therapy. Rheumati (Jpn) 1997; 37: 788±93. fascia and fibrous septa separating the fat lobules (Fig. 1a). A 7 Vogt BA, Kim Y, Jennette JC et al. Antineutrophil cytoplasmic slightly inflammatory cell infiltrate was observed in the dermis, autoantibody-positive crescentic glomerulonephritis as a compli- but no eosinophils were present in the fascia or dermis. cation of treatment with propylthiouracil in children. J Pediatr We diagnosed our patient as having EF, and treatment with 1994; 124: 986±8. 8 Lam DCC, Lindsay RH. Accumulation of 2-[14C] propylthiouracil oral prednisolone 30 mg daily was initially effective. Over the in human polymorphonuclear leukocytes. Biochem Pharmacol following 5 months, the prednisolone dose was gradually 1979; 28: 2289±96. reduced to 5 mg daily. At this time, symmetrical irregular 9 Lee H, Hirouchi M, Hosokawa M et al. Inactivation of peroxidase shaped dark-reddish erythematous areas and subcutaneous of rat bone marrow by repeated administration of propyl- stiffness of the extremities recurred (Fig. 1b) and he also thiouracil is accompanied by a change in the heme structure. complained of symmetrical hypoaesthesia, and reduced sense Biochem Pharmacol 1988; 37: 2151±3. of touch and pain on his palms. The thenar muscles were 10 Lee E, Miki Y, Katsura H et al. Mechanism of inactivation of slightly atrophic. Tinel's sign was positive. These symptoms myeloperoxidase by propylthiouracil. Biochem Pharmacol 1990; indicated carpal tunnel syndrome due to EF. 39: 1467±71. The patient refused to take more prednisolone due to the development of a moon face. We decided to use cyclosporin 3´7 mg kg21 daily. The stiffness in the thighs and forearms was greatly improved within a month, and symptoms of Eosinophilic fasciitis following exposure to carpal tunnel syndrome gradually improved. All symptoms and skin tethering disappeared within 6 months (Fig. 1c). We trichloroethylene: successful treatment with 21 cyclosporin tapered cyclosporin to 2´5 mg kg daily, and no recurrence was observed for more than 1 year. Sir, Eosinophilic fasciitis (EF) was originally described by The aetiology and pathogenesis of EF are presently Shulman1 in 1974, and is generally characterized by rapid unknown. Hypergammaglobulinaemia and tissue deposition onset of symmetrical woody induration of the extremities. of immunoglobulins have been reported. The effectiveness of Truncal involvement also occurs, but the hands and feet are oral steroids suggests immunological involvement. However, typically spared. Absence of Raynaud's phenomenon or serum autoantibodies are not consistently present in EF sclerodactyly, and normal nail-fold capillaroscopy, are useful patients.2 The aetiological relationship between EF and features to distinguish EF from . Typical labora- scleroderma is not clear. Furthermore, it is unclear whether tory findings are hypergammaglobulinaemia, elevated ery- unilateral EF represents linear scleroderma with fascial throcyte sedimentation rate, and peripheral eosinophilia.2 involvement. The aetiology of EF is usually unknown, but organic solvents, A pathogenetic mechanism for the fibrotic change in EF which are known to be inducers of autoimmune diseases, has been suggested. Eosinophils stimulate DNA synthesis and have been implicated by Waller et al.,3 who reported EF matrix production in dermal fibroblasts.4 Activated eosino- following prolonged exposure to trichloroethylene. We pre- phils release granule proteins such as the major basic protein, sent a patient with EF who had been exposed to trichloro- which in turn causes the secretion from platelet alpha ethylene for 8 years, had anti-ssDNA antibody, and was granules of many cytokines including transforming growth successfully treated with cyclosporin. factor (TGF)-b. Moreover, eosinophils themselves produce A 50-year-old Japanese man was hospitalized with stiffness TGF-b in EF.2 TGF-b induces fibroblasts to secrete connective of the extremities. He described erythema on his thighs for tissue growth factor (CTGF). Then TGF-b and CTGF stimulate 6 months without any obvious provocative factors. The fibroblasts to proliferate and to secrete excessive amounts of

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extracellular matrix components.5 The involvement of TGF-b their report, 50% of the trichloroethylene-treated mice and CTGF is similar with scleroderma.6 showed anti-ssDNA antibody. A relationship between tri- Our patient had a history of exposure to trichloroethylene chloroethylene exposure and EF has also been reported,3 and had positive serum anti-ssDNA antibody. Organic solvent supporting the hypothesis that EF might be an autoimmune exposure is a risk factor for autoimmune diseases such as disease. Long-term exposure to trichloroethylene for 8 years scleroderma.3,7 Khan et al.8 showed a trichloroethylene- may be enough to induce anti-ssDNA antibody and auto- induced autoimmune response in female MRL +/+ mice. In immune disease. Our patient was successfully treated with cyclosporin, which is an immunosuppressant.9 Laneuville10 reported a patient with coexisting EF and chronic lymphocytic leukaemia; when given cyclosporin for the latter disease, the patient's EF resolved. Peter and Ruzicka11 recommended cyclosporin as the first choice for disabling morphoea which, like EF, may cause symptoms of carpal tunnel syndrome. Several cases of scleroderma successfully treated with cyclosporin have also been reported.12,13 In our case, severe carpal tunnel syndrome was associated with EF, and the patient refused oral prednisolone. Thus, we administered cyclosporin for EF. Its effectiveness supports the hypothesis that EF is an autoimmune disease.

Department of Dermatology, N.HAYASHI Faculty of Medicine, A.IGARASHI* University of Tokyo, T.M ATSUYAMA* Hongo 7-3-1, S.HARADA* Bunkyo-ku, Tokyo 113-8655, Japan *Division of Dermatology, Kantoteishin Hospital, Higashigotanda 5-9-22, Shinagawa-ku, Tokyo 141, Japan E-mail: [email protected]

References

1 Shulman LE. Diffuse fasciitis with hypergammaglobulinemia and eosinophilia: a new syndrome? J Rheumatol 1974; 1 (Suppl. 1): 46 (Abstr.). 2 Helfman T, Falanga V. Eosinophilic fasciitis. Clin Dermatol 1994; 12: 449±55. 3 Waller PA, Clauw D, Cupps T et al. Fasciitis (not scleroderma) following prolonged exposure to an organic solvent (trichloro- ethylene). J Rheumatol 1994; 21: 1567±70. 4 Birkland TP, Cheavens MD, Pincus SH. Human eosinophils stimulate DNA synthesis and matrix production in dermal fibroblasts. Arch Dermatol Res 1994; 286: 312±18. 5 Frazier K, Williams S, Kothapalli D et al. Stimulation of fibroblast cell growth, matrix production, and granulation tissue formation by connective tissue growth factor. J Invest Dermatol 1996; 107: 404±11. 6 Igarashi A, Nashiro K, Kikuchi K et al. Significant correlation between connective tissue growth factor gene expression and skin Figure 1. (a) Photomicrograph showing dermal fibrosis, thickened sclerosis in tissue sections from patients with systemic sclerosis. fascia and fibrous septa separating the fat lobules (haematoxylin and J Invest Dermatol 1995; 105: 280±4. eosin; original magnification 20). (b) Symmetrical irregular shaped 7 Nietert PJ, Sutherland SE, Silver RM et al. Is occupational organic  dark-reddish erythematous areas and subcutaneous stiffness of the solvent exposure a risk factor for scleroderma? Arthritis Rheum thighs were apparent before cyclosporin treatment. (c) Softened 1998; 41: 1111±18. thighs after cyclosporin treatment for 6 months. 8 Khan MF, Kaphalia BS, Prabhakar BS et al. Trichloroethene- q 2000 British Association of Dermatologists, British Journal of Dermatology, 142, 812±851 832 CORRESPONDENCE

induced autoimmune response in female MRL +/+ mice. Toxicol delight of returning to an active social life. Renal transplant Appl Pharmacol 1995; 134: 155±60. function has remained unchanged over the subsequent 9 Sowden JM, Allen BR. Cyclosporine in dermatology: a historical 12 months and he has a current serum creatinine of overview. Int J Dermatol 1992; 31: 520±3. 143 mmol L21. 10 Laneuville P. Cyclosporin A induced remission of CD4+ T-CLL The introduction of the T-cell specific immunosuppressant associated with eosinophilia and fasciitis. Br J Haematol 1992; 80: agent cyclosporin A has revolutionized solid organ trans- 252±4. 11 Peter RU, Ruzicka T. Cyclosporin A in the therapy of inflammatory plantation, and more recently cyclosporin has been used to dermatoses. Hautarzt 1992; 43: 687±94. treat an increasing variety of immunologically mediated 12 Gisslinger H, Burghuber OC, Stacher G et al. Efficacy of diseases including rheumatoid arthritis, and atopic cyclosporin A in systemic sclerosis. Clin Exp Rheumatol 1991; 9: eczema. It acts predominantly by inhibition of T-cell repli- 383±90. cation due to pretranscription inhibition of interleukin-2 13 Wigley FM. Treatment of systemic sclerosis. Curr Opin Rheumatol production.1 Cyclosporin was recognized to have a narrow 1992; 4: 878±86. therapeutic window and to have dangerous side-effects including nephrotoxicity, and to provoke hypertension,2 even when levels are maintained in the therapeutic range. Tremor, gingival hyperplasia, and rarely, severe flushing, are well recognized side-effects which are often less Cyclosporin-induced flushing in a renal transplant worrying to the physician but more troublesome to the recipient resolving after substitution with tacrolimus patient. The resultant adverse cosmetic effects cause con- siderable morbidity and may even result in non-compliance Sir, We report a case of severe flushing induced by cyclosporin jeopardizing the success of the transplanted organ.3 Mild in a cadaveric renal transplant recipient, which resulted in flushing is a common, dose-independent side-effect described social isolation. Extensive erythema involving the face, upper in one series in 12´5%, 29% and 18% of patients at 1, 3 and limbs and chest wall developed within 2 h of cyclosporin 6 months, respectively, post-transplantation.4 Concomitant therapy and persisted for several hours. Conversion from a administration of calcium-channel blockers, nitrofurantoin or cyclosporin to a tacrolimus-based maintenance immuno- isoniazid may potentiate cyclosporin-induced vasodilatation.5 suppressive regimen caused immediate and complete reso- The mechanism of cyclosporin-induced flushing is unclear, lution of the flushing attacks, enabling resumption of a although the drug partially blocks thromboxane-synthase normal life-style. and stimulates phosphodiesterase activity, resulting in A 24-year-old pottery worker developed progressive increased levels of both arachidonic acid and prostaglandin 6 chronic renal failure as a child secondary to reflux nephro- I2, which are both associated with vasodilation. pathy. He commenced peritoneal dialysis at age 18 years and Tacrolimus is a macrolide lactone with potent selective received a successful cadaveric renal transplant 1 month T-cell immunosuppressant properties that has been success- later. Renal transplant function has remained stable following fully used to rescue renal transplants which are failing an initial severe rejection episode. Maintenance immuno- secondary to cyclosporin-resistant rejection.7 The side-effect suppressive therapy comprised prednisolone 10 mg, profile of tacrolimus shares some similarities with cyclosporin; azathioprine 100 mg and cyclosporin (Sandimmunw, Sandoz, both agents cause tremor and are nephrotoxic. However, the 6mgkg21 average trough level 220 ng mL21), which was drug is rarely associated with hypertrichosis or gingival converted to the new microemulsion preparation (Neoralw, Novartis, 5 mg kg21 average trough level 180 ng mL21)in August 1995. In 1997 he complained of diffuse flushing attacks affecting his face, arms and torso which charac- teristically occurred approximately 2 h after each dose of cyclosporin and continued for several hours. These flushing episodes had been present since transplantation but had markedly deteriorated since conversion to Neoralw. Exami- nation during an attack (Fig. 1) revealed macular erythema of the forearms and trunk combined with diffuse facial erythema. Linear erythema was provoked by stroking his back, consistent with vasomotor lability in the absence of concurrent antihistamines. The flushing attacks caused increasing social embarrassment, resulting in progressive social isolation. A reduction in the cyclosporin dose to 4´5 mg kg21 and introduction of beta-blockade resulted in a mild attenuation of his symptoms. Cyclosporin therapy was discontinued in July 1998 and tacrolimus (60 mgkg21)was substituted. The erythematous attacks immediately resolved Figure 1. Truncal erythema occurring 60 min after oral adminis- completely and have not recurred, allowing the patient the tration of 150 mg cyclosporin (Neoralw, Novartis).

