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Granulomatous slack skin

European Journal of Dermatology. Volume 17, Number 5, 435-8, September-October 2007, Clinical report

DOI : 10.1684/ejd.2007.0243

Summary

Author(s) : Marta Teixeira, Rosário Alves, Margarida Lima, Áurea Canelhas, Conceição Rosário, Manuela Selores , Dept of Dermatology, Hospital Geral de Santo António, Rua D. Manuel II, Edifício Ex-CICAP, 4099-001 Porto, Portugal, Dept of Hematology, Hospital Geral de Santo António, Porto, Dept of Pathology, Hospital Geral de Santo António, Porto, Dermatology Department, Hospital Maria Pia, Porto-Portugal.

Summary : Granulomatous slack skin is an extremely rare subtype of cutaneous T-cell lymphoma characterized by the slow development of folds of lax skin, especially in flexural areas and histologically characterized by a granulomatous infiltrate with clonal T cells. Notwithstanding its indolent behavior, treatment is often disappointing. We describe an additional case of this rare disorder in a 44-year-old male patient.

Keywords : cutaneous T-cell lymphoma, granulomatous slack skin, interferon-α, interferon-γ, mycosis fungoides, therapy

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Auteur(s) : Marta Teixeira¹, Rosário Alves¹, Margarida Lima², Áurea Canelhas³, Conceição Rosário⁴, Manuela Selores¹

¹Dept of Dermatology, Hospital Geral de Santo António, Rua D. Manuel II, Edifício Ex-CICAP, 4099-001 Porto, Portugal
²Dept of Hematology, Hospital Geral de Santo António, Porto
³Dept of Pathology, Hospital Geral de Santo António, Porto
⁴Dermatology Department, Hospital Maria Pia, Porto-Portugal

accepté le 28 Mars 2007

In 1973, Convit et al. [1] reported an unusual case in a 15-year-old boy characterized clinically by indurate plaques resembling cutis laxa and histologically by a peculiar granulomatous infiltrate of the entire dermis. They termed the condition progressive, atrophying, chronic granulomatous dermohypodermitis. The patient died 20 years later with Hodgkin’s disease. The term granulomatous slack skin (GSS) was coined by Ackerman, after reviewing the case in 1978, to describe the patient’s disease [2]. Nine years later Le Boit et al. [3] demonstrated the lymphoproliferative nature of the condition and suggested that it was a peculiar form of cutaneous T-cell lymphoma (CTCL) closely related to mycosis fungoides. According to the most recent consensus, cutaneous lymphomas classification proposal, the WHO-EORTC classification, GSS is classified as a rare subtype of mycosis fungoides with indolent clinical behavior [4]. To date, 52 GSS cases have been reported in the English-language literature, including the case described herein [5-15].

Case report

An otherwise healthy 44-year-old Caucasian male patient was observed in our department for pendulous, thinned and atrophic skin on both axillae which had first appeared 3 years before. The lesions had gradually increased in size and became infiltrated, assuming a pendulous appearance and developing a central painful ulceration on the left axilla during the previous 3 months. The personal and family histories were unremarkable. He had been previously treated with sporadic courses of topical corticosteroids and antifungal agents without improvement. Physical examination revealed two large circumscribed plaques on both axillae, with erythematous, thinned, atrophic and finaly scaling surface (figure 1A). The lesion on the left side was considerably more extensive, infiltrated and flaccid, with a prominent vascular network and a central ulcerated, painful 4 cm tumor (figure 1C), hampering the normal adduction of the arm. With both arms in adduction the skin assumed a pendulous sack-like appearance (figure 1B). No enlarged lymph nodes or organomegalies were detected on physical examination. Laboratory studies showed leucocytosis (13 × 10³/μL; NR = 4-11) with neutrophilia (9.23 × 10³/μL; NR = 2-7.5). Liver and renal function tests and serum β2-microglobulin, lactic dehydrogenase and immunoglobulin levels were normal. Serum C-reactive protein levels were increased (2.63 mg/dL; NR < 0.5). The skin biopsy specimen revealed a dense infiltrate of small to medium-size lymphocytes in the dermis. Non-caseating granulomas, histiocytes and Langhans multinucleated cells were also present in a scattered disposition throughout the dermis to the subcutaneous tissue. Superficial vascular plexus prominence was evident (figure 2A, B). Immunohistopathologically, most infiltrating lymphoid cells were CD3+/CD4+/CD45RO+. Verhoeff-van Gieson staining demonstrated almost complete absence of the elastic fibers and those remaining were thinner than normal and frequently fragmented (figure 2C). A diagnosis of granulomatous slack skin was made on the basis of these clinicopathological features. Flow cytometry studies of skin lymphocytes obtained from fresh biopsy tissue revealed that the lymphocytic infiltrate consisted of phenotypically abnormal CD2+, CD3+, TCR α/β+, CD4+ T-cells, with weak CD5 expression and loss of CD7. Polymerase Chain Reaction (PCR) for analysis of the β-T-cell receptor rearrangement detected a clonal T-cell population. Cytological and immunophenotypic studies of the peripheral blood and bone marrow aspirate and histological studies of bone marrow biopsy specimen were negative for malignant cells and blood cells showed a normal 46, XY karyotype. Cultures of fresh biopsy tissue for bacteria demonstrated the presence of a Pseudomonas aeruginosa and were negative for fungi and acid-fast bacilli. Chest and abdomen CT scans were normal. After being treated with ceftriaxone PO for 10 days in order to control local infection, the patient started on chemotherapy with CVP (cyclophosphamide, vincristine, and prednisone), with disappearance of the tumoral mass and closure of the ulcer, but persistence of the pendulous skin folds. However, sudden exacerbation of the lesions occurred 1.5 months after finishing CVP treatment. Subquent systemic chemotherapy with CHOP (cyclophosphamide, adriamycin, vincristine, and prednisone) did not result in any further improvement, neither did FMD (fludarabine, mitoxantrone, dexamethasone) combined chemotherapy. Subcutaneous injection of interferon-α2a (3 × 10⁶ U three times weekly) was then tried for 2 months, without clear clinical benefit. Finally, subcutaneous recombinant interferon-γ (88 μg three times weekly) was initiated. The patient has now been on interferon-γ for two months, with a decrease of the size, erythema and induration of skin lesions. The patient’s general health remains good.

