Mycosis Fungoides

Symposium on Cutaneous Signs of Systemic Disease

Mycosis Fungoides David A. Grekin, M.D.,~:c M.D.,"" and Herschel S. Zackheim, M.D. t

Mycosis fungoides is a chronic, progressive skin disease with a fatal outcome. Currently it is grouped with several malignant skin diseases termed cutaneous T cell lymphomas. 8 Alibert, a French dermatologist, described the disease in 1806 and called it pian fungoide because he felt it was a kind of yaws, although he was surprised to see such a disease in ofyaws, Paris.!1 Yaws was thought to be restricted to tropical the vicinity of Paris. climates and his patient had not travelled in those regions. In 1832 he published a book on skin diseases in which he described the same case, but now called the disease mycosis fungoides because of the tumors, which he thought resembled mushrooms. 2 Bazin more clearly defined the disease in 1870 and divided it into three stages that are still useful today:3 (1) periode erythemateuse (the erythematous stage), (2) periode lichenoide (the lichenoid stage), (3) periode fongoidique mycositique (the fungous stage). Terms used today are: (1) premycotic, nonspecific eczematous stage, (2) plaque stage, and (3) tumor stage. Bazin initially thought the disease was a form of leprosy, but also mentioned that a colleague (Gillot) connected mycosis fungoides with leukemia. Ranvier (1872), a French pathology professor, supported Gillot and others and regarded the disease as a lymphoma. 23 23 In 1885, Vidal and Brocq30 described a form (d'emblee form) that began with tumors and was not preceded by the first two stages, and in 1892 Besnier and Hallopeau 99 described a third variant, an erythroderma type (l'homme rouge). The most recent variant, a leukemic form, was described by Sezary in 1938,25 although he considered it to be a different disease at the time.

Epidemiology Mycosis fungoides is an uncommon disease. Between 1954 and 1967, an average of 71 patients died with mycosis fungoides each year in ':
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31 In Sweden (population 8.1 million), during the 10 the United States. 31 years from 1961 to 1970 an average of 15 new cases of mycosis fungoides year.44 While there were 11 new cases of mycosis were reported each year. fungoides in Sweden in 1970, a total of 779 new cases of Hodgkin's disease, reticulum cell sarcoma, and lymphosarcoma were recorded that year. 10 to In contrast, Edelson concludes that the group of cutaneous T cell lymphomas (includes mycosis fungoides, Sezary variant and other T cell lymphomas of the skin) is at least as common as Hodgkin's disease. s8 However, his series was small (36 patients) and the period of observation

Table 1. TNM Classification of Cutaneous T Cell Lymphoma CLASSIFICATION

skin· T: skin* To

DESCRIPTION

Clinically and/or histopathologically suspicious lesions Limited plaques, papules, or eczematous patches covering less than 10 per cent of the skin surface

T,

Generalized plaques, papules, or erythematous patches covering 10 per cent or more of the skin surface

T3

Tumors (lor (1 or more) Generalized erythroderma

T, nodes·· N: lymph nodes** No

No clinically abnormal peripheral lymph nodes, pathology negative for CTCL Clinically abnormal peripheral lymph nodes, pathology negative for CTCL

N,

No clinically abnormal peripheral lymph nodes, pathology positive for CTCL

N3

Clinically abnormal peripheral lymph nodes, pathology positive for CTCL

B: peripheral blood B Boo

Atypical circulating cells not present (less than 5 per cent) Atypical circulating cells present (greater than 5 per cent); totallymphocyte record total white cell and total lymphocyte counts and no. of atypical cells per 100 lymphocytes

M: visceral organs M Moo

No visceral organ involvement Visceral involvement (must have pathology confirmation and organ involved should be specified)

':
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Table 2.

Staging Classification of Cutaneous T-Cell Lymphoma

Stage

T

lA IA lE IB IIA lIB III IVA IVB

1 2 1-2 3 4 1-4 1-4

CLASSIFICATION

N

M M

0 0 1 0,1 0,1 2,3 0-3

0 0 0 0 0 0 1

short (3 years). All studies have shown the disease to be more common in males than in females and to develop most often between the ages of 40 and 60 years. 10, Ill. 14,19,22 14. 19.22 Clinical Traditionally, mycosis fungoides is divided into three stages as described by Bazin. 38 Several clinical variants, as mentioned earlier, also occur. Recently, more complex staging has been proposed (Tables 1 and 2)5 in an effort to learn more about prognosis and response to treatment. However, the three traditional stages remain useful and will be used throughout this discussion. Mycosis fungoides is characterized by the appearance and disappearance of lesions in all three stages and by transition back and forth between stages. In the first stage the lesions are nonspecific. Most often they appear as erythematous, eczematous patches, with or without sharply defined borders (Fig. 1). At other times lesions may appear

Figure 1.

