Association of cutaneous side-effects of hydroxyurea and neuroendocrine carcinoma

ARTICLE

Auteur(s) :, Marie-Anne Bouldouyre¹, Marie-Françoise Avril², Alain Gaulier³, Michèle Sigal-Grinberg^1,*

¹Department of dermatology, Victor Dupouy Hospital, 69 rue du Lieutenant colonel Prudhon, 95 107 Argenteuil, France
²Department of dermatology, Gustave Roussy Institute, Villejuif, France
³Department of pathology, Victor Dupouy Hospital, 69 rue du Lieutenant colonel Prudhon, 95 107 Argenteuil, France

accepté le 8 Octobre 2004

Case report

She was seen again in 1994 because of multiple keratotic lesions on the dorsum of both hands. Biopsies of the most important lesions showed four intra-epithelial carcinomas and an invasive one. Surgical excisions of all five carcinomas were pathologically complete. Retinoic acid (acitretine) was given for two years, and did not prevent development of new keratotic lesions.

In fact, she came back in 1996 with 15 new keratosic lesions: the lesions were located on the dorsum of the fingers, and the dorsum of the hands; some on them were on the border of previous scars, and the others on the poikilodermic skin, spared before. Surgical excision was considered difficult, and local chemotherapy by 5 fluoro-uracile (5-FU) was applied until 1999 with stabilization.

In January 2000, she came in emergency because of two suspicious lesions. The first lesion, located on the back of the left hand, was circular, thick and scabby, with local inflammation: the biopsy revealed an actinic keratosis. The second lesion, which grew up quickly in 4 months was located on the lateral side of the 3^rd left finger and had a similar aspect: a scabby thick lesion about 1.5 cm in diameter ( (figure 1) ), and appeared to be a neuroendocrine carcinoma. Pathologic examination of the biopsy showed a tumoral trabecular proliferation, close to a hyperplasic epithelium ( (figure 2) ). The trabecular proliferation was composed of small cells expressing neuron specific enolase and pancytokeratin AE1-AE3 after immunohistochemical staining, with typical dot-like paranuclear reactivity ( (figure 3) ). Chest X-ray and abdominal ultrasound did not show any visceral involvement. Regional nodes (i.e. axillary) were not palpable. A trans-metacarpus amputation was performed.

During 2001, she presented new actinic keratosis and a squamous cell carcinoma which were removed. She also developed an epitrochlear lymph-node metastasis of the neuroendocrine carcinoma.This lymph-node was treated by surgical excision followed by radiotherapy (50 Grays). In March 2002, 3 metastasis were detected in the liver: they were not biopsed, but were supposed and treated as if they were Merckel cell carcinoma metastasis. Serum neuron specific enolase was increased. Systemic chemotherapy by cysplatin and etoposide was administered. Unfortunately, she died in March 2003.

Discussion

HU is an effective antimitotic drug used in myeloproliferative syndromes, such as chronic myelogenous leukemia, polycythemia rubra vera and thrombocytemia. This useful drug is usually well tolerated with few hematological side-effects, and is easily dosed, relatively inexpensive, presenting few contraindications and subjective side-effects [1].

Cutaneous manifestations have been reported: partial alopecia, increased pigmentation, scaling, dryness, nail changes, erythema of the face and hands, atrophy of the skin and subcutaneous tissues [2], dermatomyositis like eruption [3, 4], plantar keratoderma [5].

More recently, many authors described the association of HU toxidermia and development of multiple actinic keratosis and squamous cell carcinoma, and less frequently basal cell carcinoma. About 14 patients have been reported [6-13].

An Italian retrospective study identified 5 squamous cell carcinomas in 21 patients with severe cutaneous and mucosal changes, among a sample of 158 followed because of long term HU therapy [14]. A prospective French study involving 26 patients who had been treated by HU, identified 25 patients with cutaneous lesions (including xerosis) related to HU including 8 keratosis and 2 squamous cell carcinoma [15]. Keratoses usually appear 2 to 6 years after introduction of HU, they are multiple and extend very rapidly.

