ARTICLE
Keratoacanthoma is a relatively common skin tumour characterised by fast
initial growth and slow spontaneous regression over a period of 4-12 months
[1]. It is mostly seen as a solitary lesion, but various forms of multiple,
eruptive keratoacanthomas have been described [1]. The clinical picture
now known as Grzybowski's generalised eruptive keratoacanthomas was first
reported in 1950 [2]. Since then around 20 additional cases have been
published [3, 4]. We report here the first published case of Grzybowski's
generalised eruptive keratoacanthomas in Scandinavia.
Case report
A 45-year old otherwise healthy woman developed over a period of two
years progressive pruritic eruptions on all parts of her body, initially
most profound in the face, neck and vulvae, as well as multiple skin tumours
with fast initial growth and gradual spontaneous regression within 4-8
months. As a researcher on environmental carcinogens, she had over a period
of five years, 20 years earlier, repeatedly been exposed to various carcinogenic
agents, such as arsenes, polyaromatic hydrocarbons, polychlorinated hydrocarbones,
etc., through inhalation due to lack of proper protection in violation
of safety regulations. There was no history of skin disease in her family,
except for an uncle's basal cell carcinoma.
Clinical examination revealed a generalised eruption, most profound
on the neck, shoulders, upper trunk, thighs, and vulva, consisting of
multiple (hundreds) follicular papules (Fig.
1). No erythema was apparent, and the skin of the palms and soles
was normal. On both sun exposed and unexposed parts of the body she had
multiple skin tumours with diameters from around 4 to 50 mm (Fig.
2). Most tumours were symmetrical in shape with a central cornified
excavation or invagination (Fig.
2) and some were coalescent (Fig.
3). She had similar lesions on the tongue, lips and buccal mucosa
(Fig. 4). The facial skin
showed increased consistency on palpation with ectropion and conjunctival
injection (Fig. 5).
Histological examination of excised tumours revealed typical characteristics
of keratoacanthoma: symmetrical lesions, epidermal shoulders (lips), a
central cornified excaviation or invagination, irregular epidermal proliferation
with some atypi, with eosinophilic and ground glass appearance of keratinocytes.
The lesions had various degrees of fibrosis and tumour cell infiltration,
in one case even as far as to the subcutaneous fat. No human papillomavirus
(HPV) was detected in deep frozen fresh specimens of 17 lesions by polymerase
chain reaction using two sets of consensus primers, the E1-specific CPI/CPIIG
and the L1-specific Gp5 ± Gp6+, as well as with type-specific
primers for HPV 6, HPV 16, HPV 18, HPV 31, and HPV 33 [5]. Histological
examination of small follicular lesions was compatible with the diagnosis
of early keratoacanthoma. Biopsy from the vulva showed no histological
signs of vulval lichen sclerosus et atrophicus.
A general clinical examination was negative. An extensive screening
for internal malignancy, including blood tests, X-ray, computer tomography,
ultrasound, and colonoscopi, was negative. She tested negative for HIV
antibodies and had no abnormalities on immunological tests. Determination
of arsene, using atomic absorption spectroscopy with hydride generation
[6], showed that newly grown hair of the scalp contained less than 0.01
mg arsene/kg.
After the diagnosis was made, she developed over a period of 2-3 years
more than 1,000 skin tumours of various size, of which 17 were excised.
Those that were not excised, healed spontaneously within 4-8 months, some
with atrophic scarring. Some lesions had a striking bilateral distribution.
The intensity of the follicular eruption varied somewhat with the menstruation
cycle, and some lesions formed striped patterns. The scleroderma-like
skin changes in the face (and the ectropion) increased considerably, after
three years also involving the skin over joints and on upper trunk. The
itch was increasingly annoying, especially in the external genital region.
She developed a slight depigmentation in the vulva, but no clinical sclerosis.
She reported a slightly elevated body temperature, for which no explanation
was found.
Peroral acitretin therapy 25 mg daily for three months had no effect.
Peroral antihistamine did not reduce the itching. The patient did not
want treatment with methotrexate or cyclophosphamide. The patient's ectropion
was corrected by blepharoplastic surgery, with autotransplantation of
relatively uninvolved axillar skin. After the operations, the patient
experienced reduced drainage of tears through the lacrymal ducts.
Discussion
To the best of our knowledge this is the first case report of Grzybowski's
generalised eruptive keratoacanthomas from the Scandinavian countries.
The clinical picture fits very well with the previously reported cases
of this very rare disease [3, 4]. Previously reported cases have all been
sporadic and most in elderly patients.
The cause and pathogenesis of eruptive keratoacanthomas are unknown.
Chemicals, viruses, trauma, and altered immunity have been suggested as
causative agents [3]. Chemical tumorigenesis has been demonstrated in
solitary keratoacanthoma-like tumours in animal models by painting the
skin with tar derivates [7]. In humans, one study showed a significant
increased incidence of keratoacanthomas in pitch and tar workers compared
to matched control persons [8]. A recent study indicates that employment
in a tar refinery can cause keratoacanthoma primarily or secondarily [9].
