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Home , Granulomatous slack skin, Mycosis, Mycosis fungoides

Mycosis fungoides

Author: Doctor Lorenzo Cerroni1 Creation date: October 2003

Scientific editor: Professor Benvenuto Giannotti

1Department of Dermatology, University of Graz, Auenbruggerplatz, 8, 8036 Graz, Austria. [email protected]

Abstract Keywords Definition Excluded diseases Disease course Frequency Aetiology Associated diseases Disease classification Clinical features Histopathology, immunohistology and molecular biology Clinical and histopathological variants Treatment Prognosis References

Abstract represents the most common type of cutaneous T-cell . Its incidence has been estimated to 0.36/105 person-years. It affects adults or the elderly. Three clinical stages can be recognized: one characterized by patches, one by patches and/or plaques, and one by patches, plaques, and/or tumours. In the early stages, preferential location is the buttocks and other sun-protected areas. Histology reveals predominance of small pleomorphic (cerebriform) cells. During disease course large cell transformation may occur indicating a worse prognosis (immunoblasts, large anaplastic cells, large pleomorphic cells). In most cases, immunohistology shows a memory T-helper phenotype (CD3+, CD4+, CD45Ro+, CD8-, 45Ra-). CD30 and cytotoxic markers (i.e., TIA-1) may be positive in late stages in tumors with large cell morphology. A monoclonal rearrangement of the TCR gene is absent in about 50% of patients in the early phases. Treatment strategies include in early phases mainly PUVA (photochemotherapy), α-2a, (alone or in combination), topical , topical , narrow-band UV-B (311 nm), and photodynamic therapy. Advanced disease can be treated by systemic chemotherapy, extracorporeal , and/or radiotherapy (including total body electron beam irradiation). New experimental treatment modalities include new retinoids (i.e., bexarotene), , new chemotherapeutic drugs (i.e., gemcitabine, fludarabine, pegilated doxorubicine), pentostatin, and allogeneic stem cell transplantation. Aetiology has not been determined yet.

Keywords: cutaneous T-cell lymphoma, patches, plaques, tumour, , PUVA, , interferon α- 2a, , TCR gene

Definition Mycosis fungoides represents the most common Traditionally it is divided into three clinical type of cutaneous T-cell lymphoma.1,2 phases: patch-, plaque-, and tumour-stage. The

Cerroni L. Mycosis fungoides. Orphanet Encyclopedia. October 2003. http://www.orpha.net/data/patho/GB/uk-mycosisfungoides.pdf 1 clinical course can be protracted over years or fungoides are at higher risk of developing a decades. second (non-haematological) malignancy.10

Excluded diseases Disease classification The term "mycosis fungoides" should be A staging classification system for mycosis restricted to the classical so-called "Alibert- fungoides was proposed in 1979 by the Mycosis Bazin" type of the disease, characterized by the Fungoides Cooperative Group (TNMB - tumour- typical slow evolution and protracted course. node--blood-staging) (Table 1).11 This More aggressive entities (e.g., mycosis system takes into account the percentage of fungoides "a tumeur d'emblee"), characterized body area covered by lesions, and the presence by onset with plaques and tumours, aggressive of lymph node or visceral involvement. Although course, and bad prognosis, are better classified the presence of malignant circulating cells in the among the recently described group of blood should be recorded for each patient, these cutaneous cytotoxic T- (NK/T)-cell . data are not used for staging.