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hyperplasia, and has not been reported to cause flushing.8 Digital necrosis related to cisplatin in systemic Tacrolimus may provide an alternative to cyclosporin in sclerosis patients with florid or unacceptable cutaneous side-effects Sir, Cisplatin is one of the most widely used chemotherapeutic such as flushing attacks, hypertrichosis or gingival hyperpla- agents. Adverse vascular effects are increasingly recognized sia. Currently there are limited long-term data on the safety complications of cisplatin, and in particular, myocardial and efficacy of tacrolimus, although at 1 year follow-up in infarction, angina pectoris or arterial occlusive manifesta- one series there were no significant differences between tions.1,2 Previous authors2±6 have found Raynaud's phenom- cyclosporin and tacrolimus.9 Conversion from cyclosporin to enon and digital ischaemia, in 33±40% and 29±41%, tacrolimus is an effective means of treating cutaneous side- respectively, of patients treated with cisplatin; there was no effects, but should be reserved for severe cases resistant to correlation between the cumulative drug dose and the time of other therapeutic options. onset of vascular complications. We describe a patient with diffuse cutaneous systemic sclerosis (dcSSc) and lung cancer, Department of Dermatology, H.M.RAMSAY who developed acute digital ischaemia related to cisplatin North Staffordshire Hospital, P. N . H ARDEN* chemotherapy. Central Outpatients Department, A 49-year-old female non-smoker was diagnosed with Hartshill Road, dcSSc in 1990, characterized by diffuse cutaneous sclerosis, Stoke-on-Trent, without pitting scars or digital necrosis. Systemic manifesta- Staffordshire ST4 7PA, tions included Raynaud's phenomenon, oesophageal involve- U.K. ment (absence of peristalsis in the lower two-thirds of the *Department of Nephrology, oesophageal body and low pressure in the oesophageal Royal Infirmary, sphincter) and interstitial lung disease comprising mild Princes Road, bilateral basilar pulmonary shadowing on computed tomo- Hartshill, graphy (CT) scan, and both decreased vital capacity and Stoke-on-Trent, diffusing capacity on pulmonary function tests (74% and Staffordshire ST4 7LN, 68% of predicted, respectively). Autoantibody screening tests U.K. were positive for antinuclear antibodies (1 : 1000) and anti-Scl 70 antibody. She received treatment with diltiazem, References cisapride and omeprazole. In February 1999, the patient developed broncho-alveolar cancer involving the right inferior 1 Granelli-Piperano A, Keane M, Steinman RM. Evidence that pulmonary area, probably favoured by interstitial lung disease cyclosporin inhibits cell mediated immunity primarily at the level of the T lymphocyte rather than the accessory cell. Transplantation related to dcSSc, and she received chemotherapy with 1998; 46: 53S±60S. cisplatin (150 mg monthly) and gemcitabine (1´5 g three 2 Ota B, Bradley M. Side effects of cyclosporin in 100 renal allograft times a month). In May 1999, at 3 months' follow-up of the recipients. Transplant Proc 1983; 15: 3150±6. lung malignancy, chest X-rays and thoracic CT scan revealed 3 Burrows L, Knight R, Genyk Y et al. Conversion to tacrolimus to a marked decrease of radiological abnormalities. However, in ameliorate cyclosporine toxicity in kidney recipients. Transplant Proc June 1999, 1 week after receiving an additional cycle of 1998; 30: 2030±2. chemotherapy, the patient presented with a 1 day history of 4 Douglas S, Corty E. Incidence of cyclosporine side effects in renal acute and severe ischaemia, i.e. painful coldness and pallor, transplant patients. ANNA J 1982; 14: 97±101. involving all her fingers. General physical examination was 5 Smith AG. Skin disorders. In: Textbook of Adverse Drug Reactions otherwise normal. Routine laboratory findings and comple- (Davies DM, Ferner RE, Glanville H, eds). London: Chapman & Hall ment levels were normal. Autoantibody screening was Medical, 1998; 569. positive for anti-Scl 70 antibody, and negative for cryo- 6 Sraer J, Bens M, Ardaillou R. Dual effects of cyclosporine A on globulin, anticardiolipin and antiphospholipid antibodies, arachidonate metabolism by peritoneal macrophages. Phos- lupus anticoagulant, antineutrophil cytoplasmic antibodies pholipase activation and partial thromboxane-synthase blockage. Biochem Pharmacol 1989; 38: 1947±54. and cold agglutinins. Other investigations, including arterial 7 Jordan ML, Shapiro R, Vivas CA et al. FK506 `rescue' for resistant Doppler ultrasonography of the upper limbs, electrocardio- rejection of renal allografts under primary cyclosporine immuno- gram and echocardiography, were within normal limits. The suppression. Transplantation 1994; 57: 860±5. diagnosis of severe acute digital ischaemia related to cisplatin 8 Pirsch JD, Miller J, Deierhoi MH et al. A comparison of therapy was made. The patient was treated with intravenous tacrolimus (FK506) and cyclosporine for immunosuppression nitroprusside for 2 days followed by Iloprost for 21 days, after cadaveric renal transplantation. FK506 Kidney Trans- which resulted in a marked improvement of ischaemic plant Study Group (see comments). Transplantation 1997; 63: cutaneous manifestations involving her hands. At the end 977±83. of intravenous vasodilator therapy, the patient had complete 9 Mayer AD, Dmitrewski J, Squifflet JP et al. Multicenter randomized resolution of ischaemic manifestations involving the first trial comparing tacrolimus (FK506) and cyclosporine in the prevention of renal allograft rejection: a report of the European finger of her right hand and the first and fourth fingers of her Tacrolimus Multicenter Renal Study Group. Transplantation 1997; left hand, and marked improvement of digital ischaemia of the 64: 436±43. other fingers, with gangrene only persisting at the extremity q 2000 British Association of Dermatologists, British Journal of Dermatology, 142, 812±851 834 CORRESPONDENCE

of these fingers (Fig. 1). The gangrene of the third, fourth and particularly dermatologists, should be aware of cisplatin- fifth fingers of her right hand and the second and third fingers related vascular adverse effects; therefore, avoiding the risk of of her left hand was managed by surgical debridement. severe sequelae in patients with SSc. Cisplatin chemotherapy was not reinitiated. At 5 months' follow-up, the patient remains free of ischaemic cutaneous Departments of Internal Medicine, I.MARIE features, and in particular, she has not experienced recur- *Vascular Surgery, H.LEVESQUE rence of digital ischaemia or necrosis. ²Dermatology, D.PLISSONNIER* Cisplatin chemotherapy is associated with peripheral Centre Hospitalier Universitaire de X.BALGUERIE² vascular impairment, and notably Raynaud's phenomenon, Rouen-Boisguillaume, N.CAILLEUX digital ischaemia or acral erythema.2±7 The pathological 76031 Rouen Cedex, H.COURTOIS mechanisms of vascular complications related to cisplatin France therapy are still not clearly understood, although they may be 8 5 related to vasospasm of small vessels. Hansen et al. noted References that 44% of patients treated with cisplatin had Raynaud's phenomenon with an exaggerated response to cold. Other 1 Doll DC, Yarbro JW. Vascular toxicity associated with antineoplastic investigators9 have assessed peripheral circulation, using both agents. Semin Oncol 1992; 19: 580±96. laser Doppler flowmetry and cold provocation, in eight 2 Stefenelli T, Kuzmits R, Ulrich W, Glogar D. Acute vascular toxicity after combination chemotherapy with cisplatin, vinblastine and patients previously treated with cisplatin; they also found bleomycin for testicular cancer. Eur Heart J 1988; 9: 552±6. both exaggerated and prolonged vasoconstrictor response to 3 Berger CC, Bokemeyer C, Schneider M et al. Secondary Raynaud's cold with a mean blood flow reduction of 61% and a mean phenomenon and other late vascular complications following restitution time of greater than 7 min in all patients. In our chemotherapy for testicular cancer. Eur J Cancer 1995; 31A: patient, the diagnosis of digital ischaemia related to cisplatin 2229±38. could be reasonably concluded as cisplatin was the sole drug 4 Garstin IWH, Cooper GG, Hood JM. Arterial thrombosis after likely to be responsible for vasospasm (associated therapy treatment with bleomycin and cisplatin. Br Med J 1990; 300: consisting of diltiazem, cisapride and omeprazole), and vas- 1018. cular manifestations as a paraneoplastic syndrome would be 5 Hansen SW, Olsen N, Rossing N, Rorth M. Vascular toxicity and the unlikely in a patient whose malignancy had decreased on mechanism underlying Raynaud's phenomenon in patients treated with cisplatin, vinblastine and bleomycin (see comment). Ann Oncol radiological evidence at 3 months' follow-up. Moreover, our 1990; 1: 289±92. patient did not develop recurrence of digital ischaemia or 6 Vogelzang NJ, Bosl GJ, Johnson K, Kennedy BJ. Raynaud's necrosis after discontinuation of cisplatin. In our patient, phenomenon: a common toxicity after combination chemotherapy although dcSSc had never previously led to both pitting scars for testicular cancer. Ann Intern Med 1981; 95: 288±92. and digital necrosis, it may have increased the severity of the 7 Vakalis D, Ioannides D, Lazaridou E et al. Acral erythema small vessel vasospasm involving her fingers. Our findings induced by chemotherapy with cisplatin. Br J Dermatol 1998; therefore underscore that the use of cisplatin chemotherapy 139: 750±1. may lead to a particularly high risk of serious peripheral 8 Lee TC, Hook CC, Long HJ. Severe exfoliative dermatitis associated vascular complications, i.e. gangrene of fingers in patients with hand ischemia during cisplatin therapy. Mayo Clin Proc 1994; with SSc. From a practical point of view, these data suggest 69:80±2. 9 Heier MS, Nilsen T, Graver V et al. Raynaud's phenomenon after that it is questionable to initiate cisplatin chemotherapy in combination chemotherapy of testicular cancer, measured by laser patients with SSc and malignancy. Finally, physicians, Doppler flowmetry. A pilot study. Br J Cancer 1991; 63: 550±2.

Thrombotic and necrotizing panniculitis associated with recombinant human granulocyte colony-stimulating factor treatment

Sir, The haematopoietic growth factors recombinant human granulocyte colony-stimulating factor (rhG-CSF) and recom- binant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) are currently widely used concomitantly with chemotherapeutic regimens to prevent marked and/or protracted neutropenia. Cutaneous side-effects, mainly neutro- philic disorders, have been repeatedly reported.1 Thrombotic complications involving large arteries or veins have also been 2±4 Figure 1. Marked improvement of both severe ischaemic cutaneous described with both agents. We report the first observation manifestations of the patient's hands at the conclusion of intravenous of a microthrombotic process of subcutaneous tissue associ- vasodilator therapy. ated with the use of rhG-CSF.