Discussion

This extremely rare form of CTCL is characterized clinically by asymptomatic red to violet well-circumscribed plaques, with an atrophic surface and sometimes fine scaling, with a predilection to develop in the body folds, especially in the axillary and inguinal regions. The plaques enlarge slowly, during a several year-period, to form pendulous slack skin formations. Ulceration has also been reported. GSS can develop at any age from childhood to mid-adult life, with marked male predominance (male: female ratio 2.9: 1) [4-15, 18-24]. GSS is characterized histologically by small to medium-size lymphocytes arranged in a band-like infiltrate, mainly confined to the papillary dermis, by the presence of multinucleated giant cells which may contain up to 40 nuclei per cell and by non-caseating granulomas. One of the most characteristic features is that of a wreathlike arrangement of mononuclear cells around giant cells. Multinucleated giant cells with phagocytized elastic fibers are a remarkable feature in electron microscopy. With Verhoeff-van Gieson staining the loss of elastic tissue, the histologic counterpart of the clinical slack skin aspect, is clearly observed. The distribution of the histological features affects the full thickness of the dermis and sometimes extends to the subcutaneous tissue [16-19]. Immunophenotypic studies show that the lymphocytic infiltrate mainly consists of CD4+ and CD45RO+ cells. CD30 positivity and loss of T-cell markers (CD3, CD5, and CD7) have also been reported [16, 17]. The granulomatous components are derived from the monocyte-macrophage lineages and express the monocytic CD14 antigens and the macrophage CD68 antigens [4, 11, 16, 17]. Genotypic T cell receptor γ and/or β gene rearrangement studies were performed in only 23 of the previous published GSS cases [5, 6, 8-12, 15]. In twenty-two of them monoclonality could be demonstrated as follows: β-rearrangement was documented in fifteen patients [6, 8, 11, 12], γ-rearrangement was present six cases [9, 10, 15, 18, 21], and both β and γ-rearrangements were shown in one case [5]. In the case reported by Gadzia and Kestenbaum there was no evidence of monoclonality [11]. The authors state that the sample was evaluated only for β-rearrangement, speculating that the use of paraffin-embedded material vs fresh frozen together with the unavailability of an adequate amount of tissue to perform a γ-gene rearrangement study could explain the negativity. Trisomy 8 syndrome has been reported in 2 patients with GSS [17, 18]. This chromosomal alteration is known to play a role in the pathogenesis of Hodgkin’s disease, non-Hodgkin’s lymphomas, some leukemia forms and Ewing’s sarcoma. Interestingly both patients with this chromosomal abnormality had not developed a lymphoproliferative disorder by the time of publication (3 and 15 years of follow-up). Extracutaneous involvement is rare in GSS. The only documented cases were those of granulomatous lymphadenitis in four patients and systemic granuloma formation in two patients (pulmonary and spleen involvement) [3-22]. The course of GSS is one of slow progression from flexural areas to other skin sites. The disease itself is not life-threatening, but prognosis is decided by progression or development of a malignant lymphoproliferative disease, which happens in about half of the patients. Malignancies associated with GSS in decreasing order of frequency are: Hodgkin’s disease (about 1/3 of the patients), non-Hodgkin’s lymphoma, mycosis fungoides, acute myeloid leukemia and Langerhans cell histiocytosis [4, 5, 10, 11, 22, 23]. Due to the small number of GSS cases reported, there is no standard therapy in this extremely rare subtype of CTCL. Multiple treatment modalities have been tried, both singly or in combination, with partial remissions being reported with psoralen-UVA, radiotherapy, (poly)chemotherapy, systemic steroids, azathioprine, immunomodulating drugs such as interferon-α and interferon-γ, surgery and combination therapies [5-15, 17-25]. Whatever the therapeutic option in GSS, the outcome has been uniformly disappointing, with only two complete remissions ever reported. In the case described by Balus et al. [18] a single lesion was removed surgically with no evidence of recurrence at 2 year follow-up and, more recently, Wollina et al. [7] reported complete remission in a case treated with a combination of IFN-α and radiotherapy with a disease-free follow-up of 27 months. Since GSS is a malignant disorder with potential fatal outcome, most authors prefer combined chemotherapy strategies. However, it must be remembered that patients with GSS are unique among CTCL patients with respect to the indolent progression of their disease. Thus, the choice of therapy often depends on several factors such as the stage of the disease, tolerance of treatment toxicities, geographic constraints and patient compliance. The fact that subcutaneous interferon-γ administration appeared to be clinically useful in the case presented here, after failure of multiple treatment modalities, including CVP, CHOP, FMD and interferon-α, led us to emphasise that treatment needs to be patient-tailored, avoiding overaggressive therapy whenever possible [24]. In the search for more effective and tolerable disease-specific agents, new treatment modalities for CTCL, including biological response modifiers such as topical retinoids, cytokines, fusion molecules and monoclonal antibodies, are constantly emerging [25]. Although some of these novel disease-specific agents have already been approved for the treatment of CTCL in different countries, their therapeutic usefulness in GSS remains to be established.

Acknowledgements

Financial support: none. Conflict of interest: none.

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