Early mycosis fungoides, erythematous, noninfiltrated lesions.

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Figure 2. Early mycosis fungoides, goides. extensive involvement.

psoriasiform, lichenoid, or rarely bullous. There may be one lesion or numerous lesions distributed over the trunk and extremities (Fig. 2). Pruritus is variable. This first stage may last less than a year or more the picture is than 50 years. While the diagnosis may be suspected, the nonspecific histologically, and is usually termed chronic dermatitis. Eventually the disease progresses to the plaque stage. Definite, infiltrated, thickened lesions develop (Figs. 3 and 4). The lesions may be composed of discrete lichenoid papules coalescing to form large patches (Fig. 5), or smooth, solid plaques. Occasionally scaling is present. The color varies from red to violaceous. The plaque stage may last several

Figure 3. Plaque stage mycosis fungoides.

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Figure 4. Plaque stage mycosis fungoides.

years, although rarely as long as the eczematous stage. If there was itching in the eczematous stage it usually continues into the plaque stage. Histopathologic diagnosis can be made in this stage. Inevitably tumors develop, either in previously uninvolved skin or in existing lesions (Figs. 6 and 7). While tumors may remain confined to one area for many months, eventually they become generalized. Tumors are usually firm, sessile and violaceous to deep red in color with a tense, shiny surface. They may be from one to many centimeters in size and as

Figure 5. Plaque stage mycosis fungoides, lichenoid papules coalescing to form plaque (Courtesy E. J. Van Scott, Skin and Cancer Hospital of Philadelphia).

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Figure 6. Tumor stage mycosis fungoides (Courtesy E. J. Van Scott, Skin and Cancer Hospital of Philadelphia).

in the earlier stages may spontaneously disappear, leaving no trace or only minimal hyperpigmentation. Generally tumors are painless and pruritus is rare. Some tumors continue to enlarge, ulcerate, and becom~ becom~ secondarily infected. Because of treatment, however, this phenomenon is seen less often today. Rarely, a patient may develop tumors without

Figure 7.

Tumor stage mycosis fungoides.

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previously developing the eczematous or plaque stages (d'emblee form). These patients usually have a rapidly progressive, and often fatal course despite therapy. Whether this constitutes the same disease process a~ mycosis fungoides is not known. Erythroderma can develop during any stage and may be either an exfoliative type with profuse scaling or the l'homme rouge of Hallopeau in which the skin is more red than scaly. Transitional forms occur. All forms are characterized by severe itching, which is refractory to treatment. Usually lymph nodes are grossly enlarged and often there is alopecia. The course of erythroderma is chronic with occasional spontaneous remissions. Erythroderma occurring early in the nonspecific, eczematous phase may be indistinguishable from the erythroderma of atopic dermatitis, psoriasis, contact dermatitis, drug eruption, and so forth. In Sezary 25 described two patients with erythroderma, lymphadenop1938, Sezary25 athy, and atypical mononuclear cells in the skin, blood, and lymph nodes. The histological picture of the skin was similar to that seen in plaque stage mycosis fungoides. Some authors consider this to be a separate entity,28, 33 but most now feel it is a leukemic form of mycosis entity,28,33 fungoides. G6 , 17 Often the same abnormal circulating cells can be found to a lesser degree in nonerythrodermic forms of mycosis fungoides. The total white blood cell count is usually between 12,000 and 20,000 per cu mm but it may rarely exceed 100,000 per cu mm. More than 5 per cent of the cells are abnormal. As with other forms of erythroderma associated with mycosis fungoides, there is usually severe itching. The skin may become infiltrated and thickened giving the face a leonine appearance. Lymph node involvement may develop at any stage, although it is unusual in the eczematous stage and common in the tumor stage. Palpably enlarged lymph nodes may reflect the degree and chronicity of skin involvement. Often histologic examination demonstrates atypical lymphocytes without frank lymphoma and is termed dermatopathic lymphadenopathy. These lymph nodes may regress as skin lesions resolve with treatment. EventuallY"clearly Eventually"clearly malignant cells can be seen histologic ally. and a diagnosis of malignant lymphoma can be made histologically. Systemic involvement also occurs and abnormal lymphocytes can be found infiltrating almost any organ in the body but this may not be detected until autopsy. 10 The cause of death is most often secondary infection. 10 While modern use of systemic chemotherapy may contribute to this situation, infection was the most common cause of death early in the twentieth century. 19 In a large number of patients the cause of death is unknown.