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A 49-year-old woman without any personal or family history of thrombotic disease was treated for relapsing Hodgkin's disease with a second cycle of a 5-day chemothera- peutic regimen including mitoguazone, etoposide, vinorelbine and ifosfamide. Subcutaneous injections of rhG-CSF (filgra- stim 300 mg daily) at the upper thighs were administered 2 days after completion of the chemotherapy protocol. Three days after initiation of this treatment, painful livedo and deeply infiltrated oedema suddenly appeared on the legs and thighs (Fig. 1a), accompanied by a markedly inflamed, livedoid erythema of both soles, a fever (38 8C) and general malaise. Routine laboratory data were normal except for a slight thrombocytopenia (89 109 L21 vs. 45 109 before   rhG-CSF treatment). The neutrophil count was normal, but had risen dramatically after the injections of growth factor (6´5 109 L21 vs. 0´14 109 before treatment). Deep   biopsy specimens displayed a similar picture of small vessel thrombosis and foci of necrosis and haemorrhage throughout the subcutaneous tissue without true vasculitis (Fig. 1b). The rhG-CSF treatment was discontinued, and systemic steroids (prednisone 1 mg kg21 daily) were started and maintained for 4 weeks with slow improvement of the cutaneous lesions. rhG-CSF treatment was not resumed for the following cycles of chemotherapy and the lesions did not recur. A complete haemostasis screen was normal. Platelet aggregation in the presence of adenosine diphosphate (ADP) and increasing concentrations of rhG-CSF (0´01, 0´1 and 10 ng mL21 of rhG-CSF diluted in physiological serum) showed no difference from control. We report the first observation of microthrombotic and Figure 1. (a) Livedo of the lower limbs. (b) Photomicrograph necrotic panniculitis involving small vessels, which we believe showing small vessel thrombosis in subcutaneous adipose tissue (haematoxylin and eosin; original magnification 200). was at least partially related to rhG-CSF treatment. rhG-CSF  and rhGM-CSF have already been implicated in vascular thrombotic accidents, mainly in veins especially with central vein catheters, but also in arteries leading to myocardial the neutrophil-endothelial cell homing receptor (leucocyte infarction, cerebral non-haemorrhagic infarction and peri- adhesion molecule 1) affinity, with subsequent abnormalities 7 pheral arterial occlusion of aortic, iliac, popliteal and splenic of endothelial cells in contact with activated neutrophils; arteries.2±5 A meta-analysis found a global incidence of throm- and direct effects of rhG-CSF and rhGM-CSF on endothelial 8 botic events during recombinant human colony-stimulating cells, causing proliferation and migration. factor (rhCSF) treatment of 2´8%, with a greater risk for Independent abnormalities in primary haemostasis or rhGM-CSF than for rhG-CSF.5 The delay of 3 days between the coagulation have rarely been sought in patients experiencing 2 start of rhG-CSF treatment and the occurrence of lesions in thrombotic complications during the use of rhCSF. Haemo- our patient is consistent with the chronology of the few stasis tests have been normal in all documented cases, reported cases of rhCSF-related arterial thrombosis. No including our patient. Accordingly, a previous hypercoagula- other risk factors for thrombosis were present other than tive state does not seem to be a significant risk factor for the malignancy itself and cytotoxic chemotherapy, but typical development of this side-effect. Conversely, some authors manifestations of the hypercoagulable state of malignancy think that the use of rhG-CSF should be especially cautious in consist mainly of deep venous thrombosis and migratory patients at a greater risk of vascular events because of pre- thrombophlebitis. existing arterial abnormalities, and advise checking the Various mechanisms by which rhG-CSF and rhGM-CSF leucocyte count twice weekly, in order to enable withdrawal may favour the development of vascular thrombosis have of the growth factor if this count reaches levels greater than 9 21 2 been hypothesized: a sudden increase in neutrophils and/or 20 10 L .  platelets with acute blood viscosity modification,2,4 which The outcome of rhCSF-related arterial thrombosis is was the case in our patient with regard to the neutrophil variable, depending on the localization and the quality of count; a rhG-CSF-induced rise in ADP-triggered platelet the vascular network: recanalization without further compli- aggregation both in vitro and in vivo in healthy individuals, cation,2,4 functional neurological sequelae, or death in the probably linked to the presence of specific receptors for G-CSF two cases with rhG-CSF-related myocardial infarction.3 In our on the platelet membrane;6 a dramatic upregulation of patient, partial recanalization probably occurred, as most of q 2000 British Association of Dermatologists, British Journal of Dermatology, 142, 812±851 836 CORRESPONDENCE

the cutaneous lesions slowly resolved. A relapse is not always causative mutations have been identified.2,3 However, late- seen when the growth factor is resumed, provided an onset linear inflammatory eruptions such as lichen planus anticoagulant or anti-aggregant therapy is added,2,4 but we (LP) or lichen striatus are less easy to explain. chose not to take this risk for our patient. A 36-year-old man developed a pruritic linear eruption In conclusion, rhG-CSF may trigger cutaneous micro- starting on the dorsal aspect of his right third toe and occlusive complications even in the absence of prothrombotic extending to the lateral aspect of his foot, calf and thigh risk factors. Accordingly, a cutaneous survey of patients (Fig. 1a). He was known to have biopsy-confirmed chronic receiving rhCSF should include a systematic search for hepatitis due to hepatitis C virus (HCV) infection which had panniculitis, livedo and livedoid erythema. been documented for 3 years prior to the development of the skin eruption, although it was unclear exactly when or how he had contracted his infection. He was attending the Departments of Dermatology and O.DEREURE gastroenterology department for regular review but had not Phlebology and D.BESSIS received any treatment for his chronic hepatitis. Biopsy of the *Haematological Diseases, and T.L AVABRE-BERTRAND* cutaneous lesion showed a lichenoid lymphocytic infiltrate ²Laboratory of Haematology, C.EXBRAYAT* and basal layer destruction (Fig. 1b). The responded CHRU Montpellier, N.FEGUEUX* rapidly to topical clobetasol propionate ointment, and has not HoÃpital Saint-Eloi, C.BIRON² recurred. 2 avenue Bertin Sens, J-J.GUILHOU Recently, Long and Finlay4 suggested that linear LP is due 34265 Montpellier Cedex 5, to embryonic mutation inducing susceptibility in a clone of France cells, whose difference from normal is not apparent until E-mail: [email protected] exposed to an additional factor later in life. The question of the nature of the trigger remains open. As chronic liver disease from a variety of causes, including viral hepatitis, is References 1 Johnson ML, Grimwood RE. Leukocyte colony-stimulating factors. A review of associated neutrophilic dermatoses and vasculitides. Arch Dermatol 1994; 130: 77±81. 2 Conti JA, Scher HI. Acute arterial thrombosis after escalated dose of methotrexate, vinblastine, doxorubicin and cisplatin chemotherapy with recombinant granulocyte colony-stimulating factor. Cancer 1992; 70: 2699±702. 3 Lindemann A, Rumberger B. Vascular complications in patients treated with granulocyte colony-stimulating factor (G-CSF). Eur J Cancer 1993; 29A: 2338±9. 4 Kawachi Y, Watanabe A, Uchida T et al. Acute arterial thrombosis due to platelet aggregation in a patient receiving granulocyte colony-stimulating factor. Br J Haematol 1996; 94: 413±6. 5 Barbui T, Finazzi G, Grassi A, Marchioli R. Thrombosis in cancer patients treated with hematopoietic growth factorsÐa meta- analysis. Thromb Haemost 1996; 75: 368±71. 6 Shimoda K, Okamura S, Harada N et al. Identification of a functional receptor for granulocyte colony-stimulating factor on platelets. J Clin Invest 1993; 91: 1310±13. 7 Spertini O, Kansas GS, Munro JM et al. Regulation of leukocyte migration by activation of leukocyte adhesion molecule (LAM-1) selectin. Nature 1991; 349: 691±4. 8 Bussolino F, Ziche M, Wang JM et al. In vitro and in vivo activation of endothelial cells by colony-stimulating factors. J Clin Invest 1991; 87: 986±95.

Linear lichen planus related to hepatitis C infection? Sir, Lesions which follow the linear and whorled lines of Blaschko are believed to be due to cutaneous mosaicism for 1 mutations or aneuploidy in the keratinocyte lineage. The Figure 1. (a) Linear lichenoid eruption extending along the foot. occurrence of congenital verrucous or epidermolytic naevi (b) Basal layer destruction with lichenoid lymphocytic infiltrate. in this distribution is understandable, and in a few cases (Haematoxylin and eosin; original magnification 100.) Â

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known to be associated with an increased risk of generalized 9 Tucker SC, Coulson IH. Lichen planus is not associated with LP,5 it is possible that liver disease, and in particular, hepatitis hepatitis C virus infection in patients from North West England. virus infection, could be one trigger of linear lichenoid Acta Derm Venereol (Stockh) 1999; 79: 378±9. eruptions. HCV was first isolated in 1989 and conveys a high risk of chronic active hepatitis in those infected. The occurrence of LP in a patient with HCV infection was first recorded in 1991.6 Subsequent reports from mainland Europe have Eruptive vulgaris with infectious mononucleosis associated generalized and mucosal LP7,8 with HCV, although Sir, Infectious mononucleosis (glandular fever) is for the most this association has not been replicated in recent work part a self-limiting viral illness caused by Epstein±Barr virus published from the north of England.9 Linear LP has not been (EBV), a DNA virus classified as a member of the herpesvirus reported in this context. family, that preferentially infects and transforms B lympho- The nature of the relationship between HCV and LP cytes, resulting in a subclinical infection or in an illness with remains unclear, but we suggest two possible mechanisms a constellation of symptoms and signs.1,2 We illustrate that by which the clonal abnormalities thought to underlie linear infectious mononucleosis may represent a significant factor in lesions could result in a lichenoid reaction following viral producing exacerbations of pre-existing acne vulgaris. infection. Either the clone is abnormal in being susceptible to A 17-year-old boy presented with a history of high fever, infection by the virus, whose antigens expressed on the cell malaise, sore throat and cervical lymphadenopathy. The surface then provoke a cytotoxic T-cell response, or the acute illness had developed 2 weeks previously, and was surface antigens of the keratinocytes are clonally different in accompanied by a sudden outbreak of severe inflammatory such a way so that they alone cross-react with viral antigens nodulocystic lesions affecting the face, neck, and upper trunk. recognized by the T-cell response. It is difficult to use either This previously healthy patient denied the use of systemic of these explanations to explain the development of the medication or vitamins. Risk factors for human immuno- cutaneous eruption in our patient years after the initial deficiency virus (HIV) infection were not elicited. Both parents infection. It is possible that transient fluctuations in the and the patient described a mild form of acne vulgaris during systemic viral load or in T-cell function influenced by factors puberty. such as concurrent infection or systemic medication would Skin examination revealed the presence of widespread be enough to tip the balance and provoke a cutaneous highly inflammatory papules, papulopustules and nodulo- response. cystic lesions with purulent discharge, as well as closed and open comedones affecting the face, neck, chest, and back (Fig. 1). Physical examination revealed cervical lymphadeno- Department of Dermatology, C.S.JURY pathy and a temperature of 38´5 8C. Sonography of the Southern General Hospital, C.S.MUNRO abdomen showed an evident enlargement of the liver and 1345 Govan Road, spleen. A white exudate with pseudomembrane formation Glasgow G51 4TF, U.K. affected both tonsils. The absence of ulcerative and haemor- rhagic lesions, as well as the absence of articular and muscular manifestations, excluded the diagnosis of acne References fulminans in our patient. 1 Happle R. Epidermal syndromes. Semin Dermatol 1995; 14: Gram stains and bacterial cultures of pustular lesions on 111±21. the face and upper back revealed the presence of Propioni- 2 Paller AS, Syder AJ, Chan YM et al. Genetic and clinical bacterium acnes and Staphylococcus epidermidis, respectively. A mosaicism in a type of epidermal nevus. N Engl J Med 1994; 331: 1408±15. 3 Munro CS, Wilkie AOM. Epidermal mosaicism producing localised acne: somatic mutation in FGFR2. (Letter.) Lancet 1998; 352: 704±5. 4 Long CC, Finlay AY. Multiple linear lichen planus in the lines of Blaschko. Br J Dermatol 1996; 135: 275±6. 5 Gruppo Italiano Studi Epidemiologici in Dermatologia (GISED). Lichen planus and liver disease: a multicentre case-control study. Br Med J 1990; 300: 227±30. 6 Mokni M, Rybojad M, Puppin D Jr et al. Lichen planus and hepatitis C virus. J Am Acad Dermatol 1991; 24: 792. 7 Bellman B, Reddy R, Falanga V. Generalised lichen planus associated with hepatitis C virus immunoreactivity. J Am Acad Dermatol 1996; 35: 770±2. 8 Jubert C, Pawlotsky JM, Pouget F et al. Lichen planus and hepatitis C virus-related chronic active hepatitis. Arch Dermatol 1994; 130: 73±6. Figure 1. Severe inflammatory acne is evident on the back. q 2000 British Association of Dermatologists, British Journal of Dermatology, 142, 812±851 838 CORRESPONDENCE

