British Journal of Dermatology 2003; 148: 10581087.

CORRESPONDENCE
A case of anti-p200 pemphigoid clinically mimicking Autoimmune subepidermal blistering disorders include bul-
inflammatory epidermolysis bullosa acquisita lous pemphigoid, pemphigoid gestationis, lichen planus
pemphigoides, linear IgA bullous dermatosis, cicatricial pem-
SIR, Anti-p200 pemphigoid is a new disease entity, which phigoid, anti-p200 pemphigoid, anti-p105 pemphigoid, auto-
was first described in 1996 by Hashimotos group.1,2 They anti-p450 pemphigoid, EBA and bullous systemic lupus
described an unusual case with autoimmune subepidermal erythematosus.7
bullous lesions that clinically resembled bullous pemphi- Anti-p200 pemphigoid has been identified as a new distinct
goid1 and a case with psoriasis vulgaris that developed entity and named by Zillikens et al.5 They identified IgG
extensive blister formation.2 Both the nonpsoriatic patient autoantibodies against a novel 200-kDa lower lamina lucida
and the psoriatic patient were characterized by immuno- target antigen in nonpsoriatic bullous disease and a patient
globulin (Ig)G autoantibodies against a novel 200-kDa with coexisting bullous skin disease and psoriasis.2 They also
lower lamina lucida component. To date, anti-p200 pem- described a predominance of neutrophils in the dermal
phigoid has been shown to present various clinical features. infiltrate in the histology. Several other basement membrane
This new autoimmune bullous disease seems to be classified zone components have been suggested as target antigens of
into three clinical forms: (i) coexistence with psoriasis,2,3 (ii) autoimmune bullous dermatoses; however, the 200-kDa
presenting the clinical features of vesicular pemphigoid,4 autoantigen seems to be different from laminins 1, 5 and 6,
and (iii) presenting clinically atypical blistering features.1,5 and type VII collagen.5,6 It has not been clearly suggested
In this report, we describe a new patient with anti-p200
pemphigoid clinically mimicking inflammatory epidermolysis
bullosa acquisita (EBA).
A 28-year-old Japanese male was referred to us because of
numerous pruritic bullous skin lesions on the entire body of
2 weeks duration. Neither he nor his family had a past
history of psoriasis. On physical examination, large, tense
bullae and vesicles with erythema, and erosions similar to the
skin lesions of bullous pemphigoid were found on his entire
body (Fig. 1). The blisters tended to form in an annular
arrangement resembling linear IgA bullous dermatosis or
dermatitis herpetiformis. Oral and genital mucosae were not
involved.
Laboratory examinations revealed marked leukocytosis
(218 109 L)1 mm)3) and eosinophilia (37%). Because of
the severe skin lesions, systemic prednisolone 100 mg daily
was commenced; the dose was tapered down to 60 mg daily
within 1 week. Because new blisters still appeared, the
patient was treated with the combination therapy of predn-
isolone 60 mg and azathioprine 100 mg daily. Subsequently,
no new bullae developed. The lesions healed, leaving mild
scarring or milia formation. The prednisolone and azathiop-
rine were gradually tapered down to 125 mg and 50 mg
daily, respectively, and maintained at that dosage thereafter.
Histology of lesional skin taken during the acute phase
showed subepidermal blistering with abundant neutrophils,
eosinophils and fibrin. Lymphocytes and eosinophils were
found in the upper dermis. Direct immunofluorescence
showed linear deposits of IgG and C3 at the dermoepidermal
junction. Indirect immunofluorescence using normal human
skin sections as a substrate showed circulating IgG autoan-
tibodies against the basement membrane zone (> 1 : 160),
which were reactive exclusively with dermal side of
1 mol L)1 NaCl-split human skin (> 1 : 40). Immunoblotting Figure 1. Clinical appearance of the right thigh. Large, tense bullae
with epidermal and dermal extracts of normal human skin were found on the erythema that were similar to the skin lesions of
was performed using methods described elsewhere.1,2,6 The bullous pemphigoid. Small bullae and vesicles were also seen at the
patients serum reacted with a 200-kDa protein of dermal periphery of the erythema resembling linear IgA bullous dermatosis
extract (Fig. 2). The 290-kDa EBA antigen was not detected. (seen to the right side of this figure).

1058  2003 British Association of Dermatologists

 CORRESPONDENCE 1059

anti-p200 pemphigoid were treated with various therapies

including corticosteroids, minocycline, dapsone and ciclosp-
orin, and showed favourable response to most treatments.6
Despite the severe, widespread blistering skin lesions, the
present case showed a relatively good response to predniso-
lone and azathioprine, supporting the diagnosis of anti-p200
pemphigoid rather than EBA.
Initially, the patients signs suggested of anti-p200-kDa
pemphigoid or EBA, because indirect immunofluorescence
revealed linear IgG deposits at the dermal side of the salt-split
skin. By immunoblotting using dermal extracts, our patients
serum clearly reacted with the 200-kDa antigen. From these
results, we diagnosed our case as anti-p200 pemphigoid
clinically resembling inflammatory EBA.
Further reports of similar cases will be needed to clarify the
pathomechanisms of anti-p200 pemphigoid. Molecular bio-
logical studies will also be necessary to characterize the 200-
kDa autoantigen.

Acknowledgments
We thank Miss Michiyo Noge, Miss Yuko Kawano and Miss
Ayumi Suzuki for their technical assistance, and Miss Akiko
Tanaka for secretarial assistance.

Figure 2. Results of immunoblotting with normal human dermal Departments of Dermatology and N.Umemoto
extracts. A control epidermolysis bullosa acquisita (EBA) serum *Dentistry and Oral Surgery, Jichi T.Demitsu
reacted with the 290-kDa EBA antigen (lane 1). Most of the protein Medical School, Omiya Medical S.Toda
bands seen in the lower part of this lane were considered to be Centre, 1-847 Amanuma-machi, T.Noguchi*
degradation of type VII collagen. A control anti200-kDa pemphigoid S.-I.Suzuki
Saitama 3308503, Division of
serum reacted with the 200-kDa (lane 2). IgG of the present patient M.Kakurai
Surgery, Kameari Central Hospital,
reacted most strongly with the 200-kDa (lane 3), although several T.Yamada
nonspecific background protein bands were also seen.
Tokyo, Department of Dermatology, M.Suzuki
Jichi Medical School, School of H.Nakagawa
Medicine, Tochigi, and Department A.Komai
that the IgG antibodies against the 200-kDa lamina lucida
of Dermatology, Kurume University, T.Hashimoto
antigen play a causative role in the pathogenesis of this
School of Medicine, Kurume, Japan.
bullous disease.
Corresponence: T.Demitsu.
Kawahara et al.6 have evaluated nine cases of subepider-
E-mail: demitsu@omiya.jichi.ac.jp
mal blistering disease with autoantibodies against a novel
dermal 200-kDa antigen with regard to clinicopathological
features and immunological findings. In their analysis, five References
cases showed bullous pemphigoid-like features, one case
1 Zillikens D, Kawahara Y, Ishiko A et al. A novel IgG-mediated
resembled dermatitis herpetiformis, and another case presen-
subepidermal blistering disease with autoantibodies against a 200-
ted mixed features of bullous pemphigoid and linear IgA kD antigen of the basement membrane zone. J Invest Dermatol
bullous dermatosis. Four of nine cases had coexisting 1996; 106: 46570.
psoriasis. Our case had no psoriatic background and clinically 2 Chen KR, Shimizu S, Miyakawa S et al. Coexistence of psoriasis and
resembled inflammatory EBA. In the nine cases, histology an unusual IgG-mediated subepidermal bullous dermatosis: iden-
showed subepidermal blistering with neutrophils (five cases), tification of a novel 200-kDa lower lamina lucida target antigen.
predominance of eosinophils (two cases) and a mixed Br J Dermatol 1996; 134: 3406.
infiltrate (two patients). In the present case, eosinophils and 3 Saeki H, Hayashi N, Komine M et al. A case of generalized pustular
lymphocytes were seen in the dermis, although subepidermal psoriasis followed by bullous disease: an atypical case of bullous
pemphigoid or a novel bullous disease? Br J Dermatol 1996; 134:
bullae contained numerous neutrophils as well as eosinoph-
1525.
ils. The patients serum reacted with a 200-kDa protein of
4 Inoh Y, Nishikawa T, Hashimoto T. The vesicular pemphigoid
dermal extract, while the 290-kDa EBA antigen was com- phenotype may be related to antibodies to a 200 kDa antigen in the
pletely negative (Fig. 2). A few additional weak protein bands lower lamina lucida. Br J Dermatol 1998; 139: 7389.
were also seen in the lane of this patients serum. However, 5 Zillikens D, Ishiko A, Jonkman MF et al. Autoantibodies in anti-
because the reactivity of these bands was very weak, we p200 pemphigoid stain skin lacking laminin 5 and type VII colla-
consider them to be nonspecific reactivity. The patients with gen. Br J Dermatol 2000; 143: 10439.

 2003 British Association of Dermatologists, British Journal of Dermatology, 148, 10581087

1060 CORRESPONDENCE

6 Kawahara Y, Zillikens D, Yancey KB et al. Subepidermal blistering mentation rate, 41 mm in the first hour (normal, N: < 15),
disease with autoantibodies against a novel dermal 200-kDa decreased IgA 16 g L)1 (N: 176342), and polyclonal
antigen. J Dermatol Sci 2000; 23: 93102. hypergammaglobulinaemia on serum protein electrophoresis.
7 Schmidt E, Zillikens D. Autoimmune and inherited subepidermal Anti extractable nuclear antigens (ribonuclear protein [RNP],
blistering diseases: advances in the clinic and the laboratory. Adv
Scl-70, Sm, SSA, SSB), antinuclear antibody, and rheumatoid
Dermatol 2000; 16: 11357.
factor were all negative. Complement levels, IgG and IgM
were normal, as were chest X-rays.
Serial examinations did not show involvement of other
Cutaneous RosaiDorfman disease: remission
organs. Histology of a skin biopsy taken from the right
with thalidomide treatment
mandibular area revealed a dense dermal infiltrate in close
contact with the basal layer of the epidermis, extending
SIR, Sinus histiocytosis with massive lymphadenopathy
deeply into the subcutis. The infiltrate was composed mainly
(SHML) is a nonX histiocytosis that usually presents with
of histiocytes with large vesicular nuclei and abundant
cervical lymphadenopathy. It was first described by Rosai and
cytoplasm with feathery borders; lymphocytes and plasma
Dorfman in 1969.1 The cutaneous form of sinus histiocytosis
cells were seen within the cytoplasm of these histiocytes
without involvement of lymph nodes or other organs is now
(emperipolesis). Lymphocytes, plasma cells, and neutrophils
generally known as cutaneous RosaiDorfman disease (CRD)
were seen in the background infiltrate (Fig. 2). These
rather than SHML.2 There are few treatments for extensive
histiocytes were positive for S-100 and CD68. A diagnosis
CRD. We describe a case of CRD successfully treated with
of CRD and anterior uveitis was made. She was treated with
thalidomide.
hydroxychloroquine sulphate 200 mg twice daily for 7 days
A 45-year-old woman, who did not have any significant
and dapsone 100 mg daily for 21 days, but this was
past medical history, consulted us because she developed
ineffective. Prednisolone 30 mg daily was given for 14 days,
nontender, infiltrated erythematous skin eruptions on the
but she did not respond to this either. Because of the extensive
inner thighs and both mandibular areas extending on to the
and disfiguring skin lesions, after informed consent was
neck, over a period of 5 months (Fig. 1a). She had blurred
obtained she was treated with thalidomide 300 mg daily.
vision and photophobia which had started several months
Numbness of the face and hands were noticed initially but
previously. Examination revealed a 10 10 cm area of
resolved spontaneously without any abnormal nerve
confluent pea-sized, elasticfirm dark red papules located on
conduction velocity. She had regular menses and no family
both cheeks. Similar dusky red papules and plaques were
history of premature menopause. The urinary pregnancy test
found around the periorbital areas, on the neck and on the
was negative before thalidomide therapy. However, amenor-
inner thighs. No cervical, supraclavicular, axillary or ingu-
rhoea occurred after 3 weeks of treatment (cumulative dose
inal nodes could be palpated. Ophthalmological examinations
approximately 6 g).
showed cells in the anterior chambers and in the vitreous
The lesions underwent gradual regression over 3 months
bodies, more profuse on the right side. Fluorescein angiog-
(Fig. 1b). Histology of a skin biopsy taken from the right
raphy showed staining of the discs and suspicious cystoid
cheek after treatment showed a decreased dermal infiltrate of
macular oedema without definite diffuse vasculitis. Abnormal
lymphocytes and plasma cells admixed with only few S-100-
laboratory results included an increased erythrocyte sedi-
positive histiocytes. After 3 months therapy was temporarily

Figure 2. Histiocytes with large, vesicular nuclei and an abundant

Figure 1. (a) Indurated, erythematous plaques with an irregular and pale cytoplasm, are interspersed with lymphocytes and plasma cells.
shiny surface located on right cheek of the patient. (b) Regression of A few leucocytes are seen within the cytoplasm of the histiocytes
the plaques after 3 months treatment with thalidomide. (haematoxylin and eosin, original magnification, 400).

