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Oxford, 2001 International IJD Blackwell 0011-9059 January Cameo 000 UK Science Science, Journal Ltd 2001 of Dermatology Palencia Nail changes et al.in graft vs. host disease January 2001 000

Cameo

Lichenoid nail changes as sole external manifestation of graft vs. host disease Nail changes Palencia et al.in graft vs. host disease

Sara Isabel Palencia, MD, Jose Luis Rodríguez-Peralto, MD, Esther Castaño, MD, Francisco Vanaclocha, MD, and Luis Iglesias, MD

From the Departments of Dermatology and Pathology, Hospital Universitario 12 de Octubre, Madrid, Spain Correspondence Jose Luis Rodríguez-Peralto, MD Departamento de Anatomía Patológica Hospital Universitario 12 de Octubre Ctra Andalucía km 5,400, 28041 Madrid E-mail: [email protected]

A 56-year-old-man who had refractory anemia with an excess of blasts underwent an allogeneic peripheral blood stem cell transplantation (PBSCT) from his brother after preparation with melphalan and fludarabin. He received GvHD (graft-vs.-host disease) prophylaxis with cyclosporine from day –1 at a daily dose of 5 mg / kg of body weight. The daily dosage was tapered gradually from day +20. On post-PBSCT day 68 he developed acute cutaneous GvHD grade 3 and acute gastrointestinal GvHD grade 2 – 3, which was resolved with a daily dose of 1 mg/kg of body weight of prednisone. The patient was discharged in good clinical condition and without signs of GvHD, and he started tapering his immunosuppressive treatment. By day 160 he developed oral lichen planus-like changes, with several reticulate white lesions on the oral mucosa. A biopsy specimen was microscopically consistent with lichenoid GvHD (Fig. 1). By day 150 after PBSCT, when he was being treated with CsA 100 mg once daily and prednisone 10 mg once daily, his fingernails started to grow abnormally and gradually became dystrophic and painful. Two months later his toenails became similarly affected. Although affecting all finger and toe nails, the lesions were especially important in both thumbs. Physical examination revealed multiple findings on his nails (Fig. 2): thickening, fragility, onycholysis, longitudinal striations, and even pterygium. The micological cultures were negative. A biopsy specimen showed an sparse papillary dermis lymphoid infiltrate with focal exocytosis and presence of isolated multiple necrotic keratinocytes (Fig. 3). These findings were interpreted as a lichenoid GvHD with oral and nail involvement. The patient did not have other associated cutaneous lesions. He did not develop signs or symptoms consistent with hepatic GvHD. In May 2000 thalidomide was added to the immunosuppressive therapy, at a daily dose from 100 to 300 mg according to tolerance (constipation, sedation, ...). The lesions on the oral mucous showed a substantial improvement, but the nail changes remained more or less stable. Thalidomide was discontinued after 7 months because the patient displayed numbness and tingling in the hands and feet consistent with a peripheral neuropathy. Twenty days later he stopped taking thalidomide and the oral lichenoid lesions worsened, resulting in difficulty in eating. He also developed periungueal erythema, swelling and intense pain after minimal trauma. The daily dose of prednisone increased to 20 – 30 mg with moderate improvement. However, the dose could not be increased because of the secondary immunosuppressive effects. Twenty-three months post-PBSCT the patient remains with intense oral and nail lichenoid lesions.

Discussion

44

GvHD is a frequent complication of allogeneic bone marrow transplantation (BMT). GvHD occurs when immunocompetent cells from a donor recognize and react against “foreign” tissue antigens in an immunocompromised host, and BMT is the commonest stimulus for such reactions. GvHD is divided into two forms: acute GvHD, which occurs during the first 3 months following BMT, and chronic GvHD, which includes all the International Journal of Dermatology 2002, 41, 44 –45

manifestations that develop after the third month following transplantation. Chronic GvHD develops in 10% of all patient undergoing allogeneic BMT and may develop de novo, a gradual progression from acute GvHD, or following resolution of acute GvHD, as in our patient. Traditionally, chronic GvHD includes lichenoid and sclerodermoid forms.1 Lichen planus-like GvHD can affect the skin, the oral mucosa2 and the genital organs. Nail manifestations of chronic GvHD are rare, nonspecific3,4 and include atrophy, dystrophy, thickening, © 2002 The International Society of Dermatology

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Figure 1 Oral mucosa with a lichenoid hiperplasia and a

band-like lymphoid infiltrate. Note the basal lymphocytosis with isolated necrotic keratinocytes

Figure 3 Panoramic view of the nail epithelium. Dermal

lymphocytes with basal exocytosis and apoptotic keratinocytes (arrow) are evident

References

Figure 2 Lichenoid graft-vs.-host disease showing marked nail

involvement with a ridge in the midline

fragility, onycholysis, periungueal erythema, swelling, white superficial onychomycosis.5 The typical nail changes of lichen planus in GvHD are extremely uncommon. Although these changes are named in some articles6,7 there are few publications which describe in detail these lesions. Liddle et al. in 19908 reported a case of pterygium developing in a patient with chronic GvHD. We describe a patient who developed nail manifestations characteristic of lichen planus with pterygium formation as a manifestation of chronic GvHD. This manifestation enhances the spectrum of GvHD. Overall, nail changes are usually not of concern to the patient but, as they may be a very early manifestation, detailed clinical examination of the nails should be included in the assessment of a patient for GvHD.4