Pathology In the majority of cases, the diagnosis of mycosis fungoides is first made by the clinician. clinician!7 Histopathological specimens in the eczematous dermatitis, Even in the stage generally show a nonspecific, chronic dermatitis. plaque stage the picture may only be suggestive of mycosis fungoides with some atypical lymphocytes. When the diagnosis is strongly suspectatypicallymphocytes. ed on clinical grounds, it is advisable to perform multiple biopsies from various lesions. In the typical lesion there is a dense dermal infiltrate

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composed of abnormal lymphocytes, and so-called Pautrier's microabscesses in the epidermis, also composed of abnormallymphocytes abnormal lymphocytes (Figs. 8, 9). Electron microscopic examination may demonstrate sheets of cells with cerebriform nuclei (Fig. 10). These cells appear identical to those found in the lymph nodes and viscera in patients with systemic involvement and in the blood in patients with the Sezary variant. The infiltrate becomes increasingly abnormal and dense as tumors develop. Study of cell surface markers has shown the infiltrating cells to be T lymphocytes,8.17 and the disease is accordingly called a cutaneous T celllymphoma. rna.

Etiology The etiology of mycosis fungoides is unknown. While a vast amount of knowledge has been accumulated, it is basically descriptive in nature. Thus, even though this is a disease we can scrutinize at the ultramicroscopic and chemical level from its seemingly benign beginnings, and follow as increasingly abnormal cells infiltrate the skin and tumors develop, we still do not know why these cells flock to the skin and why they become abnormal. Sometimes mycosis fungoides develops in a long-standing dermatosis (atopic dermatitis, psoriasis, etc);10.14 sometimes it appears after a chronic allergic or irritant dermatitis or prolonged exposure to chemicals;14 sometimes it gradually develops de novo. The associations noted may be entirely fortuitous. Nevertheless, abnormal lymphocytes similar to those seen in mycosis fungoides may be abnormallymphocytes 11 Furthermore, these abnormal found in a variety of benign dermatoses. 11 lymphocytes can be produced in vitro by stimulating normal lympho-

Figure 8. Plaque stage mycosis fungoides. Note· Note the dense dermal infiltrate with exocytosis of cells into epidermis.

Figure 9. Plaque stage mycosis fungoides with typical Pautrier microabscess in the lower epidermis.

Figure 10. Electron micrograph, abnormal abnormallymphocyte. lymphocyte. Courtesy of S. McNutt, Veterans Administration Hospital, San Francisco, California.

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cytes with potent mitogens. 34 Whether the abnormal lymphocytes found abnormallymphocytes in mycosis fungoides are capable of autonomous proliferation or continue to respond to an unknown stimulus is not known. One group has postulated that this is a disease of antigen persistence,27 yet no antigen has been found.

Prognosis The prognosis is unfavorable. In Epstein's series of 144 patients 10 the median survival after biopsy diagnosis was 5 years, but for unknown reasons, those patients younger than 50 years at the time of diagnosis had a median survival twice as long as those older than 50 years. Half of the patients died within 2% 2Y2 years after the appearance of cutaneous tumors, ulcers, or palpably enlarged lymph nodes. When tumors, ulcers, and enlarged lymph nodes were all present, only 50 per cent of the patients lived more than a year, and with clinically recognized hepatomegaly or splenomegaly the median survival was only three months. These figures differ little from those reported early in this century. 19 century.19 Treatment Because the etiology is unknown, treatment remains nonspecific and palliative in nature. Although arsenic enjoyed popularity in the nineteenth century,22 ionizing radiation, initially used in 1902,20 became the first effective therapy. It is still in use today, although more commonform of high energy electrons. 12, 12. 16 Repeated courses are not ly in the fornl recommended because they produce radiation dermatitis. 21 In the last 20 years, two systemic chemotherapeutic agents have produced prolonged remissions when applied topically to the skin. These agents, nitrogen 26 . 29, 32 and BCNU,35-37 offer certain advantages over ionizing mustard26.29.32 mustard radiation, in that they can be used repeatedly for an indefinite number of courses and the patient can treat himself at home. Although not limited in total dose as with ionizing radiation, both drugs can cause severe irritation and allergic contact dermatitis. Topical BCNU can produce bone marrow depression as well. Some patients fail to respond to any therapy, and in others resistance develops. In later stage disease, systemic chemotherapy has been used, but with only limited success and no prolonged remissions. 15. IS 18 Recently, long wave ultraviolet light and (PUVA) have produced remissions in early stage systemic psoralens (PUVA) disease. 13, 24 As with topical chemotherapy, repeated courses and mainte13.24 PUV A may prove especially valuable as nance therapy are possible and PUVA adjunctive therapy in patients treated with ionizing radiation or chemounable to therapy, and as primary therapy in those who are resistant to or unab~e tolerate other forms of treatment. Whatever the treatment, only the expression of the disease seems unchanged_ 10 altered. The course and eventual outcome probably remain unchanged. Indeed, some patients using topical therapy have developed frank systemic involvement while their skin was clinically free of disease. It seems likely that this state of affairs may continue until the precise etiology is determined.