 2003 British Association of Dermatologists, British Journal of Dermatology, 148, 10581087


discontinued for 2 weeks because of short supply; a mildly
increased infiltrate was observed over the previously flattened
lesions. Her menses reappeared after this short break in
medication. After a further 2 months thalidomide treatment
(total dose in 5 months was approximately 45 g), all lesions
resolved clinically except for scattered lesions in the axillae.
Her visual disturbance improved little even with the addition
of a potent steroid-containing ophthalmic preparation.
Examination still showed a cellular infiltrate in the anterior
chamber.
The pathogenesis of SHML and cutaneous sinus histiocy-
tosis remains unknown. Most CRD has a limited distribution
and a benign, self-limiting course,3 and treatment is not
indicated. However, the extensive cutaneous involvement
affecting the face and neck caused significant physical,
mental and social distress to our patient. The cheek seems
to be a common site of involvement.2,3 In localized CRD,
many treatments have been reported including steroids,4
surgical excision and superficial X-ray radiation therapy.3
Thalidomide has been used in many inflammatory skin
diseases,5 including a case of extensive CRD.6 CRD runs an
unpredictable clinical course with spontaneous remission.
However, in our patient the minor recurrence of the lesions
during a short break in therapy argues against spontaneous
remission of the disease. Anterior uveitis associated with
RosaiDorfman disease is rare and only a few cases have been
reported in the literature.7 It was thought that the anterior
uveitis might be due to a histiocytic infiltration of the anterior
uvea, though this was not proven histologically.7 Our
patients disorder may not be purely cutaneous: she was the
second reported case of chronic uveitis and RosaiDorfman
disease without nodal involvement.7
The efficacy of thalidomide may be due to the predomin-
antly cutaneous pharmacological effect of the drug and
immunomodulatory or anti-inflammatory properties. Tha-
lidomide seemed to have only a limited effect on this patients
uveitis. Teratogenic effects and peripheral sensory neuropathy
are the most severe adverse effects of thalidomide.5 Almost all
adverse effects disappear after cessation of treatment, but
peripheral neuropathy due to thalidomide may be permanent
in those patients who develop it.5 Recently amenorrhoea was
reported as a new side-effect.811 The mechanism of thalido-
mide causing amenorrhoea is unknown. Some authors have
speculated that it might act like other immunosuppressive
drugs such as cyclophophamide,8,9,11 by destroying follicular
cells, at the follicle stimulating hormone (FSH) receptor level,
by directly inhibiting FSH binding, or through a postreceptor
mechanism.11 This case suggests that thalidomide may be a
useful treatment for extensive CRD.
Departments of Dermatology J-W.Tjiu
and *Pathology, C-H.Hsiao*
National Taiwan University Hospital, T-F.Tsai
7 Chung-Shan South Road, Taipei,
Taiwan
Correspondence: T-F. Tsai
E-mail: tftsai@yahoo.com
 2003 British Association of Dermatologists, British Journal of Dermatology, 148, 10581087
CORRESPONDENCE 1061
References
1 Rosai J, Dorfman RF. Sinus histiocytosis with massive lympha-
denopathy: a newly recognized benign clinicopathological entity.
Arch Pathol 1969; 87: 6370.
2 Thawerani H, Sanchez RL, Rosai J et al. The cutaneous manifes-
tation of histiocytosis with massive lymphadenopathy. Arch Der-
matol 1978; 114: 1917.
3 Annessi G, Giannetti A. Purely cutaneous RosaiDorfman disease.
Br J Dermatol 1996; 134: 74953.
4 Salim A, Williamson M, Barker F et al. Steroid responsive cuta-
neous RosaiDorfman disease associated with uveitis and hypo-
thyroidism. Clin Exp Dermatol 2002; 27: 2779.
5 Tseng S, Pak G, Washenik K et al. Rediscovering thalidomide: a
review of its mechanism of action, side effects, and potential uses. J
Am Acad Dermatol 1996; 35: 96979.
6 Viraben R, Dupre A, Gorguet B. Pure cutaneous histiocytosis
resembling sinus histiocytosis. Clin Exp Dermatol 1988; 13: 1979.
7 Silvestre JF, Aliaga A. Cutaneous sinus histiocytosis and chronic
uveitis. Pediatr Dermatol 2000; 17: 37780.
8 Ordi J, Cortes F, Martinez N et al. Thalidomide induces amenor-
rhea in patients with lupus disease. Arthritis Rheum 1998; 41:
22735.
9 Ordi-Ros J, Cortes F, Cucurull E et al. Thalidomide in the treatment
of cutaneous lupus refractory to conventional therapy. J Rheu-
matol 2000; 27: 142933.
10 Passeron T, Lacour J-P, Murr D et al. Thalidomide-induced
amenorrhoea: two cases. Br J Dermatol 2001; 144: 12923.
11 Gompel A, Frances C, Piette JC et al. Ovarian failure with thalido-
mide treatment in complex aphthosis: comment on the concise
communication by Ordi et al. Arthritis Rheum 1999; 42: 225960.
Classic Kaposis sarcoma of the palm in a metallurgist:
role of iron filings in its development?
SIR, Kaposis sarcoma (KS) is a vascular tumour which has
been isolated in four distinct epidemiological settings: classic
KS, African-endemic KS, immunosuppressive drug-related KS
and AIDS-associated KS. A large body of evidence indicates
that human herpesvirus (HHV)-8 has an important aetiolo-
gical role in the pathogenesis of KS. However, the incidence of
HHV-8 infection is far higher than the prevalence of KS,
suggesting that viral infection per se is not sufficient for the
development of malignancy and that one or more additional
cofactors are required.1
We and others have suggested that iron may act as a cofactor
in the pathogenesis of KS.2,3 The involvement of iron in the
pathogenesis of KS may partly explain the high prevalence of
classic and endemic KS in geographical areas with iron oxide-
rich volcanic clays, such as Sicily, Iceland and the East African
rift system.24 It may also provide a nonhormonal explanation
for the lower prevalence of KS among women,5 as they are
known to have lower iron reserves than men.
A 68-year-old man was referred for a 6-month history of a
well-demarcated macule involving his left palm (Fig. 1a).
Cutaneous examination was otherwise normal, with the
exception of the presence of a faint purple macule on a toe.
He was otherwise healthy and took no medication. He had an
Italian origin and had worked as a metallurgist for more than
1062 CORRESPONDENCE

(a) 30 years in a steel manufactory (Clabecq, Belgium), where he

used to handle steel blades with bare hands. A biopsy of the
palm showed a proliferation of small, irregular and jagged
endothelial lined spaces suggestive of early patch-stage KS.
The presence of HHV-8 DNA sequences in the skin sample was
evidenced by hot-start polymerase chain reaction amplification
with KS 330233 primer sequences.6 Serological testing for
human immunodeficiency virus types 1 and 2 was negative.
Magnetic resonance imaging of the hands was performed and
gradient-echo images showed a lack of signal in the thenar
subcutaneous tissues of the left hand, strongly suggesting
ferromagnetic artifacts due to metallic particles (Fig. 1b).
Classic KS usually first occurs on the lower extremities,
which may be related to lymph stasis,7 and more rarely
involves the upper extremities. Palmar involvement is usually
not reported in the clinical descriptions of classic KS.8 We
suggest that in our patient, the handling of steel blades with
bare hands may have played a role in the development of KS
at this site. Iron is known to be carcinogenic through several
mechanisms: (i) iron may promote the formation of muta-
genic hydroxyl radicals;5 (ii) iron loading can enhance host
cell production of viral nucleic acids,5 which may be of
importance in view of the involvement of HHV-8 in the
pathogenesis of KS; (iii) iron can induce the expression of
antiapoptotic signals in endothelial cells,9 which might play a
role in neoangiogenesis; (iv) iron excess diminishes host
defences through inhibition of the activity of macrophages
and lymphocytes;5 (v) iron is necessary for the activity of
ribonucleotide reductase, an enzyme that plays a key role in
DNA replication and cellular metabolism. More specifically,
we have previously shown that iron salts could stimulate
(b) in vitro growth of KS-derived cells, irrespective of their
epidemiological setting.3 Inversely, iron chelators inhibit the
growth and induce the apoptosis of KS cells in vitro.10
In conclusion, we suggest that percutaneous penetration of
iron filings, in combination with other factors known to be
involved in the pathogenesis of KS (i.e. HHV-8 infection and
genetic susceptibility), may have induced the development of
palmar KS in this patient. Further studies are, however,
required to determine whether KS could be viewed as an
occupational disease in some particular cases.

Departments of Dermatology and T.Simonart

*Radiology, Erasme University G.De Dobbeleer
Hospital, 808 Route de Lennik, B.Stallenberg*
B-1070 Brussels, Belgium.
E-mail: tsimonar@ulb.ac.be

Figure 1. (a) Well-demarcated macular lesion of Kaposis sarcoma
on the palm. (b) Magnetic resonance sagittal image (TR TE Flip
angle: 39 18 14) of the hands showing a lack of signal (arrow) in
the soft tissues of the left thenar eminence.
References
1 Gallo RC. The enigmas of Kaposis sarcoma. Science 1998; 282:
18379.
2 Ziegler JL. Endemic Kaposis sarcoma in Africa and local volcanic
soils. Lancet 1993; 342: 134851.
3 Simonart T, Noel JC, Andrei G et al. Iron as a potential cofactor in
the pathogenesis of Kaposis sarcoma. Int J Cancer 1998; 78: 720
6.

 2003 British Association of Dermatologists, British Journal of Dermatology, 148, 10581087


4 Simonart T, van Vooren JP, Herbauts J, Boelaert JR. High pre-
valence of Kaposis sarcoma in Iceland and the Faroe Islands
[letter]. Br J Cancer 1999; 79: 373.
5 Simonart T, van Vooren JP, Parent D et al. Role of iron in der-
matology. Dermatology 2000; 200: 1569.
6 Noel JC, Hermans P, Andre J et al. Herpesvirus-like DNA
sequences and Kaposis sarcoma. Relationship with epidemiology,
clinical spectrum, and histologic features. Cancer 1996; 77:
21326.
7 Ruocco V, Schwartz RA, Ruocco E. Lymphedema: an immuno-
logically vulnerable site for development of neoplasms. J Am Acad
Dermatol 2002; 47: 1247.
8 Tappero JW, Conant MA, Wolfe SF, Berger TG. Kaposis sarcoma:
epidemiology, pathogenesis, histology, clinical spectrum, staging
criteria and therapy. J Am Acad Dermatol 1993; 28: 37195.
9 Simonart T, Degraef C, Stordeur P et al. Iron induces Bcl-2
expression in human dermal microvascular endothelial cells. Free
Radic Res 2001; 34: 22135.
10 Simonart T, Degraef C, Andrei G et al. Iron chelators inhibit the
growth and induce the apoptosis of Kaposis sarcoma cells and of
their putative endothelial precursors. J Invest Dermatol 2000; 115:
893900.
Agranulocytosis and total scalp alopecia
following acitretin
SIR, An 84-year-old woman was admitted with erythrodermic
psoriasis. She had a 40-year history of chronic plaque
psoriasis, previously treated with a variety of topical agents
and broadband ultraviolet B phototherapy. Family members
had previously reported excessive alcohol consumption,
although the patient denied this.
Initial blood results revealed normal renal and liver
function: alkaline phosphatase (ALP) 93 U L)1 (normal
40130), alanine aminotransferase (ALT) 12 U L)1 (normal
253), bilirubin 8 lmol L)1 (normal 317). Haemoglobin
(Hb) was 92 g dL)1, with normal platelet count and white
cell count (WCC). She was started on acitretin 25 mg twice
daily, with rapid reduction in erythema. However, 2 days
later her ALT had risen to 237 U L)1, ALP to 440 U L)1 and
bilirubin to 41 lmol L)1. Acitretin was stopped and ALT
returned to normal over 5 days. ALP peaked at 679 U L)1,
and remained elevated at 191 U L)1 6 months later. Seven
days after the acitretin was discontinued, the patients WCC
was 13 109 L)1 with a neutrophil count of 01 109 L)1
(normal 1575 109). Hb had dropped to 8 g dL)1; plate-
lets were 289 109 L)1 (normal 140400 109). Bone
marrow examination was reported to show features consis-
tent with early recovery from acute temporary agranulocy-
tosis, likely to have been drug-induced. The neutropenia was
managed conservatively and after 7 days her neutrophil
count rose to 06 109 L)1 and thereafter normalized. Before
discharge our patient noted that her hair had begun to shed
and 4 weeks later she had developed total scalp alopecia. Six
months later her hair had regrown.
Acitretin is a synthetic monoaromatic retinoid that is
commonly employed as a first-line agent for the treatment of
erythrodermic or pustular psoriasis. Hepatic toxicity and
 2003 British Association of Dermatologists, British Journal of Dermatology, 148, 10581087
CORRESPONDENCE 1063
alopecia are well-recognized side-effects of retinoid therapy,
but do not usually occur so rapidly after treatment is started.
Up to 30% of patients treated with acitretin develop raised
aminotransferase levels and 10% have elevations in ALP.
These abnormalities are generally mild and transient and
genuine toxic hepatitis is rare. Alopecia occurs less frequently
with acitretin than with etretinate, and such rapid and severe
alopecia has not been previously reported in the literature.
Etretinate alopecia has been shown to be a continuing telogen
effluvium coupled with an arrest at the onset of anagen.1
There are only two reports of retinoid-associated agranu-
locytosis, both related to isotretinoin and not to acitretin.2,3
Drug-induced agranulocytosis occurs either by a direct
suppressive effect on the bone marrow or by immune-
mediated destruction of circulating neutrophils. In our
patient the bone marrow examination supports the former
mechanism, as was the case in isotretinoin-induced neu-
tropenia.2
There are two possible mechanisms for this bone marrow
toxicity, cell cycle arrest or apoptosis, both of which are
reported as retinoid effects. Reported mechanisms of retinoid-
induced cell cycle arrest include inhibition of cyclin D1, D3, B1
and cyclin-dependent kinase (CDK) 2 and 4.4,5 Reported
retinoid proapoptotic mechanisms include induction of cera-
mide pathways,6 downregulation of transforming growth
factor-a gene expression,7 and activation of cyclin A and B
CDKs.8 Possible mechanisms specific to the marrow are
inhibition by retinoids of the antiapoptotic effects of both
granulocyte colony-stimulating factor and granulo-
cyte macrophage colony-stimulating factor on marrow pre-
cursor (CD34+) cells.9
The underlying mechanism for retinoid-induced alopecia is
unknown, but potential causes are as for marrow suppres-
sion, i.e. cell cycle arrest or apoptosis. Cell cycle arrest would
seem more likely, as the hair loss is of normal telogen hairs,1
not tapered as in anagen effluvium. Hepatotoxicity from
retinoids could also be the result of apoptosis, or be a direct
toxic effect causing necrosis, as demonstrated in animal
models.
Why did acitretin produce such profound toxicity in our
patient? An increased acitretin effect could result from
abnormally high intracellular concentrations of acitretin
itself and or increased concentrations of an active receptor-
binding metabolite. The dose of acitretin was relatively high
for an elderly patient, but the treatment time was only
2 days. Increased levels of active metabolites could result
from decreased catabolism of acitretin. The normal catabolic
process is not well described but involves oxidation and
glucuronidation to a variety of metabolites by several
microsomal cytochrome P450 isoenzymes. Our patient is
likely to have had a large alcohol intake prior to admission
and this may have contributed to decreased P450 activity. In
addition, chronic alcohol intake has been reported to induce
the P450 enzyme 2E1, which is responsible for the produc-
tion of toxic metabolites from environmental xenobiotics
including excess vitamin A.10 It is possible that there is a
similar effect on acitretin.
1064 CORRESPONDENCE
Department of Dermatology, Leicester T.A.Chave
Royal Infirmary, Infirmary Square, N.J.Mortimer
Leicester LE1 5WW, U.K. P.E.Hutchinson
E-mail: toby@chave.fsbuisness.co.uk
References
1 Berth-Jones J, Shuttleworth D, Hutchinson PE. A study of etreti-
nate alopecia. Br J Dermatol 1990; 122: 7515.
2 Stephen MAJ, Friedman J. Leukopenia and neutropenia associated
with isotretinoin therapy. Arch Dermatol 1987; 123: 2934.
3 Waisman M. Agranulocytosis from isotretinoin. J Am Acad Der-
matol 1988; 18: 3959.
4 Spinella MJ, Freemantle SJ, Sekula D et al. Retinoic acid promotes
ubiquitination and proteolysis of cyclin D1 during induced tumor
cell differentiation. J Biol Chem 1999; 274: 2201318.
5 Zhu WY, Jones CS, Kiss A et al. Retinoic acid inhibition of cell
cycle progression in MCF-7 human breast cancer cells. Exp Cell
Res 1997; 234: 2939.
6 Maurer BJ, Metelitsa LS, Seeger RC et al. Increase of ceramide and
induction of mixed apoptosis necrosis by N-(4-hydroxyphenyl)-
retinamide in neuroblastoma cell lines. J Natl Cancer Inst 1999;
91: 113846.
7 Nakamura N, Shidoji Y, Moriwaki H, Muto Y. Apoptosis in human
hepatoma cell line induced by 4,5-didehydro geranylgeranoic acid
(acyclic retinoid) via down-regulation of transforming growth
factor-alpha. Biochem Biophys Res Commun 1996; 219: 1004.
8 Hsu SL, Yin SC, Liu MC et al. Involvement of cyclin-dependent
kinase activities in CD437-induced apoptosis. Exp Cell Res 1999;
252: 33241.
9 Josefsen D, Blomhoff HK, Lomo J et al. Retinoic acid induces
apoptosis of human CD34+ hematopoietic progenitor cells:
involvement of retinoic acid receptors and retinoid X receptors
depends on lineage commitment of the hematopoietic progenitor
cells. Exp Hematol 1999; 27: 64253.
10 Lieber CS. Interaction of alcohol with other drugs and nutrients.
Implication for the therapy of alcoholic liver disease. Drugs 1990;
40: 2344.
Mucinous naevus with atypical features
SIR, Mucinous naevus is a rare entity classified as either
cutaneous mucinosis1,2 or a connective tissue naevus.3,4
Clinically, multiple brownish papules or plaques develop at
birth1 or in early adulthood,24 and grow to form verrucous
or naevoid features with a unilateral or often zosteriform
distribution on the trunk. The naevoid clinical features can be
confused with epidermal naevus, conventional connective
tissue naevus, naevus lipomatosus superficialis, or other
cutaneous harmatomas. Histologically, however, mucinous
naevus is characterized by mucin deposits localized in the
papillary dermis,15 clearly distinguishing this entity from
other types of cutaneous mucinosis. We report two patients
with mucinous naevus, one of whom presented with an
unusual clinical feature: a huge bag-like pedunculated mass.
Both cases showed increased numbers of collagen fibres in the
dermis, in addition to mucin deposits in the papillary dermis.
Patient 1. A 24-year-old man presented with multiple
grouped papules and plaques on his left buttock. The lesions
 2003 British Association of Dermatologists, British Journal of Dermatology, 148, 10581087
had appeared at the age of 10 years, and had slowly increased
in both size and number. He had not realized this problem
until one of the lesions rapidly grew into a huge pedunculated
mass that was twisted and caused him severe pain. On
examination, multiple brownish papules were noted, which
coalesced to form verrucous plaques in a naevoid arrange-
ment, and a huge bag-like pedunculated mass was observed
near the lower margin of these plaques (Fig. 1a). He denied
previous trauma at the site of the lesions, and there was no
family history of similar lesions. A multiple punch biopsy was
performed. Representative papules showed an acanthotic
epidermis with thin, elongated rete ridges, and mild hyper-
keratosis. In the papillary dermis, fine collagen fibres were
interspersed in an abundant background substance that
stained positively with alcian blue at pH 25 (Fig. 1c). Van
Gieson elastic stain showed an absence of collagen and of
elastic fibres in the mucinous area. Excision biopsy of the
pedunculated mass showed thick epidermal hyperplasia and
an increased number of collagen fibres with a vascular
proliferation in the dermis (Fig. 1d). Alcian blue staining was
weakly positive in the papillary dermis. Van Gieson elastic
staining and Masson trichrome staining demonstrated a
moderate increase in the number of collagen fibres, but not
of elastic fibres. The other lesions were treated by simple
excision and electrodesiccation. During 3 months of follow-
up, there was no recurrence.
Patient 2. A 30-year-old man presented with multiple
grouped, skin-coloured to brownish, soft plaques composed of
coalescent linearly distributed papules (Fig. 1b). Histopatho-
logically, representative plaques demonstrated an acanthotic
epidermis, an abundant background substance in the papil-
lary dermis and increased numbers of collagen fibres in the
mid and lower dermis. These findings were consistent with
mucinous naevus. The lesions were excised and did not recur
over 4 months of follow-up.
Mucinous naevus was first described by Redondo Bellon
et al. in 1993,1 and was determined to be a type of cutaneous
mucinosis. The term mucinous naevus was proposed
because of its naevoid appearance and characteristic pattern
of mucin deposits in the papillary dermis. The previously
reported cases of mucinous naevus and our two cases share
certain clinical features. They appear to consist of multiple
brownish, coalescent papules or plaques with a unilateral,
linear or zosteriform distribution.24 The lesions usually
develop at birth1 or in early adulthood,24 and the lower
part of the trunk is the most commonly affected site. The
naevoid features and early onset of mucinous naevus strongly
suggest that this entity is a type of connective tissue naevus.
The histopathological features of mucinous naevus are
unique, so it can easily be distinguished from other types of
cutaneous mucinosis. It shows homogeneous mucin deposits
completely occupying the uppermost portion of the dermis,
and therefore it can be detected as a band-like deposit in the
papillary dermis.1 As mucin staining gives a positive reaction
with alcian blue at pH 25, but is negative at pH 05, the
mucin in the lesion is thought to be composed of hyaluronic
acid.3 The origin of the mucin deposited in the lesion remains
 CORRESPONDENCE 1065

