Copyright 2005 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.2005
Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma (CTCL). Patients with limited patch and/or plaque disease have a normal life expectancy. Neutrophilic dermatosis (ND) may be associated with various hematologic disorders. However, its association with CTCL is exceptional and has been reported only twice with leukemic forms of CTCL.
Three patients with MF developed ND resistant to conventional therapies and responsible for an impaired quality of life due to constitutional symptoms and painful cutaneous lesions. All patients underwent an aggressive treatment course despite their varying initial clinical stages of MF, and all experienced a fatal outcome less than 18 months after the onset of ND.
The association of MF with ND is exceptional and carries a poor prognosis, but the pathophysiologic nature of this association remains unclear. It may involve neutrophil chemoattractant cytokine production by tumor cells. A triggering role of interferon alfa is also possible.
Mycosis fungoides (MF) is the most common form of cutaneous T-cell lymphoma (CTCL) and is characterized by an epidermotropic skin infiltrate of atypical CD4+ (helper) T cells.1 The most important clinical predictive factors for survival include patient age, type and extent of skin involvement (T of TNM classification2), and the presence or absence of extracutaneous disease.3 Mycosis fungoides is often indolent, and patients with limited patch and/or plaque (T1) disease have a normal life expectancy.3,4 Patients with disease transformation to large-cell lymphoma have a poor prognosis.5,6 Follicular MF is more refractory to treatment and has a worse prognosis than the classic type of MF.7 Theassociation of neutrophilic dermatosis (ND) with hemoproliferative disorders is well documented.8 However, only 2 cases of the leukemic form of CTCL associated with ND have been reported.9,10 We report the association of MF-type CTCL with ND in 3 patients with a fatal outcome.
A 35-year-old man presented with itchy papular erythroderma and alopecia of the scalp, eyebrows, and arms of 2 years’ duration. Skin biopsy specimens showed a papillary dermal infiltrate of atypical CD3+CD4+ lymphocytes, epidermotropism, marked pilotropism, and slight syringotropism. Alcian blue staining revealed follicular mucinosis. A diagnosis of a stage IIIA (T4 N0 M0) CTCL-type MF was made. Despite treatment with topical corticosteroids, nitrogen mustard, and psoralen plus UV-A and systemic acitretin and pentostatin, his cutaneous status worsened, and his alopecia became complete.
Six years after onset of MF, interferon alfa therapy was started, with doses ranging from 3 to 5 million IU, 3 times weekly. Three months later, the patient presented with fever, erythematous painful nodules on the scalp and the body, and numerous aseptic pustules on the face and the scalp (Figure 1A) associated with neutrophilic leukocytosis (neutrophil count, 20.1 × 109/L to 30.8 × 109/L) and increased erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level (50-369 mg/L). Biopsy specimens of pustules showed features of CTCL associated with a neutrophilic infiltrate of the dermis around and within hair follicles, exocytosis of the neutrophils, and superficial spongiform and subcorneal pustules (Figure 1B). Biopsy specimens of nodules showed a neutrophilic dermal infiltrate with features of neutrophilic eccrine hidradenitis mixed with CTCL infiltrate (Figure 1C). There was no transformation to large pleomorphic T-cell lymphoma. A marked syringotropism of the CTCL infiltrate was noted on the last skin samples. A peripheral blood smear, lactate dehydrogenase level, and bone marrow biopsy findings were normal.
Clinical and histopathologic images from case 1. A, Erythroderma, alopecia, pustules, and nodules on the face and scalp. B, Spongiform pustules mixed with an exocytosis of atypical lymphocytes of mycosis fungoides (hematoxylin-eosin, original magnification ×400). C, Neutrophilic eccrine hidradenitis with neutrophilic infiltrate around and within the eccrine secretory coils mixed with the atypical lymphocytic infiltrate of cutaneous T-cell lymphoma and edema (hematoxylin-eosin, original magnification ×200).
T-cell receptor γ-chain gene rearrangement studies11 showed the presence of an identical T-cell clone in both skin and blood samples that was not detected in the bone marrow specimen. Thoracoabdominal computed tomography (CT) showed no involvement by CTCL. Interferon alfa treatment was stopped, and methotrexate therapy (25 mg/wk for 2 months) was initiated with no improvement of MF. Total skin electron-beam therapy induced a transient and partial improvement. No improvement of the ND was achieved despite systemic corticosteroids (prednisone at 1 mg/kg per day) and colchicine. The patient’s status deteriorated, and he died of respiratory failure 7 years after the onset of MF and 17 months after the onset of ND.
A 68-year-old Chinese man presented with a few erythematous and scaly patches of 11 years’ duration. Skin biopsy specimens showed a sparse papillary dermal infiltrate of atypical CD3+CD4+ lymphocytes and epidermotropism. A diagnosis of a stage IA (T1 N0 M0) MF was made. He was then lost to follow-up for the next 6 years, and his cutaneous status deteriorated. When he was seen again, he reported having been treated in Taiwan with interferon alfa (3 million IU, 3 times weeks) and isotretinoin (80 mg/d).
