ARTICLE
Keratoacanthoma is a rapidly growing, locally destructive tumour that
develops from pilosebaceous follicles and histologically resembles squamous
cell carcinoma. KA predominantly occurs in men and is most frequent in
middle life. It usually presents as a rapidly growing papule, developing
within weeks to months to a dome-shaped tumour with a central keratotic
plug covering a keratin-filled crater. The nature of KA is not quite clear.
Because of the carcinoma-like histological appearance and the occasional
spontaneous regression, KA is considered as an immunologically well-controlled
low-grade squamous cell carcinoma [1].
Principally, KA has a tendency for spontaneous regression that, however,
requires at least 9 — 12 months [2]. Because of its
rapid growth, unpredictable final size, preferential facial occurrence,
and the possibility of vast tissue destruction due to ulceration and secondary
infection, treatment of KA is usually required.
Several treatment modalities are currently available. Most common is
excision as it allows proper histological classification, but also curretage,
radiation therapy, and intralesional injection of 5-fluorouracil, bleomycin,
methotrexate, interferon (IFN)-alpha , or triamcinolone acetonide have
been successfully used [3-8].
The imidazoquinoline imiquimod (Aldara®) is a novel immune response
modifier. It promotes antiviral and antitumour immune responses and may
be effective in the treatment of genital and perianal warts, basal cell
carcinoma [9], actinic keratosis [10], or bowenoid papulosis [11]. We
report four cases of KA treated with imiquimod in compassionate use.
Case reports
Patient 1
A 64-year-old Caucasian man reported a nodule growing rapidly on the
left side of the nose since five weeks. Clinical examination revealed
a dome shaped tumour of about seven mm in diameter with a central keratotic
plug (Fig. 1A). Histological
examination considered KA, a highly differentiated squamous cell carcinoma
could not be excluded.
Imiquimod 5 % cream was applied every second day. Within two weeks
the skin lesion had already decreased remarkably in size (Fig.
1B). Therefore, imiquimod therapy was continued for another nine weeks.
During this treatment the nodule disappeared (Fig.
1C). A second biopsy taken 12 weeks after treatment onset showed
only collagen bundles with fibrocytes in the dermis and a slight lymphohistiocytic
infiltrate typical of a scar.
Patient 2
A 63-year-old Caucasian woman reported a nodule that had rapidly grown
on the tip of the nose during the previous six weeks. Clinical examination
revealed a dome shaped tumour of about ten mm in diameter with a central
keratotic plug. Histological evaluation of a biopsy raised the possibility
of KA and squamous cell carcinoma.
Imiquimod 5 % cream was applied every second day. Within four weeks
the tumour had disappeared clinically and histologically, leaving only
a small hemorrhagic crust that could easily be removed.
Patient 3
A 47-old Caucasian woman had observed the growth of a nodule on the
upper lip during the previous four weeks. Clinical examination revealed
a dome shaped tumour of about eight mm in diameter with a central keratotic
plug. Histologically, the tumour was diagnosed as a squamous cell carcinoma.
Because of the short history and the typical picture the diagnosis of
KA was decided clinically.
Imiquimod 5 % cream was applied every second day. The tumour completely
regressed, and imiquimod treatment was stopped six weeks after onset.
Patient 4
An 82-year old Caucasian man reported that a nodule had grown during
the previous eight days on the back of the nose (Fig
2A). Clinical examination revealed a dome shaped tumour of about seven
mm in diameter with a central keratotic plug. Because of an anticoagulation
therapy no biopsy was taken. Within six weeks of treatment with imiquimod
5 % cream every second day, KA fully regressed (Fig.
2B).
Discussion
Although KA is not ultimately a malignant tumour and may regress spontaneously,
rapid growth and the probability of ulcerative tissue destruction with
secondary infection and formation of mutilating scars usually requires
active treatment. Excision of facial KA, however, may be difficult and
also result in cosmetically disturbing scars. All other treatment options
such as injection of interferons or methotrexate are merely based on case
reports. Therefore, the search for new efficient and reproducible treatment
alternatives for KA appears warranted.
Imiquimod, an imidazoquinoline, stimulates immune defence mechanisms
by inducing the release of proinflammatory cytokines such as IFN-alpha
, IFN-beta , IFN-gamma , tumor necrosis-factor-alpha , interleukin- (IL)-6,
and IL-8 [12-14]. This effect has been successfully employed for
the treatment of viral warts and various localised cutaneous malignancies.
Spontaneous regression of KA seems to be promoted by T cell mediated
immune reactions, with activated T cells infiltrating into the tumour
tissue [1, 15]. Therefore, enhancing of the local immune defence by imiquimod
appeared to be a reasonable approach for KA treatment.
We report on four cases of KA that were successfully treated with imiquimod.
In two of the patients the diagnosis had been confirmed histologically.
In the third patient, the tumour had been classified histologically as
squamous cell carcinoma, which is the chief distracting differential diagnosis
of KA in histopathology. Because of the typical appearance and the short
history KA was diagnosed clinically. In the fourth patient a biopsy was
omitted because of an anticoagulant therapy.