Figure 1. (a) Multiple grouped, brownish, verrucous papules and plaques distributed in a naevoid arrangement and a pedunculated mass at the
lower margin of the lesions on the left buttock (patient 1). (b) Multiple grouped, confluent plaques with a linear distribution on the lower back
(patient 2). (c) Positive staining with alcian blue at pH 25 in the papillary dermis (patient 1; original magnification 100). (d) Histology of the
huge pedunculated mass shows thick epidermal hyperplasia and an increased number of collagen fibres with vascular proliferation in the dermis
(patient 1; haematoxylin and eosin; original magnification 40).

unclear, but it seems to be the result of a primary metabolic
process (overproduction) rather than of a secondary catabolic
process.4 This idea is supported by the fact that in all reported
cases the lesions developed early in life, even at birth, without
evidence of trauma or a pre-existing pathological change at
the site of the lesions. In addition to the mucin deposits in the
papillary dermis, certain epidermal changes including ac-
anthosis, hyperkeratosis and elongation of the rete ridges
were seen in our cases as well as in most previously reported
cases.25 This alteration of the epidermis supports Rongioletti
and Reboras description of this entity as a harmatoma
combining features of an epidermal naevus with those of a
connective tissue naevus of proteoglycan type.5
Patient 1 is unusual in that along with the typical verrucous
papules and plaques there was an atypical lesion that developed
into a huge pedunculated mass. This has not been observed in
previous cases. We think that repeated pressure and minor
trauma on the buttock can give rise to secondary changes in the
lesion. On histopathological examination, this mass was
composed of increased numbers of collagen fibres and vascular
proliferation in the dermis, with mucin deposits in the papillary
dermis. The histopathological findings in patient 2 also showed
an increased number of collagen fibres in the dermis. These
findings suggest the possibility that dermal components, such
as collagen and vascular structures other than mucin, may
become elevated in some forms of mucinous naevus.

 2003 British Association of Dermatologists, British Journal of Dermatology, 148, 10581087

1066 CORRESPONDENCE
In conclusion, these two cases suggest a new possibility,
namely, that there is a simultaneous pathological
proliferation of more than two connective tissue compo-
nents (hyaluronic acid, collagen fibres and vessels) within
some lesions of mucinous naevus.
Department of Dermatology, J-H.Lim
Kangnam St Marys Hospital, College S-H.Cho
of Medicine, The Catholic University H-O.Kim
of Korea, 505 Banpo-dong, Seocho-ku, C-W.Kim
Seoul 137701, Korea. Y-M.Park
Correspondence: Young-Min Park.
E-mail: knderma@cmc.cuk.ac.kr
References
1 Redondo Bellon P, Vazquez-Doval J, Idoate M et al. Mucinous
nevus. J Am Acad Dermatol 1993; 28: 7978.
2 Suhr KB, Ro YW, Kim KH et al. Mucinous nevus: report of two cases
and review of the literature. J Am Acad Dermatol 1997; 37: 31213.
3 Brakman M, Starink TM, Tafelkruyer J et al. Linear connective
tissue naevus of the proteoglycan type (naevus mucinosis). Br J
Dermatol 1994; 131: 36870.
4 Rongioletti F, Rebora A. Mucinous nevus. Arch Dermatol 1996;
132: 15223.
5 Rongioletti F, Rebora A. Cutaneous mucinoses. Am J Dermatopathol
2001; 23: 25767.
Delayed presentation of persistent unilateral
cutaneous mottling of the arm following coarctation
of the aorta
SIR, We report a 12-year-old boy who presented with
persistent, nonpruritic white macules restricted to his left
arm. At age 15 months he had a cardiac murmur associated
with upper limb hypertension. This was confirmed by
echocardiography to be isolated coarctation of the aorta just
distal to the usual position (the site of the insertion of the
ductus arteriosus). The coarctation was treated urgently by
balloon angioplasty. Since then he has been well, is on no
regular medications, and regularly plays rugby.
Examination revealed scattered white macules of up to
10 mm diameter, restricted to the left arm (Fig. 1a). The
white macules disappeared on blanching the surrounding
skin and on elevation of the arm (Fig. 1b). Blood pressure
was 120 90 mmHg in the left arm and 120 87 mmHg
in the right arm. No change in the appearance of the
macules was seen when the blood pressure cuff was
inflated above systolic pressure on the left arm (Fig. 1c),
but the appearance became more marked with hyperaemia
on cuff deflation. The changes were also exaggerated
when the cuff was inflated to occlude venous return
(Fig. 1d). No murmurs were heard and there was no
radiofemoral delay. Neurological examination and a chest
X-ray were normal.
Echocardiography revealed no restenosis at the area of
previous coarctation. No abnormality of the arterial or venous
systems of the left arm was detected with Doppler ultrasound
 2003 British Association of Dermatologists, British Journal of Dermatology, 148, 10581087
studies. A magnetic resonance imaging scan showed no
stenosis at the site of previous angioplasty. A diagnosis of
unilateral cutaneous mottling of the arm was made.
In 1898 Bier described white spots on the forearm which
appeared with external compression occluding blood flow to
the arm.1 In 1922 Rehberg and Carrier stated that these
white spots were of two kinds, white spots and red spots.2 The
white spots were dependent on temperature and the red spots
were formed by collateral arterial blood from the medullary
branch (intraosseous) of the superior profunda artery which
is unaffected by external compression of the arm. Wolf further
divided the white spots into two types, one caused by cold-
induced contraction of superficial vessels and the other by
collateral arterial blood flow.3
More recently, Wilkin and Martin have undertaken laser
Doppler velocimetry studies on healthy volunteers and post
mortem subjects, aiming to solve the confusion behind the
aetiology of these vascular spots.4 They concluded that the
differences in colour were due to a venous capacitance
phenomenon with venoconstriction in the white areas and
venodilatation in the dark areas. This would explain the
exaggeration of the white macules in our patient when
venous return was occluded, and their disappearance on
increasing venous return (raising the arm).
A similar case in which all four limbs manifested white
macules was reported by Graham and James as exaggerated
physiological mottling of the limbs.5 The macules persisted
during experiments to block sympathetic nerve supply and
sweating and only cleared when the affected limbs were
immersed in warm water. They concluded that the cause was
an exaggerated physiological response of cutaneous arterioles
to local temperature changes and that this is a separate
phenomenon to Biers spots.
Are the changes in the left arm related to the coarctation of
the aorta or its treatment? The classical site of native
coarctation is the insertion of the ductus arteriosus just distal
to the left subclavian artery. Our patients coarctation was
just distal to the classical site and the haemodynamic effects
would be greatest in the left subclavian artery which supplies
the affected arm. Before balloon angioplasty the blood
pressure in his left arm was elevated in comparison with his
right arm (and markedly elevated above leg blood pressures).
This increased blood pressure may have affected the sympa-
thetic tone of the cutaneous arterioles in the left arm more
than in the right arm, leading to the unilateral appearance.
Years after repair of aortic coarctation, upper limb hyper-
tension may be seen during exercise, and is not caused by
anatomical narrowing but by enhanced sympathetic nerve
activity and response to this by precoarctation vessels.6 This
may explain the 10-year delay of cutaneous changes in our
patient which may have been exposed by his recent involve-
ment in rugby football.
Balloon angioplasty is an effective treatment for native
coarctation in most children over 12 months.7 Complications
include restenosis, aneurysm formation and cerebrovascular
accidents.8 The clinical appearance in our patient is difficult
to explain as a new complication. Our patient has certainly
 CORRESPONDENCE 1067

1 Figure 1. (a) Scattered white macules of up to 10 mm diameter, restricted to the left arm. (b) The white macules disappeared on elevation of the
arm. (c) No change in the appearance of the macules was seen when the blood pressure cuff was inflated above systolic pressure on the left arm. (d)
The changes were exaggerated when the cuff was inflated to occlude venous return.

 2003 British Association of Dermatologists, British Journal of Dermatology, 148, 10581087

1068 CORRESPONDENCE

benefited from the procedure and has no evidence of other producing Staphylococcus.3 Frozen-section histology of a
complications. blister roof is a method for differentiating between SSSS and
This case illustrates cutaneous mottling of the left arm TEN within minutes.4,5 In SSSS the epidermal cleavage is
which appears to be caused by differences in venous within the stratum granulosum and the blister roof should
capacitance between the two arms. We postulate that these comprise stratum corneum and a few granular cells. In TEN
changes are secondary to the vascular and sympathetic the blister roof generally comprises the whole of the epider-
nervous system effects of coarctation of the aorta affecting mis.4 Histology is often not necessary in rapidly improving
predominantly the vessels supplying the left arm. children. The more poorly responding adult disease may
result in a greater need for histology.
Department of Dermatology, I.C.Pearson We present a case of adult SSSS in which the blister roof
St Helier Hospital, Wrythe Lane, C.A.Holden histology had a spurious resemblance to that seen in TEN.
Carshalton SM5 1AA, UK. Recrudescence was a further unusual feature. A 53-year-old
E-mail: ianpearson@doctors.org.uk woman, 8 days postcessation of antibiotics for a chest infec-
tion and pressure sores, developed sudden-onset, rapidly
progressive, painful, tender erythroderma with extensive
References
sheet-like desquamation (Fig. 1a). The Nikolsky sign was
1 Bier A. Die Enstehung Collateralkreislaufs. Teil II. Der Ruckfluss des positive. There were no mucosal lesions. She was pyrexial,
Blutes aus ischamischen Korpertheilen. Arch Path Anat 1898; 153: tachycardic and hypotensive.
30634. Bacteriological culture from the pressure sores grew
2 Rehberg PB, Carrier EB. Studies on the physiology of capillaries. V. S. aureus; immunodiffusion assay for exfoliative toxin was
Concerning the reaction of the human skin capillaries to venous not performed, nor was staphylococcal phage typing. Blood
blood. Scand Arch Physiol 1922; 42: 25065.
3 Wolf EP. Local changes of colour in the skin deprived of its blood
supply. Heart 1924; 11: 32735.
4 Wilkin JK, Martin H. Biers spots reconsidered: a tale of two spots,
with speculation on a humerus vein. J Am Acad Dermatol 1986; 14:
41119.
5 Graham RM, James MP. Exaggerated physiologic speckled mottling
of the limbs. Arch Dermatol 1985; 121: 41517.
6 Guenthard J, Zumsteg U, Wyler F. Arm-leg pressure gradients on
late follow-up after coarctation repair. Possible causes and impli-
cations. Eur Heart J 1996; 17: 15725.
7 Mendelsohn AM, Lloyd TR, Crowley DC et al. Late follow-up of
balloon angioplasty in children with a native coarctation of the
aorta. Am J Cardiol 1994; 74: 696700.
8 Treacy EP, Duncan WJ, Tyrrell MJ, Lowry NJ. Neurological com-
plications of balloon angioplasty in children. Pediatr Cardiol 1991;
12: 98101.

Adult staphylococcal scalded skin syndrome:

histological pitfalls and new diagnostic perspectives

SIR, Staphylococcal scalded skin syndrome (SSSS) is an

extensive desquamative erythematous condition caused by
circulating exfoliative toxins produced by Staphylococcus
aureus. The condition usually affects children and generally
responds rapidly to antibiotic therapy. SSSS is rare in adults
due to the increased capacity of mature kidneys for exfoliative
toxin excretion. Adult SSSS is usually associated with renal
impairment or immune deficiency,1 and prognosis is poorer,
with a reported mortality of over 50%.1
Distinction between SSSS and toxic epidermal necrolysis
(TEN) is vital. Antibiotic therapy is indicated in SSSS, whereas
Figure 1. (a) Erythroderma. Sheet-like desquamation is evident over
in TEN routine administration may be associated with a
the lower chest. (b) Frozen-section histology of shed membrane: the
worse prognosis.2 Differentiation of SSSS from TEN is usually basket-weave stratum corneum overlies a cohesive multilayered
made clinically by the absence of mucosal lesions, the absence squamous layer. However, the latter does not show the characteris-
of risk factors for TEN (notably drugs), and the rapid tics of stratum Malpighii, but is entirely composed of agglomerated
therapeutic response. Confirmation of the diagnosis is by mature squames, with no parabasal or basal layer (haematoxylin and
histology and by bacteriological culture of an exfoliatin- eosin; original magnification 200).