Disease course Clinical features In the past mycosis fungoides has been Cutaneous involvement considered as an "incurable", albeit slowly Lesions of mycosis fungoides can be divided progressive disease, that inevitably ended in morphologically into patches, plaques, and death of patients. Recently, identification and tumours. Itching is often a prominent symptom. definition of criteria for clinicopathologic Erythroderma may develop at some point, diagnosis of small patches allowed identification making it difficult to distinguish it from Sezary of patients with early mycosis fungoides,3-5 who syndrome without proper clinical history. Patches often present with a relatively mild course and of mycosis fungoides are characterized by prolonged survival, without progression into variably large, erythematous, finely scaling plaque and tumour-stage. The inevitability of lesions mostly located on the buttocks and other disease progression and death due to sun-protected areas. Plaques of mycosis lymphoma, thus, has to be questioned. fungoides are characterized by infiltrated, scaling, reddish-brown lesions. In tumour-stage Frequency mycosis fungoides a combination of patches, Mycosis fungoides is a rare disease. According plaques and tumours is usually found, but to a survey, incidence was reported to be tumours may be observed also in the absence of 0.36/105 person-years from 1973 to 1992 in the other lesions. United States6. Extracutaneous involvement Lymph nodes, , spleen and liver are the Aetiology most frequent sites of extracutaneous The aetiology of mycosis fungoides is yet involvement, but specific lesions can arise in all unknown. Genetic predisposition may play a role organs. Because of the presence of ulcerated in some cases, and familial occurrence has been tumours and of immune deficiency (due to both reported in a few instances. Association with lymphoma and the many treatments typically long-term exposure to various allergens has also administered to these patients), septicaemia been advocated, as well as exposure to and/or are the major causes of environmental agents and association with death. chronic skin disorders and viral . In some countries, mycosis fungoides-like Histopathology, immunohistology and disorders are clearly associated with viral molecular biology infections (i.e., HTLV-I-associated adult T-cell It should be clearly stated that, although precise lymphoma/leukaemia), but search for viral histopathologic criteria for the diagnosis of early particles in patients with mycosis fungoides has mycosis fungoides have been identified, in many been unsuccessful. cases only correlation with the clinical features of the disease allows a precise diagnosis to be Associated diseases made. Mycosis fungoides has been described in patients with other haematological disorders, especially and Hodgkin's lymphoma. In occasional patients, the same clone has been detected in mycosis fungoides and associated lymphomas, raising questions about a common origin of the diseases.7-9 In addition, patients with mycosis

Cerroni L. Mycosis fungoides. Orphanet Encyclopedia. October 2003. http://www.orpha.net/data/patho/GB/uk-mycosisfungoides.pdf 2