throat swab showed no pathogenic organisms on culture. In conclusion, our case adds support to an association of Numerous atypical lymphocytes were seen on examination of EBV infection and an unusually vigorous course of inflam- a peripheral blood smear. The haemoglobin was 13´9 g dL21 matory acne. Hence, patients with a sudden exacerbation and the white cell count 13´5 109 L21, with a mono- of previously relatively mild acne should be checked for  cytosis of 18% and presence of atypical mononuclear cells. infectious mononucleosis. Serum levels of testosterone, luteinizing hormone and follicle- stimulating hormone were normal. Non-classical congenital Departments of Dermatology and Allergology, T.JANSEN adrenal hyperplasia was excluded after an adrenocortico- Ruhr-University Bochum, R.ROMITI* trophic hormone stimulation test. A Paul±Bunnel test was Gudrunstrasse 56, S.WOITALLA* positive while serology showed a rising titre of IgG antibodies D-4479 Bochum, Germany G.PLEWIG* to EBV capsid antigen and early antigen complex, confirming *Department of Dermatology, a primary infection with EBV. The patient was seronegative Ludwig-Maximilians-University of Munich, for HIV infection. Frauenlobstrasse 9±11, Owing to the disfiguring nature of the skin lesions, D-80337 Munich, Germany treatment was initiated with methylprednisolone 60 mg daily. After 2 weeks, isotretinoin 20 mg daily was also References given. This led to rapid improvement of all inflammatory lesions, and the corticosteroid dosage was slowly tapered over 1 Chetham MM, Roberts KB. Infectious mononucleosis in adolescents. the next 2 weeks. Although isotretinoin was maintained, new Pediatr Ann 1991; 20: 206±13. crops of papular and pustular lesions were again observed 2 Peter J, Ray CG. Infectious mononucleosis. Pediatr Rev 1998; 19: on the face and upper trunk after the next couple of weeks. 276±9. Staphylococcus aureus was isolated from new pustules on 3 Reed WB. Eruptive acne vulgaris with infectious mononucleosis. Arch Dermatol 1967; 96: 470. culture. A second 4-week course of methylprednisolone 4 Cohen SJ, Dicken CH. Generalized lichen spinulosus in an HIV- 30 mg daily was necessary, and roxythromycin 300 mg positive man. J Am Acad Dermatol 1991; 25: 116±18. daily was added during the first 5 days of treatment. The 5 Martin AG, Weaver CC, Cockerell CJ, Berger TG. Pityriasis rubra general symptoms as well as the enlargement of the liver, pilaris in the setting of HIV infection: clinical behavior and spleen and lymph nodes gradually improved. No further association with explosive cystic acne. J Am Acad Dermatol 1992; recurrences were observed during the following 6 months. 26: 617±20. The patient did not fulfil the criteria for , 6 Resnick SD, Murrell DF, Woosley J. and a which is an important differential diagnosis. There are only a generalized lichen spinulosus-like eruption in a man seropositive few previously documented cases of acne vulgaris in for human immunodeficiency virus. J Am Acad Dermatol 1992; 26: 1013±14. association with infectious mononucleosis. In 1967, Reed3 7 Jansen T, Plewig G. Advances and perspectives in acne therapy. Eur reported a 18-year-old patient with eruptive acne vulgaris J Med Res 1997; 2: 321±34. associated with fatigue, enlargement of cervical lymph nodes, 8 Sudderick RM, Narula AA. Steroids for airway problems in and sore throat. The white cell count was suggestive of glandular fever. J Laryngol Otol 1987; 101: 673±5. infectious mononucleosis. Interestingly, the acne improved 9 Sheehan T, McClymont L, O'Donnell JR. Infectious mononucleosis with clearance of the infectious mononucleosis. A second presenting as thrombocytopenic haemorrhage. Scott Med J 1986; patient had infectious mononucleosis with a temperature over 31: 116±17. 37´8 8C and severe inflammatory acne on the face, neck and trunk. Previous to infectious mononucleosis, he had had low- grade acne vulgaris. The author mentioned an additional four Successful treatment using clarithromycin for a patients with this association, but no details were given. cutaneous lesion caused by Mycobacterium szulgai There are no studies on the effect of viral infections on acne Sir, Mycobacterium szulgai has been known to be a rare cause vulgaris. It is unlikely, however, that this is a specific of human infections since its discovery in 1972.1 The precise relationship. We suggest that viral infections may lead to an environmental source of M. szulgai is unknown because the impaired immune response of the skin and thus cause organism is so rare in the environment. When present as a worsening of pre-existing acne vulgaris. Bacterial infections pathogen, it is mostly known to cause lung infection. The usually complicate virus infections, as virus infections reduce non-tuberculous mycobacteria are responsible for consider- resistance to bacteria. Eruptive acne vulgaris has also been able morbidity in immunocompromised and immunocompe- 4±6 reported in the setting of HIV infection. tent hosts. We report a patient with systemic lupus In our patient, a therapeutic regimen including isotre- erythematosus (SLE) who developed a cutaneous nodule tinoin, methylprednisolone and antibiotics was eventually caused by M. szulgai. highly beneficial. Systemic corticosteroids have been demon- A 41-year-old woman with clinically active SLE who 7 strated to be of benefit in severe acne and in complications of received prednisolone 60 mg daily, noted painless slight 8 EBV infection such as airways obstruction and severe erythema with inflammation at the right extensor side of 9 thrombocytopenia. It was therefore felt reasonable to give the forearm. Four weeks later, the subcutaneous nodule had corticosteroids to this young man. gradually increased in size and tenderness (Fig. 1a). There

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clarithromycin, and has remained well without recurrent skin lesions during 2 years of follow-up. M. szulgai is a scotochromogenic mycobacterium (Runyon group II) distinguished from the other scotochromogens by a positive nitrate reductase test, weak or absent hydrolysis of polysorbate 80 and a strongly positive catalase reaction.3 Since the early 1970s, M. szulgai has been recognized as a cause of infection throughout the world. It is a rare human pathogen; there have been 34 reported cases of pulmonary disease (which is similar to that caused by M. tuberculosis) caused by M. szulgai.3 Surveillance in Japan between 1971 and 1984 revealed eight cases, which accounted for only 0´6% of all cases of non-tuberculous lung mycobacteriosis.4 Recently, pulmonary infection caused by M. szulgai has been reported in persons with AIDS.5 Only four patients with cutaneous M. szulgai infection could be found in the literature. One was a patient on long- term corticosteroid therapy for sarcoidosis who exhibited multicentric, purely cutaneous infection.6 The second had disseminated disease involving the skin, bones and lung, and was shown to have a diminished proportion of T lymphocytes and a suppressed response to mitogens.7 The third patient had multiple inflammatory skin lesions and osteomyelitis, and had been receiving prednisone therapy for desquamate interstitial pneumonitis.8 The fourth patient was aged 6 months, with a carbuncle over the angle of the jaw which grew a scotochromogenic mycobacterium identified as M. szulgai.9 Cutaneous development of M. szulgai infection seems mostly to be associated with immunosuppression secondary to medication or active disease, as also occurs in Figure 1. (a) A subcutaneous nodule is evident on the right extensor 3 side of the forearm. (b) Histological examination showed granuloma- cases of pulmonary infection with this organism. In our tous inflammation with epithelioid histiocytes, and lymphocytes patient, we believe that the prolonged use of prednisolone was (haematoxylin and eosin; original magnification 80). the factor predisposing infection, but we were not able to  identify how it caused a localized . M. szulgai is was no history of preceding trauma. The patient did not feel susceptible to antimycobacterial drugs,10 but we could not ill and denied fever. Chest X-ray showed no significant use antimycobacterial agents because of side-effects. Clari- abnormalities. Needle aspiration yielded purulent material thromycin has a broader antimicrobial spectrum than with numerous acid-fast bacilli. Histological examination erythromycin against mycobacteria. We were able to reduce showed granulomatous inflammation with epithelioid histio- the dose of prednisolone with the patient's gradually cytes, and lymphocytes (Fig. 1b). Cultured material from the improving symptoms of SLE during the course of cutaneous aspiration grew acid-fast bacilli, and M. szulgai was identified therapy, and treatment with clarithromycin in combination by the DNA±DNA hybridization method,2 a recently deve- with drainage led to complete healing without recurrence. loped genetic technique (performed by the Department of Microbiology, Hokkaido University School of Medicine, Departments of Dermatology and T.S HIMIZU Director Y.Shimizu). The lesion was treated by excision, *Internal Medicine II, K.KODAMA drainage and antimycobacterial therapy with isoniazid, Hokkaido University School of Medicine, H.KOBAYASHI rifampicin and ethambutol (the minimum inhibitory con- Kita-ku, A.OHKAWARA 21 centration of isoniazid was between 1 and 5 mgmL , that of Sapporo 060-8638, K.OGAWA* 21 rifampicin between 10 and 50 mgmL , and that of Japan S.TANIGUCHI* ethambutol between 2´5 and 5 mgmL21). One week later, E-mail: [email protected] leucopenia occurred, possibly due to the antimycobacterial drugs, and treatment was changed to oral clarithromycin therapy. Sensitivity testing of the cultured organisms to References clarithromycin was not available. The skin lesion began to 1 Marks J, Jenkins PA, Tsukamura M. Mycobacterium szulgai: a new flatten and then gradually improved in 1 month. The patient pathogen. Tubercle 1972; 53: 210±14. received clarithromycin for 3 months. The prednisolone dose 2 Kusunoki S, Ezaki T, Tamesada M et al. Application of colorimetric of 60 mg daily was continued for 4 weeks, but then gradually microdilution plate hybridization for rapid genetic identification of tapered over 4 months to 20 mg daily. The patient is now off 22 Mycobacterium species. J Clin Microbiol 1991; 29: 1596±603. q 2000 British Association of Dermatologists, British Journal of Dermatology, 142, 812±851 840 CORRESPONDENCE

3 Benator DA, Kan V, Gordin F. Mycobacterium szulgai of the lung: mass jutting out of the epidermal surface, in order to hasten case report and review of an unusual pathogen. Am J Med Sci re-epithelialization. Results were quite impressive, and very 1997; 313: 346±51. rapid: Figure 1(c) shows the patient's leg as it appeared after 4 Tsukamura M, Kita N, Shimoide H et al. Studies on the epidemio- 14 days of treatment. After 2 months, terbinafine was logy of nontuberculous mycobacteriosis in Japan. Am Rev Respir discontinued. No recurrences have occurred for 9 months Dis 1988; 137: 1280±4. up to now. Sensitivity to terbinafine of the involved strain was 5 Newshan G, Torres RA. Pulmonary infection due to multidrug- subsequently confirmed in vitro. resistant Mycobacterium szulgai in a patient with AIDS. Clin Infect Dis 1994; 18: 1022±3. 6 Sybert A, Tsou E, Garagusi VF. Cutaneous infection due to Mycobacterium szulgai. Am Rev Respir Dis 1977; 115: 695±8. 7 Gur H, Porat S, Haas H et al. Disseminated mycobacterial disease caused by Mycobacterium szulgai. Arch Intern Med 1984; 144: 1861±3. 8 Cross GM, Guill MA, Aton JK. Cutaneous Mycobacterium szulgai infection. Arch Dermatol 1985; 121: 247±9. 9 Cookcon BD, Dunger D. Mycobacterium szulgaiÐa case of cutaneous infection? Tubercle 1985; 66:65±7. 10 Maloney JM, Gregg CR, Stephens DS et al. Infections caused by Mycobacterium szulgai in humans. Rev Infect Dis 1987; 9: 578±80.