The lesions seem to result from the cumulative toxicity of HU on the basal layer of the epidermis. HU is a potent inhibitor of DNA synthesis and in vitro it induces chromosome damage and inhibition of DNA repair in ultraviolet-irradiated human cell [16]. Skin atrophy induced by HU (due to increased sensitivity of the skin to antimetabolites because of high turn over) may increase the action of ultraviolets on the basal layer [17].

Conclusion

The role of HU remains speculative, either on well known actinic keratosis or cutaneous carcinoma. Concerning the Merckel cell carcinoma, imputing an inducing role of HU has to be very carefully speculated.

References

2 Kennedy B, Smith L, Goltz R. Skin changes secondary to hydroxyurea therapy. Arch Dermatol 1975; 111: 183-7.

3 Senet P, Aractingi S, Porneuf M, Perrin P, Duterque M. Hydroxyurea-induced dermatomyositis-like eruption. Br J Dermatol 1995; 133: 455-9.

4 Oskay T, Kutluay L, Ozyilkan O. Dermatomyositis-like eruption after long-term hydroxyurea therapy for polycythemia vera. Eur J Dermatol 2002; 12: 586-8.

5 Sigal M, Crickx B, Blanchet P, Perron J, Simony J, Belaich S. Lésions cutanées induites par l’utilisation au long cours de l’hydroxyurée. Ann Dermatol Venereol 1984; 111: 895-900.

6 Grange F, Couillet D, Audhuy B, Krzisch S, Schlecht P, Guillaume JC. Keratoses multiples induites par l’hydroxyurée. Ann Dermatol Venereol 1995; 122: 16-8.

7 Salmon-Ehr V, Grosieux C, Potron G. Multiple actinic keratosis and skin tumors secondary to hydroxyurea treatment. Dermatology 1998; 196: 274.

8 Papi M, Didona B, DePita O, Abruzzesz E, Stasi R, Papa G, et al. Multiple skin tumors on light-exposed areas during long-term treatment with hydroxyurea. J Am Acad Dermatol 1993; 28: 485-6.

9 Best P, Petitt R. Multiple skin cancers associated with hydroxyurea therapy. Mayo Clin Proc 1998; 73: 961-3.

10 Callot-Mellot C, Bodemer C, Chosidow O, Frances C, Azgui Z, Varet B, et al. Cutaneous carcinoma during long term hydroxyurea therapy: A report of 5 cases. Arch Dermatol 1996; 132: 1395-7.

11 De Simone C, Guerriero C, Guidi B, Rotoli M, Venier A, Tartaglione R. Multiple squamous cell carcinomas of the skin during long term treatment with hydroxyurea. Eur J Dermatol 1998; 8: 114-5.

12 Esteve E, Georgescu V, Heitzman P, Martin L. Carcinomes cutanés et buccaux multiples après traitement par hydroxyurée. Ann Dermatol Venereol 2001; 128: 919-21.

13 Kelly R, Bull R, Marsden A. Cutaneous manifestations of long-term hydroxyurea therapy. Australas J Dermatol 1994; 35: 61-4.

14 Vassallo C, Passamonti F, Merante S, Ardigo M, Nolli G, Mangiacavalli S, et al. Muco-cutaneous changes during long-term therapy with hydroxyurea in chronic myeloid leukemia. Clin Exp Dermatol 2001; 26: 141-8.

15 Salmon-Ehr V, Leborgne G, Vilque JP, Potron G, Bernard P. Effets secondaires de l’hydroxyurée: étude prospective de 26 patients consultant dans un service de dermatologie. Rev Med Interne 2000; 21: 30-4.

16 Francis A, Blevins R, Carrier W. Inhibition of DNA repair in ultraviolet-irradiated human cells by hydroxyurea. Biochim Biophys Acta 1979; 563: 385-92.

17 Stasi R, Cantonetti M, Abruzzese E, Papi M, Didona B, Cavalieri R. Multiple squamous cell carcinomas of the skin during long term treatment with hydroxyurea. Eur J Haematol 1992; 48: 121-2.