Table 1. TNMB* staging of mycosis so-called Pautrier’s collections are a common 2-5 finding at this stage. Cytomorphologically, small fungoides pleomorphic (cerebriform) cells predominate. In tumours of mycosis fungoides a dense, Skin nodular or diffuse infiltrate is found within the T1 Patches, or plaques covering entire involving the subcutaneous fat. <10% of the skin surface Epidermotropism may be lost. T2 Patches, papules or plaques covering >10% of the skin surface Large cell transformation T3 Tumours In later stages, patients with mycosis fungoides T4 Generalized erythroderma usually develop lesions with many large cells (immunoblasts, large pleomorphic cells or large Lymph nodes anaplastic cells).12-14 N0 No clinically abnormal lymph nodes; Tumours with a large cell morphology may or histology negative may not express CD30. Expression of the N1 Clinically abnormal peripheral lymph antigen does not have any prognostic nodes significance in these patients. Large cell N1o Histology not performed transformation of mycosis fungoides bears a N1n Histology negative poor prognosis and usually heralds the terminal N1r Histology reactive stage of the disease. N1d Dermopathic lymphadenitis Immunohistology N2 No clinically abnormal peripheral lymph Mycosis fungoides is characterized by an nodes; histology positive infiltrate of T-helper memory lymphocytes (βF1+, + + + - + N3 Clinically abnormal peripheral lymph CD3 , CD4 , CD5 , CD8 , CD45Ro ).Only α/β a nodes; histology positive minority of cases exhibit a T-suppressor (βF1+, CD3+, CD4-, CD5+, CD8+) γ/δ (βF1-, CD3+, CD4-, Visceral organs CD5+, CD8+) lineage, without clinical and/or M0 No visceral involvement prognostic differences. In late stages there may M1 Visceral involvement be a (partial) loss of pan-T-cell antigen expression. Blood Cytotoxic markers are negative in mycosis B0 <5% of atypical circulating cells fungoides, but in late stages of the disease a B1 >5% of atypical circulating cells cytotoxic profile of neoplastic cells may be observed, with positivity for TIA-1 and granzyme Stages B. These cases should not be classified as Ia T1N0M0 Ib T2N0M0 cytotoxic lymphomas, but as tumour stage IIa T1-2N1M0 IIb T3N0-1M0 mycosis fungoides with cytotoxic phenotypes. III T4N0-1M0 Molecular genetics IVa T1-4N2-3M0 IVb T1-4N0-3M1 No specific abnormalities have been reported. *Tumor-node-metastasis-blood Using cDNA microarray analysis, a signature of 27 genes, including oncogenes and other genes Histopathology involved in the control of apoptosis, has been Early lesions of mycosis fungoides reveal a recently identified in cases of early- and late- patchy lichenoid or band-like infiltrate in an stage mycosis fungoides.15 expanded papillary dermis. Small lymphocytes Rearrangement of the TCR gene is commonly predominate and atypical cells can be observed found in plaques and tumours, but is present only in a minority of the cases. Epidermotropism only in approximately 50% of the cases in early of solitary lymphocytes is usually observed, but (patch) lesions. so-called Pautrier’s microabscesses are rare. Useful diagnostic clues are the presence of Clinical and histopathological variants epidermotropic lymphocytes with nuclei slightly Several clinical and/or histopathological variants larger than those of lymphocytes within the of mycosis fungoides have been described upper dermis and/or the presence of (Table 2)16 Patients with these variants of the lymphocytes aligned along the basal layer of the disease often show also features of "classical" . The papillary dermis shows a mycosis fungoides at other sites of the body. moderate to marked fibrosis with coarse bundles of collagen. Plaques of mycosis fungoides are characterized by a dense, band-like infiltrate within the upper dermis. Intraepidermal lymphocytes arranged in

Cerroni L. Mycosis fungoides. Orphanet Encyclopedia. October 2003. http://www.orpha.net/data/patho/GB/uk-mycosisfungoides.pdf 3