 2003 British Association of Dermatologists, British Journal of Dermatology, 148, 10581087


culture was negative. Retrospective assay for exfoliative toxin
A on stored serum was negative. Analysis of immunoglob-
ulins, complement levels, differential lymphocyte count and
neutrophil oxidative burst assay showed no immunodefi-
ciency. Serum pemphigus and pemphigoid antibody assays
were negative. The corrected glomerular filtration rate was
7209 mL min)1 per 173 m2 (normal 80120).
A diagnosis of adult SSSS was made and she was treated
with intravenous cefuroxime, fluid replacement, and nursed
on an air-flow mattress. Topical fusidic acid 2% cream was
applied under a fenestrated nonadhesive silicone dressing
(Mepitel; Molnlycke, Dunstable, U.K.). Within 12 h there
was significant improvement. The erythroderma settled over
a few days, clinically confirming the diagnosis of SSSS.
However, a recrudescence following switching to oral cefaclor
necessitated a repeat course of intravenous cefuroxime, plus
triclosan 2% soaks, and topical 2% mupirocin ointment to the
nasal septum for staphylococcal eradication.
Blister roof was sampled for histology during the initial
desquamative episode, 8 h after commencement of antibiotic
therapy. Frozen-section histology at first gave a confusing
impression of shed full-thickness epidermis (Fig. 1b), unlike
SSSS. Later, the frozen section block was fixed in formalin,
and standard paraffin-block histology prepared. This showed
the confusing histology to be due to agglomeration of
subsequently shed superficial squames (lacking parabasal
and basal layers) to the originally cleaved stratum corneum,
entirely consistent with SSSS. On review, this could be
discriminated from true full-thickness desquamation, even on
the frozen section.
Staphylococcal exfoliatins A and B target desmoglein 1 (the
same desmosomal adhesion molecule targeted in pemphigus
foliaceus).6 Traditional immunological and bioassay methods
of demonstrating staphylococcal exfoliatins from S. aureus
culture take several days. Techniques for purification of the
toxins from culture within 36 h,7 and for isolating exfoliatin
A from serum within hours,8 are not yet routinely available.
Amon and Dimond described histology of a fresh Nikolsky-
induced blister roof.4 We sampled spontaneously cleaved
semidetached membrane, several hours old. In this situation,
there would have been some further desquamation from the
denuded stratum Malpighii; in the presence of serous exudate
and topical creams, such shed squames would tend to adhere
to each other and also to the membrane, hence giving rise to
the confusing histology. However, once this pitfall is recog-
nized, diagnosis should not be difficult. Standard full-thick-
ness skin biopsy histology avoids this pitfall, and allows
immunofluorescence to rule out immunobullous disorders.
However, that procedure may be delayed due to the practical
difficulties in performing a biopsy on a ward, particularly if at
night or over a weekend. Therefore, blister roof histology may
still be a useful preliminary test.
SSSS in immunocompetent adults with normal renal
function has previously been reported only rarely.9 In our
patient with mild renal impairment, possibly the degree of
S. aureus colonization toxin production was pivotal, perhaps
also accounting for the recrudescence of the disease, another
phenomenon only rarely described previously.10
 2003 British Association of Dermatologists, British Journal of Dermatology, 148, 10581087
CORRESPONDENCE 1069
Given the poor prognosis of adult SSSS, vigilance for
recrudescence is necessary, even days after clinical healing.
Departments of *Dermatology and C.M.Dobson*
Histopathology, Royal Liverpool C.M.King*
University Hospital, Prescot Street,
Liverpool L7 8XP, U.K.
E-mail: cdobson8@hotmail.com
References
1 Farrell AM, Ross JS, Umasankar S, Bunker CB. Staphylococcal
scalded skin syndrome in an HIV-1 seropositive man. Br J Der-
matol 1996; 134: 9625.
2 Schulz JT, Sheridan RL, Ryan CM et al. A 10-year experience with
toxic epidermal necrolysis. J Burn Care Rehabil 2000; 21: 199
204.
3 Hardwick N, Parry CM, Sharpe GR. Staphylococcal scalded skin
syndrome in an adult. Influence of immune and renal factors. Br J
Dermatol 1995; 132: 46871.
4 Amon RB, Dimond RL. Toxic epidermal necrolysis. Rapid differ-
entiation between staphylococcal- and drug-induced disease. Arch
Dermatol 1975; 111: 14337.
5 Roujeau JC, Chosidow O, Saiag P, Guillaume JC. Toxic epidermal
necrolysis (Lyell syndrome). J Am Acad Dermatol 1990; 23: 1039
58.
6 Amagai M, Yamaguchi T, Hanakawa Y et al. Staphylococcal
exfoliative toxin B specifically cleaves desmoglein 1. J Invest
Dermatol 2002; 118: 84550.
7 Ladhani S, Cameron J, Chapple DS et al. A novel method for rapid
production and purification of exfoliative toxin A of Staphylococcus
aureus. FEMS Microbiol Lett 2002; 212: 359.
8 Ladhani S, Robbie S, Garratt RC et al. Development and evaluation
of detection systems for staphylococcal exfoliative toxin A respon-
sible for scalded-skin syndrome. J Clin Microbiol 2001; 39: 20504.
9 Cribier B, Piemont Y, Grosshans E. Staphylococcal scalded skin
syndrome in adults. A clinical review illustrated with a new case.
J Am Acad Dermatol 1994; 30: 31924.
10 Shelley ED, Shelley WB, Talanin NY. Chronic staphylococcal
scalded skin syndrome. Br J Dermatol 1998; 139: 31924.
Sarcomatoid carcinoma of the liver with skin
and pleural metastases
SIR, We report an interesting case of sarcomatoid carcinoma
of the liver with skin metastases. A 53-year-old Japanese man
with liver cirrhosis due to alcohol abuse presented with
asymptomatic cutaneous nodules that had developed over a
5-month period. Examination showed five 152-cm reddish-
coloured hard cutaneous nodules on his face and head
(Fig. 1a). He also had venous varix of the oesophagus due to
liver cirrhosis, a 4-cm tumour of the S6 segment of the liver
(Fig. 2a), and osteolytic lesions of the left pelvis and the right
small trochanter, which strongly suggested metastasis.
Laboratory tests showed liver dysfunction (aspartate amino-
transferase 46 U L)1, alanine aminotransferase 41 U L)1,
c-glutamyltransferase 106 U L)1), leucopenia (white cell
count 26 109 L)1) and thrombocytopenia (platelet count
36 109 L)1). Hepatitis B surface antigen, antihepatitis C
antibody and serum level of a-fetoprotein (AFP) were within
 1070 CORRESPONDENCE
Figure 1. (a) An ulcerated nodule on the face. (b) Histologically, the
neoplastic cell proliferation involves subcutaneous fatty tissue and the
orbicular muscle of the mouth. Necrosis is seen in the central part of
the tumour (haematoxylin and eosin). (c) Higher magnification of (b),
rectangular area, shows that the tumour consists of atypical spindle
cells with a mainly storiform pattern (haematoxylin and eosin).
normal limits. Two years prior to the development of
cutaneous lesions, a 15-cm, irregularly demarcated, low-
density intrahepatic mass with marginal enhancement was
detected by computed tomography (CT) at the S6 segment of
the liver, and percutaneous ultrasonically guided needle
biopsies of the liver mass had been performed twice.
Incisional biopsy of a facial nodule showed aggregation of
atypical spindle cells that mostly demonstrated a storiform
pattern with invasion into the orbicular muscle of the mouth
(Fig. 1b,c). There was necrosis at the centre of the nodule.
Needle biopsy of the liver tumour showed spindle cells that
proliferated with a storiform pattern, similar to cells from the
skin lesion (Fig. 2b). Immunohistochemical staining of neo-
plastic cells of the liver (Fig. 2c) and the skin were strongly
1 positive for cytokeratin (CAM 5.2; Dako Glostrup, Denmark),
and weakly positive for vimentin (clone V9; Dako) and
 2003 British Association of Dermatologists, British Journal of Dermatology, 148, 10581087
a1-antitrypsin (Dako). Staining for CD34 (Becton Dickinson,
Mountain View, CA, U.S.A.), S-100 (Dako), desmin (D33;
Dako), neurone-specific enolase (V1-H14; Dako), carcino-
embryonic antigen (CEA; Mochida, Tokyo, Japan), AFP
(Dako) and epithelial membrane antigen (clone E29; Dako)
was negative in both liver and skin specimens. The skin
nodules were diagnosed as metastatic liver cancer. Aggres-
sive therapy could not be performed because of his other
medical problems. One month later he died of respiratory
insufficiency due to pleural metastasis. A post mortem could
not be performed.
Skin metastases from hepatocellular carcinoma (HCC) or
cholangiocellular carcinoma (CCC) are extremely rare. In
large studies by Brownstein and Helwig1 and Lookingbill
et al.,2 skin metastases of liver carcinoma were seen in only
four cases (04%) among 1144 patients with metastatic skin
cancers. Skin metastasis from HCC occurs as a terminal
event, and the average survival after skin metastasis was
reported to be 6 months.3
HCC and CCC have some histological variations, and
anaplastic sarcomatoid change is known to occur, with a
reported frequency of 2239%.46 Histologically, sarcoma-
toid carcinoma of the liver is characterized by atypical spindle
cells that proliferate with a prominent storiform pattern and
multinucleated giant cells, and it often coexists with ordinary
HCC rather than CCC.5 However, sarcomatoid carcinoma
without the coexistence of HCC or CCC has also been reported.7
Such cases should be differentiated from true sarcoma such as
malignant fibrous histiocytoma (MFH), which has also occa-
sionally been reported as arising in the liver. MFH developing
in the liver shows spindle-shaped cells with a variable
pleomorphism and storiform pattern, as does ordinary MFH
of the soft tissue.8 Positive expression of both CEA and AFP
may be helpful to diagnose sarcomatoid carcinoma of the
liver;5 however, these markers have also been reported to be
absent.9 Recently, the epithelial differentiation marker CAM
5.2, which recognizes intermediate filament cytokeratin 8, 18
and 19, has been shown to be expressed in neoplastic spindle
cells of sarcomatoid liver cancers.6,7,9 Cytokeratin 8 and CAM
5.2 have been recommended for use in differentiating sarco-
matoid carcinoma of the liver from true sarcomas.6 In our
case, strong expression of cytokeratin (CAM 5.2) was seen in
neoplastic cells of the liver and the skin.
Clinically, sarcomatoid HCC frequently metastasizes to
distant organs.5 So far, only one case of sarcomatoid HCC
with skin metastasis has been reported, in which all meta-
static lesions, including those to the skin, heart and intestinal
tract, demonstrated sarcomatoid neoplastic cell proliferation.
Nevertheless, the primary HCC of the liver consisted of equal
amounts of trabecular and sarcomatoid lesions.10 In our case,
sarcomatoid neoplastic cells, probably derived from HCC or
CCC, might have developed at the metastasis sites, and
ordinary HCC or CCC might have coexisted in the liver. It was
difficult to make a precise diagnosis at an early stage. Careful
diagnosis will be required when spindle-cell proliferation is
seen in liver biopsies, and repeat biopsies and follow-up CT
will be required.

Figure 2. (a) Computed tomographic
scanning shows a 4-cm irregularly shaped
low-echo mass (arrows) with marginal
enhancement at the S6 segment of the liver.
(b) Needle biopsy of the liver tumour shows
spindle cells with a storiform pattern
(haematoxylin and eosin). (c) Immunohisto-
chemical staining of neoplastic cells of the
liver shows strong positivity for cytokeratin
(CAM 5.2).
Departments of Dermatology and W.Nishie
*Internal Medicine, Kin-ikyo Sapporo M.Iitoyo
Hospital, Kikusui 4-1-9-22, T.Koshiyama*
Shiroishi-ku, Sapporo 003-8510, T.Kusama
Japan, and Department of Internal
Medicine, Kin-ikyo Central Hospital,
Sapporo, Japan.
E-mail: wataru@seagreen.ocn.ne.jp
References
1 Brownstein MH, Helwig EB. Metastatic tumors of the skin. Cancer
1972; 29: 1298307.
2 Lookingbill DP, Spangler N, Helm KF. Cutaneous metastases in
patients with metastatic carcinoma: a retrospective study of 4020
patients. J Am Acad Dermatol 1993; 29: 22836.
3 Knight TE. Hepatocellular carcinoma invasive to chest wall. Int J
Dermatol 1992; 31: 2736.
4 Nakashima T, Okuda K, Kojiro M et al. Pathology of hepatocel-
lular carcinoma in Japan. Cancer 1983; 51: 86377.
5 Kakizoe S, Kojiro M, Nakashima T. Hepatocellular carcinoma with
sarcomatous change. Cancer 1987; 59: 31016.
6 Haratake J, Horie A. An immunohistochemical study of sarco-
matoid liver carcinomas. Cancer 1991; 68: 937.
7 Eriguchi N, Aoyagi S, Okuda K et al. Unusual liver carcinomas
with sarcomatous features: analysis of four cases. Surg Today
2001; 31: 5303.
8 Fujita S, Lauwers GY. Primary hepatic malignant fibrous histio-
cytoma: report of a case and review of the literature. Pathol Int
1998; 48: 2259.
9 Oda Y, Katsuda S, Nakanishi I. An autopsy case of hepatic sar-
comatoid tumor: immunohistochemical comparison with a sar-
comatous component of hepatocellular carcinoma. Pathol Int
1994; 44: 2306.
10 Tsujimoto M, Aozawa K, Nakajima Y, Kariya M. Hepatocellular
carcinoma with sarcomatous proliferation showing an unusual
and wide-spread metastasis. Acta Pathol 1984; 34: 83945.
 2003 British Association of Dermatologists, British Journal of Dermatology, 148, 10581087
CORRESPONDENCE 1071
Exudative hyponychial dermatitis associated
with capecitabine and docetaxel combination
chemotherapy for metastatic breast carcinoma:
report of three cases
SIR, Capecitabine is a novel selective fluoropyrimidine carba-
mate chemotherapeutic agent, producing clinically active
levels of fluorouracil at tumour sites through the action of
thymidine phosphorylase.1 It is the only effective treatment
for patients with advanced or metastatic breast carcinoma in
whom anthracycline or taxoid treatment has failed.1 In
addition to fatigue, diarrhoea, nausea and vomiting, cutane-
ous adverse effects of capecitabine include handfoot syn-
drome, onychomadesis and onycholysis.2
Taxoids, including paclitaxel and docetaxel, represent
another novel class of antineoplastic drugs and share a
similar mechanism of action, with depolymerization inhibi-
tion of tubulin, showing superior antitumour activity.3 The
clinical use of docetaxel as a single agent or in combination
with other cytotoxic drugs gave favourable response rates for
metastatic or locally advanced breast cancer, ovarian cancer
and non-small cell lung cancer.3 Cutaneous adverse effects
may occur in 5070% of patients, and include maculopap-
ular rash, erythema and oedema followed by desquamation,
dry skin, fixed erythrodysaesthesia, acral erythema and
alopecia.4
The combination of capecitabine and docetaxel is a
potential treatment for metastatic breast cancer, colorectal
cancer and adenocarcinoma of unknown primary, with
significantly superior efficacy in overall survival compared
with docetaxel (145 vs. 115 months).1,5 The synergistic or
additive effects of this combination chemotherapy may be
due in part to the upregulation of thymidine phosphorylase
by the cytotoxic agents.1 The major systemic toxicity is
1072 CORRESPONDENCE

neutropenia, observed at all dose levels in 68% of all

treatment courses.1 Cutaneous side-effects include alopecia,
handfoot syndrome and nail toxicity.1 The incidence of nail
toxicity is approximately 26%; the changes consist of
discoloration, ridging, onycholysis and paronychia.1 We
describe the development of an unusual nail toxicity,
exudative hyponychial dermatitis, in three women with
metastatic breast carcinoma treated with the combination of
capecitabine and docetaxel.
Three Taiwanese women, aged 40, 52 and 50 years, all
having breast cancer with distal metastases, had been treated
with modified radical mastectomy, radiotherapy and multiple
courses of chemotherapeutic regimens, including cyclo-
phosphamide, epirubicin, 5-fluorouracil, mitomycin-c, paclit-
axel and vinorelbine. Due to recalcitrant courses, the above
chemotherapeutic agents were discontinued for 2 weeks,
2 weeks and 3 months, respectively, and combination ther-
apy was performed with oral capecitabine (Xeloda, Roche)
1250 mg m)2 twice daily for 2 weeks at 3-week intervals
and intravenous docetaxel (Taxotere, Aventis) 75 mg m)2
on the first day of each treatment course.5 Handfoot
syndrome developed after 4 weeks, 5 days and 6 weeks,
respectively. Nail changes (Fig. 1) included onycholysis,
subungual hyperkeratosis and transparent malodorous non-
viscous exudative discharge from all fingernails and or toe-
nails, especially upon squeezing. Microbiological examination
revealed colonization by Klebsiella, Enterococcus, Pseudomonas
and Citrobacter in the first patient and coagulase-negative
Staphylococcus in the second patient. No fungal infection was
identified. Treatment was initiated with soaking the nails
with 05% potassium permanganate solution and application
of garamycin ointment. The hyponychial exudation and
onychomadesis gradually resolved after cessation of docetaxel
for 12 months, in spite of the continuing use of capecitabine.
Nail biopsy for further diagnosis was recommended, but was
refused by all three patients.
The exudative hyponychial dermatitis seen in our patients
was unique in that exudation coexisted with subungual
hyperkeratosis and onycholysis. Similar findings have been
described by Zaias in a mechanic with psoriasiform dermatitis
involving the fingertips, hyponychium and distal nail bed for
2 years.6 In that case, contact dermatitis was suspected, but Figure 1. (a) Patient 1: exudative hyponychial dermatitis with
skin patch testing of all suspected solvents in use gave onycholysis and transparent non-viscous exudative discharge of the
negative results. Profuse exudation of serum-like material ring and little fingers of the right hand. (b) Patient 2: onycholysis,
was the characteristic histopathological feature.6 In our discoloration and multiple Beaus lines of the fingers of the right
cases, the onycholysis could be due to the following reasons: hand. (c) Patient 3: onycholysis, subungual hyperkeratosis, discol-
(i) damage of the nail bed epithelium with epidermolysis and oration and multiple Beaus lines of the fingers of the right hand.
loss of adhesion between nail bed and nail plate; (ii) complete
destruction of epithelium with formation of haemorrhagic
bulla; or (iii) inhibition of angiogenesis.7,8 The serum-like secondary bacterial infection of onycholysis associated with
material was believed to lift up the nail bed and to generate a chemotherapy,10 seemed to be of some help in our patients.
potential site for secondary bacterial infection. Finally, the The incidence of nail changes caused by capecitabine is still
erosive process in the nail bed may lead to onychomadesis. ill-defined.2 Nail changes associated with taxoids, primarily
The risk of developing nail toxicities might be more related to docetaxel, have been reported in up to 3040% of patients.9
the dosing interval rather than to the highest single dose Nail changes caused by docetaxel include dark pigmentation,
administered.9 Treatment with gentamicin solution or dilute Beaus lines, subungual haemorrhage, subungual abscess,
vinegar (025% acetic acid), as recommended by Daniel for orange discoloration, acute paronychia, onycholysis, subun-