Effectiveness of terbinafine in cutaneous alternariosis Sir, Dematiaceous fungal infections represent an increasing problem in modern medicine, owing to the fact that these agents are facultative pathogens favoured by either naturally arising or iatrogenic immunodeficiencies. Alternaria spp. belong to this group, and are able to cause either systemic or purely cutaneous infections, even in otherwise healthy subjects. Treatment of such deep mycoses represents a major challenge. A 58-year-old woman was admitted in October 1998 with hyperkeratotic, crusted and partially ulcerated nodules of the posterior aspect of the lower right leg, just above the Achilles tendon (Fig. 1a), which had been evolving since April 1998. The bottom of the ulcers was vegetating, and the lesions were indolent. She had received a kidney cadaveric allograft in January 1995. In spite of immunosuppressive prophylaxis (cyclosporin, azathioprine and methylprednisolone), acute rejection had ensued, and was treated with methylpredniso- lone intravenous boluses. Such treatment proved ineffective, and muromonab CD3 was administered for 7 days. Func- tional response was satisfying, with substantial lowering of plasma creatinine levels, but azathioprine had to be sus- pended because of concomitant leucopenia. In June 1996, chronic renal rejection developed, but the nephrologists did not deem it necessary to increase immunosuppression. Histopathology of an incisional biopsy of a medium-sized lesion showed pseudoepitheliomatous hyperplasia and sup- purative granulomas throughout the whole dermal thickness. Both periodic acid-Schiff and thioflavine T special stains confirmed the presence of short septate hyphae, which could be clearly seen in high magnification haematoxylin and Figure 1. (a) Lesions of 6 months duration are evident on the right eosin-stained sections (Fig. 1b). Tissue cultures yielded A. leg. (b) Photomicrograph showing a short septate hypha surrounded tenuissima. by macrophages and neutrophils (haematoxylin and eosin; original The patient was immediately put on oral terbinafine magnification 100). (c) Complete healing is seen after 2 weeks of  250 mg daily. On the fifth day of treatment, she underwent terbinafine treatment. The biggest lesion had to be electrosurgically electrosurgical superficial destruction of the biggest vegetating `debulked', and was the last to re-epithelialize.

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For general consideration regarding the ecology and reÂveÂlatrice d'une maladie de Cushing. Un cas avec eÂtude ultra- taxonomy of Alternaria spp. the reader is referred to Acland structurale. Ann Dermatol Venereol 1982; 109: 841±6. et al.1 A. tenuissima, together with A. alternata and A. 3WaÈtzig V, Schmidt U. PrimaÈre kutane Alternariose. Hautarzt 1989; chartarum, are the species most involved in human pathol- 40: 718±20. ogy,1 but other rarer Alternaria spp. have also been reported.2 4 Viviani MA, Tortorano AM, Laria G et al. Two new cases of cutaneous alternariosis with a review of the literature. Mycopatho- Factors such as immunosuppression, local wounds or logia 1986; 96: 3±12. systemic disease are generally present, but cases without 5 Villars VV, Jones TC. Special features of the clinical use of oral predisposing factors are described, and are probably due to terbinafine in the treatment of fungal diseases. Br J Dermatol 1991; 3 factors inherent to the fungus. Formerly said to be rare, 126 (Suppl. 39): 61±9. cutaneous alternariosis could be more frequent than thought, and we suspect that it is under-diagnosed. This might be due to either extreme variability and non-specificity of the appearance of infected skin, or to insufficient use of myco- 3,4 A case of follicular mucinosis treated successfully with logical investigations. Alternatively, it may be apparently minocycline under-reported simply because many case reports are spread in a myriad of either low-impact or vernacular journals of Sir, We describe a Japanese man with primary follicular various ages.4 Treatment of cutaneous Alternaria infections is mucinosis who was treated successfully with oral mino- not standardized,1 and lack of consensus will probably persist, cycline. Follicular mucinosis1 is classified as a primary owing to the fact that such cases are relatively infrequent idiopathic disease and a secondary lymphoma-associated and multicentre case±control studies are not easily feasible. dermatosis. Histopathologically, it is characterized by mucin However, these patients, who often are in a critical condition, deposition in hair follicles and sebaceous glands. Minocycline have to be treated immediately. Following examples of is an antibiotic thought to have pleiotropic effects. Although treatment of systemic dematiaceous fungal infections with treatment of follicular mucinosis patients with minocycline terbinafine,5 we propose the use of this well-tolerated and has been reported, only minor improvement has been rapid-acting drug in cutaneous alternariosis. obtained.1 In our case, it led to a dramatic improvement of the skin lesions in only 2 weeks, with no recurrence Department of Dermatology and G.F.ALTOMARE thereafter. Therefore, we recommend that minocycline should *Institute of Hygiene and Preventive Medicine, G.L.CAPELLA be the first choice drug to treat primary follicular mucinosis. University of Milan, V. B ONESCHI A 36-year-old Japanese man visited our clinic in March Ospedale Maggiore IRCCS, M.A.VIVIANI* 1999 because of severe itching and eruptions on his face and Via Pace 9, upper trunk which had started in November 1998. Under the 20122 Milan, Italy diagnosis of prurigo, antiallergic drugs and steroid cream had E-mail: [email protected] been administrated by a dermatologist in another clinic, without success. The patient had no family history or past history of allergic disorders such as asthma and rhinitis. The References multiple papules varied from skin-coloured to red, were 1 Acland KM, Hay RJ, Groves R. Cutaneous infection with Alternaria 2±4 mm in size, and were distributed on his forehead, cheek, alternata complicating immunosuppression: successful treatment submandibular region, occipital region, nape of neck and with itraconazole. Br J Dermatol 1998; 138: 354±6. chest (Fig. 1a). Laboratory data were normal, including the 2 Verret JL, Gaborieau F, Chabasse F et al. Alternariose cutaneÂe level of IgE. The minimal erythema dose for ultraviolet (UV) B

Figure 1. (a) Erythematous papules and indurated erythema are evident on the face before treatment with minocycline. (b) The eruption resolved 2 months after beginning minocycline therapy. q 2000 British Association of Dermatologists, British Journal of Dermatology, 142, 812±851 842 CORRESPONDENCE

by MMP.7 Furthermore, there is evidence that the production and transcription of TNF-a is downregulated by minocycline in the initial stage of epidermal inflammation.8 Even though there have been no reports on TNF-a production in lesions of follicular mucinosis, minocycline should be considered as a therapeutic agent for treating this disorder.

Department of Dermatology, S.YOTSUMOTO Faculty of Medicine, H.UCHIMIYA Kagoshima University, T.K ANZAKI 8-35-1 Sakuragaoka, Kagoshima 890-0025, Japan E-mail: [email protected]

Figure 2. Photomicrograph showing mucinous change in a seba- References ceous gland adjacent to a hair follicle (haematoxylin and eosin; 1 Wittenberg GP, Gibson LE, Pittelkow MR, el-Azhary RA. Follicular original magnification 135). Â mucinosis presenting as an : report of four cases. J Am Acad Dermatol 1998; 38: 849±51. 2 Kubba RK, Stewart TW. Follicular mucinosis responding to and UVA was normal. A biopsy specimen showed mono- dapsone. Br J Dermatol 1974; 91: 217±20. nuclear cell infiltration in the perifollicular region, and 3 Kodama H, Umemura S, Nohara N. Follicular mucinosis: response to indomethacin. J Dermatol 1988; 15:72±5. reticular degeneration staining bluish in haematoxylin and 4 Meissner K, Weyer U, Kowalzick L, Altenhoff J. Successful treatment eosin staining in the sebaceous gland (Fig. 2). Immuno- of primary progressive follicular mucinosis with interferons. JAm histochemically, infiltrating lymphocytes were dominated by Acad Dermatol 1991; 24: 848±50. CD3-positive and CD8-positive cells. There were some CD79a- 5 Guerriero C, De Simone C, Guidi B et al. Follicular mucinosis positive B cells intermingled, and CD4-positive cells were successfully treated with isotretinoin. Eur J Dermatol 1999; 9: scarce. We made a diagnosis of primary follicular mucinosis. 22±4. At first indomethacin was given, without effect. Minocycline 6 O'Dell JR, Paulsen G, Haire CE et al. Treatment of early seropositive 200 mg daily for 2 weeks had a dramatic effect on the rheumatoid arthritis with minocycline. Four-year followup of a eruptions and the itching, so was continued for a further double-blind, placebo-controlled trial. Arthritis Rheum 1999; 42: 2 weeks. His eruptions subsided, leaving pigmentation with- 1691±5. out pruritus. Further administration of minocycline 100 mg 7 Gearing AJH, Beckett P, Christodoulou M et al. Processing of tumour necrosis factor-a precursor by metalloproteinases. Nature 1994; daily for 1 month resulted in complete remission (Fig. 1b). 2 3 370: 555±7. It has been reported that dapsone, indomethacin, 8 Celerier P, Litoux P, Dreno B. In vitro modulation of epidermal 4 5 interferons and isotretinoin are beneficial. For lymphoma- inflammatory cytokines (IL-1a, IL-6, TNFa) by minocycline. Arch associated cases, therapy for the lymphoma itself, including Dermatol Res 1996; 288: 411±14. radiotherapy, would be required. Minocycline has been used for the treatment of inflammatory diseases, granulomatous disorders, and sometimes lymphomas. It has antimicrobial activity, inhibits matrix metalloproteinase (MMP), nitric oxide production, tumour progression, angiogenesis and inflam- Clear cell acanthoma developing on a psoriatic plaque: mation, and has immunomodulating effects.6 In follicular further evidence of an inflammatory aetiology? mucinosis, it is believed that deposition of mucin secreted from the epithelial cells within the pilosebaceous follicle may Sir, Clear cell acanthoma was first described by Degos et al.1 occur primarily, inflammation and subsequent degenerative in 1962, who suggested that it was a benign tumour derived changes of hair follicles and sebaceous glands being a from the epidermis. However, the pathogenesis has never been secondary effect. Minocycline might work on the secondary clearly defined and more recent work has suggested it to be a process, i.e. by inhibiting proinflammatory cytokines such as non-specific reactive dermatosis rather than a neoplastic tumour necrosis factor (TNF)-a and/or proteinases such as lesion.2 We report a clear cell acanthoma developing on a MMP secreted by macrophages and lymphocytes. TNF-a psoriatic plaque and discuss how this further supports the precursor is a type II membrane protein and its mature form, hypothesis that the lesion is of inflammatory origin. TNF-a, is proteolytically processed from the precursor and A 60-year-old woman presented with a 6-month history of becomes biologically active. One of the processing enzymes a small lump in the natal cleft. She had been diagnosed as which cleave TNF-a has been found to be MMP.7 Our having psoriasis at the age of 15 years, and the disease had hypothesis is drawn by the fact that minocycline inactivates been well controlled with topical preparations alone. On MMPs and blocks the post-translational processing of TNF-a examination, there was a 1-cm dome-shaped, red nodule

