Ichthyosiform mycosis fungoides

ARTICLE

Acquired ichthyosis in the elderly can be secondary to serious disorders. Indeed, the underlying etiologies of acquired ichthyosis include a wide variety of diseases, especially endocrine, metabolic or hematologic disorders, renal failure, leprosy, HIV infection, bone marrow transplantation, autoimmune diseases or malignancy [1, 2]. In patients with malignancy, ichthyosis usually follows a paraneoplastic evolution. Regardless of the etiology of acquired ichthyosis, histopathological changes are similar to ichthyosis vulgaris and are not related to the etiological condition.

We hereby report on two patients with clinical features of acquired ichthyosis and a histological pattern of mycosis fungoides (MF). Such a presentation has only rarely been reported in the literature.

Case reports

Case no. 1

A 67-year-old male patient was investigated for ichthyosis of 5 years duration. The ichthyotic lesions were widespread but mainly present on thighs, knees, and ankles and did not spare large folds. Follicular keratosis was present as well. Clinical examination was otherwise unremarkable, without any enlarged lymph nodes. Skin biopsies disclosed a non specific histologic picture of acquired ichthyosis (orthokeratotic hyperkeratosis, focal parakeratosis, acanthosis, and thinned granular cell layer) associated with lymphocytic exocytosis in the basal cell layer forming small epidermal lymphocytic micro-abcesses. Lymphocytes had small nuclei with an irregular contour. A band line of lymphocytic infiltrate was present as well in the upper dermis. Immunostaining showed that dermal and epidermal cells were CD2, CD3 and CD4 positive but CD 20 and CD 30 negative, a pattern typical of T helper lymphocytes. Accordingly, a diagnosis of mycosis fungoides was established.

Standard biological and immunological tests were normal. Tumor markers (CEA, CA19.9, CA12.5) were negative. Computerised tomography scanning was unremarkable, without lymph node or internal organ enlargement. The diagnosis of mycosis fungoides stage Ib was retained.

The patient received a treatment with PUVA therapy. After 6 months, a complete clinical remission was achieved without relapse after a 3 years follow-up.

Case no. 2

A 67-year-old male patient was referred for ichthyosiform hairless patches localized on lower limbs of one-year duration (Fig. 1). Skin biopsies showed a papillomatous epidermis with marked orthokeratotic hyperkeratosis, a dermal lymphocytic infiltrate with convoluted nuclei and epidermal cells clustered in microabcesses (Fig. 2). Immunostaining confirmed the T helper pattern of dermal and epidermal lymphocytes (CD2, CD3 and CD4 positive, CD 20 and CD30 negative). Using a PCR/DGGE method targeting T-cell receptor, a dominant T-cell clone was detected in an ichthyosiform skin lesion but not in peripheral blood (Fig. 3). Briefly, DNA was extracted from a lesional skin frozen punch-biopsy using standard proteinase K digestion and phenol/chloroform precipitation and from peripheral lymphocytes after Ficoll gradient. Two hundred and fifty micrograms of DNA were submitted to PCR/DGGE with four oligonucleotides matching the four Vgamma segment families and four nucleotides matching the Jgamma junction segments as previously described [3].

Clinical and radiological examination were normal and standard biological tests remained in the normal range. The diagnosis of mycosis fungoides stage I b was finally established. A daily treatment using topical mechlorethamine (2 ml diluted in 50 ml of water) and topical corticosteroids applied on the lesions led to a complete remission of cutaneous lesion within 3 months, with no relapse after a 4-year follow-up.

Discussion

Acquired ichthyosis, in contrast to the hereditary type, occurs in middle and old age. It is usually associated with internal diseases such as malignancy and often behaves as a paraneoplastic syndrome. Different malignancies have been associated with acquired ichthyosis [4] including Hodgkin's disease [5] and non-Hodgkin's lymphomas [6, 7]. However, histologic pictures of paraneoplastic ichthyosis usually do not shown any aspect related to maligancy in the skin. Diagnosis of malignancy can be established before or after the appearance of ichthyosis. In patients with paraneoplastic ichthyosis, treatment of the underlying neoplasia can result in disappearance of the ichthyotic skin [6].

Our two cases of epidermotropic cutaneous T-cell lymphoma clinically presented with acquired ichthyosis. The ichthyosis was generalized in the first patient and localized to the lower limbs in the second one. Drug-induced ichthyosis and other causes, especially malignacies, had been excluded in our patient: the patients denied intake of any drug classically responsible for ichthyosis and laboratories or radiological investigations did not show reminiscence of internal malignancy or lymphoma. In contrast to the paraneoplastic ichthyosis, the histopathologic pattern of MF was found in the ichthyotic lesions themselves in addition to the epidermal changes of acquired ichthyosis. Neither of the two patients had classical clinical lesions of cutaneous lymphoma. Lesions of ichthyosis in these patients were specific malignant skin manifestations and not a mere non-specific clinical sign of underlying malignancy or other pathology.