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REFERENCES 1. Alibert, J. L.: Description des maladies de la peau; Observees a I'hopital l'hiipital Saint-Louis, et exposition des meillures methods suivies pour leur traitement. Paris, Barrois L'Aine et Fils, 1806, p. 157. 2. Alibert, J. L.: Monographie des dermatoses ou precis theorique et pratique des maladies de la peau. Paris, Daynac, 1832. 3. Bazin, E.: Lelcons sur le Ie traitement des maladies chroniques en general affections de la l'emploi l'hydrotherapie et des peau en particulier par l' emploi compare des eaux minerales de I'hydrotherapie moyens pharmeceutiques, Paris, Adrien Delahaye, 1870, p. 425. 4. Brehmer-Andersson, E.: Mycosis fungoides and its relation to Sezary's syndrome, lymDermvenereoI. phomatoid papulosis, and primary cutaneous Hodgkin's disease. Acta Dermvenereol. (Stockholm), 56 (Suppl. (SuppI. 75) 1976. 5. Bunn, P. A., Jr., and Lamberg, S. 1.: I.: Report of the committee on staging and classificaT-celllymphomas, tion of cutaneous T-cell lymphomas, Cancer Treat Rep, 63:725-728, 1979. 6. Clendenning, W. E.: Mycosis fungoides, history, clinical features, controversies. Bull. du 64:167-176,1977. Cancer, 64:167-176, 1977. 7. Clendenning, W. E., and Rappoport, H. W.: Report of the Committee on Pathology of Cutaneous T-cell T-celllymphomas. lymphomas. Cancer Treat. Rep., 63:719-724, 63 :719-724, 1979. 8. Edelson, R.: Cutaneous T cell lymphoma: Mycosis fungoides, Sezary syndrome, and other variants. J. Amer. Acad. Derm., 2:89-106, 1980. 9. Besnier, E., and Hallopeau, H.: Sur les erythrodennies erythrodermies du mycosis fongoide. Ann. DermatoI. Syph. (Paris), 3:987, Dermatol. 3 :987, 1892. aI.: Mycosis fungoides. Survival, prognostic 10. Epstein, E., Jr., Levin, D. L., Croft, J. D., et al.: features, response to therapy and autopsy findings. Medicine, 15:61-72, 1972. 11. Flaxman, B. A., Zelazny, G., and Van Scott, E. J.: N onspecificity of characteristic cells in 104:141-147,1971. mycosis fungoides. Arch. Derm., 104:141-147, 1971. '12. Fuks, A., and Bagshaw, M. A.: Total-skin electron treatment of mycosis fungoides. Radiology, 100: 145, 1971. 13. Gilchrest, B. A., Parrish, J. A., Tanenbaum, L., et al.: Oral methoxsalen photochemotherapy of mycosis fungoides. Cancer, 38:683, 38 :683, 1976. aI.: Mycosis fungoides: Epidemiologic 14. Greene, M. H., Dalager, N. A., Lamberg, S. 1., I., et al.: observations. Cancer Treat. Rep., 63:597-606, 1979. 15. Grozea, P. N., Jones, S. E., McKelvey, E. M., et al.: Combination chemotherapy for mycosis fungoides: A Southwest Oncology Group study. Cancer Treat. Rep., 63:647, 1979. 16. Hoppe, R. T., Cox, R. S., Fuks, Z., et al.: Electron-beam therapy for mycosis fungoides: The Stanford University experience. Cancer Treat. Rep., 63 :691-700, 1979. 17. Lutzner, M., Edelson, R., Schein, R., et al.: Cutaneous T-cell T-celllymphomas: lymphomas: The Sezary syndrome, mycosis fungoides and related disorders. Ann. Intern. Med., 83: 83 :534-552, SYndrome, 534-552, 1975. 18. Minna, J. D., Roenigk, H. H., Jr., and Glad,stein, Glad~tein, E.: Report of the Committee on therapy syndrome, Cancer Treat. Rep., 63:729, 1979. for mycosis fungoides and Sezary SYndrome, 19. Ormsby, O. S.: Diseases of the Skin. Philadelphia, Lea & Febiger, 1915, pp. 816-829. 20. Ormsby, Onnsby, O. S.: Preliminary report in the case of a patient in the practice of Drs. Hyde and Montgomery, in the prefungoid stage of mycosis fungoides, treated with radiotherapy. Medicine, 9:904-906, 1903. 21. Price, N. M.: Radiation dermatitis following electron beam therapy. Arch. Derm., 114:63-66, 1978. pp. 22. Radcliffe-Crocker, H.: Diseases of the Skin. Philadelphia, P. Blakiston Son and Co., PP. 1042-1057, 1905. 23. Ranvier, L. A.: Rapport sur la candidature de M. Deboves au titre de membre adjoint.Mycosis fongoide. Bull. Soc. Anat. Paris, Sere Ser. 3, 7:477, 1872. 24. Roenigk, H. H., Jr.: Photochemotherapy for mycosis fungoides: Long-term follow-up study. Cancer Treat. Rep., 63:669, 1979. Erythrodennie avec presence de cellules monstreuses 25. Sezary, A., and Bouvrain, Y.: Erythrodermie dans derme et dans sang circulant. Bull. Soc. Framc. Derm. Syph., 45:254-260, 1938. helyi alkamazasa nehany biobetagseglien. 26. Sipos, K., and Jasko, G.: A mustarnirogen helyj B6urgyogyaszati es Venerologiai Szemle, 32:198, 1956. 27. Tan, R. S., Butterworth, C. M., McLaughlin, H., et al.: Mycosis fungoides - a disease of antigen persistence. Brit. J. Derm., 91 :607-616, 1974. 28. Taswell, H. F., and Winkelmann, R. K.: Sezary syndrome - a malignant reticulemic 177 :465, 1961. erythroderma. J.A.M.A., 177:465,