© 2002 The International Society of Dermatology

1 Black MM. Graft-versus-host disease. In: Rook A, Wilkinson DS, Ebling FJG, eds. Textbook of Dermatology, 6th edn. Oxford: Blackwell Science, 1998 pp 1919–1921. 2 Schubert MM, Sullivan KM, Morton TH, et al. Oral manifestations of chronic graft-versus-host disease. Arch Intern Med 1984; 144: 1591–1595. 3 De Berker DAR, Baran R, Dawber RPR. The nail in dermatological diseases. In: Handbook of Diseases of the Nails and Their Management (de Berker DAR, Baran R. Dawber RPR), 2nd edn. Oxford: Blackwell Science Limited 1994; pp 175–176. 4 Andrews ML, Robertson I, Weedon D. Cutaneous manifestations of chronic graft-vs.-host disease. Australas J Dermatol 1997; 38: 53– 62. 5 Basuk PJ, Scher BK. Onichomycosis in graft-versus-host disease. Cutis 1987; 40: 237 – 241. 6 Saurat JH, Gluckman E. Lichen planus-like eruption following bone marrow transplantation. a manifestations of the graft-versus-host disease. Clin Exp Dermatol 1977; 2: 335–344. 7 Shulman HM, Sale GE, Lerner KG, et al. Chronic cutaneous graft-versus-host disease in man. Am J Pathol 1978; 92: 545 –570. 8 Liddle BJ, Cowan MA. Lichen planus-like eruption and nail changes in a patient with graft-versus-host disease. Br J Dermatol 1990; 122: 841–843.

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Cameo Prolidase deficiency

Cameo

Prolidase deficiency Prolidase deficiency

Aysin Kokturk, MD, Tamer Irfan Kaya, MD, Guliz Ikizoglu, MD, and Aynur Koca, MD

From the Department of Dermatology, Faculty of Medicine, Mersin University, Mersin, Turkey Correspondence Aysin Kokturk, MD Mersin Üniversitesi Tıp Fakültesi Hastanesi Dermatoloji Anabilim Dalı 33070 Zeytinlibahce Mersin Turkey E-mail: [email protected]

A 32-year-old mentally retarded woman was admitted to hospital with recurrent ulcers on her legs, which appeared for the first time at 8 years of age. Apart from recurrent lower respiratory tract infections and chronic otitis media, her personal history was unremarkable. Her parents were second-degree relatives. The family history showed no similar disease or mental retardation. Physical examination revealed that the patient had an unusual facial appearance, with a high-arched palate; she had multiple tooth caries (Fig. 1). There was edema and induration on both legs; extensive polygonal ulcers with elevated borders were noted. All lesions were 2 – 4 mm deep with vertical margins and a necrotic base. The surrounding skin was atrophic, and depigmented cicatricial lesions were detected (Fig. 2). She had crops of erythematous lesions and telangiectasias over the face, shoulders, arms, and extremities. She also showed photosensitivity, palmar hyperkeratosis, verrucous papules and plaques on the dorsal aspects of both feet consistent with lymphedematous changes, pes planus deformity, and hyperextensible joints. There was a scleroatrophic appearance and flexion contracture of the little fingers on both hands. Her abdomen was relatively protuberant and she had splenomegaly. Laboratory analysis revealed an elevated erythrocyte sedimentation rate, hypergammaglobulinemia, and iron deficiency anemia. A large amount of hydroxyproline was detected after hydrolysis of a 24-h urine specimen (205 mg /day). Her plasma manganese level was 1.94 mg /dL (normal) and her vitamin C level was 1.4 mg /dL (below normal). Skin biopsies showed nonspecific inflammatory changes. Topical silver sulfadiazine and oral vitamin C (3 g / day) treatment was started.

Discussion Prolidase deficiency is a rare autosomal recessive disorder causing iminopeptiduria due to the absence of prolidase enzyme activity, and is associated with various clinical manifestations, such as chronic skin ulcers, recurring infections, mental retardation, splenomegaly, and a characteristic facial appearance, e.g. low hairline, saddle nose, frontal bossing, thick lips, and hypertelorism.1–7 It was first described by Goodman in 1968. In 1974, Powell et al. demonstrated a deficiency of prolidase, an enzyme that splits dipeptides containing C-terminal proline or hydroxyproline; this results in the impairment of the normal recycling of proline.2 –4 In prolidase deficiency, large amounts of proline and hydroxyproline are excreted in the urine, bound to amino acids as iminodipeptides, resulting in the depletion of the total pool of proline.2–5 Prolidase enzyme activity in erythrocytes, leukocytes, and fibroblasts is very low or undetectable in affected individuals.1,2,5 Iminopeptiduria has also been described in conditions such as rickets, hyperparathyroidism, and Paget’s disease, but the degree of iminopeptiduria is much higher in prolidase deficiency.1,2,6 International Journal of Dermatology 2002, 41, 46 44 –48 –45