Treatment modalities of KA were discussed extensively with each patient.
Upon careful consideration of the therapeutic options all patients agreed
to the therapeutic use of imiquimod 5 % cream that was applied every
second day as suggested for the treatment of genital warts. Clinical controls
were done at short term intervals to allow an appropriate therapeutic
response in case of fast tumour progression.
Duration of therapy ranged from four to twelve weeks. In each patient
KA fully regressed. As confirmed histologically in two of the patients,
healing left a discrete fibrous tissue reaction representative of a small
scar. Patients without histological examination after treatment were observed
during a follow up period of six months to exclude squamous cell carcinoma
clinically.
Application of imiquimod was accompanied by
a slight erosive dermatitis.
KA has a self healing tendency in some of the cases. Spontaneous involution
is not predictable, however, it may require several months, and the final
outcome can not be anticipated. On the other hand, wide destruction and
mutilations of rapidly growing KA are not uncommon. In the four cases
of KA reported here rapid tumour regression was observed under application
of imiquimod 5 % cream. It became visible after only two weeks of
treatment, and in three of the four patients was complete after four to
six weeks. Only in the first patient, was imiquimod continued for a total
of twelve weeks in order to assure a complete response. The promptness
of regression suggested that imiquimod considerably enhanced the self-healing
tendency of KA by promoting the local immune mechanisms. Thus, our observations
indicate that imiquimod may have actively contributed to regression of
KA in these patients. Based on this case report, we suggest that imiquimod
may have clinical utility in the treatment of KA and should be examined
in a larger properly controlled clinical study.
We would like to thank the dermatologists Thomas Schleußinger,
Alexander Boroda, MD, Friedrich Bofinger, MD, and Annette von Zumbusch,
MD, for referring the patients.
Article accepted on 28/10/2002
REFERENCES
Patel A, Halliday GM, Cooke BE, Barnetson RS. Evidence that regression
in keratoacanthoma is immunologically mediated: a comparison with squamous
cell carcinoma. Br J Dermatol 1994; 131: 789-98.
Ramselaar CG, van der Meer JB. The spontaneous regression of keratoacanthoma
in man. Acta Dermatovener 1976; 56: 245-51.
Nedwich JA. Evaluation of curettage and electrodesiccation in treatment
of keratoacanthoma. Australas J Dermatol 1991; 32: 137-41.
Donahue B, Cooper JS, Rush S. Treatment of aggressive keratoacanthomas
by radiotherapy. J Am Acad Dermatol 1990; 23: 489-93.
Goette DG, Odom RB. Successful treatment of keratoacanthoma with intralesional
fluorouracil. J Am Acad Dermatol 1980; 2: 212-6.
Melton JL, Nelson BR, Stough DB, Brown MD, Swanson NA, Johnson TM. Treatment
of keratoacanthomas with intralesional methotrexate. J Am Acad Dermatol
1991; 25: 1017-23.
Grob JJ, Suzini F, Richard MA, Weiller M, Zarour H, Noe C, Munoz MH,
Bonerandi JJ. Large keratoacanthomas treated with intralesional interferon
alpha-2a. J Am Acad Dermatol 1993; 29: 237-41.
Santosa Pham JC, Shelley ED, Shelley WB. Aggressive giant keratoacanthoma
of the face treated with intramuscular methotrexate and triamcinolone
acetonide. Cutis 1997; 59: 329-32.
Hannuksela-Svahn A, Nordal E, Christensen OB. Treatment of multiple
basal cell carcinomas in the scalp with imiquimod 5 % cream. Acta
Derm Venereol 2000; 80: 381-2.
Stockfleth E, Meyer T, Benninghoff B, Christophers E. Successful treatment
of actinic keratosis with imiquimod cream 5 %: a report of six cases.
Br J Dermatol 2001; 144: 1050-3.
Wigbels B, Luger T, Metze D. Imiquimod: a new treatment possibility
in bowenoid papulosis ? Hautarzt 2001; 52: 128-32.
Slade HB. Cytokine induction and modifying the immune response to human
papilloma virus with imiquimod. Eur J Dermatol 1998; 8: 13-6.
Kono T, Kondo S, Pastore S, Shivji GM, Tomai MA, McKenzie RC, Sauder
DN. Effects of a noval topical immunomodulator, imiquimod, on keratinocyte
cytokine gene expression. Lymphokine Cytokine Res 1994; 13: 71-6.
Testerman TC, Gerster JF, Imbertson LM, Reiter MJ, Miller RC, Gibson
SJ, Wager TC, Tomai TH. Cytokine induction by the immunomodulators imiquimod
and S-27609. J Leukoc Biol 1995; 58: 365-72.
Halliday GM, Patel A, Hunt MJ, Tefany FJ, Barnetson RS. Spontaneous
regression of human melanoma/nonmelanoma skin cancer: association with
infiltrating CD4+ T cells. World J Surg 1995; 19: 352-8.
|
Printable version