To our knowledge, only six cases with ichthyosiform MF with histological features reminiscent of both ichthyosis and cutaneous T-cell lymphoma have been reported in the literature [8-10]. Whereas MF usually occurs in old age as in our patients and in the patients respectively described by De Graciansky et al. [8] and by Marzano et al. [10], however, ichthyosiform mycosis fungoides occurred in a 25-year-old patient as well [9]. Clinical remission was obtained with non agressive therapies such as topical treatment, Puvatherapy or an association of alpha interferon and retinoids. Lymphomatous infiltrate in the skin does not always elicit specific cutaneous symptoms as reported in that rare form of cutaneous T cell lymphoma and in the so called invisible lymphoma [11]. Ichthyosiform mycosis fungoides is different from acquired ichtyosis associated with cutaneous lymphoma. In this latter condition [12], the ichtyotic lesions reveal the lymphoma and the patient presents with both cutaneous specific lesions of lymphoma and ichthyosis. However a skin biopsy of ichtyotic lesions does not show any pathological aspect of lymphoma but only epidermal hyperplasia. Ichthyosiform mycosis fungoides must be added to the newly described atypical forms with epidermal hyperplasia such as mycosis fungoides presenting as keratosis lichenoides chronica [13], or pilotropic mycosis fungoides [14]. It is notworthy that 3 among the 4 patients described by Marzano et al. [10] have simultaneously ichthyotic and comedo-like lesions, underlining a probable link between these two clinical forms. In these patients, as in our cases, it has been hypothesized that epidermal or lymphocytic growth factors could play a crucial role in the increase of the epidermal thickness. Such a phenomenon has already been reported in cutaneous T cell lymphomas with pseudo-epitheliomatous hyperplasia [15]. In these cases, an increase in the epidermal expression of epidermal growth factor (EGF), epidermal growth factor receptor (EGFr) and transforming growth factor alpha (TGFalpha), associated with an over expression of EGF and TGFalpha in lymphomatous T cells has been evidenced [15].

Ichthyosis either can reflect the presence of underlying severe disorder or may be an atypical form of some skin diseases notably cutaneous T cell lymphoma. A knowledge of these atypical cases should lead to an earlier diagnosis if other causes of acquired ichthyosis are not otherwise identified.

Article accepted on 30/7/02

REFERENCES

1. Humbert P, Dupond JL, Agache P. Acquired ichthyosis. Ann Dermatol Venereol 1988; 115: 937-42.

2. Higgins EM, du Vivier AW. Cutaneous manifestations of malignant disease. Br J Hosp Med 1992; 48: 552-4, 558-61.

3. Theodorou I, Delfau-Larue MH, Bigorgne C, Lahet C, Cochet G, Bagot M, Wechsler J, Farcet JP. Cutaneous T-cell infiltrates: analysis of TCRgamma gene rearrangement by PCR and denaturing gradient gel electrophoresis. Blood 1995; 86: 305-10.

4. Kurzock R, Cohen PR. Cutaneous paraneoplastic syndrome in solid tumors. Am J Med 1995; 99: 662-71.

5. Tamura J, Shinohara M, Matsushima T, Sawamura M, Murakami H, Kubota K. Acquired ichthyosis as a manifestation of abdominal recurrence of non-Hodgkin's lymphoma. Am J Hematol 1994; 45: 191-2.

6. Lucker GP, Steijlen PM. Acrokeratosis paraneoplastic (Bazex syndrome) occurring with acquired ichthyosis in Hodgkin's disease. Br J Dermatol 1995; 133: 322-5.

7. Estines O, Grosieux-Dauger C, Derancourt C, Patey M, Durlach A, Bernard P. Paraneoplastic acquired ichthyosis revealing non-Hodgkin's lymphoma. Ann Dermatol Venereol 2001; 128: 31-4.

8. De Graciansky P, Timsit E, Bassenne C. Mycosis fungoïde érythrodermique. Aspect d'ichtyose. Bull Soc Fr Derm Syph 1968; 75: 437.

9. Kutting B, Metze D, Luger TA, Bonsmann G. Mycosis fungoides presenting as acquired ichthyosis. J Am Acad Dermatol 1996; 34: 887-9.

10. Marzano AV, Borghi A, Facchetti M, Alessi E. Ichthyosiform mycosis fungoides. Dermatologica 2002; 204: 124-9.

11. Dereure O, Guilhou JJ. Invisible mycosis fungoides: a new case. J Am Acad Dermatol 2001; 45: 318-9.

12. Kato N, Yasukowa K, Kimura K, Yoshiba K. Anaplastic large-cell lymphoma associated with acquired ichthyosis. J Am Acad Dermatol 2000; 42: 914-20.

13. Bahadoran P, Wechsler J, Delfau-Larue MH, Gabison G., Revuz J, Bagot M. Mycosis fungoides presenting as keratosis lichenoides chronica. Br J Dermatol 1998; 138: 1067-9.

14. Vergier B, Beylot-Barry M, Beylot C, De Mascarel A, Delaunay M, De Muret A, Vaillant L, Tortel MC, Grange F, Bagot M, Laroche L, Wecshler J and the French Study Group of Cutaneous Lymphomas. Pilotropic cutaneous T-cell lymphoma without mucinosis. Arch Dermatol 1996; 132: 683-7.

15. Courville P, Wechsler J, Thomine E, Vergier B, Fonck Y, Souteyrand P, Beylot-Barry M, Bagot M, Joly P and the French Study Group of Cutaneous Lymphomas. Pseudoepitheliomatous hyperplasia in cutaneous T-cell lymphoma. A clinicopathological and immunohistochemical study with particular interest in epithelial growth factor expression. Br J Dermatol 1999; 140: 421-6.