Prolidase deficiency is a multisystem disorder with the skin as its primary target organ. The onset of clinical symptoms is before the age of 12 years.5 Recurrent, multiple ulcers of the lower extremities are the most characteristic lesions, described in approximately two-thirds of the reported cases. Most patients have residual scars, eczematous lesions, telangiectasia, and purpura. Photosensitivity, dry skin, hyperkeratosis of the elbows and knees, lymphedema, premature graying of the hair, and poliosis have been described in a few patients. Other common features include a characteristic unusual facial appearance, mental retardation, splenomegaly, and susceptibility to recurrent infections. A high-arched palate, protuberant abdomen, joint laxity, short stature, simian creases, canities, keratosis pilaris, ocular involvement, deafness, and osteoporosis are some of the less frequently associated features. Hypergammaglobulinemia, iron deficiency anemia, thrombocytopenia, and elevated immunoglobulins have been reported as accompanying abnormal laboratory findings.1–8 An unusual feature in our patient was the presence of flexion contracture of the little fingers on both hands that has not been reported previously. © 2002 The International Society of Dermatology

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Figure 1 Facial appearance of the patient

Prolidase deficiency Cameo

the synthesis of new collagen, is blocked and the result is disturbed connective tissue metabolism of the skin and vessels.1,2 Amorphous vascular deposits, often Congo red-positive, and ultrastructural changes in collagen molecules have been reported.1–3,9 Although the pathogenic mechanisms leading to the skin changes are poorly understood, the induction of the release of histamine from isolated mast cells and of collagenase from polymorphonuclear leukocytes by dipeptides containing proline and hydroxyproline, resulting in an inflammatory reaction and ulceration, is a plausible explanation.10 Impairment of the immune system leads to recurrent infections, and the coexistence of prolidase deficiency and lupus erythematosus has been described, suggesting that prolidase deficiency might be a risk factor for the development of systemic lupus erythematosus.3,6 Effective treatment of prolidase deficiency is still not available. Bed rest, occlusive dressings, topical antiseptics and skin grafting, large doses of oral proline supplements, topical application of glycine and proline, topical application of growth hormone and growth hormone replacement, oral dapsone at 75 mg /day, the transfusion of normal erythrocytes, and oral supplements of manganese and ascorbic acid, both modulators of prolidase activity, are among the treatment modalities, all with limited and temporary effects.1–3,8,11,12 The case reported here is, to our knowledge, the first report from Turkey of a patient with prolidase deficiency, suffering from chronic and recurrent leg ulceration. We suggest that patients presenting with chronic and recurrent leg ulcers and suggestive signs of the disease should have urine analyses performed in order to reveal a possible underlying prolidase deficiency. References

Figure 2 Ulcers and depigmented cicatricial lesions on the legs

The pathophysiology of the biochemical defect in prolidase deficiency still remains to be elucidated. Proline and hydroxyproline are among the major constituents of collagen. In the absence of prolidase, the recycling of proline, necessary for © 2002 The International Society of Dermatology

1 Bishara JF, Kaloustian VMD. Prolidase deficiency. Int J Dermatol 1986; 7: 431–433. 2 Milligan A, Graham-Brown RAC, Burns DA, Anderson I. Prolidase deficiency: a case report and literature review. Br J Dermatol 1989; 121: 405–409. 3 Bissonette R, Friedmann D, Giroux JM, et al. Prolidase deficiency: a multisystemic hereditary disorder. J Am Acad Dermatol 1993; 29: 818 – 821. 4 Goodman SI, Solomons CC, Muschenheim F, et al. A syndrome resembling lathyrism associated with iminopeptiduria. Am J Med 1968; 45: 152–159. 5 Leoni A, Cetta G, Tenni R, et al. Prolidase deficiency in two siblings with chronic leg ulcerations. Arch Dermatol 1987; 123: 493–499. 6 Shrinath M, Walter JH, Haeney M, et al. Prolidase deficiency and systemic lupus erythematosus. Arch Dis Child 1997; 76: 441–444. 7 Powell GF, Rasco MA, Maniscalo RM. A prolidase deficiency in man with iminopeptiduria. Metabolism 1974; 23: 505–513. 8 Ogata A, Tanaka S, Tomoda T, et al. Autosomal recessive prolidase deficiency. Arch Dermatol 1981; 117: 689–694. International InternationalJournal JournalofofDermatology Dermatology2002, 2002,4141 , 46– , 44– 4845

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Cameo Cutaneous ciliated cyst on the cheek

9 Arata J, Tada J, Yamada T, et al. Angiopathic pathogenesis of clinical manifestations in prolidase deficiency. Arch Dermatol 1991; 127: 124–125. 10 Rao VH, Royce HM, Steinmann B. Normal production, nature, and extent of intracellular degradation of newly synthesized collagen in fibroblasts from a patient with prolidase deficiency. Connect Tissue Res 1993; 29: 23 –30. 11 Arata J, Hatekenako K, Oono T. Effect of topical

application of glycine and proline on recalcitrant leg ulcers of prolidase deficiency. Arch Dermatol 1989; 122: 626 – 627. 12 Monafo V, Marseglia GL, Maghnie M, et al. Transient beneficial effect of GH replacement therapy and topical GH application on skin ulcers in a boy with prolidase deficiency. Pediatr Dermatol 2000; 17: 227 – 230.