One year later, he presented with fever, more than 30 infiltrated cutaneous plaques, and 2 ulcers resembling pyoderma gangrenosum (PG). His neutrophil count was normal, but his ESR and CRP level (108 mg/L) were increased. A plaque biopsy specimen showed a cytologic transformation of MF to large pleomorphic T-cell lymphoma. An ulceration specimen showed no specific CTCL infiltrate but a neutrophilic infiltrate throughout the dermis suggesting PG.T-cell receptor γ-chain gene rearrangement studies showed the presence of a T-cell clone in the skin not detected in the blood. Interferon alfa treatment was stopped, and methotrexate therapy was initiated (15-30 mg/wk) leading to partial remission of MF, healing of PG, and improvement of general status.
Five months later, general and cutaneous status worsened. The patient presented with fever, weight loss, numerous painful cutaneous tumors of MF, aseptic pustules, and erythematous painful plaques resembling those of Sweet syndrome (Figure 2A) associated with peripheral neutrophilia (neutrophil count, 10 × 109/L to 13 × 109/L) and increased ESR and CRP level (60-241 mg/L). Biopsy specimens of tumors revealed an infiltrate of atypical large T cells of the entire dermis with extension into the subcutis and syringotropism. In some tumors, the expression of CD30 was positive in more than 75% of atypical lymphocytes and negative in others. Skin biopsy specimens of pustules and papules showed several patterns: subcorneal pustules, intraepidermal neutrophilic microabscesses, an exocytosis of neutrophils, a dermal neutrophilic infiltrate with edema (Figure 2B), and a neutrophilic infiltrate around eccrine secretory coils. This neutrophilic infiltrate was mixed with CTCL infiltrate. Peripheral blood smear, lactate dehydrogenase level, and thoracoabdominal CT findings were normal.
Clinical and histopathologic images from case 2. A, Plaques suggesting Sweet syndrome (edema over a plaque of mycosis fungoides). B, Dermal neutrophilic infiltrate with edema and exocytosis of atypical lymphocytes and neutrophils with spongiosis (hematoxylin-eosin, original magnification ×200).
The MF did not improve despite an increase in methotrexate dose to 40 mg/wk. A partial and transient improvement of ND under treatment with systemic steroids (prednisone at 1 mg/kg per day) was followed by a worsening of both ND (despite the addition of colchicine to the treatment regimen) and MF with the appearance of numerous ulcerated tumors. The patient died of respiratory failure 18 years after the onset of CTCL and 13 months after the onset of ND.
A 59-year-old man presented with itchy erythematous patches on his body of 2 years’ duration. Skin biopsy specimens showed a superficial dermal infiltrate of atypical CD3+CD4+ lymphocytes with epidermotropism and pilotropism without follicular mucinosis. A diagnosis of a stage IB (T2 N0 M0) MF was made. No remission was achieved despite treatment with topical corticosteroids, nitrogen mustard, and psoralen plus UV-A. T-cell receptor γ-chain rearrangement studies showed the presence of a T-cell clone in the skin not detected in the blood.
Five years after the onset of MF, several painful tumors developed. Skin samples revealed a dense atypical lymphocytic infiltrate of the entire dermis with extension into the subcutis, pilotropism, and syringotropism. There was no large-cell transformation. Interferon alfa therapy was initiated, with doses ranging from 5 million IU, 3 times weekly to 9 million IU/d 5 times weekly.
Five months later, he presented with fever, cutaneous pain, and numerous coalescent and aseptic pustules and crusts over all MF lesions, sparing the healthy skin (Figure 3A), associated with peripheral neutrophilia (neutrophil count, 14.9 × 109/L to 41.3 × 109/L) and increased ESR and CRP level (25-194 mg/L). Skin samples showed spongiform and subcorneal pustules, intraepidermal neutrophilic microabscesses, an exocytosis of neutrophils, and neutrophilic infiltrate in the dermis (Figure 3B) around hair follicles and eccrine glands. This neutrophilic infiltrate was mixed with CTCL infiltrate. A peripheral blood smear, lactate dehydrogenase level, and thoracoabdominal CT findings were normal.
Clinical and histopathologic images from case 3. A, Pustules and crusts over tumors of the hand. B, Spongiform and subcorneal pustules, exocytosis of neutrophils, intraepidermal neutrophilic microabscess, and neutrophilic infiltrate with edema in the dermis mixed with the atypical lymphocytic infiltrate of cutaneous T-cell lymphoma (hematoxylin-eosin, original magnification ×400).
The ND dramatically improved under treatment with systemic steroids (prednisone at 1 mg/kg per day), but symptoms returned within 1 month and were not responsive to systemic steroids, colchicine, indomethacin, or thalidomide. Interferon alfa treatment was stopped 7 months after its initiation. Treatment with methotrexate (25 mg/wk for 6 weeks) was initiated, but the MF lesions did not respond until treated with 5 courses of multiagent chemotherapy (cyclophosphamide, doxorubicin, vincristin, and prednisone), which brought them under control. Concomitantly the ND necessitated administration of high-dose steroids but with a poor response. The MF relapsed with patches and tumors 4 months after the end of the polychemotherapy. Bexarotene therapy (2 months) was ineffective, and the patient died of respiratory failure 8 years after the onset of MF and 16 months after the onset of ND.