 2003 British Association of Dermatologists, British Journal of Dermatology, 148, 10581087


gual hyperkeratosis and onychomadesis.6,7 Paclitaxel was
less commonly associated with nail changes, with pigmenta-
tion, discoloration of the nail bed and onycholysis occurring
in 2% of patients.9 In our patients, both capecitabine and
docetaxel contributed to onychomadesis and onycholysis,
while exudative hyponychial dermatitis seemed to be much
more related to docetaxel.
Acknowledgements
We gratefully acknowledge the valuable suggestions of Prof.
J.Yu-Yun Lee during preparation of the manuscript.
Departments of *Dermatology and G-Y.Chen*
Surgery, College of Medicine, T-W.Chang
National Cheng Kung University, W-C.Chen*
138 Sheng-Li Road,
Tainan 704, Taiwan
Department of Dermatology, Armed
Forces Taichung General Hospital,
348, Sec. 2, Chung-Shan Road,
Tai-Ping, Taichung 411, Taiwan
Correspondence: WenChieh Chen.
E-mail: wchen@mail.ncku.edu.tw
References
1 Pronk LC, Vasey P, Sparreboom A et al. A phase I and pharmaco-
kinetic study of the combination of capecitabine and docetaxel in
patients with advanced solid tumours. Br J Cancer 2000; 83: 229.
2 Chen GY, Chen YH, Hsu ML et al. Onychomadesis and onycholysis
associated with capecitabine. Br J Dermatol 2001; 145: 5212.
3 Pazdur R, Kudelka AP, Kavanagh JJ et al. The taxoids: paclitaxel
(Taxol) and docetaxel (Taxotere). Cancer Treat Rev 1993; 19:
35186.
4 Pavithran K, Doval DC. Nail changes due to docetaxel. Br J Der-
matol 2002; 146: 70910.
5 Shaughnessy JO, Miles D, Vukelja S et al. Superior survival with
capecitabine plus docetaxel combination therapy in anthracy-
cline-pretreated patients with advanced breast cancer. J Clin Oncol
2002; 20: 281223.
6 Zaias N. The Nail in Health and Disease. New York: SP Medical
Books, 1990.
7 Piraccini BM, Tosti A. Drug-induced nail disorders. Drug Saf 1999;
21: 137201.
8 Battegay E. Angiogenesis: mechanistic insights, neovascular dis-
ease, and therapeutic prospects. J Mol Med 1995; 73: 33346.
9 Flory SM, Solimando DA Jr, Webster GF et al. Onycholysis asso-
ciated with weekly administration of paclitaxel. Ann Pharmacother
1999; 33: 5846.
10 Daniel CR. Onycholysis: an overview. Semin Dermatol 1991; 10:
3440.
Acute pigmentation due to minocycline therapy in
atopic dermatitis
SIR, Minocycline is widely prescribed to treat acne vulgaris,
rosacea and superficial cutaneous infections. However, long-
 2003 British Association of Dermatologists, British Journal of Dermatology, 148, 10581087
CORRESPONDENCE 1073
term use of minocycline may result in cutaneous and dental
pigmentation.14 The length of administration of minocycline
before pigmentation developed ranged from 3 months to
5 years in these studies. We report nine patients with atopic
dermatitis who developed diffuse cutaneous pigmentation
after relatively short-term minocycline therapy, 328 days.
Their details are listed in Table 1.
The patients comprised four men and five women, age
range 1937 years. All had had atopic dermatitis for at least
10 years (range 1035). Their atopic dermatitis deteriorated
after the age of 15 years and spread to their face, neck, trunk
and extremities. They had exudative erythema on the face,
pigmented erythematous scales on the neck, and exudative
erythrodermic erythema on the trunk and extremities with
lichenified lesions. These features are characteristic of the
adult type of atopic dermatitis5 that has recently become
common in Japan. Oral minocycline was prescribed in seven
patients for superficial skin infections and in two patients for
tonsillitis and fever of unknown origin, respectively. Pigmen-
tation appeared after administration of oral minocycline for a
mean SD duration of 12 7 days (range 328). The mean
SD total dose of minocycline given before onset of the
abnormal pigmentation was 35 40 g (range 09140).
None of the patients had hypertriglyceridaemia. An intense
black pigmentation appeared on their faces (Fig. 1) and necks
as well as their trunks and extremities. Dental pigmentation
was not found in our patients.
We report acute pigmentation caused by minocycline in
patients with adult-type atopic dermatitis. The pigmentation
appeared after administration of minocycline for a shorter
period of time than in previous reports, in which most cases
developed after 372 months (total dose 9365 g) of
minocycline therapy for acne vulgaris, acne rosacea and
persistent exudative dermatitis. Ridgway et al. reported a
patient with bronchoectasia in whom skin pigmentation
was induced after 9 weeks (total dose 126 g) of minocy-
cline treatment.6 A patient with Mycobacterium chelonae
infection, reported by Fenske et al.,7 developed skin pigmen-
tation after 3 weeks (total dose 9 g) of treatment with
minocycline. The latter two patients developed pigmentation
after a shorter period of minocycline therapy. All our patients
showed exudative erythematous lesions over the entire body.
Seven of our nine patients had superficial bacterial skin
infections. The mechanism of the acute skin pigmentation is
difficult to explain at present. Superficial bacterial skin
infection might play some role in inducing skin pigmenta-
tion. Siderosis is implicated in the pathogenesis of skin
pigmentation induced by minocycline. Okada et al.2 demon-
strated minocycline in the pigmented skin by high-perform-
ance liquid chromatography. Iron in the pigmentation may
bind to minocycline or minocycline metabolites. In our
patients, the inflammatory process including superficial
bacterial infection may damage elastic fibres supporting
lymphatic function in the dermis, causing delay of lympha-
tic clearance of abnormal products. Delayed clearance of
minocycline complexes in the skin may have resulted in
acute strong pigmentation in our patients, where strong
1074 CORRESPONDENCE

Table 1. Patients with atopic dermatitis who developed pigmentation after receiving minocycline treatment
Patient no. Sex age (years) Total dose (g) Period (days) Focus Associated organism
1 F 19 32 16 Skin Staphylococcus aureus
2 F 20 28 28 Skin ND
3 F 35 30 15 Tonsil a-haemolytic Streptococcus
4 M 27 18 9 FUO ND
5 M 31 09 9 Skin Staphylococcus aureus
6 M 32 140 3 Skin Acinetobacter lwoffi
7 M 37 14 7 Skin Staphylococcus aureus
8 F 31 14 7 Skin ND
9 F 21 28 14 Skin Staphylococcus aureus

ND, not determined; FUO, fever of unknown origin.

References
1 Rondnes S, Baster W, Kohnen PW. Localized hemosiderosis as a
sequela of acne. Acta Dermatol 1978; 114: 16957.
2 Okada N, Moriya K, Nishida K et al. Skin pigmentation associated
with minocycline therapy. Br J Dermatol 1989; 121: 24754.
3 Ridgway HB, Reizner GT. Acquired pseudo-Mongolian spot
associated with minocycline therapy. Arch Dermatol 1992; 128:
5656.
4 Dwyer CM, Cuddihy AM, Kerr REI et al. Skin pigmentation due to
minocycline treatment of facial dermatoses. Br J Dermatol 1993;
129: 15862.
5 Nishioka K. Atopic eczema of adult type in Japan. Australas J
Dermatol 1996; 37 (Suppl. 1): S79.
6 Ridgway HA, Sonnex TS, Kennedy CTC et al. Hyperpigmentation
associated with oral minocycline. Br J Dermatol 1982; 107: 95
102.
7 Fenske NA, Millns JL, Geer KE. Minocycline-induced pigmentation
at sites of cutaneous inflammation. JAMA 1980; 244: 11036.

Phakomatosis pigmentokeratotica associated

with hypophosphataemic vitamin D-resistant rickets:
improvement in phosphate homeostasis after partial
laser ablation

SIR, The term epidermal naevus syndrome (ENS) is applied to

a group of phenotypically distinct syndromes having an
association of an epidermal naevus with various neurological,
ophthalmological and skeletal anomalies. A relatively recent
addition to this group has been named phakomatosis
pigmentokeratotica (PP), which comprises a sebaceous nae-
vus (SN), speckled and lentiginous naevi, hemiatrophy and
neurological defects.1
Figure 1. Patient 1: facial pigmentation developed after 16 days of Rarely, vitamin D-resistant rickets has been described in
minocycline therapy. association with the ENS.25 It has been proposed that this
is a type of tumour-induced osteomalacia, which is a rare
inflammatory processes including superficial bacterial infec- association of a mesenchymal neoplasm with vitamin
tion played an important role. D-resistant rickets. We report the first case of PP with
associated hypophosphataemic vitamin D-resistant rickets
Department of Dermatology and S.Nakamura (HVRR). Carbon dioxide (CO2) laser ablation of the SN
Environmental Immunodermatology, H.Yokozeki resulted in improvement of phosphate homeostasis, confirm-
Tokyo Medical and Dental University, K.Nishioka ing the lesion as the cause of the hypophosphataemia.
Yushima 1-5-45, Bunkyoku, Tokyo A 22-year-old man, born at term to nonconsanguineous
1138519, Japan. parents, presented with multiple pigmented skin lesions and
E-mail: ruggle@msn.com bony deformities. Since birth, he had numerous, light brown

 2003 British Association of Dermatologists, British Journal of Dermatology, 148, 10581087


areas of speckled pigmentation, mostly localized to the left
side of the body, on the neck, shoulder, arm, lower back and
thigh. Several 025 cm deeply pigmented papules and
plaques, some with overlying coarse hair, were also present.
A large brownish lesion on the left cheek was observed at the
age of 3 years, which became corrugated and reddish-tan in
colour at puberty (Fig. 1a). There was no relevant family
history. A biopsy from a hairy pigmented lesion revealed the
characteristic histopathology of a congenital melanocytic
naevus, and the facial lesion was confirmed to be an SN.
Since the age of 2 years, he had seen several physicians for
bone pains, myalgia and progressive bony deformities. Repea-
ted investigations at ages 2, 5, 8 and 11 years had revealed
radiological changes consistent with rickets. Serum calcium
had been normal, but serum phosphate levels had been in the
low normal range (2228 mg dL)1). Serum alkaline phos-
phatase and urinary phosphate levels had been raised
throughout. Sporadic HVRR was diagnosed when continuous
high-dose vitamin D (4000 IU daily to 600 000 IU weekly)
and oral phosphate supplementation produced only mild
symptomatic improvement, with persistently low serum
phosphate.
At presentation, he had severe musculoskeletal deformities,
including short stature (< 5th centile), partial hemiatrophy
in the form of hypoplasia of the left deltoid, trapezius and
pectoralis muscles, noncorrectable kyphosis and dextrosco-
liosis of the dorsal spine, lumbar lordosis, ulnar deviation of
the forearms, and severe bilateral anterior bowing of the
legs (Fig. 1b). A skeletal survey revealed diffuse osteopenia,
two collapsed lumbar vertebrae, anterior bowing of both
tibiae and evidence of old healed rickets in almost all long
bones. Neurological evaluation was unremarkable except
for mild weakness of the left arm. Ophthalmological exam-
ination and a computed tomographic scan of the head were
normal.
Figure 1. (a) Facial naevus sebaceus with
speckled and lentiginous naevus on the neck,
shoulder and upper arm. (b) Short stature,
hypoplasia of the left shoulder and chest
region, and anterior bowing of legs.
 2003 British Association of Dermatologists, British Journal of Dermatology, 148, 10581087
CORRESPONDENCE 1075
Biochemistry for calcium-phosphate homeostasis revealed
serum calcium 78 mg dL)1 (normal 811), serum phosphate
24 mg dL)1 (normal 254), alkaline phosphatase 46 U dL)1
(normal 514), urinary phosphate 25803600 mg day)1
(normal 600800) and normal serum parathyroid hormone
levels. Liver and kidney function tests were within normal
limits. A diagnosis of PP with HVRR was made.
The patient was advised to continue oral phosphate,
calcium and vitamin D supplementation and a partial CO2
laser ablation of the facial SN was done, removing about 50%
of the lesion. Three days after ablation, there was a rise in
serum phosphate, which reached the low normal range
(28 mg dL)1), and a marked fall in urinary phosphate
excretion (1400 mg day)1). Complete ablation of the SN is
planned, and the patient continues to be followed.
Tumour-associated rickets with osteomalacia is a rare but
well-recognized association of various tumours with HVRR.
Since 1959, when Prader et al.6 reported an 11-year-old girl
with rickets that healed after excision of a giant-cell granu-
loma of the rib, fewer than 85 patients with tumour-
associated rickets have been reported.7 Most patients had
mesenchymal tumours, with more than 50% having bony
tumours, although ectodermal tumours of the breast and
prostate, and oat cell carcinomas have also been reported.
To explain this phenomenon, it has been suggested
that these tumours release products that impair renal
1a-hydroxylation of calcidiol and phosphate transport.
Animal experiments have provided positive proof of this,
with phosphaturia seen in animals transplanted with tumour
tissue from these patients.8 This phosphate-wasting factor has
been named phosphatonin by Econs and Drezner,9 although
it is still to be identified.
To our knowledge, this is the 11th case report of an
association of ENS with HVRR, and the first report of the PP
type of ENS with this metabolic abnormality. Characteristic
1076 CORRESPONDENCE
biochemical features present in all reported patients inclu-
ding the index case were recalcitrant rickets with persistently
low serum phosphate, normal parathyroid hormone and
dietary phosphorus, phosphaturia, low normal serum cal-
cium and elevated alkaline phosphatase levels. Low to
undetectable levels of calcitriol and normal calcidiol levels
are also characteristic, but these could not be measured in
our patient due to financial constraints. As there was no
history of parental consanguinity or a family history of
rickets in any of these patients, hereditary HVRR was
excluded.
Improvement in phosphate homeostasis after excision of
skin lesions of ENS was first reported by Aschinberg et al.2
in a patient with the linear SN type of ENS. They also
1 Mineral Metabolism. New York: Raven Press, 1993; 27982.
confirmed by animal experiments the phosphaturic effects
of the fibroangiomatous parts of the naevus. Subsequently,
Ivker et al.10 reported a sustained increase in serum phos-
phate levels in a child after total excision of the organoid
naevus. This prompted us to undertake CO2 laser ablation of
the lesion, which resulted in significant elevation in serum
phosphate and reduction of urinary phosphate loss.
The preceding discussion suggests that ENS-associated
rickets is very similar to the better-characterized phenomenon
of tumour-associated osteomalacia. Nevertheless, until fur-
ther studies identify the cellular source of phosphaturic
stimulus in these patients and consistent benefit from excision
of SN lesions can be demonstrated, this assertion remains
speculative.
This report describes the first patient with the association of
PP with HVRR. This adds to 10 prior case reports of
epidermal naevus-associated rickets, consolidating the evi-
dence that these cases represent a type of tumour-associated
rickets and osteomalacia. In spite of its rarity, it is important
to remember that surgical excision or laser ablation of SN can
lead to improvement or total correction of the disturbed
calcium-phosphate homeostasis in these patients. This can
potentially prevent such severe deformities as were present in
the patient reported here. With very extensive naevi, there is
evidence that even partial excision or debulking may make
the rickets more amenable to management with oral calcitriol
and phosphate supplementation.
Departments of Dermatology, A.Saraswat
Venereology and Leprology and S.Dogra
*Endocrinology, Postgraduate A.Bansali*
Institute of Medical Education and B.Kumar
Research, Sector 12, Chandigarh
160,012, India
Correspondence: Bhushan Kumar
E-mail: kumarbhushan@hotmail.com
References
1 Happle R, Hoffmann R, Restano L et al. Phacomatosis pigmento-
keratotica: a melanocytic-epidermal twin nevus syndrome. Am J
Med Genet 1996; 65: 3635.
2 Aschinberg LC, Solomon LM, Zeis PM et al. Vitamin D-resistant
rickets associated with epidermal nevus syndrome: demonstration
 2003 British Association of Dermatologists, British Journal of Dermatology, 148, 10581087
of a phosphaturic substance in dermal lesions. J Pediatr 1977; 91:
5660.
3 Stosiek N, Hornstein OP, Hiller D et al. Extensive linear epidermal
nevus associated with hemangiomas of bones and vitamin D-re-
sistant rickets. Dermatology 1994; 189: 27882.
4 Oranje AP, Przyrembel II, Meradji M et al. Solomons epidermal
nevus syndrome (type: linear nevus sebaceus) and hypophos-
phatemic vitamin D-resistant rickets. Arch Dermatol 1994; 130:
116771.
5 Tokatli A, Coskun T, Ozalp I. Hypophosphatemic vitamin D-re-
sistant rickets associated with epidermal nevus syndrome: a case
report. Turk J Pediatr 1997; 39: 24751.
6 Prader A, Illig R, Uehlinger E et al. Rachitis infolge Knochen-
tumors. Helv Paediatr Acta 1959; 14: 5549.
7 Favus MJ., ed. Primer on Metabolic Bone Diseases and Disorders of
8 Miyauchi A, Fukase M, Tsutsumi M et al. Hemangiopericytoma-
induced osteomalacia: tumor transplantation in nude mice causes
hypophosphatemia and tumor extracts inhibit renal 25-hydroxy-
vitamin D1-hydroxylase activity. J Clin Endocrinol Metab 1988;
67: 4653.
9 Econs MJ, Drezner MK. Tumor-induced osteomalacia: unveiling a
new hormone. N Engl J Med 1994; 330: 167981.
10 Ivker R, Resnick SD, Skidmore RA. Hypophosphatemic vitamin
D-resistant rickets, precocious puberty, and the epidermal nevus
syndrome. Arch Dermatol 1997; 133: 155761.
Azathioprine hypersensitivity in a patient
with peripheral demyelinating polyneuropathy
SIR, For decades, azathioprine has been widely prescribed for
immunosuppression in autoimmune diseases and organ
transplantation.1 Azathioprine hypersensitivity is a rare but
severe complication characterized by nausea, diarrhoea,
dizziness, rigor, renal dysfunction and haemolytic anae-
mia.24 Liver toxicity, leucocytosis, increased C-reactive
protein, fever and hypotension have also been reported.5,6
Cutaneous symptoms of azathioprine hypersensitivity include
a macular or maculopapular erythema, vesicles or pustules,
urticaria, vasculitis, erythema multiforme, erythema nodo-
sum, petechiae and purpura.2,
We describe a 71-year-old white woman with a history of
chronic inflammatory demyelinating peripheral polyneurop-
athy. During hospitalization in July 2001 for treatment of the
polyneuropathy she received azathioprine, amoxicillin plus
clavulanic acid, omeprazole and heparin. Several days after
the medication was started she developed oedema of the face,
chest and arms. All medications were withdrawn and were
not administered again. As her neuropathy deteriorated in
January 2002, the question was addressed whether she could
be treated with azathioprine again.
To investigate a possible role of a type I or type IV allergy
we performed prick and patch tests with azathioprine,
amoxicillin plus clavulanic acid, omeprazole and heparin,
with negative results 20 min and 72 h after testing. As
results of the prick and patch tests were negative for
azathioprine, oral challenge was performed after informed
consent was obtained. Treatment with azathioprine 150 mg
daily was planned. Therefore, the patient received azathiop-

