Mycosis fungoides

MYCOSIS FUNGOIDES MARY ELLEN GAEKE, M.D. DIANA VARIAKOJIS, M.D. DONALD L. SWEET, M.D.

0147-0272/81/090001-0039506.50 9 1981, Year Book Medical Publishers, Inc.

INTRODUCTION

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V A R I A N T S OF M F

CLINICAL EV.~ LUATION

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LABORATORY FINDINGS

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THE ABNOBMAL CELL

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DIAGNOSIS

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TREATMENT

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CONCLUSIONS AND RECOMMENDATIONS CONCERNING THERAPY SURVIVAL .

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CAUSE CF DEATH

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was a Fellow in hematology and oncology in Middleton, Ohio, and is currently in private practice. Dr. Gaeke received her medical degree, postgraduate, and Fellowship training at The University of Chicago.

is Associate Professor of Pathology and is currently engaged in research in hematopathology at The University of Chicago. Dr. Variakojis received her medical degree at Basel University, Basel, Switzerland, and her postgraduate training in pathology and hematopathology at The University of Chicago.

is Assistant Professor of Medicine at The University of Chicago and is currently engaged in research regarding the clinical management of the malignant lymphomas. Dr. Sweet received his medical degree from Marquette University. His residency in medicine and postgraduate training in hematology and oncology were completed at The University of Chicago.

INTRODUCTION MYCOSIS F U N G O I D E S (MF) is a m a l i g n a n t T cell lymphoma t h a t first appears in the skin, usually as a persistent, nonspecific rash. Most patients develop the first skin lesions between the ages of 40 and 60 years, but some have been diagnosed as young as 20 years of age. Twice as m a n y m en as women have MF, but the disease occurs in all races, most frequently in whites. The lesions are nonspecific and occasionally regress spontaneously, and because most patients usually feel well until late in the disease, a definitive biopsy-proved diagnosis m a y not be made until 3

long after the onset of the rash. The time between onset of skin lesions and positive biopsy results varies from 0.1 to 50 years, with an average of 6 to 10 years. Thus, the duration of the disease is difficult to ascertain. Despite this variability, most patients die from widespread visceral involvement and infection within five years of the biopsy-proved diagnosis. The etiology of mycosis fungoides is unknown. It is known, however, that dysplastic or neoplastic thymus-derived lymphocytes are involved in the pathogenesis of the disease. Mycosis fungoides is more common in patients with atopic dermatoses, and in many patients its onset coincides with a drug reaction or chronic c~ntact dermatitis. Mycosis fungoides may be the result of an immune system response to persistent, unidentified antigens. Although occasional familial clusterings have been reported, only minor variations from the expected HLA haplotype have been detected. 1 Specific toxins have not been etiologically linked with the development of MF, although it has been observed that many MF patients have been exposed to potential carcinogens in the environment, the workplace, or during medical treatment. 2 VARIANTS OF MF Mycosis fungoides was the name chosen by Alibert in 1806 to describe a skin disease with mushroom-like tumors. Several forms of the disease have since been recognized. In 1876 Bazin described the three phases through which most MF patients progress: a "premycotic" phase characterized by nonspecific skin lesions; a plaque phase; and a tumor phase. These three phases constitute the classic and most common forms of MF. In 1885 Vidal and Brocq described mycosis fungoides d'embl~e, a less common form in which the patient manifests only the tumor phase. In 1892 Hallpeau and Besnier described erythrodermic MF, in which a generalized erythroderma predominates. The unfortunate choice of name and the variable clinical manifestations have led to confusion over the exact nature of MF and its variants. In 1938 the International Conference on the Classification of the Causes of Death grouped MF with diseases caused by fungi. As late as 1955, Bluefarb asked, ~Is mycosis fungoides an entity? ''3 and Symmers termed MF a "pathologic nonexistent. ''4 Another variant, described by S~zary and Bouvrain in 1938, further confused the identity of MF. Patients with this variant, the S6zary syndrome (SS), have generalized and intensely pruritic erythroderma, circulating "monstrous histiomonocytes" (the S6zary cells), and frequently, lymphadenopathy and hepatosulenomegaly. Skin biopsy specimens from MF patients are indistinguishable from those of SS patients; however, tumors and 4