Cameo

Cutaneous ciliated cyst on the cheek in a male Cutaneous ciliated cyst on the cheek

Norihiro Ohba, MD, Daisuke Tsuruta, MD,* Michinari Muraoka, MD, Tomoko Haba, MD, and Masamitsu Ishii, MD

From the Departments of Plastic and Reconstructive Surgery and Dermatology, Osaka City University Medical School, and Department of Pathology, Osaka City University Hospital, Osaka, Japan Correspondence Norihiro Ohba, MD Department of Plastic and Reconstructive Surgery Osaka City University Medical School 1-4-3, Asahimachi Abeno-ku Osaka 545-8585 Japan E-mail: [email protected] *Present address: Department of Cell and Molecular Biology, North-western University Medical School, Chicago, IL

A 53-year-old man presented with a 2-year history of a painless mass on the right cheek. On physical examination, the lump was a solitary, well-demarcated, mobile lesion. There was no abnormality in the surrounding skin. Ultrasonography demonstrated a single, cystic, well-defined, subcutaneous cyst, measuring 20 mm in diameter. Laboratory tests, including sex hormones, were within the normal range. The tumor was resected surgically under local anesthesia. The cyst had a slightly yellow wall and contained clear, watery fluid. The patient had no other medical problems and no history of other skin disease. Histopathologically, the unilocular cyst was lined with two layers of epithelium and was devoid of papillary infolding. The inner layer of the cyst was composed of cuboidal to columnar epithelial cells, most of which demonstrated prominent cilia. The outer layer consisted of polygonal cells that contained clear cytoplasm (Fig. 1). No foci of squamous metaplasia were present and the cyst wall did not contain adnexal structures. The inner layer of the epithelium was positive for periodic acid–Schiff (PAS) stain, but contained no diastase-resistant granules. Immunohistochemical staining revealed strong staining in the membrane for epithelial membrane antigen (EMA) and diffuse cytoplasmic reaction to cytokeratin in the epithelial component, but carcinoembryonic antigen (CEA) staining was negative. Staining for α-smooth muscle actin (αSMA) and S-100 protein was positive in the outer layer (Fig. 2), suggesting myoepithelial cells. There were no desmin, vimentin, amylase or estrogen receptor-positive cells in the epithelium.

Discussion Cutaneous ciliated cyst (CCC) is an unusual lesion found largely in women during their reproductive years that typically occurs on the lower limbs. Since the original report of Hess in 1890,1 a total of 32 cases of CCC have been published.1–10 Our case is unique for several reasons: (i) there is no known report of CCC located on the face; (ii) our patient is unusually old (cysts normally found in individuals 20–50 years of age); and (iii) our patient is male. In the 32 reported cases, International Journal of Dermatology 2002, 41, 44 48 –45 –49

the affected sites were the thigh (n = 8), foot (n = 8), buttock (n = 6), calf (n = 6), knee, back,1 shoulder,5 and scalp (one case each).6 In other words, CCC was located on the lower limbs in 29 cases.2–4,7–10 The affected age range was 14– 42 years. Furthermore, there were only three reported cases in males compared with 29 in females. The underlying pathomechanisms of CCC are unclear, but two major theories have been proposed: (i) the theory of sequestration and migration (heterotopia) of the ciliated epithelium from the Müllerian epithelium;7–10 and (ii) ciliated © 2002 The International Society of Dermatology

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Figure 1 Hematoxylin and eosin staining. A unilocular cyst

lined with two layers of epithelium (original magnification, × 200)

Cutaneous ciliated cyst on the cheek Cameo

CCC, but cannot explain the following three points: (i) the molecular markers that are relatively specific to the fallopian tube are not consistently expressed in all CCC;4 (ii) three known male cases have been reported; and (iii) three of the reported cases of CCC were not located on the lower limbs. The latter explanation of metaplasia or preservation of embryonal remnants is based on the presence of embryonal eccrine glands containing cilia in their secretory and ductal epithelia. This theory is reinforced by the presence of remnants of cilia in eccrine and apocrine spiradenoma. This theory, however, cannot explain the predominant localization of CCC on the lower extremities and immunoreactivity for carcinoembryonic antigen (CEA). Strong immunoreactivity for α-smooth muscle actin (αSMA) and S-100 protein in the outer layer suggests the existence of myoepithelial cells, which supports the eccrine origin of CCC. Further studies are required to determine whether the immunohistochemical findings in our case resemble those of the eccrine gland and to establish the eccrine origin of CCC. References

Figure 2 α-Smooth muscle actin (αSMA) staining was positive

in the outer layer (original magnification, × 100)

metaplasia of the eccrine glands.2–4,6 In support of the former theory, several groups have reported that the ciliated cells of CCC are morphologically similar to the epithelium of the fallopian tube and show positive staining for various fallopian tube markers, such as amylase,9 S-100 protein,10 and sex steroid receptors.6 Furthermore, the anatomical proximity of the fallopian tube and lower limb buds further explains the anatomical predilection of CCC for the lower extremities. This theory is quite intriguing and plausible in most cases of