rine 15 mg, 15 mg, 30 mg, 45 mg and 60 mg at 30-min
intervals, resulting in a cumulative dose of 150 mg. Two
hours after the last dose of azathioprine was administered, the
patient developed a macular erythema affecting the entire
skin with partial confluency and a discrete oedema of the
eyelids (Fig. 1).
Furthermore, she developed chills with pyrexia of up to
39 C and blood pressure of 230 110 mmHg. She was
treated with methylprednisolone 500 mg, the H1-receptor
blocker dimetinden 8 mg and the H2-receptor blocker ranit-
idine 50 mg, resulting in a decrease in the intensity of
the erythematous exanthem. Six hours after oral challenge,
liver-specific enzymes were above normal levels (aspar-
tate aminotransferase 24 U L)1, c)glutamyltransferase
99 U L)1), C-reactive protein was increased to 104 mg L)1
and a leucocytosis (175 109 L)1) could be detected.
Activity of thiopurine methyltransferase (TPMT) was normal.
Due to persistence of the exanthem the patient was treated
with oral methylprednisolone 100 mg daily for 2 weeks with
gradual dose reduction until the erythema completely
resolved and all serological markers returned back to normal
levels.
The macular erythema with chills, fever, hepatotoxicity,
leucocytosis and increased C-reactive protein, as well as the
short interval between oral azathioprine challenge and
appearance of symptoms, led us to the diagnosis of
azathioprine hypersensitivity. In relation to its widespread
use for autoimmune diseases, azathioprine hypersensitivity is
a rare complication, which has been published in only 50
cases.1 The pathogenesis of azathioprine hypersensitivity is
not well understood. Chemically, azathioprine consists of a
nitroimidazole ring bound to 6-mercaptopurine. After separ-
ation of both components in vivo, the nitroimidazole may
bind to a protein to form a hapten, which may induce the
hypersensitivity reaction.7 In general, drug-related risk
factors and patient-specific risk factors need to be considered
in drug allergy. The latter include association with HLA
haplotypes and genetic polymorphisms of enzymes involved
Figure 1. Clinical appearance. Note the periorbital erythema and
oedema.
 2003 British Association of Dermatologists, British Journal of Dermatology, 148, 10581087
CORRESPONDENCE 1077
in drug metabolism.8 In vivo, azathioprine is rapidly conver-
ted to 6-mercaptopurine, which is further metabolized by
three different enzymes. 6-Mercaptopurine can be oxidized
by xanthinic oxidase to thiouric acid, metabolized by
hypoxanthine guanine phosphoribosyl transferase to
6-thioinosinic acid, or methylated by TPMT. The activity of
TPMT is reduced by 75% in 10% of the caucasian
population, and TPMT activity is undetectable in as many
as 1 in 220 caucasians.9 As a consequence, the risk of side-
effects with a standard dose regimen of azathioprine is
unexpectedly high in patients with absent TPMT activity. In
the case described here, TPMT activity was normal, indica-
ting a hypersensitivity reaction as the most likely cause for
the described clinical picture. In summary, patients with
non-functional TPMT need to be identified before azathiop-
rine therapy is initiated. Secondly, no marker is currently
available to characterize those patients at risk for a
hypersensitivity reaction, which should be documented to
avoid rechallenge.
Department of Dermatology and R.Hinrichs
Allergy, University of Ulm, L.A.Schneider
Maienweg 12, 89081 Ulm, C . O z d e m i r
Germany G.Staib
Correspondence: Karin Scharffetter- K.Scharffetter-
Kochanek. Kochanek
E-mail: karin.scharffetter-
kochanek@medizin.uni-ulm.de
References
1 Anstey A, Lear JT, Amess J et al. Azathioprine: clinical pharma-
cology and current indications in autoimmune disorders. Biodrugs
1998; 9: 3347.
2 Sofat N, Houghton J, McHale J et al. Azathioprine hypersensitivity.
Ann Rheum Dis 2001; 60: 71920.
3 Knowles SR, Gupta AK, Shear NH et al. Azathioprine hypersensi-
tivity-like reactions a case report and review of the literature. Clin
Exp Dermatol 1995; 20: 3536.
4 Farthing MJ, Coxon AY, Sheaff PC. Polyneuritis associated with
azathioprine sensitivity reaction. Br Med J 1980; 280: 367.
5 Pozniak AL, Ahern M, Blake DR. Azathioprine-induced shock.
Br Med J 1981; 283: 1548.
6 Brown G, Boldt C, Webb JG et al. Azathioprine-induced multisystem
organ failure and cardiogenic shock. Pharmacotherapy 1997; 17:
81418.
7 Davis M, Eddleston A, Williams R. Hypersensitivity and jaundice
due to azathioprine. Postgrad Med J 1980; 56: 2745.
8 Merk H. Allergische Krankheitsbilder. Dtsch Arztebl 2000; 97:
301321.
9 Holme SA, Duley JA, Sanderson J et al. Erythrocyte thiopurine
methyl transferase assessment prior to azathioprine use in the UK.
Q J Med 2002; 95: 43944.
Hold on the amputation
SIR, Dobson et al.1 describe the diagnosis and treatment of a
squamoid subungual lesion that they designate a squamous
1078 CORRESPONDENCE
cell carcinoma (SCC). As they acknowledge, the histological
distinction between SCC, verrucous carcinoma (VC) and
subungual keratoacanthoma (SUKA) can be difficult. How-
ever, the rapid exophytic evolution and the underlying
radiolucency of the phalanx is characteristic of a SUKA, with
which the histology was consistent. The issue then arises
concerning the management and the reason why the
phalanx was involved. In an SCC and a VC, the phalanx
may be involved by tumour extension. In a SUKA, the
lucency is a reversible pressure effect related to the rapid
expansion of the tumour, as seen here. This means that it is
best to avoid amputation in the first instance, as the lesion
may frequently be fully removed by excision down to bone, or
by using Mohs micrographic surgery.2 If this is the case, and
the bone returns to normal, then the diagnosis of SUKA is
further confirmed and the digit retained. If no lower soft tissue
level can be reached by excision to bone, then amputation is
indicated.
Even if there were SCC in the bone in this instance,
graduated excision would still be the plan of choice as there is
no doubt that radiology can be misleading: some digits can be
saved in this way. As it is, Dobson et al. make no comment on
the lower margin of the tumour and bone histology.
Accordingly, I strongly disagree with their assertion that
amputation of the involved distal phalanx is the preferred
option, citing a paper that is over 30 years old. Micrographic
surgery and our understanding of the biology of subungual
tumours have moved on. Advocating amputation over Mohs
on the basis that VC has metastatic potential is also odd, as it
is exactly for that reason that Mohs is the treatment of
choice for invasive cutaneous SCC at many other sites.3
Periungual SCC of all types should be treated with retention
of the digit unless there is histological evidence of extension
into bone.
Bristol Dermatology Centre, Bristol D.de Berker
Royal Infirmary, Bristol BS2 8HW,
U.K.
E-mail:
david.deberker@ubht.swest.nhs.uk
References
1 Dobson CM, Azurdia RM, King CM. Squamous cell carcinoma
arising in a psoriatic nail bed: case report with discussion of
diagnostic difficulties and therapeutic options. Br J Dermatol 2002;
147: 1449.
2 Zaiac MN, Weiss E. Mohs micrographic surgery of the nail unit and
squamous cell carcinoma. Dermatol Surg 2001; 27: 24651.
3 Motley R, Kersey P, Lawrence C. Multiprofessional guidelines for
the management of the patient with primary cutaneous squamous
cell carcinoma. Br J Dermatol 2002; 146: 1825.
Hold on the amputation: reply from authors
SIR, Dr de Berker raises some interesting points. The histology
in our case1 was thought to be squamous cell carcinoma
 2003 British Association of Dermatologists, British Journal of Dermatology, 148, 10581087
(SCC) by three consultant pathologists, and our report details
the pathological features which led to this conclusion. We
agree that the histology should not be viewed in isolation
from the clinical and radiological features. The lesion had
been present for at least 4 months, and in the first 2 months
its growth had been slow and painless, not typical of
subungual keratoacanthoma (SUKA). The radiological bone
erosion was relatively shallow in comparison with most cases
of SUKA.
Well-demarcated bone radiolucency, as seen in SUKA, is
indeed a reversible pressure effect, but it is not entirely
attributable to rapidity of tumour expansion. Rather, it is a
reflection of the bluntness of the advancing front of a lesion,
be it pressure from a benign tumour or blunt invasion from
a malignancy: such a well-demarcated lytic effect was
reported in a subungual perineuroma that had been present
for 5 years.2 More importantly, at other sites SCC does not
always invade bone as permeative tongues, but may erode
as a blunt advancing front;3 with the latter there is usually
a thin rim of fibrosis between the advancing tumour front
and the affected bone.3 Such blunt erosive histology usually
correlates radiologically with an excavation that has well-
delineated margins.4 Well-demarcated radiolucency has not
previously been reported for subungual SCC, but this may
partly reflect reporting bias, with reluctance to report better
differentiated lesions as SCC. Accordingly, if the clinical
picture and histology are typical of SUKA, then a radiolu-
cent sharply demarcated deficit on X-ray is highly supportive
of a diagnosis of SUKA. Otherwise, as in our case, we feel it
better to err on the side of caution and designate the lesion
an SCC.
We do, in fact, make comment on the lower margin of the
tumour, indicating that there was bony erosion. However, we
did not clarify that this was blunt invasion with no
permeation into cancellous bone spaces.
Intraosseous spread with no demonstrable connection to
an overlying SCC has been reported.5 Our pointing out that
micrographic surgery cannot offer an absolute guarantee of
clearance, in a tumour which may have satellite foci separate
from the main lesion, is not unreasonable. Dr de Berker
himself has acknowledged rare post-Mohs recurrences in
three series of subungual SCC (respectively two of 24 patients,
two of 25 patients and two of seven patients).6 We are not
aware of any reported recurrences following amputation.
Nonetheless, we do accept the criticism that we should have
advocated referral for consideration of Mohs surgery as the
generally preferred alternative to amputation, for definite SCC
not histologically extending into bone, and are grateful to Dr
de Berker for pointing this out. As we stated in the article, our
patients management decision was complicated by severe
psoriatic nail dystrophy.
Departments of *Dermatology and C.M.Dobson*
Histopathology, Royal Liverpool R.M.Azurdia*
University Hospital, Prescot Street, C.M.King*
Liverpool L7 8XP, U.K.
E-mail: cdobson8@hotmail.com
 CORRESPONDENCE 1079

References
1 Dobson CM, Azurdia RM, King CM. Squamous cell carcinoma
arising in a psoriatic nail bed: case report with discussion of
diagnostic difficulties and therapeutic options. Br J Dermatol 2002;
147: 1449.
2 Baran R, Perrin C. Subungual perineurioma: a peculiar location.
Br J Dermatol 2002; 146: 1258.
3 Slootweg PJ, Muller H. Mandibular invasion by oral squamous cell
carcinoma. J Craniomaxillofac Surg 1989; 17: 6974.
4 Totsuka Y, Usui Y, Tei K et al. Mandibular involvement by squa-
mous cell carcinoma of the lower alveolus: analysis and compar-
ative study of histologic and radiologic features. Head Neck 1991;
13: 4050.
5 Lukinmaa PL, Hietanen J, Soderholm AL et al. The histologic pat-
tern of bone invasion by squamous cell carcinoma of the man-
dibular region. Br J Oral Maxillofac Surg 1992; 30: 27.
6 de Berker DA, Dahl MG, Malcolm AJ et al. Micrographic surgery for
subungual squamous cell carcinoma. Br J Plast Surg 1996; 49:
41419.