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29. Van Scott, E. J., and Kalmanson, J. D.: Complete remissions of mycosis fungoides lymphoma induced by topical nitrogen mustard (HN2): Control of delayed hypersensitivity to HN2 by desensitization and by induction of specific immunologic tolerance. Cancer, 32: 18, 1973. 2:946, 957, 30. Vidal, E., and Brocq, L.: Etude sur le Ie mycosis fongoide. La France Medical, 2:946,957, 969, 983, 993, 1005, 1019, 1885. U. S. Department of Health, Education and Welfare. 31. Vital Statistics of the United States, U.S. Nat'l. Center for Health Statistics. Annual Volumes 1954-1967. Nat'!. 32. Vonderheid, E. C., Van Scott, E. J., Wallner, P. E., et al.: A 10-year experience with topical mechlorethamine for mycosis fungoides: comparison with patients treated by :681--690, 1979. total-skin electron beam radiation therapy. Cancer Treat. Rep., 63 :681-690, 33. Winkelman, R. K., and Linman, J. W.: Erythroderma with atypical lymphocytes (Sezary atypicallymphocytes syndrome). Amer. J. Med., 55:192-198, 55:192-198,1973. sYndrome). 1973. Sezary-like cells from 34. Yeckley, J. A., Weston, W. L., Thorne, E. G., et al.: aI.: Production of ofSezary-like normal human lymphocytes. Arch. Derm., 111 :29-32, 1975. 35. Zackheim, H. S.: Treatment of mycosis fungoides with topical nitrosourea compounds. Arch. Derm., 106:177,1972. 36. Zackheim, H. S., Epstein, E. H., Jr.: Treatment of mycosis fungoides with topical 111::1564, 1564, 1975. nitrosourea compounds. Arch. Derm., 111 37. Zackheim, H. S., Epstein, E. H., Jr., and Grekin, D. A.: Treatment of mycosis fungoides with topical BCNU. Cancer Treat. Rep., 63:623, 1979. University of California, San Francisco 400 Parnassus, A-342 San Francisco, California 94143