© 2002 The International Society of Dermatology

1 Hess K. Ueber eine subcutane flimmerzyste. Beitr Pathol 1890; 8: 98–109 (in German). 2 Leonforte JF. Cutaneous ciliated cystadenoma in a man. Arch Dermatol 1982; 118: 1010 –1012. 3 Trotter SE, Rassl DM, Saad M, et al. Cutaneous ciliated cyst occurring in a male. Histopathology 1994; 25: 492–493. 4 Ashton MA. Cutaneous ciliated cyst of the lower limb in a male. Histopathology 1995; 26: 467–469. 5 Sabourin JC, Grossin M, Potet F. Cutaneous ciliated cyst of the scapular area. Ann Dermatol Venereol 1993; 120: 383– 385. 6 Sickel JZ. Cutaneous ciliated cyst of the scalp: a case report with immunohistochemical evidence for estrogen and progesterone receptors. Am J Dermatopathol 1994; 16: 76 – 79. 7 Farmer ER, Helwig EB. Cutaneous ciliated cysts. Arch Dermatol 1978; 114: 70 – 73. 8 Park CH, Grisoni E, Reid JD. Cutaneous ciliated cyst: case report and discussion of pathogenesis. J Pediatr Surg 1982; 17: 410 – 411. 9 Varma SK, Rayner SS, Brown LJ. Cutaneous ciliated cyst: case report and literature review. Plast Reconstr Surg 1990; 86: 344 –346. 10 Al Nafussi A, Carder P. Cutaneous ciliated cyst: a case report and immunohistochemical comparison with fallopian tube. Histopathology 1990; 16: 595 –598.

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Cameo Stingray injury in a domestic aquarium

Cameo

Stingray injury in a domestic aquarium Stingray injury in a domestic aquarium

Alberto Schiera, MD, Maria Luisa Battifoglio, MD, Gabriele Scarabelli, MD, and Dario Crippa, MD

From the Department of Dermatology, San Gerardo Hospital, Monza, Italy Correspondence Alberto Schiera, MD Department of Dermatovenereology San Gerardo Hospital Via Donizetti, 106 20052 Monza (MI) Italy E-mail: [email protected]

A 36-year-old man presented with acute blistering on the dorsal aspect of his left hand and a bullous eruption on the dorsal aspect of the fingers, which were erythematous and edematous. A small, deep laceration, partially covered by a crust, was also visible on the same hand (Fig. 1). The patient stated that he had been stung by a freshwater stingray (Potamotrygon reticulatus) (Fig. 2) while he was feeding the animal in his aquarium. He complained of quite intense pain, beginning a few minutes after envenomation at the site of the injury, and progressively extending into the surrounding areas. He received intravenous fentanyl + morphine + tramadol, while the affected part was immersed in hot water (45 °C) in order to denature the heat-labile venom and provide pain relief. The patient refused prophylactic injection of tetanus toxoid. The area was infiltrated with 1% lidocaine and examined carefully. Pieces of foreign material were removed. The wound was thoroughly irrigated and cleansed with antiseptic solution and left open. A plain radiographic study of the injured area excluded retained barbs or other foreign material. A neurologic examination revealed reduction of tactile sensitivity at the distal part of the left forearm and fingers. There were no obvious abnormal physical signs: electrocardiogram was normal, as well as blood pressure, heart rate and temperature. The patient received a prophylactic short course of oral antibiotic therapy with an advanced generation cephalosporin and a macrolide. Over the next 2 months, the wound healed slowly by second intention, the wound was allowed to heal from the edge without surgical closure. At a 5-month follow-up visit, the wound appeared to be completely healed, although the patient still complained of sporadic para-anesthesia of the left hand and forearm.

Discussion Stingrays are cartilaginous fishes with a flattened body and one or more stout spines on the tail. They are not aggressive towards people; however, injuries from these animals are very common. Most injuries due to stingrays occur in coastal regions of the tropics and subtropics. Several reports of stingray injuries can be found in the literature. These are caused mostly by the sting contained in the tail of the animal, which has retroserrated teeth (Fig. 3) and is surrounded by glandular epithelia that rupture to release venom when the sting enters the victim.1 The ray defensively whips its tail upwards and forwards when stepped on or threatened.2 The majority of wounds are therefore located on the dorsum of the foot or the lower leg.3 Wounds on the upper arms have occurred to fishermen stung while attempting to remove rays from their lines or nets, to divers International Journal of Dermatology 2002, 41, 50 44 –51 –45

Figure 1 Blistering on the dorsal aspect of the hand and bullous

eruption on the dorsal aspect of the fingers. A small, deep ulceration, partially covered by a crust, is also visible © 2002 The International Society of Dermatology

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engaged in feeding rays at popular dive locations,2–4 and to a devotee of aquarium fishes, in the same circumstances as described in our case.5 When stingray spines penetrate the thorax or abdomen, the resulting wounds may prove to be fatal.2,3 In order to prevent stingray injuries in countries at risk, fishermen should be aware that these fishes must be treated with respect, while waders in shallow water should wear heavy clothing on their legs and strong boots, and carefully prod the area with a stick.2 In countries not at risk, people who keep a stingray in an aquarium might be a victim of stingray injury to the hand, as illustrated in this case report. Therefore, practitioners, not only in countries at risk, but world-wide, should be aware of the specific features and treatments of this kind of injury.5 Figure 2 Juvenile specimen of stingray, Potamotrygon reticulatus

Acknowledgments Dr Alessandro Mancini, photographer and devotee of aquarium fishes, provided a rare and very good image of Potamotrygon reticulatus. References

Figure 3 A view of a stingray stinger devoid of the outer

membrane, demonstrating the retroserrated teeth

1 Burnett JW, Calton GJ, Morgan RJ. Venomous stingray injuries. Cutis 1986; 38: 112. 2 Fenner PJ, Williamson JA, Skinner RA. Fatal and non-fatal stingray envenomation. Med J Aust 1989; 151: 621–625. 3 Barss PL. Wound necrosis caused by the venom of stingrays. Pathological findings and surgical management. Med J Aust 1984; 141: 854 – 855. 4 Evans LA, Evans CM. Stingray hickey. Cutis 1996; 58: 208–210. 5 Van Offel JF, Stevens WJ. A stingray injury in a devotee of aquarium fishes. Acta Clin Belg 2000; 55: 174–175. January 2001 000

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Cameo Regression of a melanoma with Tubercin

Palencia Chung et etal. al.