Cryoglobulinaemic vasculitis, cryofibrinogenaemia

and low-grade B-cell lymphoma

SIR, Cryoglobulins and cryofibrinogen are cold-precipitable

proteins that can occur without an identifiable underlying
condition (essential cryopathies) or in association with
infectious, autoimmune or lymphoproliferative diseases (sec-
ondary cryopathies).1,2 Cryoglobulinaemic vasculitis (CV) is
an immune-complex-mediated vasculitis that clinically pre-
sents as palpable purpura precipitated by cold exposure.3 It is
associated with type II mixed cryoglobulinaemias (MC)
(monoclonal component, usually immunoglobulin (Ig)M,
polyclonal component, usually IgG) or type III MC (one or
more polyclonal components). Chronic hepatitis C (HCV)
infection is present in 4298% of affected individuals
with CV.2 Chronic antigenic stimulation may eventuate in
mono- and oligoclonal expansion of B lymphocytes producing
low-grade lymphoma of the CD5-positive phenotype.4 Cryo-
fibrinogen consists of aggregates of fibrin, fibrinogen and
fibronectin that precipitate at 4 C and resolubilize on
rewarming.5 Cutaneous manifestations of cryofibrinogenae-
mia (CF) include purpura, livedo and ulcerations.6
An 83-year-old white woman presented with a 1-year
history of lower extremity palpable purpura aggravated by
cold exposure. Treatment with prednisone and azathioprine
produced some remission of symptoms. Six weeks later she
developed a fever (381 C) and several large haemorrhagic
ulcers covered with black eschar on her lower limbs.
Examination at her first visit revealed purpuric macules in a
livedo-like pattern on both legs with larger confluent purpuric
patches on the shins and ankles (Fig. 1a). Several, large Figure 1. (a) Initial presentation with palpable purpuric macules
ulcerations with violaceous borders and necrotic centres were and plaques symmetrically on both extremities. (b) Large violaceous
ulcers with haemorrhagic crusts on the lower legs. Postinflammatory
present on the posterior calves, shins and medial malleoli
hyperpigmentation consistent with previously healed vasculitis is also
(Fig. 1b). Both index fingers were violaceous with small
present.
fingertip ulcers. Blood results showed elevated cryoglobulins
20% by volume (005%), cryofibrinogen 5% by volume
(< 1%), rheumatoid factor 1158 IU mL)1 (< 20 IU mL)1),

 2003 British Association of Dermatologists, British Journal of Dermatology, 148, 10581087

1080 CORRESPONDENCE

Figure 2. (a) The majority of the cells in the lymphoid aggregates of the bone marrow biopsy are CD5 positive (original magnification 100).
(b) Right calf biopsy from the ulcer edge: thrombus in the vessel wall with minimal inflammation (haematoxylin and eosin, original magnification
60).

C3 70 mg dL)1 (83188 mg dL)1), C4 2 mg dL)1 (18
45 mg dL)1), total haemolytic complement < 100 U mL)1
(180320 U mL)1), C-reactive protein 22 mg dL)1
)1 )1
(< 06 mg dL ), IgG 612 mg dL (8001700 mg dL)1),
)1 )1
IgM 623 mg dL (60370 mg dL ), serum protein electro-
phoresis showed monoclonal IgMj, and separate monoclonal
free j and polyclonal IgG. Serum viscosity was 23 cp (15
19 CP). Urinary protein electrophoresis demonstrated mono-
clonal IgMj and monoclonal free j. Bone marrow biopsy
revealed atypical CD20 and CD5-positive lymphoid aggre-
gates (Fig. 2a). The flow immunophenotyping cytochemistry
of the peripheral blood was consistent with low-grade B-cell
lymphoproliferative disorder. Protein C, protein S, anticard-
iolipin antibodies, lupus anticoagulant, prothrombin time,
partial thrombin time, international normalized ratio, anti-
nuclear antibodies, antineutrophilic cytoplasmic antibodies,
HCV antibodies ( 3), HBV surface antigen were normal or
negative. Polymerase chain reaction for HCV RNA was
negative (< 600 IU mL)1). Radiological studies did not show
evidence of multiple myeloma. Biopsy from an area of
palpable purpura demonstrated a dense perivascular infiltrate
comprising extravasated red blood cells, neutrophils and
nuclear dust. Biopsy from the edge of an ulcer revealed
thrombi within the vessel wall and evidence of recanalization
with minimal inflammation (Fig. 2b). Direct immunofluores-
cent testing demonstrated perivascular deposits of IgG, IgM
and C3.
The patient was treated with plasmapheresis, chlorambucil
4 mg twice daily, stanozolol 2 mg twice daily, pentoxyphyl-
line 400 mg three times daily and aspirin 325 mg once a
day. Topical treatment consisted of whirlpool baths, silver
sulfadiazine and debridement. Ten weeks later the ulcerations
had healed completely with scarring and postinflammatory
hyperpigmentation. The cryofibrinogen value and serum
viscosity had returned to normal (05% by volume and
16 CP) and cryoglobulin and rheumatoid factor concentra-
tions had decreased significantly with values of 07% by
volume and 62 IU mL)1, respectively.
Our patient presented with cold-aggravated purpura,
vasculitis and leg ulcers with concomitant demonstration of

 2003 British Association of Dermatologists, British Journal of Dermatology, 148, 10581087


Table 1. Reported cases of concomitant occurrence of cryoglobulinaemia and cryofibrinogenaemia
Age
(years) Sex Clinical manifestation
70 F Purpura, livedo reticularis, ulceration
43 M Purpura, arthritis, erythrocyanosis of the lips and oral mucosa
3 M Raynauds phenomenon
83 F Purpura, livedo ulcers
type II MC, CF and low-grade B-cell lymphoma of CD5
phenotype. Occlusion of superficial and deep dermal blood
vessels by fibrin thrombi without inflammation is usually
seen in CF and type I cryoglobulinaemia.1 Inflammatory
purpura and vasculitis usually accompany type II MC
associated with immune-complex diseases and some infec-
tions.2 A high titre of monoclonal IgMj rheumatoid factor
(RF) is essential for the development of cutaneous vasculitis,
especially with HCV infection.2 All attempts (serologies,
molecular studies, cryoprecipitate serological analysis) to
confirm HCV infection in our patient were unsuccessful.
Monoclonal IgMj RF with strong affinity for fibronectin (even
without the presence of immune complexes) may be the
contributing factor for CF.7 Chronic antigenic stimulation
may result in immune dysregulation and expansion of B cells
of CD5 phenotype in bone marrow, liver and peripheral
blood.8
The differential diagnosis6 of CV and CF should include
other occlusive vasculopathies such as antiphospholipid
syndrome, thrombotic thrombocytopenic purpura, couma-
rin-induced skin necrosis, protein C deficiency, septic vascu-
litis, homocystinuria and disseminated intravascular
coagulopathy, none of which was present in our patient.
The concurrent presentation of CV and CF is rare, with only
three cases, to our knowledge, reported in the literature911
(Table 1). The prognosis depends on the severity of vasomo-
tor, cutaneous, renal or liver involvement, the presence of an
underlying disorder and the possibility of therapeutic inter-
vention.2 The specific mechanisms of the interaction of the
different pathogenic factors causing the various clinical
manifestations of the cryopathies are yet to be defined.
Section of Dermatology, University of A.L.Krunic
Chicago, MC 5067, 5841 South M.M.Medenica
Maryland Ave., Chicago, IL 60637, A.E.Laumann
U.S.A., *Section of Dermatology, J.C.Shaw*
University of Toronto, Toronto, ON,
Canada
E-mail: sasakrun@hotmail.com
References
1 Brouet J-C, Clauvel J-P, Danon F et al. Biological and clinical
significance of cryoglobulins. Am J Med 1974; 53: 77588.
2 Dispenzieri A, Gorevic D. Cryoglobulinemia. Hematol Oncol Clin
North Am 1999; 13: 131549.
3 Lamprecht P, Gause A, Gross WL. Cryoglobulinemic vasculitis.
Arthritis Rheum 1999; 42: 250716.
 2003 British Association of Dermatologists, British Journal of Dermatology, 148, 10581087
CORRESPONDENCE 1081
Associated condition Reference
Homocystinuria, axillo-femoral bypass 9
None 10
Mycoplasma pneumonia 11
B-cell lymphoma, polyneuropathy Our case
4 De Re V, De Vita S, Marzotto A et al. Pre-malignant and malignant
lymphoproliferations in an HCV-infected type II mixed cryoglob-
ulinemic patient are sequential phases of an antigen-derived
pathological process. Int J Cancer 2000; 87: 2116.
5 Smith SB, Arkin C. Cryofibrinogenemia: incidence, clinical cor-
relations and a review of the literature. Am J Clin Pathol 1972; 58:
52430.
6 Beightler E, Diven DG, Sanchez RL, Solomon AR. Thrombotic
vasculopathy associated with cryofibrinogeneima. J Am Acad
Dermatol 1991; 24: 3425.
7 Reininger L, Berney T, Shibata T et al. Cryoglobulinemia induced
by murine IgG3 rheumatoid factor: skin vasculitis and glome-
rulonephritis arise from distinct pathogenetic mechanisms. Proc
Natl Acad Sci USA 1990; 87: 1003842.
8 De Vita S, De Re V, Gasparotto D et al. Oligoclonal non-neoplastic
B cell expansion is the key feature of type II mixed cryoglobu-
linemia: clinical and molecular findings do not support a bone
marrow pathologic diagnosis of indolent B cell lymphoma. Arth-
ritis Rheum 2000; 43: 94102.
9 Williamson AE, Lawrence AC, Huard GS II. Spontaneous
necrosis of the skin associated with cryofibrinogenemia, cryo-
globulinemia and homocystinuria. Ann Vasc Surg 1996; 10:
3659.
10 Vithayasai P, Rungruangtanakit K, Vithayasai V. First report case
of cryoglobulinemia and cryofibrinogenemia in Thailand. J Med
Assoc Thai 1989; 72: 53640.
11 Furioli J, Bourdon C, Le Loch H. [Mycoplasma pneumoniae infec-
tion. Manifestation in a 3-year-old child by Raynauds phenom-
enon.] (French). Arch Franc Pediatr 1985; 42: 3134.
BDS Melanoma Guidelines
SIR, We would like to take issue with the recent guidelines for
the management of melanoma printed in your journal.1
Guidelines are, of necessity, didactic but we feel that those
published are excessively so, and do not reflect the differences
of opinion that exist in important areas among doctors
treating melanoma.
The role of sentinel node biopsy is controversial, but the
recommendations for its use are too restrictive. One of the
main problems with the interpretation of trials of adjuvant
therapies in melanoma has been the heterogeneity of patient
populations studied. The use of sentinel node staging allows
better identification of at-risk groups and better selection
of patients for trial entry. It is inconsistent to advocate
adoption of the new AJCC staging system and participation in
co-operative group studies underpinned by the procedure but
not the procedure itself. To cite the lack of a survival benefit
for what is a diagnostic test is disingenuous.
 1082 CORRESPONDENCE

Cancer Research UK, Medical M.Middleton N.H.Cox

Oncology Unit and *Department of A.L.Harris on behalf of the British Association of
Dermatology, Churchill Hospital, Old H.Kurwa* Dermatologists
Road, Headington, Oxford OX3 7LJ, P.Millard
Department of Pathology, John K.Hollowood
Radcliffe Hospital, Headley Way, O.Cassell Zinc sulphate for viral warts
Headington, Oxford OX3 9DU, and
Department of Plastic Surgery, SIR, I was most interested to see the remarkable results that
Radcliffe Infirmary, Woodstock Road, Al-Gurairi et al. achieved with zinc sulphate for refractory
Oxford OX2 6HE, U.K. warts.1 If their findings are genuine then this represents a
E-mail: revolutionary advance in wart treatment and oral zinc
mark.middleton@cancer.org.uk sulphate should probably be the treatment of choice from
now on. However, on closer inspection of the paper I think
there are some problems with the methodology that should
Reference
not pass without comment.
1 Roberts DLL, Anstey AV, Barlow RJ et al. U.K. guidelines for the man- The authors describe systematic random sampling as the
agement of cutaneous melanoma. Br J Dermatol 2002; 146: 717. method of allocation. My understanding of this technique is
that it is normally used to collect a sample from a larger
BDS Melanoma Guidelines: reply from authors population for epidemiological studies rather than as a
method of randomization for clinical trials. From the authors
SIR, We reply to the letter from Middleton et al. The description, which could be clearer, it would appear that the
melanoma guidelines have indeed been written with the patients may have been allocated alternately. If this is the
intention of reflecting differences in opinion within the U.K. case, then this is not a randomized trial and selection bias has
and indeed around the world. We, and Drs Middleton et al. not been eliminated.
agree that the role of sentinel node biopsy is controversial. Although the patients were blinded, the person who
There are as many voices within the U.K. who are of the assessed the outcome of the treatment was not. Double
opinion that sentinel node biopsy should not be adopted, as blinding could easily have been built into the study and
there are voices who feel it must be supported. The guidelines would have eliminated this source of potentially very
are intended to reflect this debate. As stated, the guidelines significant bias.
will be revised as clinical trial data mature. The statistical analysis was carried out only on those
In the days of NICE (U.K. National Institute for Clinical subjects who completed the trial and the problem of the
Excellence) and evidence-based medicine, it seems entirely extremely high drop-out rate (nearly 50% overall) was dealt
appropriate to base national guidelines on data. The guide- with rather briefly in the discussion section. It is true that if
lines essentially suggest that it is imprudent to adopt this intention-to-treat analysis is carried out on their data oral
invasive technique wholesale without data collection and in zinc still appears to be significantly more effective than
the absence of effective adjuvant therapy. Diagnostic tests do placebo. However, if one assumes that all drop-outs were
not usually carry the morbidity that is associated with treatment failures, the cure rate is only 50% rather than the
sentinel node biopsy and therefore the text of the guidelines in 869% stated. This, together with the biases mentioned above,
relating the test to mortality rather than screening does not perhaps brings us a little closer to the actual effectiveness of
seem disingenuous at all. this treatment.
We would agree that stratification within clinical trials is In addition to these methodological points the biological
valid. The authors of the guidelines, moreover, are entirely hypothesis that zinc somehow enhances immune function in
supportive of the use of sentinel node biopsy in the context of those highly unlikely to be zinc deficient is not at all
clinical trials, as indeed the guidelines document indicates. convincing. Serum zinc measurements can fluctuate widely
both diurnally and also with feeding and fasting and are a
St Jamess University Hospital, Leeds, J . A . N e w t o n B i s h o p very poor reflection of total body zinc status unless very low
*Addenbrookes Hospital, P.G.Corrie* indeed.2
Cambridge, Nuffield Hospital, J.Evans
Plymouth, The Royal Marsden M.E.Gore Department of Dermatology, S.Gibbs
Hospital, London, Royal Sussex P.N.Hall* The Ipswich Hospital, Heath Road,
County Hospital, Brighton, N.Kirkham Ipswich, Suffolk IP4 5PD, U.K.
Singleton Hospital, Swansea, on behalf of the E-mail: sgibbs@fish.co.uk
**Royal Gwent Hospital, Newport, Melanoma
St Johns Institute of Dermatology, Study Group
St Thomas Hospital, London, and D.L.L.Roberts References
Cumberland Infirmary, Carlisle, A.V.Anstey** 1 Al-Gurairi FT, Al-Waiz M, Sharquie KE. Oral zinc sulphate in
1 U.K. R.J.Barlow the treatment of recalcitrant viral warts: randomized placebo-
controlled clinical trial. Br J Dermatol 2002; 146: 42331.