We describe 3 patients who developed clinical, biological, and histologic features highly suggestive of ND during the course of a CTCL-type MF. Most of the clinical and histologic forms encompassed within the spectrum of ND were present (PG, pustules, Sweet syndrome–like papules, and neutrophilic eccrine hidradenitis). There was no evidence of the systemic disorders ususally reported in association with ND (ie, inflammatory bowel diseases, inflammatory arthritis, solid tumors, or other hemoproliferative disorders).12,13
The association of ND with hemoproliferative disorders is well documented,8 but only 2 cases of CTCL with ND have been reported.9,10 One case of erythrodermic and leukemic CD4+CD8+ CTCL presented with disseminated pustulosis, a high neutrophil count, and a cutaneous neutrophilic infiltrate. The patient died despite various treatments.9 The second patient developed Sweet syndrome sensitive to systemic steroids during the course of Sézary syndrome.10 In contrast to our patients, these 2 cases presented with a leukemic form of CTCL.
The cases reported herein share 3 common features: (1) the association of ND with a poor prognosis (fatal outcome within 13 to 17 months) regardless of initial MF staging; (2) inefficacy of conventional ND therapies, leading to an impaired quality of life due to constitutional symptoms and painful cutaneous lesions; and (3) marked pilotropism and a late marked syringotropism.
The association of ND with MF is probably not fortuitous, but the pathogenesis is not clear. One suggested possibility is abnormal cytokine production by neoplastic T cells, which interferes with the traffic of neutrophils in both skin and blood. Production of the neutrophil chemoattractant cytokine interleukin 8 by the lymphocytes was found in a patient who developed ND during the course of leukemic CTCL.9 In addition, Tensen et al14 reported expression of interleukin 8 messenger RNA in the epidermis in 2 CTCL cases, both of which also demonstrated accumulation of neutrophils. This finding suggests that paracrine secretion of high amounts of interleukin 8 by neoplastic cells may recruit neutrophils in skin lesions.
Finally, a triggering role for interferon alfa is suggested in the present 3 cases in that the ND occurred 3 to 12 months after interferon alfa therapy for CTCL was begun. Interferon alfa is known to induce or exacerbate psoriasis (with exocytosis of neutrophils)15- 17 and has once been implicated in the occurrence of PG.18 In addition, 1 study showed that interferon alfa administration in healthy humans was followed by increased neutrophil counts and associated with neutrophil activation.19 However, the discontinuation of interferon alfa therapy was not associated with improvement of ND in our cases, and neither of the 2 patients previously described received interferon alfa before the onset of ND.
The association of ND and CTCL is exceptional but probably not fortuitous. Both CTCL and ND were resistant to conventional therapies in our 3 cases. The occurrence of ND in the course of CTCL was associated with a fatal outcome less than 18 months after its onset. The pathophysiologic nature of this association remains unclear and may implicate neutrophil chemoattractant cytokine production by tumor cells.
Correspondence: Nathalie Franck, MD, Service de Dermatologie et Vénérologie, Salle Louis Brocq, Pavillon Cornil, Hopital Cochin, 27 rue du Faubourg Saint Jacques, 75014 Paris, France (firstname.lastname@example.org).
Accepted for Publication: July 23, 2004.
Previous Presentation: This work was presented as a poster at “Les Journées Dermatologiques de Paris”; December 2-6, 2003; Paris, France.
Financial Disclosure: None.
M. P. Algros, L. Andrac, F. Aubin, M. F. Avril, H. Bachelez, M. Bagot, B. Balme, S. Barette, K. Beljord, F. Berger, P. Bernard, M. Beylot-Barry, C. Bodemer, J. Bosq, A. Carlotti, E. Cassagneau, T. Clerici, A. Colson, P. Cornillet, P. Courville, S. Dalac, S. Dalle, P. Dechelotte, A. Decouvelaere, E. Delaporte, M. Delaunay, M. H. Delfau-Larue, A. De Muret, O. Dereure, V. Descamps, M. D’Incan, B. Dreno, P. Dubus, A. Dupuy, A. Durlach, E. Esteve, C. Ferrand, C. Frances, S. Fraitag, F. Franck, N. Franck, M. P. Gaub, F. Grange, P. Joly, C. Juillard, L. Laroche, B. Lenormand, F. Le Pelletier, L. Machet, E. Maitre, E. Marinho, E. Maubec, J. P. Merlio, C. Michel, T. Petrella, H. Poirel, G. Quereux, P. Saiag, P. Souteyrand, L. Thomas, E. Vaillant, B. Vergier, D. Vignon-Pennamen, J. Wechsler.
Franck N, Carlotti A, Gorin I, Buffet M, Mateus C, Dupin N, . Mycosis Fungoides–Type Cutaneous T-Cell Lymphoma and Neutrophilic Dermatosis. Arch Dermatol. 2005;141(3):353-356. doi:10.1001/archpedi.161.4.356