Cameo

Regression of an acral lentiginous melanoma with an immunotherapy using a Mycobacterium tuberculosis-extracted polysaccharide complex (Tubercin) Regression of a melanoma with Tubercin

Tai Ho Chung, MD, PhD, Jae Bok Jun, MD, Jae Won Jang, MD, and Hai Lee Chung, MD

From the WHO Collaboration Viral Hepatitis Center, Department of Dermatology, School of Medicine, Kyungpook National University, and the Catholic University of Taegu, Taegu, Korea Correspondence Tai Ho Chung, MD PhD WHO Collaboration Viral Hepatitis Center School of Medicine Kyungpook National University 101 Dong-In Dong Taegu Korea 700 – 422 E-mail: [email protected]

A 77-year-old-female presented with a painless, pigmented lesion, which had been present for approximately 10 years but had increased significantly in size during the last 3 months. Her past history was unremarkable, but she had been a farmer for more than 50 years and was routinely exposed to excessive amounts of sunlight. On examination, a lesion measuring 11 × 15 mm was noted on the base of left thumb. The lesion was black, slightly elevated and irregularly shaped with a relatively demarcated border. Histological examination of the biopsy specimen was consistent with an acral lentiginous melanoma (ALM) with a thickness of 4 mm. Whole body computed tomographic examination and bone scan demonstrated no distant metastases. The patient refused not only the surgical treatment but also the recommended chemotherapeutic regimen due to her advanced age. She was then referred to the WHO Collaboration Viral Hepatitis Center at Kyungpook National University for consideration for immunotherapy with Tubercin. The patient consented to a trial of Tubercin, which was initiated on December 24, 1999. She received three 0.3 mL subcutaneous intralesional injections of Tubercin and 2 mL intramuscular injections on the buttock every other day. After 10 months of treatment the lesion appeared as a faint brown-colored macule and almost complete regression was noted. The follow-up histological examination performed after 1 year showed no evidence of melanoma (Fig. 1). The treatment regimen was reduced to biweekly treatments consisting of two 0.2 mL intralesional injections and one 2 mL intramuscular injection. After an additional year, the treatment will be further reduced to a biweekly 1 mL intramuscular injection. The patient has remained free of any metastases and demonstrated no local or systemic reactions.

Discussion Malignant melanoma is an immunogenic tumor to which various types of immunotherapy have been applied.1 Several attempts with nonspecific immune adjuvants such as BCG2 and levamisole3 were not convincing. Recent studies have demonstrated that high dose interferon (IFN)-alpha has been reported to improve overall survival rate4 but the IFN treatment must be considered in relation to its availability, cost and significant toxicities. Given these limitations, other therapeutic regimens are still being actively pursued. Tubercin is a polysaccharide complex free of lipids and proteins, which was isolated from Mycobacterium tuberculosis (H37RV) in 1974.5 The immunotherapeutic properties of Tubercin were shown in many previous studies. When administered as an adjuvant treatment in 500 patients with advanced cancers, including melanoma, patients had a significantly longer disease-free survival.6,7 During this trial, no significant International Journal of Dermatology 2002, 41, 52 44 –53 –45

adverse effects were noted. A significant number of anergic patients with various malignant diseases developed a delayed cutaneous hypersensitivity reaction to 2,4-dinitrochlorobenzene after treatment with Tubercin. Interestingly, the development of a hypersensitivity reaction in these patients positively correlated with an improved survival rate8 suggesting that Tubercin may restore the impaired cell-mediated immunity. This hypothesis is further supported in this case. The follow-up histological examinations after Tubercin treatment showed the appearance of many tumor-infiltrating lymphocytes around melanoma cells which was absent before treatment. Acral lentiginous melanoma (ALM) is relatively uncommon in Caucasians, but frequently seen in all pigmented races. While a few cases of melanoma have been reported to regress spontaneously, ALM is a more aggressive tumor with a higher mortality rate and no reported cases of spontaneous regression.9 In the present case, after 1 year of an aggressive treatment with © 2002 The International Society of Dermatology

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Three cases of Nattrassia mangiferae Cameo

reactions. We suggest that Tubercin, which is safe and easily administered at a relative low cost, may be efficacious as an immunotherapeutic agent for malignant melanoma. References

Figure 1 Gross and histologic findings of the melanoma before

(A) and after (B) Tubercin treatment

Tubercin, the primary tumor became histologically undetectable and she has remained free of any known metastases. Furthermore, she has demonstrated no local or systemic