 2003 British Association of Dermatologists, British Journal of Dermatology, 148, 10581087


2 Aggett PJ. The assessment of zinc status: a personal view. Proc Nutr
Soc 1991; 50: 917.
Zinc sulphate for viral warts: reply from authors
SIR, We thank Dr Gibbs for his comments on our article.1 Our
study was designed as a randomized placebo-controlled
clinical trial. The so-called systematic random sampling was
used as the method for selection of the study participants.
Patient recruitment and randomization are detailed compre-
hensively in the paper.
We agree with Dr Gibbs that a double-blind study would be
less biased, but single-blind studies are well-recognized
methods in therapeutic trials. Our aim now is to repeat the
same study on a larger scale using a double-blind technique.
Regarding the drop-outs, it is well known that it is a common
habit among patients in Iraq and elsewhere in this region to
withdraw from trials.24 We believe that the reason for this is
that our patients expect a good and dramatic response in a
short period of time. Our trial lasted for 2 months, so they
could not wait that long to see an improvement. Even if we
assume that all drop-outs were treatment failures, the 50%
success rate is still a very good response to a condition that,
until recently, was chronic and untreatable.
We do not agree with Dr Gibbs regarding the point of serum
zinc. In all the patients and healthy controls the blood
sampling was carried out at the same time under the same
conditions. Diurnal fluctuation and type of diet do not cause
that much difference in zinc levels. In addition, we found a
significant difference between the patients (who had low zinc
levels) and the controls regarding the level of serum zinc.
Furthermore, when the patients showed improvement in
their clinical picture the level of zinc increased dramatically,
while in the nonresponders the level of zinc remained low: a
further indication that zinc itself plays a major role in the
healing of these recalcitrant viral warts.
We have been using oral zinc sulphate to treat viral warts
for the last 10 years and have noticed a clinical improvement
in our patients. For this reason we decided to conduct this
clinical trial in a scientific way that will pave the way for
further research in the future.
Department of Dermatology and K.E.Sharquie
Venereology, College of Medicine, M.Al-Waiz
University of Baghdad, PO Box F.Al-Gurairi
61269, Medical Collection Post
Office 12114, Baghdad, Iraq
E-mail: sharquie@warkaa.net
References
1 Al-Gurairi FT, Al-Waiz M, Sharquie KE. Oral zinc sulphate in
the treatment of recalcitrant viral warts: randomized placebo-
controlled clinical trial. Br J Dermatol 2002; 146: 42331.
2 Sharquie KE, Najim RA, Farjou IB, Al-Timimi DJ. Oral zinc
sulphate in the treatment of cutaneous leishmaniasis. Clin Exp
Dermatol 2001; 26: 216.
 2003 British Association of Dermatologists, British Journal of Dermatology, 148, 10581087
CORRESPONDENCE 1083
3 Griffiths WAD. Use of metronidazole in cutaneous leishmaniasis.
Arch Dermatol 1976; 112: 1791.
4 Kubeyinje EP, Belagavi CS. Atopic dermatitis: incidence, presen-
tation and management problems as seen in Arar, Northern Sau-
dia Arabia. Saudi Med J 1997; 18: 5946.
Genital lichen sclerosus, squamous cell carcinoma
and circumcision
SIR, We read with great interest the study by Powell et al.,
which highlighted the high incidence of lichen sclerosus (LS)
in patients with squamous cell carcinoma (SCC) of the penis.1
It is an extremely informative report that may prove to be a
turning point in our current outlook towards the apparently
benign course and prognosis of LS of the male genitalia. We
have previously reported a similar patient developing SCC
over long-standing LS.2 We wish to highlight an equally
increased risk of development of SCC in genital LS in Asian
men with or without circumcision. A circumcised Asian man
who developed SCC within a lesion of genital LS is reported.
A 60-year-old Indian man presented with an asymptomatic
erythematous lesion over the glans penis of 3 months
duration. The patient reported that he had undergone
circumcision 20 years previously for whitish discoloration
of the prepuce and glans along with phimosis suggestive of
LS, although no histological evidence for that was available.
His general health was good and there was no history
suggestive of immunosuppression, genital warts or arsenic
exposure. On examination, there was a 1 15 cm irregular,
indurated erythematous plaque overlying a pale atrophic
area over the glans penis (Fig. 1). There were hypopigmented
atrophic plaques over other areas of the glans and coronal
sulcus, extending to the penile surface proximal to the line of
circumcision. The urethral meatus was narrowed, while the
scrotum and perianal areas were normal. There was no
regional lymphadenopathy. Histopathology of a biopsy from
the suspicious looking erythematous plaque revealed a well-
differentiated SCC along with changes of LS. Studies for
1 Figure 1. Elevated ulcerated area over glans (squamous cell carci-
noma) overlying depigmented area of lichen sclerosus.
1084 CORRESPONDENCE
detection of human papillomavirus (HPV) could not, how-
ever, be done. Unfortunately, after the diagnosis was
discussed with the patient, he declined to undergo penectomy
and further management, and was lost to follow-up.
The association between vulval LS and SCC is well
established, but the same is not well recognized in men with
genital LS. Recently, two studies have highlighted that there
appears to be a definite association between SCC and LS in
men, similar to that in women. Nasca et al. have reported
malignant or premalignant changes in five of 86 men with
genital LS studied over a period of several years. All the
86 men studied were white and uncircumcised, and the time
lag from diagnosis of LS to the diagnosis of SCC was
1023 years.3
Powell et al. retrospectively studied 20 cases of penile SCC
and obtained a clinical history and or histological evidence of
LS in 11 cases. Six of these 11 patients had been circumcised:
three in childhood and three in adulthood, at the onset of
penile symptoms. In two of the adult cases, LS was
documented on the circumcision specimen. In these patients
the interval from diagnosis of previous LS was up to
12 years.1
Although lack of circumcision is a well-established risk
factor for the development of penile SCC,4,5 even early
circumcision in men with genital LS does not appear to confer
protection against future malignant transformation. Powell
et al. have also observed that LS may be asymptomatic,
clinically undetected or not be diagnosed histologically
despite circumcision.1 Moreover, circumcision removes only
preputial skin while genital LS can affect the prepuce, glans
and urethral meatus. Circumcision in cases of genital LS can
reduce the bulk of tissue that can develop malignant change,
but cannot confer total protection. Coexistent HPV infection
or carriage predisposing to genital SCC should, however, be
excluded in such patients.
The present patient, although circumcised 20 years previ-
ously, had clinical evidence of persistent LS over the glans,
and thus a malignant change was immediately suspected
clinically and subsequently confirmed on histopathology.
Despite an absence of large series from developing nations,
clinicians in these nations also need to be extremely vigilant
regarding this serious complication. The need for detailed
counselling at the time of diagnosis of LS cannot be
overemphasized, as recommended by Powell et al.1
Department of Dermatology and G.P.Thami
Venereology, Government Medical S.Kaur
College Hospital, Sector 32 B,
Chandigarh 160030, India
E-mail:
drgurvinder@mantraonline.com
References
1 Powell J, Robson A, Cranston D et al. High incidence of lichen
sclerosus in patients with squamous cell carcinoma of the penis.
Br J Dermatol 2001; 145: 859.
 2003 British Association of Dermatologists, British Journal of Dermatology, 148, 10581087
2 Kanwar AJ, Thami GP, Kaur S et al. Squamous cell carcinoma
arising in long standing untreated lichen sclerosus et atrophicus of
penis. Urol Int 2002; 68: 2914.
3 Nasca MR, Innocenzi D, Micali G. Penile cancer among patients
with genital lichen sclerosus. J Am Acad Dermatol 1999; 41: 911
14.
4 Maden C, Sherman KJ, Beckmann AM et al. History of circumci-
sion, medical conditions, and sexual activity and risk of penile
cancer. J Natl Cancer Inst 1993; 85: 1924.
5 Bailis SA. Association between invasive squamous cell carcinoma
and lichen sclerosus et atrophicus. Scand J Urol Nephrol 2001; 35:
4356.
A case of naevus lipomatosus cutaneus superficialis
of the scalp associated with pedunculated basal cell
carcinoma
SIR, Naevus lipomatosus cutaneus superficialis (NLCS) is a
rare disorder characterized by ectopic growth of mature
adipocytes between collagen bundles. NLCS is classified as
either the more common multiple type (or classical type)1 or
the solitary type.2 The former type is frequently distributed on
the lower trunk, gluteal region or thigh, whereas the latter
type has no location of predilection. However, its occurrence
on the scalp is extremely rare: there have been only two
reports to date.3,4 We report a further case, which was
associated with pedunculated basal cell carcinoma (BCC).5
A 31-year-old Japanese woman first visited our outpatient
clinic in June 1999. At birth, her scalp had contained an area
of skin with only villus hairs. At approximately 10 years of age,
the lesion had gradually started to enlarge. One year prior to
attendance at our clinic, she had noticed the presence of a
dark-reddish tumour on the nodular lesion. Examination
showed a solitary nodule of approximately 100 80 mm
covered with villus hairs on the right side of her scalp (Fig. 1a).
A dark-reddish pedunculated tumour of 9 mm in diameter was
seen on the posterior of the nodule (Fig. 1b). Head X-ray
showed osteolytic changes of the parietal bone (Fig. 1c).
Angiography of cerebral arteries revealed aneurysms of the
basilar top and arteriovenous malformation (Fig. 1d).
Biopsy of the nodule revealed ectopic growth of mature
adipocytes between collagen bundles and a decreased number
of skin appendages (Fig. 2a). Histologically, the pedunculated
tumour consisted of tumour nests of basophilic palisading
cells with continuity to the epidermis (Fig. 2b). Toluidine blue
and alcian blue staining showed a metachromatic pattern of
deposition (Figs 2c,d), indicating that the tumour produced
mucopolysaccharides. Mucopolysaccharide deposits were also
observed in the dermis of a lesion of loose anagen hair (not
shown). Based on the above findings, our patient was
diagnosed as having NLCS of the scalp associated with
pedunculated (adenoid-type) BCC producing mucopolysac-
charide.5
The solitary type of NLCS usually forms a dome-shaped
papule or plaque. Lesions mostly appear in adult life, and
grow slowly. Histopathological findings are characterized by
the presence of ectopic adipocytes among the collagen
 CORRESPONDENCE 1085

a b

1 Figure 1. (a) A solitary nodule with villus hair was observed on the right side of the scalp. Anagen hairs grew on the surrounding normal scalp
skin surrounding the nodule. (b) A dark-reddish pedunculated tumour of 9 mm diameter was seen on the nodule. (c) X-ray analysis showed
osteolytic changes of the parietal bone as indicated (yellow arrows). (d) Angiography of the cerebral arteries demonstrating an aneurysm of the
basilar top (red arrow) and nidus formation (yellow arrow) caused by arteriovenous malformation.

bundles of the reticular dermis. Clusters of ectopic fat tissues
may sometimes be seen in the papillary dermis. In the present
case, ectopic fat tissues were localized in collagen bundles in
the reticular dermis, occasionally in close proximity to skin
appendages, and the boundary between the dermis and
hypodermis was ill-defined, consistent with NLCS. Another
unique feature of our case is the association with pedunculated
BCC. This type of BCC may be classified as polypoid-type
BCC.5,6 There are two earlier reports describing pedunculated
BCC. This occurs on the scalp or ears, and is more common in

 2003 British Association of Dermatologists, British Journal of Dermatology, 148, 10581087

1086 BOOK REVIEW
Figure 2. Histopathological examination of specimens derived (a) from the nodule and (b) from the pedunculated dark-reddish tumour
(haematoxylin and eosin). Mucopolysaccharide staining of the pedunculated tumour with (c) toluidine blue (pH 25) and (d) alcian blue (pH 25).
women than in men. Neither report described production of
mucopolysaccharides by the tumour.5,6 In addition, our case
is different from previously reported cases because of the
occurrence of alopecia with sparse anagen hairs surrounding
the tumour. In our case, the alopecia seems to have occurred
by deposition of mucopolysaccharides produced by the
tumour cells possibly causing degeneration of hair follicles
in the surrounding skin. The present case was also accom-
panied by cerebral arteriovenous malformation, cerebral
aneurysm and osteolytic changes of the parietal bone. As
the patient does not have a relevant family history, it is
presently not known whether the condition is hereditary.
Department of Dermatology, A.Maeda
Kinki University School of Medicine, Y.Aragane
Osakasayama, Japan K.Ueno
Correspondence: Yoshinori Aragane F.Yamazaki
E-mail: nori@kindai.ac.jp A.Kawada
T.Tezuka
Book review
Cosmetic Dermatology Principles and Practice (2002).
LESLEY BAUMAN. New York: McGraw-Hill. 226 pages. ISBN:
0071362819. Price: $149.
This book is best described as an overview of cosmetic
dermatology, a rapidly expanding area of dermatology in
many countries. The author is an assistant professor at the
University of Miami in Florida, USA and has partly drawn on
her personal experiences to develop this book. In the foreword
she refers to her goal of creating a link between the fields of
dermatology and cosmetic science. I think she has partially
succeeded in this goal.
The part of the book dealing with topical agents is well
written, well referenced and can be recommended. However, I
think there are weaknesses are in the procedure-orientated
section. Some examples of areas of concern are as follows:
Chapter 18 on the cosmetic uses of Botox fails to document
many important references on the subject. In addition, the
author advocates that Nitrous Oxide can be used as a
means of anaesthesia prior to the injection of Botox. I
 2003 British Association of Dermatologists, British Journal of Dermatology, 148, 10581087
References
1 Hoffmann E, Zurhelle E. Uber einen Naevus Lipomatosus Cutaneus
Superficialis der linken glutaal Gegend. Arch Dermatol Syphilol
1921; 130: 32733.
2 Abel R, Dougherty JW. Nevus lipomatosus cutaneus superficialis
(Hoffmann-Zurhelle) a report of two cases. Arch Dermatol 1962;
85: 5246.
3 Wielzner S. Solitary nevus lipomatosus cutaneus superficialis of the
scalp. Arch Dermatol 1968; 97: 5402.
4 Chanoki M, Sugimoto I, Suzuki S, Hamada T. Nevus lipomatosus
cutaneus superficialis of the scalp. Cutis 1989; 43: 1434.
5 Megahed M. Polypoid basal cell carcinoma: a new clinicopatho-
logical variant. Br J Dermatol 1999; 140: 7013.
6 Morita K, Ikoma A, Takagaki K. Pedunculated basal cell epitheli-
oma which is not Pinkus tumor. J Dermatol 2001; 28: 1035.
would suggest that this is, at best, unwise in the absence of
a fully equipped surgically approved facility, with the
availability of anaesthetist or anaesthesiologist (USA).
Figure 16 shows too much lateral elevation of the eyebrow,
but this problem (of glabella Botox) is not discussed.
In Chapter 19, the author mentions several fillers that have
actually been withdrawn from use. This is confusing,
especially for a newcomer.
Chapter 21 gives a review of techniques for hair removal,
but is lacking in relevant references, particularly relating to
laser hair removal.
In summary, I can recommend the section dealing with
Topical therapy and cosmeceuticals, which is thorough and
helpful. I have some reservations about the other sections of
the book because I feel they may be misleading for the
neophyte and contain insufficient detail for physician sur-
geons practising in this field.
N.J.Lowe

News and Notices
14th International Symposium on Contact Dermatitis
1921 September 2003, Seoul, Korea
The winning entry of the Niels Hjorth Prize will be
presented at the symposium. For further information, please
contact the Chairman of the International Contact Dermatitis
Research Group, Professor J-M.Lachapelle, Department of
Dermatology, Louvain University, UCL 3033, Clos Chappelle-
aux-Champs 30, B-1200 Brussels, Belgium. Tel.: + 32 2 764
3335; fax: + 32 2 764 3334.
International Short Course on Dermoscopy
July 1519, 2003, University of Graz, Austria
This course is designed for all colleagues interested in
learning dermoscopy for diagnosing and managing equivocal
 2003 British Association of Dermatologists, British Journal of Dermatology, 148, 10581087
NEWS AND NOTICES 1087
pigmented skin lesions more effectively. Special emphasis will
be given to correlating meticulously the clinical and derm-
oscopic images of pigmented skin lesions with its underlying
histopathic findings.
Academic Directors: H. Peter Soyer, M.D., Professor of
Dermatology, Department of Dermatology, University of Graz,
Graz, Austria and Giuseppe Argenziano M.D., Assistant
Professor of Dermatology, Department of Dermatology, Sec-
ond University of Naples, Naples, Italy.
The detailed programme is presented on the website: http://
dermoscopy.uni-graz.at
For further information please contact: cme.dermoscopy@
uni-graz.at