Table 2. Clinicopathologic variants of immune response modifiers such as imiquimod. mycosis fungoides At present not enough data are available to Acanthosis nigricans-like mycosis evaluate the efficacy of these new modalities in fungoides terms of remission and recurrence rates. Angiocentric mycosis fungoides In late stages, in addition to PUVA, retinoids and Bullous (vesiculo-bullous) mycosis interferon α-2a, conventional systemic fungoides chemotherapy, extracorporeal photopheresis Dyshidrotic mycosis fungoides and radiotherapy have been applied. Allogeneic Erythrodermic mycosis fungoides stem cell transplantation has been performed in Follicular (pilotropic) mycosis fungoides a few patients, and seems to be a promising Granulomatous mycosis fungoides/ treatment modality, perhaps with potential for cure thanks to the graft-versus-tumour response. Hyperpigmented mycosis fungoides However, toxicity is still very high, and it is Ichtyosis-like mycosis fungoides unclear whether allogeneic stem cell Interstitial mycosis fungoides transplantation should be considered a treatment Invisible mycosis fungoides option for early tumour-stage mycosis fungoides. Mucinous mycosis fungoides New chemotherapeutic or immunological agents, Mycosis fungoides palmaris et plantaris including, among others, gemcitabine, Mycosis fungoides with eruptive fludarabine, pegilated doxorubicyn, pentostatin, infundibular cysts interleukin-12, DAB389-IL-2 fusion protein, Mycosis fungoides with follicular mucinosis vaccination, and trimetrexate, have also been Mycosis fungoides with large-cell used in a few patients. However, treatment of transformation advanced (tumour stage) mycosis fungoides has (Woringer-Kolopp) remained unsatisfactory, and the disease usually Papular mycosis fungoides progresses in spite of aggressive therapy. Papuloerythroderma Ofugi Perioral -like mycosis fungoides Prognosis Pigmented purpura-like mycosis fungoides Mycosis fungoides is a malignant lymphoma of Poikilodermatous mycosis fungoides low-grade malignancy with prolonged survival, Pustular mycosis fungoides and progression from the clinical stage of Small-plaque patches to those characterized by plaques, Syringotropic mycosis fungoides tumours, and extracutaneous spread usually 1,2 Unilesional (solitary) mycosis fungoides takes place over many years or decades. Verrucous/hyperkeratotic mycosis Development of plaques and/or tumours, or of fungoides large cell transformation, heralds the terminal Zosteriform mycosis fungoides stages of the disease (patients may survive several years with tumor-stage mycosis Treatment fungoides, though). As the disease arises more The standard treatment of early lesions includes commonly in the elderly, however, most patients psoralens in association with UV-A irradiation do never progress to plaque- or tumor-stage, (PUVA - psoralens and UVA), interferon α-2a, and die of disease-unrelated causes. In fact, it has been estimated that only 15-20% of patients retinoids, or a combination of these three 19 modalities.17,18 Several other treatments have die of their disease. However, a small subset of been used in the past (and are still in use at patients experience a more rapidly aggressive present), including UV-B irradiation (or narrow- course with extracutaneous spread and death band UV-B - 311nm), and topical application of due to complications of the disease (usually chemotherapic agents. In many cases, patients or other severe infections). Moreover, a with localized patches of the disease can be substantial subset of patients are middle-aged or treated also with local ointments. The young adults, and a few are children, thus a administration of total body irradiation, proposed having higher risk of progression during their by some authors as a first-line treatment, should lifetime. probably be restricted to patients with mycosis The most important prognostic parameters are fungoides in later stages. stage at diagnosis, absence of complete In the last years, many new protocols have been remission after first treatment, age, race (prognosis is worse in Blacks, but this may be introduced for treatment of early mycosis 18 fungoides, including, among others, related also to different access to therapy). No photodynamic therapy with 5-aminolaevulinic significant differences in survival have been acid, new retinoids such as bexarotene observed between stages Ia and Ib (TNM classification), or between patients with tumours (administered orally or topically), new 18 chemotherapeutic drugs for topical use, and and erythroderma. Once extracutaneous