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within the natal cleft, which had developed on an active light-coloured cells overlying a normal basal layer. There was psoriatic plaque (Fig. 1a). There was no associated lympha- intercellular oedema and an infiltrate of neutrophils. The denopathy. General examination was otherwise unremark- adjoining skin showed typical psoriasiform hyperplasia able apart from chronic plaque psoriasis covering less than (Fig 1b,c). The clear cells stained positively with the periodic 10% of the total body surface area. acid-Schiff reaction, indicating the presence of glycogen A diagnostic biopsy was taken from the lesion, and showed within the cytoplasm. The histology therefore confirmed the a thickened epidermis with sharply demarcated areas of clinical suspicion of a clear cell acanthoma. The lesion was treated initially with cryotherapy, to good effect. It recurred 12 months later and was formally excised, with no evidence of subsequent recurrence. To our knowledge the only report in the English language literature regarding the association of clear cell acanthomas and psoriasis refers to the development of acanthomas in psoriatic patients after short-term high-potency Goeckerman therapy,3 a treatment not undertaken in our patient. In this report, the acanthomas were considered to be benign neoplasms which were induced by a combination of crude coal tar and ultraviolet B, both capable of initiating skin tumours. The tendency for clear cell acanthomas to persist for years with little progression, the sharp demarcation of the lesions and the absence of spontaneous resolution have been used as arguments for a neoplastic rather than inflammatory aetiology. The histological appearance of a well circum- scribed, non-invasive lesion which lacks cellular atypia is indicative of its benign nature. However, the assumption that clear cell acanthomas are benign neoplasms of the epidermis has never been confirmed and other theories have been suggested. Clear cell acanthomas have been hypothesized as arising from either the sweat gland4 or the hair follicle.5 These sites were excluded as they lack similarities in cytokeratin expression with clear cell acanthomas. Kwittken6 suggested that the lesion was a metabolic variant of seborrhoeic keratosis, but this seems unlikely as clear cell acanthomas stain positively with antiepithelial membrane antigen whereas seborrhoeic keratoses fail to react.7,8 An eccrine poroma variant has also been postulated but again the cytokeratin expression is dissimilar in the two lesions.9 A better suggestion might be that clear cell acanthomas originate as non-reactive dermatoses. Compared with normal epidermis, clear cell acanthomas demonstrated positive stain- ing with AE1 (cytokeratins 10, 14±16 and 19) suprabasally, but showed reduced staining in the basal layer.8 This pattern has been shown to occur in a number of benign hyper- proliferative dermatoses including psoriasis.10 Immunoreac- tivity to PKK1 (cytokeratins 8, 18 and 19) was also reduced in the basal layer of clear cell acanthomas; this has also been previously reported in cases of psoriasis and may be a result of abnormal differentiation or maturation.11 Interestingly, the similarities between psoriasis and clear cell acanthomas are not only immunohistochemical. A recent Figure 1. (a) Clear cell acanthoma developing on a psoriatic plaque pathological comparative study showed only limited differ- in the natal cleft. (b) Photomicrograph of the clear cell acanthoma ences in histology between the two lesions, namely in the showing a sharply demarcated acanthotic area of clear cells on the left, while typical psoriasiform hyperplasia adjoins the lesion on the degree of epidermal thickening, spongiosis, numbers of right. (c) Inset showing a high-power view of the junction between neutrophils infiltrating the epidermis, and dilatation and the clear cells and the adjacent epidermis. Haematoxylin and eosin: tortuosity of the papillary capillaries, all of which were more original magnification (b) 4; (c) 20. prominent in clear cell acanthomas.12 The authors suggested   q 2000 British Association of Dermatologists, British Journal of Dermatology, 142, 812±851 844 CORRESPONDENCE

that the histological features of clear cell acanthomas were an The lateralization of lichen simplex is independent of exaggeration of those seen in psoriasis and postulated that, hand dominance although the underlying cause of the two disorders might be Sir, Itch is the fundamental symptom of skin disease and is different, the intimate pathogenesis appears quite similar. believed by some to play a significant part in perpetuating Our patient developed a clear cell acanthoma on an active 1 eczema through the itch±scratch pathway. The relative psoriatic plaque. This observation would appear to provide influence of local and cortical factors on itch is difficult to further evidence of an inflammatory rather than neoplastic determine. aetiology for clear cell acanthomas. It may even support the Lichen simplex is a condition initiated and perpetuated by hypothesis that clear cell acanthomas are a localized form of rubbing and scratching in the absence of a predisposing skin psoriasis. Psoriasis is proving to have a complex aetiology, disorder. Patients with lichen simplex scratch more readily part of which involves enhanced keratinocyte proliferation. 2 following an itch stimulus than controls. The lesions are The similarities in histology and the shared changes in commonly situated in areas that are conveniently reached, cytokeratin expression between psoriasis and clear cell particularly the nape of the neck, arm, leg and the anogenital acanthomas may suggest that they both share a similar region. On the upper forearm, lichen simplex has been abnormality in the maturation pathway of keratinocytes. observed to be more common on the non-dominant side, although this has not been quantified.3 In the absence of Birmingham Skin Centre, T.M.F INCH other localizing factors, one could hypothesize that itch and City Hospital NHS Trust, C.Y.TAN scratch will be more strongly expressed on the dominant Dudley Road, lower limb, and this will be manifest by unilateral lichen Birmingham B18 7QH, U.K. simplex on the leg being concordant with handedness. We investigated this hypothesis. Forty-two patients were identified from their hospital References records as having lichen simplex localized to either lower limb. Of these, 37 (20 men, 17 women) were contactable by 1 Degos R, Delort J, Civatte J, Poiares BA. Tumeur eÂpidermique telephone and their hand dominance ascertained. Hand d'aspect particulier: acanthome aÁ cellules claires. Dermatologica 1962; 129: 361±71. dominance was defined as the hand that would be 2 Fukushiro S, Takei Y, Ackerman AB. Pale-cell acanthosis. A preferentially used to write with or to hold a tool or racket. distinctive histologic pattern of epidermal epithelium. Am J The patients' ages ranged between 26 and 80 years (median Dermatopathol 1985; 7: 517±27. 58). Twenty of the patients had lichen simplex on the right 3 Schillinger B, Brody N. Acanthoma induction in psoriasis patients leg, and 17 on the left leg. Thirty-four patients were right- after short-term high potency Goeckerman treatment. Cutis handed and three were left-handed. No patient was ambidex- 1981; 28: 568±70. trous. Analysis of the data showed that 19 were concordant, 4 Lindgren AGH, Neumann E. Some evidence concerning the sweat having lichen simplex on the same side as their dominant duct origin of clear cell acanthoma. Acta Derm Venereol (Stockh) hand, and 18 were discordant. Handedness of patients has no 1973; 53: 511±14. predictive value in the lateralization of lichen simplex lesions 5 Watanabe S, Wagatsuma K, Takahashi H. Immunohistochemical as evidenced by the equal numbers in both groups. localization of cytokeratins and involucrin in calcifying epi- thelioma: comparative studies with normal skin. Br J Dermatol The reasons why lichen simplex is localized to a particular 1994; 131: 506±13. site or sites are multifactorial and involve an interplay of 2 6 Kwittken J. Clear cell acanthoma: a metabolic variant of conditioning, emotional tensions and predisposition. Hand seborrhoeic keratosis. Mt Sinai J Med 1980; 47: 49±51. dominance does not play a part in the lateralization of lichen 7 Cotton DWK, Mills PM, Stephenson TJ, Underwood JCE. On simplex on the leg, suggesting that cortical influences have a the nature of clear cell acanthoma. Br J Dermatol 1987; 117: smaller influence on lichen simplex than local factors. 569±74. 8 Ohnishi T, Watanabe S. Immunohistochemical characterization Department of Dermatology, M.MURPHY of keratin expression in clear cell acanthoma. Br J Dermatol 1995; South Cleveland Hospital, A.J.CARMICHAEL 133: 186±93. Middlesbrough TS4 3BW, U.K. 9 Watanabe S, Mogi S, Ichikawa E et al. Immunohistochemical analysis of keratin distribution in eccrine poroma. Am J Pathol 1993; 142: 231±9. 10 Weiss RA, Guillet GYA, Freedberg IM et al. The use of monoclonal References antibody to keratin in human epidermal disease: alterations in immunohistochemical staining pattern. J Invest Dermatol 1983; 1 Cole WC, Roth HL, Sachs LB. Group psychotherapy as an aid in 81: 224±30. the medical treatment of eczema. J Am Acad Dermatol 1988; 18: 11 Watanabe S, Wagatsuma E, Ichikawa E, Takahashi H. Abnormal 286±91. distribution of epidermal protein antigens in psoriatic epidermis. 2 Robertson IM, Jordan JM, Whitlock FA. Emotions and the skin J Dermatol 1991; 18: 143±51. (III)Ðthe conditioning of scratch response in the cases of lichen 12 InaloÈz HS, Laidler P, Marks R. Is clear cell acanthoma a form of simplex. Br J Dermatol 1975; 92: 407±12. localized psoriasis? Br J Dermatol 1999; 141 (Suppl. 55): 121 3 Lawrence CM, Cox NH. Physical Signs in Dermatology. London: Wolfe (Abstr.). Publishing, 1993: 236.