There are case reports on solitary keratoacanthomas in machine workers
with constant contact with oil [10], and on multiple keratoacanthomas
and squamous cell carcinomas in psoriatic patients treated with tar and
UVB [11]. However, chemical exposure has not been specifically implicated
in the development of eruptive keratoacanthomas.
The association between arsenic intake, in the form of therapeutic,
occupational or industrial exposure, and skin tumours, both arsenic keratoses,
basal cell carcinomas, and squamous cell carcinomas, often multiple, is
well recognised, although the mechanism of the carcinogenic effect by
arsene is unknown [12]. The occurrence of basal cell carcinomas in patients
previously treated with arsene is characterised by a long latency period,
i.e. up to 30 years. In our patient, previous exposure to arsene
through inhalation was well documented. However, the patient did not show
the classical signs of chronic arsenic intoxication in the form of multiple
punctiform or verruciform hyperkeratoses of the palms and soles [12].
Moreover, there were no basal cell carcinoma or carcinomas in situ
(Bowen's disease). In our view, the facial appearance and bilateral ectropium
are more probably signs of a genetic defect and not compatible with a
diagnosis of arsenic intoxication.
An association between of human papillomaviruses and keratoacanthoma
has been postulated, but the results from studies are conflicting [1,
3]. Our findings regarding human papillomavirus are consistent with the
results of Höpfl and co-workers [13], who found no human papillomavirus
in one multilocular and 30 solitary keratoacanthomas.
Multiple keratoacanthomas are known to occur in organ transplant recipients
as a result of long-term immunosuppressive therapy [1, 14]. This is compatible
with the hypothesis that an immune mediated process is involved in the
development of multiple keratoacanthomas, possibly through combined genetic
and environmental factors. Some patients with Grzybowski's generalised
eruptive keratoacanthomas have been diagnosed with cancer, but this association
appears to be coincidental. Our patient was not immunosuppressed, and
no signs of cancer were found.
Article accepted on 18/10/99
CONCLUSION
Acknowledgements
We thank Unni Kirste, Arvid Bjørneklett, and Kristin Eidal for
their involvement in the medical care of this patient. The analyses on
human papillomavirus in keratoacanthomas were performed by Torkjel Matzow
and Bjørn Hagmar, and the arsene analysis in hair by Dag Grønningen.
REFERENCES
1. Schwartz RA. Keratoacanthoma. J Am Acad Dermatol 1994;
30: 1-19.
2. Grzydowski M. A case of peculiar generalized epithelial tumours
of the skin. Br J Dermatol 1950; 62: 310-3.
3. Jaber PW, Cooper PH, Greer KE. Generalized eruptive keratoacanthoma
of Grzybowski. J Am Acad Dermatol 1993; 29: 299-304.
4. Kavannagh GM, Marshman G, Hanna MM. A case of Grzybowski's
generalized eruptive keratoacanthomas. Australas J Dermatol 1995;
36: 83-5.
5. Matzow T, Boysen M, Kalantari M, Johansseon B, Hagmar B. Low
detection rate of HPV in oral and laryngeal carcinomas. Acta Oncol
1998; 37: 73-6.
6. Egaas E, Brækkan OR. The arsenium content in some Norwegian
fish products. Fisk Dir Ser Ernær 1977; 1: 93-7.
7. Ghadially FN. The experimental production of keratoacanthoma
in the hamster and the mouse. J Pathol Bact 1959; 77: 277-82.
8. Rook A, Champion RH. Keratoacanthoma. Natl Cancer Inst
Monogr 1963; 10: 257-63.
9. Letzel S, Drexler H. Occupational related tumors in tar refinery
workers. J Am Acad Dermatol 1998; 39: 712-20.
10. Patel MR, Desai SS. Subungual keratoacanthoma in the hand.
J Hand Surg 1989; 14A: 139-42.
11. Maddin WS, Wood WS. Multiple keratoacanthomas and squamous
cell carcinomas occurring at psoriatic treatment sites. J Cutan Pathol
1979; 6: 96-100.
12. Braun-Falco O, Pleweig G, Wolff HH, Winkelmann RK. Dermatology.
3rd ed. Berlin: Springer-Verlag, 1991: 1001, 1018, 1026.
13. Höpfl RM, Schir MM, Fritsch PO. Keratoacanthomas: human
papillomavirus associated? Arch Dermatol 1992; 128: 563-4.
14. Jensen P, Clausen OPF, Geiran O, Simonsen S, Relbo A, Hansen
S, et al. Cutaneous complications in heart transplant recipients
in Norway 1983-1993. Acta Derm Venereol 1995; 75: 400-3.
|
Printable version