1 Brinckerhoff LH, Thompson LW, Slingluff CL Jr. Melanoma vaccines. Curr Opin Oncol 2000; 12: 163–173. 2 BCG immunotherapy of malignant melanoma: summary of a seven-year experience. Ann Surg 1974; 180: 635–643. 3 Spitler LE. A randomized trial of levamisole versus placebo as adjuvant therapy in malignant melanoma. J Clin Oncol 1991; 9: 736 – 740. 4 Cole BF, Gelber RD, Kirkwood JM, Goldhirsch A, Barylak E, Borden E. Quality of life adjusted survival analysis of interferon alfa-2b adjuvant treatment of high-risk resected cutaneous melanoma: an Eastern Cooperative Oncology Group Study. J Clin Oncol 1996; 14: 2666–2673. 5 Chung TH. Anti-tumor effect of a Tuberculo-protein complex, Tubercin-3, and its isoelectrofocusing analysis. J Korean Med Assoc 1974; 6: 427– 431. 6 Chung TH. Trial of immunotherapeutic approach with Tuberculo-protein carbohydrate complex, Tubercin-3 on 500 cases of various cancers in men. Korean J Biochem 1983; 15: 65 – 70. 7 Lee BH, Gu BM, Eun HC. Effect of Tubercin-3 on two cases of malignant melanoma. Kor J Dermatol 1979; 5: 373– 376. 8 Chung TH, Kim SM, Shin TS, Kim DY. Effect of Tubercin-3 to the delayed cutaneous hypersensitivity to 2,4-dinitrochloroben-zene (DNCB) in cancer patients. J Kor Surg Soc 1978; 20: 651–657. 9 Koh HK, Bhawan J. Tumors of the skin. In: Moschella SL, Hurley HJ eds. Dermatology, 3rd Edn. Philadelphia: W. B. Saunders, 1992: 1721–1808.

Cameo

Three cases of Nattrassia mangiferae (Scytalidium dimidiatum) infection in Singapore Three cases of Nattrassia mangiferae

Anthony Teik-Jin Goon, MBBS, MRCP. (UK) and Chew-Swee Seow, MBBS, M Med (Int Medical)

From the National Skin Center, Singapore. Correspondence Anthony Goon Teik Jin, MBBS, MRCP (UK) National Skin Center 1 Mandalay Road Singapore 308205 E-mail: [email protected]

Case no. 1 A 70-year-old Indian man had lateral onycholysis of his left big toe since 1989. Nail scrapings from the left big toenail were negative three times in 1989 and 1990. Fungal cultures from the left big toenail were negative for dermatophyte and nondermatophyte molds in 1990. The condition did not respond to topical itraconazole 1% lotion (prepared by our pharmacy from itraconazole capsules), ketoconazle cream, tolnaftate lotion and nonstaining Castellani paint as well as oral itraconazole 100 mg daily for 4 weeks. In 1993, there was distal onycholysis of the fingernails on the left thumb, left ring and index and right little fingers as well. Once again, the skin scrapings from the finger- and toenails were

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negative. The condition did not respond to topical tolnaftate lotion, clotrimazole 1% lotion, miconazole 1% lotion, thiabendazole 10% lotion and nonstaining Castellani paint. In September 1999, both big toenails had crumbling nail plates and ragged distal edges. Nail scrapings showed the presence of mycelium and the fungal culture result was reported Scytalidium dimidiatum and Fusarium species. The Fusarium was thought to be a nonpathogenic coloniser. He was treated with oral griseofulvin, thiabendazole 10% lotion and nonstaining Castellani paint without much improvement. He was last seen in January 2001. There was still destruction of the nail plate and separation of the nail plate from the nail bed. Case no. 2 A 45-year-old Chinese man who worked as a clerk in a cosmetic company was first seen in July 1994 for scaly hyperkeratotic rashes on both soles for 10 years. He had tried using miconazole cream but the problem persisted. Skin scrapings revealed the presence of mycelium and fungal culture result war reported as Hendersonula toruloidea. He was born in Singapore and had never lived overseas. The condition persisted despite 9 weeks of oral griseofulvin 250 mg twice daily and miconazole 2% cream, 3 months of 10% thiabendazole lotion, 2 weeks of oral thiabendazole 500 mg twice daily and ung Whitfield. He subsequently defaulted after the last visit in April 1995, when he was prescribed amorolfine cream. He was seen again in July 1998 for acne vulgaris. His soles were still hyperkeratotic but skin scrapings were not taken. He defaulted again after 3 visits. Case no. 3 A 33-year-old Indian man who had been working in a machine assembly line for 12 years presented with an itchy scaly rash on his feet for 3 years and on the hands for 1 year in November 1996. The rash was especially prominent on the toewebs and occasionally formed vesicles and became secondarily infected. He had been treated with antifungal creams, with the addition of oral antibiotics for episodes of secondary infection, but the skin condition deteriorated. He wore shoes at work and had been exposed to coolants for 3 years. There was no history of atopy or allergies. On examination, there was maceration and scaling between the right second and third toes. Scaling was seen in the toewebs and near the thumbs bilaterally. The nails and groin were normal. Skin scrapings were negative on the hands, but showed a few hyphae on the toewebs. Fungal cultures from the toewebs were negative but bacterial cultures of the toewebs grew Acinetobacter baumanii and Klebsiella species, both of which were sensitive to gentamicin. The diagnoses of secondarily infected tinea pedis and hand dermatitis were made. The infection settled with oral cloxacillin and topical gentamicin cream but the skin of the hands and feet remained dry and fissured. He was then treated as for hand and foot dermatitis with moderately potent topical corticosteroids with minimal improvement. Repeated skin scrapings were negative in January and May 1997. He defaulted in September 1998. He returned in March 2000 with an acute exacerbation of a dry itchy rash on his palms and soles. He was treated as for dermatitis with cephalexin and a tapering course of prednisolone with significant improvement. Due to the persistent rashs, a skin scraping of the feet was repeated in May 2000 and this showed the presence of mycelium. He was treated with a course of oral griseofulvin 250 mg twice daily for 4 weeks with no improvement. He was then treated empirically with oral terbinafine 250 mg daily for 3 weeks and miconazole 2% cream, as cultures were not available. In June 2000 he had an infected exacerbation of his rash, which required treatment with oral cephalexin followed by oral cotrimoxazole. The skin scraping of the toewebs was negative and a diagnosis of acute dermatitis was made. He was given a tapering course of prednisolone with improvement. A patch test was negative. In November 2000, he still had a rash on the palms and soles. The fungal culture result was reported as Scytalidum dimidiatum but fungal scrapes had not been done. He was treated with oral itraconazole 200 mg daily for 4 weeks, oral cloxacillin and miconazole 2% cream. International Journal of Dermatology 2002, 41, 53 44 –55 –45