Cerroni L. Mycosis fungoides. Orphanet Encyclopedia. October 2003. http://www.orpha.net/data/patho/GB/uk-mycosisfungoides.pdf 4 spread takes place, prognostic parameters have and cutaneous T-cell lymphoma derived from a no influence on survival, and prognosis is bad. common T-cell clone. N Engl J Med 1992; The detection of a malignant clone in blood is an 326:1115-1122. independent prognostic criterion, whereas the 8. Wood GS, Crooks CF, Uluer AZ. exact implications of the detection of a clone in Lymphomatoid papulosis and associated the skin in early phases of the disease is yet cutaneous lymphoproliferative disorders exhibit a unclear. Although the influence of the presence common clonal origin. J Invest Dermatol 1995; of follicular mucinosis on survival is yet debated, 105:51-55. it certainly complicates treatment of these 9. Joly P, Lenormand B, Bagot M, et al. patients. Finally, analysis of histopathologic Sequential analysis of T-cell receptor gene features of specimens of early mycosis rearrangement in skin biopsy specimens from 6 fungoides failed to detect histological parameters patients with Hodgkin disease, lymphomatoid that could help predict the progression (or papulosis, mycosis fungoides and CD30+ large absence of progression) of the disease. cell lymphoma. J Invest Dermatol 1997; 109:485. Although most treatments are efficacious in early 10. Väkevä L, Pukkala E, Ranki A. Increased phases, and long-term remissions can be risk of secondary cancers in patients with achieved, it is unlikely that cure can be obtained, primary cutaneous lymphoma. J Invest with the possible exception of the solitary Dermatol 2000; 115:62-65. variants of the disease (life-long follow-up, 11. Bunn P, Lamberg S. Report of the however, should be suggested in these patients committeeon staging and classification of as well). The use of the PCR technique has cutaneous T-cell lymphoma. Cancer Treatment been advocated for the detection of minimal Reports 1979; 63:725-728. residual disease after treatment, but the value of 12. Cerroni L, Rieger E, Hödl S, et al. this method as a routine investigation should be Clinicopathologic and immunologic features confirmed by large studies. associated with transformation of mycosis fungoides to large-cell lymphoma. Am J Surg References Pathol 1992;16:543-552. 1. Willemze R, Kerl H, Sterry W, et al. EORTC 13. Vergier B, De Muret A, Beylot-Barry M, et al. classification for primary cutaneous lymphomas: Transformation of mycosis fungoides: a proposal from the Cutaneous Lymphoma clinicopathologic and prognostic features of 45 Study Group of the European Organization for cases. Blood 2000; 95:2212-2218. Research and Treatment of Cancer. Blood 1997; 14. Diamandidou E, Colome-Grimmer MI, Fayad 90:354–371. L, et al. Transformation of mycosis fungoides / 2. Fink-Puches R, Zenahlik P, Bäck B, et al. Sézary syndrome: clinical characteristics and Primary cutaneous lymphomas: applicability of prognosis. Blood 1998; 92:1150-1159. current classification schemes (European 15. Tracey L, Villuendas R, Dotor AM, et al. Organization for Research and Treatment of Mycosis fungoides shows concurrent Cancer, World Health Organization) based on deregulation of multiple genes involved in the clinicopathologic features observed in a large TNF signaling pathway: an expression profile group of patients. Blood 2002;99: 800-805. study. Blood 2003; 102:1042-1050. 3. Sanchez JL, Ackerman AB. The patch stage 16. LeBoit PE. Variants of mycosis fungoides of mycosis fungoides. Criteria for histologic and related cutaneous T-cell lymphomas. Sem diagnosis. Am J Dermatopathol 1979;1:5-26. Diag Pathol 1991; 8:73-81. 4. Shapiro PE, Pinto FJ. The histologic spectrum 17. Chiaron-Sileni V, Bononi A, Veller Fornasa of mycosis fungoides/Sezary syndrome C, et al. Phase II trial of interferon-a-2a plus (cutaneous T-cell lymphoma). A review of 222 psoralen with light A in patients with , including newly described patterns and cutaneous T-cell lymphoma. Cancer 2002; the earliest pathologic changes. Am J Surg 95:569-575. Pathol 1994;18:645-667. 18. Stadler R, Otte HG, Luger T, et al. 5. Santucci M, Biggeri A, Feller AC, et al. Prospective randomized multicenter clinical trial Efficacy of histologic criteria for diagnosing early on the use of interferon a-2a plus acitretin versus mycosis fungoides. An EORTC Cutaneous interferon a-2a plus PUVA in patients with Lymphoma Study Group investigation. Am J cutaneous T-cell lymphoma stages I and II. Surg Pathol 2000;24:40-50. Blood 1998; 92:3578-3581. 6. Weinstock MA, Gardstein B. Twenty-year 19. Zackheim HS, Amin S, Kashani-Sabet M, et trends in the reported incidence of mycosis al. Prognosis in cutaneous T-cell lymphoma by fungoides: associated mortality. Am J Public skin stage: long-term survival in 489 patients. J Health. 1999; 89:1240-1244. Am Acad Dermatol 1999; 40:418-425. 7. Davis TH, Morton CC, Miller-Cassman R, et al. Hodgkin’s disease, lymphomatoid papulosis,

Cerroni L. Mycosis fungoides. Orphanet Encyclopedia. October 2003. http://www.orpha.net/data/patho/GB/uk-mycosisfungoides.pdf 5