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Chronic actinic dermatitis in young on any oral medication. Monochromator light testing showed sufferers abnormal MEDs to UVB and to shorter wavelength UVA (Table 1). A 10-J cm22 broadband UVA provocation test to an Sir, We noted with interest the article by Russell et al.1 on the area on the right forearm caused an eczematous reaction. photosensitivity dermatitis and actinic reticuloid syndrome Photopatch tests to sunscreen ingredients and musk ambrette (chronic actinic dermatitis). Between 1992 and 1996 in their and patch testing with the standard battery, musk ambrette unit, they noted a group of young patients with atopic and fragrance mix were negative. Autoantibody and porphyrin dermatitis who also had severe photosensitivity which could screening tests were also negative. DNA repair studies on skin not be attributed to photoaggravation of their atopic from provoked lesions were normal; histology was not performed. dermatitis. They went on to observe that the patients also Our patients have the typical features of this newly had allergic contact dermatitis and felt that they met the described syndromeÐyoung individuals with a history of diagnostic criteria for chronic actinic dermatitis despite their atopic eczema, severely low erythema thresholds and youth. We have recently seen two teenagers with this dermatitis at phototest sites. Both patients were aware of syndrome. the part that sunlight played in the aetiology of their rash. All The first patient was a 17-year-old female of Indian descent the Dundee patients had positive patch tests and/or photo- with mild atopic eczema and asthma since early childhood. patch tests, whereas in both our patients these tests are She gave a history of photosensitivity from 10 years of age, negative.1 However, in chronic actinic dermatitis, generally developing a sunburn reaction after 30±60 min of sunlight only 70% of patients show evidence of contact or photo- exposure despite her dark skin. She would then go on to contact allergy.2 We agree with Russell et al. that photo- develop a pruritic eruption with exudation and scaling of the investigation is important in such patients, thereby permitting skin. Initially the eruption occurred during summer but had diagnosis of their severe photosensitivity condition and become persistent, affecting mainly exposed sites. There was a facilitating appropriate management. family history of atopy but not of photosensitivity. She was not on any oral medication. Monochromator light testing Photobiology Unit, M.I.OGBOLI showed very low erythema thresholdsÐminimal erythema Department of Dermatology, L.E.RHODES doses (MED)Ðto ultraviolet B (UVB) and ultraviolet A (UVA) Royal Liverpool University Hospital, from 300 to 400 nm (Table 1). Focal dermatitis developed in Prescot Street, the irradiated areas from 300 to 400 nm. A broadband UVA Liverpool L7 8XP, U.K. challenge of 10 J cm22 to an area on the right forearm provoked an eczematous response. Photopatch tests to sunscreen ingredients and musk ambrette and patch testing with the standard, facial and fragrance batteries were References negative. Porphyrin and autoantibody screens were negative 1 Russell SC, Dawe RS, Collins P et al. The photosensitivity dermatitis and HLA typing results were unremarkable. The histology of and actinic recticuloid syndrome (chronic actinic dermatitis) skin removed from the provoked site showed spongiosis and a occurring in seven young atopic dermatitis patients. Br J Dermatol non-specific dermal perivascular cell infiltrate. 1998; 138: 496±501. The second patient was a 17-year-old Caucasian male with 2 Menage H, Ross JS, Norris PG et al. Contact and photocontact a history of infantile eczema and hay-fever who developed a sensitization in chronic actinic dermatitis: sesquiterpene lactone photosensitive rash for the first time at 16 years of age. He mix is an important allergen. Br J Dermatol 1995; 132: 543±7. described itching and erythema of exposed skin with as little as 30 min of sun exposure, followed 6 h later by the development of an eczematous rash. The condition only Fixed due to phenylpropanolamine occurred between May and October. There was a family hydrochloride history of atopic eczema but not photosensitivity. He was not Sir, Fixed drug eruption (FDE) is a common cutaneous reaction caused by various drugs.1±3 In many cases, the causative agent is confirmed by the patient history; however, Table 1. Minimal erythema doses (MED) at 24 h following mono- in some uncertain cases, oral challenge4 or topical testing5 is chromator light testing (abnormal results in bold typeface) useful. The exact pathomechanisms of FDE are unknown; Waveband and Normal MED Patient 1 MED Patient 2 MED however, cell-mediated rather than humoral immunity is ^ bandwidth (nm) (J cm22) (J cm22) (J cm22) thought to be more important in the development of FDE.6 300 ^ 5 0´014 0´0025 , 0´0025 Phenylpropanolamine hydrochloride shares the pharmaco- 320 ^ 10 $ 1 , 0´6 , 0´25 logical properties of ephedrine and is used alone or in 330 ^ 10 $ 3´5 , 0´15 3´5 combination preparations to elevate the threshold for cough- 350 ^ 20 $ 10 0´63 20 ing and to relieve nasal congestion.7 To our knowledge, FDE 370 ^ 20 $ 20 3´5 57 due to phenylpropanolamine hydrochloride has not been 400 ^ 20 $ 40 28 . 113 previously reported. 500 ^ 20 $ 50 . 50 . 50 In February 1999, a 36-year-old women was referred for 600 ^ 20 $ 50 . 50 . 50 evaluation of recurrent multiple erythematous plaques on the q 2000 British Association of Dermatologists, British Journal of Dermatology, 142, 812±851 846 CORRESPONDENCE

left hand, thighs and legs. On account of the clinical picture, FDE was suspected. She had earlier suffered from allergic rhinitis and conjunctivitis but was otherwise healthy. The first eruption emerged on the second finger of the right hand in December 1997 and the reaction cleared in 3±4 weeks without leaving any postinflammatory pigmentation. Before the eruption, she had taken 10 mL of cough mixture containing codeine phosphate 2 mg mL21, brompheniramine maleate 0´4 mg mL21, phenylephrine hydrochloride 1mgmL21, phenylpropanolamine hydrochloride 1 mg mL21 and guaiphenesin 20 mg mL21. During 1998 she developed a similar reaction three times at the same sites and at additional ones. In February 1999, 1 week before coming to the hospital, she had a cough and sinusitis. Doxycycline and a symptomatic drug containing phenylpropanolamine hydro- chloride 50 mg and carbinoxamine maleate 12 mg was prescribed by her general practitioner. Over the subsequent 10 h she noticed 11 red, slightly tender and oedematous plaques on the hand, thighs and legs, the largest of the plaques being 7´5 9 cm in diameter. Â In April 1999, peroral provocation with 3 mg phenylpro- panolamine hydrochloride was performed. Within 2 h the patient felt burning at the old FDE plaques and after 8 h they turned red (Fig. 1a). A skin biopsy taken from a lesion after 24 h revealed oedema in the epidermis and hydropic degeneration in the basal cell layer. There was a slight mononuclear cell infiltrate around superficial dermal capil- laries, and epidermal lymphocytes and neutrophils were present. The histological findings were in agreement with those found in FDE. In May 1999, a local open provocation test with 5% phenylpropanolamine hydrochloride in petrolatum was per- formed on a previous FDE lesion at the left thigh. After 6 h, the patient felt itching and burning at this site and at 7 h the area was red and swollen (Fig. 1b). The reaction was considered to be positive. Later, an open provocation test and test under occlusion (Finn Chamber method) with the same ointment was performed on the normal intact skin of the patient. The test was followed for 5 days and was negative. We also carried out the same test in 10 healthy volunteers, with negative results. FDE is one of the most common reactions to drugs.3 The most frequent agents associated with FDE are phenazones, sulphonamides and tetracyclines.1±3,5 Phenylpropanolamine hydrochloride has for many years been used alone or in combination preparations as an antitussive and to relieve nasal congestion.7 Five different preparations containing phenylpropanolamine hydrochloride are available in Finland. The causative agent of FDE is usually confirmed by oral challenge, the dose of the drug being one-third of the initial dose.4 Our patient had at first used 10 mL mixture containing 10 mg phenylpropanolamine hydrochloride. The last time

Figure 1. (a) Multiple fixed drug eruptions photographed 18 h after peroral provocation with phenylpropanolamine hydrochloride 3 mg. (b) Topical provocation test with phenylpropanolamine hydro- chloride. The drug was applied at 5% concentration in petrolatum vehicle to the site of a previous fixed drug eruption lesion.

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when she took a depot tablet containing 50 mg of phenyl- review 1 month later, the treated lesions had resolved propanolamine hydrochloride the reaction was more severe. without scarring or postinflammatory pigmentary changes. We therefore challenged her very cautiously, with 3 mg of The freeze/thaw process was repeated to a further crop of phenylpropanolamine hydrochloride; the reaction was, how- papules and thereafter at 6-monthly intervals to good effect, ever, quite marked, producing 11 lesions. with clinical resolution of the papules; no recurrences have In this case a topical provocation test performed on a previous FDE lesion was also positive. The negative result of local provocation in many cases of FDE can either be due to insufficient penetration of the drug, or due to the FDE being caused by a derivative of the drug rather than the compound itself.8

Department of Dermatology and Venereology, H.HEIKKILAÈ Helsinki University Central Hospital, A-L.KARINIEMI Meilahdentie 2, S.STUBB 00250 Helsinki 25, Finland E-mail: [email protected]

References 1 Bork K. Fixed drug eruptions. In: Cutaneous Side Effects of Drugs (Bork K, ed.). Philadelphia: W.B.Saunders Company, 1988; 98±108. 2 Stubb S, HeikkilaÈ H, Kauppinen K. Cutaneous reactions to drugs: a series of in-patients during a five-year period. Acta Derm Venereol (Stockh) 1994; 74: 289±91. 3 Kauppinen K, Stubb S. Fixed eruptions: causative drugs and challenge tests. Br J Dermatol 1985; 112: 575±8. 4 Kauppinen K, Alanko K. Oral provocation: uses. Semin Dermatol 1989; 8: 187±91. 5 Alanko K, Stubb S, Reitamo S. Topical provocation of fixed drug eruption. Br J Dermatol 1987; 116: 561±7. 6 Breathnach SM. Drug reactions. In: Textbook of Dermatology (Champion RH, Burton JL, Burns DA, Breathnach SM, eds), 6th edn, Vol. 4. Oxford: Blackwell Science, 1998; 3367. 7 Norman W. Norepinephrine, epinephrine, and the sympathomi- metic amines. In: The Pharmacological Basis of Therapeutics (Gilman AG, Goodman LS, Rall TW, Murad F, eds), 7th edn. New York: Macmillan Publishing Company, 1985; 145±80. 8 Stubb S, Reitamo S. Fixed-drug eruption due to dextromethorphan. Arch Dermatol 1990; 126: 970±1.

Treatment of pearly penile papules with cryotherapy Sir, A 23-year-old Nigerian man was referred with a 3-year history of small flesh-coloured papules around the coronal rim of his glans penis (Fig. 1a). He was stigmatized by their appearance and by his female partner's reaction to them. He had applied various topical preparations to no avail and was very anxious to be treated effectively. A clinical diagnosis of pearly penile papules (angiofibromas) was made. A few of his lesions were treated with liquid nitrogen from a Cry-Ac gun (Galderma Laboratories, TX, U.S.A.), tip spray C, for two 10-s cycles and without anaesthesia. He was instructed to apply a cream containing clobetasone butyrate, Figure 1. (a) A double row of angiofibromas is evident around the w oxytetracycline and nystatin (Trimovate , GlaxoWellcome, corona of the glans penis. (b) Clinical resolution occurred after Uxbridge, U.K.) to the treated areas for the next week. At cryotherapy. q 2000 British Association of Dermatologists, British Journal of Dermatology, 142, 812±851 848 CORRESPONDENCE

been noted after 2 years (Fig. 1b). The patient was delighted matrix lichen planus, with nail plate thinning and splitting. with the success of the treatment, and no dysfunction, In one patient the fingernails showed mild scarring or pigmentary changes have been reported. associated with subungual hyperkeratosis and onycholysis. Pearly penile papules are smooth, dome-shaped, flesh- All patients had similar toenail abnormalities, consisting of coloured papules which are symptomless and without patho- marked yellow discoloration of the toenails that were also logical significance, usually occurring after puberty in a thickened and transversely over-curved (Fig. 1). The cuticles circumferential distribution on the corona and sulcus of the were absent and one patient also had onycholysis of the great glans penis. They are acral angiofibromas1 and consist of a toenails. When questioned, patients complained that their core of normal connective tissue covered by a centrally thin toenail growth had slowed down or arrested. All five patients and peripherally acanthotic epidermis over a rich vascular were in good health and were not taking any medications. network surrounded by dense connective tissue and a None of them had either altered respiratory function or limb lymphocytic infiltrate. They are most readily misdiagnosed lymphoedema. as viral or . A nail bed punch biopsy taken from an affected toenail was Despite reassurances, many patients request treatment. diagnostic for nail lichen planus in all cases. Treatment with Previous authors have described treatment by circumcision, systemic steroids (intramuscular injections of triamcinolone podophyllin, electrodesiccation and curettage and carbon acetonide 0´5 mg kg21 every 20±30 days for 6 months) dioxide laser. The latter two modalities can be successful,2,3 produced complete regression of the fingernail abnormalities but they require local anaesthesia, are more time-consuming, in all five patients. Yellow toenails, in contrast, slowly and pigmentary change and scarring are more likely to occur responded to treatment and 1 year from the beginning of compared with cryotherapy. This treatment method has been treatment we observed a mild improvement in only three of reported once before, with similarly successful results: the five patients. 80±90% of lesions were removed after two treatments, with Our cases document that -like good patient tolerance and no complications.4 Cryotherapy changes may be a possible sign of lichen planus in the offers an effective treatment modality for penile papules. Topical local anaesthesia should be available for the more nervous patient.