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Discussion Nattrassia mangiferae has been increasingly reported as a cause of human disease, which may be clinically impossible to distinguish from dermatophytosis. It is common to have mixed infections with dermatophytes, where both organisms should be considered as pathogens.1,2 The most commonly affected parts in immunocompetent hosts are the feet, palms and nails. This mold is limited primarily to tissue containing keratin, and may remain viable in dry skin scrapings at room temperature for 6 months.3 Infections are acquired by direct contact, especially in those individuals without protective clothing or footwear.4 It is difficult to prove anthropophilic transmission as infected individuals typically reside in or have visited endemic areas. It is presumed that infection is a result of direct contact with soil or plants. Proven transmission from human to human or animal to human is not known. A diagnostic clue is positive KOH but no growth on cycloheximide-containing agars. This combined with a history of griseofulvin failure should alert the physician to a possible nondermatophytic infection. Culture is diagnostic, and biopsy is not usually indicated. It is important to keep in mind that these organisms do not grow in the presence of cycloheximide. Since dermatophytosis can coexist, both cycloheximide and noncycloheximide media should be used for isolation and identification of fungal agents. There is no orally effective treatment. Griseofulvin and ketoconazole are ineffective.5,6 Oral itraconazole7,8 and intravenous amphotericin B9 have been reported to induce clinical and mycological remission. Terbinafine and fluconazole have not been shown to be effective against nondermatophytes. Topical antifungals including azoles are ineffective. In vitro, H toruloidea may be sensitive to clotrimazole but in vivo use of clotrimazole results in therapeutic failure.5 There has been a case report of successful treatment of Hendersonula toruloidea onychomycosis with nail avulsion followed by topical ciclopiroxolamine under occlusion nightly for 3– 4 months, but the same patient’s palm and sole infection was resistant to ciclopiroxolamine.10 Another report showed successful treatment of Scytalidium hyalinum onychomycosis with 5% amorolfine nail lacquer twice a week for 8 weeks.11 Terbinafine and amorolfine have been shown to have in vitro activity against Scytalidium species.12

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As dermatophytosis and dermatomycosis often coexist, conventional antifungal therapy might result in resolution of dermatophyte and overall apparent improvement, but complete mycological cure could only be verified by reculture on both cycloheximide and noncycloheximide media.

References 1 Moore MK. Hendersonula toruloidea and Scytalidium hyalinum infections in London, England. J Med Vet Mycol 1986; 24: 219 – 230. 2 Moore MK. Skin and nail infections by non-dermatophyte filamentous fungi. Mykosen Suppl 1978; 1: 128–132. 3 Kong BHP, Kapka L, Lee R. Keratin invasion by Hendersonula toruloidea; a tropical pathogenic fungus resistant to therapy. Int J Dermatol 1984; 23: 65– 66. 4 Elewski B. “Phaeohyphomycosis” In: Demiss, J, eds. Clinical Dermatology, Philadelphia, Pa: JB Lippincott, 1991. 5 Moore MK, Palacio-Hernanz AD, Lopez-Gomez S. Scytalidium infection diagnosed in Spain. J Med Vet Mycol 1984; 22: 243– 245. 6 Abramson C. Athlete’s foot and onychomycosis caused by Hendersonula toruloidea. Cutis 1990; 46: 128 –132. 7 Gupta AK, Elewski BE. Nondermatophyte causes of onychomycosis and superficial mycoses. Curr Top Med Mycol 1996; 7: 87 – 97. 8 Romano C, Valenti L, Difonzo EM. Two cases of tinea pedis caused by Scytalidium hyalinum. J Eur Acad Dermatol Venereol 1999; 12: 38 – 42. 9 Sigler L, Summerbell RC, Poole L, et al. Invasive Nattrassia mangiferae infections. case report, literature review, and therapeutic and taxonomic appraisal. J Clin Microbiol 1997; 35: 433–440. 10 Rollman O, Johansson S. Hendersonula toruloidea infection. Successful response of onychomycosis to nail avulsion and topical ciclopiroxolamine. Acta Derm Venereol (Stockh) 1987; 67: 506 – 510. 11 Downs AMR, Lear AT, Archer CB. Scytalidium hyalinum onychomycosis successfully treated with 5% amorolfine nail lacquer. Br J Dermatol 1999; 140: 555. 12 Clayton YM. Relevance of broad-spectrum and fungicidal activity of antifungals in the treatment of dermatomycoses. Br J Dermatol 1994; 130 (Suppl. 43): 7–8.

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