Department of Dermatology, W. M . P ORTER Chelsea and Westminster Hospital, C.B.BUNKER Imperial College School of Medicine, London SW10 9NH, U.K. E-mail: [email protected]

References

1 Ackerman AB, Kornberg R. Pearly penile papules: acral angio- fibromas. Arch Dermatol 1973; 108: 673±5. 2 Magid M, Garden JM. Pearly penile papules: treatment with carbon dioxide laser. J Dermatol Surg Oncol 1989; 15: 552±4. 3 Fleming MG, Brody N. A new technique for laser treatment of cutaneous tumours. J Dermatol Surg Oncol 1986; 12: 1170±5. 4 Ocampo-Candiani J, Cueva-Rodriguez J. Cryosurgical treatment of pearly penile papules. J Am Acad Dermatol 1996; 35: 486±7.

Nail changes in lichen planus may resemble those of yellow nail syndrome

Sir, The occurrence of yellow nail syndrome-like lesions in nail lichen planus was reported by Haneke in 1983.1 Since then, no other patients with similar features have been described in the literature. We have recently observed five patients (three men and two women, age range 43±61 years, mean 54´4) with nail lichen planus presenting toenail abnormalities mimicking the yellow nail syndrome. In all our patients lichen planus involved both the fingernails and Figure 1. (a,b) Yellow nail syndrome-like changes of the toenails are the toenails. One patient also had oral involvement. Four of associated with fingernail lesions typical of lichen planus in two the five patients had fingernail abnormalities typical for nail patients.

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toenails. The yellow nail syndrome is an uncommon disorder yellow nail syndrome.5 The slow physiological growth of the of unknown aetiology characterized by the triad of yellow toenails compared with that of the fingernails may be another nails, lymphoedema and respiratory tract involvement.2 predisposing factor. Although all three signs do not occur in every patient, the presence of typical nail alterations is considered an absolute Department of Dermatology, A.TOSTI requirement for the diagnosis. Nail changes usually affect University of Bologna, B.M.PIRACCINI both fingernails and toenails and are typically associated with Via Massarenti 1, N.CAMELI a very slow growth rate. The nails are thickened, yellow± 40138 Bologna, Italy green in colour, and lack cuticles. An excessive transverse E-mail: [email protected] curvature causes a mild to severe onycholysis that in some patients can cause shedding of the nail plate. The possibility that our patients may have had yellow nail References syndrome was excluded by the clinical features typical for nail 1 Haneke E. Isolated bullous lichen planus of the nails mimicking lichen planus seen in their fingernails, by the pathology of the yellow nail syndrome. Clin Exp Dermatol 1983; 8: 425±8. toenail lesions and by the absence of lymphoedema and 3 2 Tosti A, Baran R, Dawber RPR. The nail in systemic diseases and respiratory abnormalities. Although there is only one similar drug-induced changes. In: Diseases of the Nails and Their Manage- 1 case reported in the literature, this modality of presentation ment (Baran R, Dawber RPR, eds), 2nd edn. Oxford: Blackwell of lichen planus is possibly not uncommon, and should be Science, 1994: 175±261. included among the symptoms of lichen planus of the nail 3 Hiller E, Rosenow EC, Olsen AM. Pulmonary manifestations of the bed.4 The reason why these yellow nail syndrome-like yellow nail syndrome. Chest 1972; 61: 452±8. changes due to nail lichen planus are only observed in the 4 Tosti A, Peluso AM, Fanti PA et al. Nail lichen planus: clinical and toenails may possibly be explained by the fact that lower limbs pathologic study of twenty-four patients. J Am Acad Dermatol 1993; have a relatively worse lymphatic function than the upper 28: 724±30. 5 Bull RH, Fenton DA, Mortimer PS. Lymphatic function in the yellow limbs. Impaired lymphatic drainage due to a functional nail syndrome. Br J Dermatol 1996; 134: 307±12. disorder is believed to be the cause of the nail changes in the

Erratum

Miyagawa S, Amagai M, Iida T, Yamamoto Y, Nishikawa T & A decimal point was omitted from Table 1 in this paper. In Shirai T. Late development of antidesmoglein 1 antibodies in the first line of the table, the ELISA index for Patient 1 pemphigus vulgaris: correlation with disease progression. Br J was incorrectly printed as 90.5/28. It should have read Dermatol 1999: 141; 1084±8. 90.5/2.8.

News and Notices

Tuberous Sclerosis Association Multi-Disciplinary Programmes and application forms may be obtained from Study Days on Janet Medcalf, TSA, Little Barnsley Farm, Catshill, Broms- 16 May 2000, Queen Elizabeth Hospital, Birmingham, grove B61 0NQ, U.K. Tel.: + 44 1527 871898, fax: + 44 U.K. 1527 579452; e-mail: [email protected] Programmes and application forms may be obtained from Janet Medcalf, TSA, Little Barnsley Farm, Catshill, Broms- Cosmoderm grove B61 0NQ, U.K. Tel.: + 44 1527 871898, fax: + 44 25±27 July 2000, Cannes, France 1527 579452; e-mail: [email protected] Cosmoderm will be held at the Royal Hotel, Cannes- Mandelieu, Cannes, France. For details, contact Christopher Tuberous Sclerosis Association Multi-Disciplinary Rowland Payne, European Society for Cosmetic & Aesthetic Study Days on Tuberous Sclerosis Dermatology, 19 Cambridge Street, London SE1V 4PR, U.K. 14 June 2000, St. George's Hospital, Tooting, London, Fax: + 44 20 7233 7393. U.K. q 2000 British Association of Dermatologists, British Journal of Dermatology, 142, 812±851 850 CORRESPONDENCE

Announcement BSF Small Grant Awards, reference: BSFISGA. One-off British Skin Foundation 2000 Awards Call for Grant payments of up to £10 000. May be used to purchase Applications equipment or for less costly projects. 113SID/BSF Studentship, reference: BSFISSD. A 3-year The Trustees of the British Skin Foundation wish to announce package, value £44 000, covering tuition fees, expenses and that funding is again available for skin disease research. This some consumables. year there are six categories of award as listed below. Vitiligo/BSF Studentship, reference: 13SFNIT. A 3-year Applicants are asked to apply for funding from the category package, value £44 000, covering tuition fees, expenses and that they feel is must appropriate. The closing date is 20 some consumables. Available specifically for research into September 2000. vitiligo. BSF Research Awards, reference: BSFIRES. 1- or 2-year SSF/Kimberly Clark Paediatric Research Award, reference: project grants of up to £50 000 per annum. BSFIKIM. A 1- or 2-year project grant of up to £40 000 per The BSF Fellowship, reference: 13SFIFEL. A grant of annum for research into paediatric skin disease. £40 000 to support a specialist registrar in dermatology For application forms, please contact: British Skin Founda- through 1 year of research. Candidates should submit details tion, 19 Fitzroy Square, London W1P SHQ, U.K. Tel.: + 44 of their proposed research in the manner described below. 207 383 0266, fax + 44 0207 388 5263, quoting the Selection will be by interview in late 2000. It is envisaged that appropriate reference. the successful candidates will already hold an NTN or will have just completed their training.

Book Reviews

Photodamaged skin: clinical signs, causes and manage- greying of the hair, seborrhoeic warts and a whole chapter on ment J-P.Ortonne and R.Marks (1999) London: Martin intrinsic ageing of the skin. Dunitz Ltd. ISBN 1-H5317-345-2, 126 illustrations, 149pp. The sections on the mechanism, measurement and treat- Price £49.95 ment of photoaging are very thoroughly covered. The authors do not shy away from the science of UV damage or of the This book covers the subject of photodamage and ageing very mechanisms of action of retinoids. Each chapter is very well comprehensively. As such it is going to appeal to dermato- referenced. This book will not find its way onto many hospital logists and plastic surgeons involved in the management of dermatology library shelves in this country where the need solar damage who wish to have more information on will be to have books dedicated to photodermatology and skin mechanisms, measurement and treatment. The illustrations cancer but it will certainly appeal to dermatologists who treat are of high quality and plentiful. The writing style is relaxed photodamage and who wish to understand its mechanisms and the book is very readable. more thoroughly. I suspect it will sell better in North America and Europe than in the United Kingdom. Even in private practice only a Dr Charles R.Darley small minority of dermatologists and plastic surgeons in this country are involved with topical retinoids and resurfacing Photodermatology J.L.M.Hawk (ed.) (1999) London: techniques. Arnold. ISBN 0-340-74094-9 310pp. Price £85. The authors start by discussing the physics of UV radiation Photodermatology is a wide-ranging book, aimed at trainee and its effect. Chapters are then devoted to solar elastosis, and practising dermatologists and photobiologists. Chapters dyspigmentation, photodysplasia and nonmelanoma skin range from basic science, including molecular biology, physics cancer, intrinsic ageing of the skin, the effects of sun exposure and immunology, to the acute and chronic effects of UVR on on the immune response, the measurement of photodamage the skin, that is, the sunburn response, photosensitivity and finally its treatment. The authors do not pretend to cover disorders, carcinogenesis and ageing, and to therapy with melanoma and non-melanoma skin cancer or the subject of ultraviolet and laser light. The book is rounded off by four photodermatoses in any detail. practical appendices, including guidelines for photoinvesti- Some conditions are covered in rather more depth than gation procedures and for setting up phototherapy units. This others. For example the section on idiopathic guttate hypo- is all achieved within a compact, modestly priced and easily melanosis includes a detailed literature review of several digestable book of just over 300 pages. controversial treatments whereas the section on disseminated The largest portion of the book (seven of the 17 chapters) is superficial actinic porokeratosis does not offer any treatment dedicated to photosensitivity disorders. Some of the discourses suggestions. The text does not restrict itself purely to photo- are relatively brief, reflecting the current gaps in our damage but includes other aspects of skin ageing including understanding. The authors give an up-to-date and readily

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understandable appraisal of current research findings, and will be considered in future editions of the textbook; it clearly state where areas are speculative and require further would fit well with the section on phototherapy and laser study. The comprehensive overview of the molecular events therapy. following UV radiation of keratinocytes summarizes under- Is there a need/niche for this book? Certainly, yes. The lying mechanisms, including signal transduction and DNA nearest book in content and size is Clinical Photomedicine (Lim damage, and gives a good framework of basic photobiology HW & Soter NA, (eds), New York: Dekker), a commendable science to clinical dermatologists. The chapters on human source, but now 6 years old, and less mechanistic in exposure to UVR, including behavioural patterns and effects approach. Another interesting book published in 1999 is of stratospheric ozone depletion, and on photocarcino- Photoimmunology (Krutmann J & Elmets CA (eds), Oxford: genesis, are other welcome additions to a photodermatology Blackwell Science); however the books clearly occupy textbook. different niches. 1 recommend that all dermatology trainees Are there any omissions? Yes, the puzzling omission of a have access to this new book and that all clinicians with an chapter on photodynamic therapy, an area of rapidly interest in photodermatology add it to their collection; many advancing science and increasingly practiced treatment, scientists working in photobiology will also find it useful. prevents this from being a fully comprehensive text on the r esley hodes current state of play in photodermatology. Perhaps a chapter D L R

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