ulcers are rare in SS patients. The S~zary syndrome sometimes developed in patients who had classic MF. The distinction was further blurred when Clendenning, Brecher, and Van Scott discovered small numbers of S~zary cells in the blood of 20% of MF patients. 5 Although many more S~zary cells are found in the blood of patients with SS, the presence of these cells in the blood of MF patients suggests that S~zary syndrome is a leukemic variant of mycosis fungoides. Recent electron-microscopic, cytogenetic, and immunohistochemical studies have shown the same neoplastic process and the same neoplastic cells, the S~zary cells, in both MF and SS. In view of these findings, we consider SS to be the leukemic variant of MF and not a separate disease entity. CLINICAL EVALUATION PHYSICAL FINDINGS

The typical mycosis fungoides patient is a middle-aged man with a nonspecific rash. Patients often note that the lesions have had periods of growth and shrinkage over several years. Some lesions improve when exposed to sunlight, regressing in the summer only to recur in the winter. The patient's major complaint often is intolerable itching. In the early, undiagnosed stages, the lesions m a y be mistaken for eczema, psoriasis, neurodermatitis, poikiloderma, or parapsoriasis en plaque. However, if the lesions persist for a year or more, the physician should suspect MF. About 80% of MF patients have parapsoriasis en plaque before MF develops. As the disease progresses, lesions become indurated, forming elevated plaques (Fig 1). Both normal and previously affected skin m a y give rise to plaques. The neoplastic cells m a y infiltrate

Fig 1.--Multiple tumors on the face and scalp; some are ulcerating.

Fig 2.--Massive confluent tumors on the abdomen.

the eyebrows, nose, and mouth, a process that produces the classic '~leonine" facies. As more malignant cells accumulate, the plaques become elevated tumors (Figs 2 and 3). These tumors are usually painless, vary in size, and tend to ulcerate. Lesions progress to the tumor stage at variable rates: a spectrum of new lesions, clearing lesions, plaques, and tumors is seen (Fig 4). In the later stages of MF, the development of lymphadenopathy and hepatosplenomegaly indicates disseminated disease. The involved lymph nodes are not matted or tender but are firm and freely movable. Fever, weight loss, eosinophilia, and lymphocytosis also suggest dissemination of the disease.

Fig 3.--Small, indurate plaques that microscopically already showed dense infiltrate by large, bizarre lymphoid cells with convoluted nuclei.

Fi 0 4.--Illustration of the presence of both plaques and ulcerated tumors distributed over the entire body.

In patients with the SS variant, initial symptoms are exfoliative erythroderma with associated pruritus, generalized edema, and alopecia. Hyperkeratosis of the palms and soles, dystrophic changes of the nails, and problems that result from local skin infiltration, such as ectropion and priapism, also occur. Lymphadenopathy and splenomegaly are more common in SS than in MF. LABORATORY FINDINGS HEMATOLOGIC FINDINGS

Early in the course of the disease the complete blood count and examination of the peripheral blood smear in MF without S~zary syndrome usually yield normal findings. Anemia is found in fewer than 15% of patients; neutrophilia is usually related to infection, and platelet counts are normal. The differential white blood cell count often shows abnormalities: lymphocytopenia is present in more than 75% of patients at some stage of the disease and indicates an accelerated course; eosinophilia occurs in 15% and abnormal mononuclear cells are detectable, even in early stages of the disease, in 4% to 20% of patients. With the exception of mild eosinophilia and plasmacytosis, the bone marrow is normal until late in the course of the disease, when it may be infiltrated by S~zary cells. 3

Patients with SS m a y have strikingly elevated numbers of circulating S~zary cells (SC). The number is apparently unrelated to the extent of cutaneous involvement, although in one report the greatest numbers of SC were found in patients with lymphadenopathy and visceral involvement. 6 The blood chemistry results are generally normal except for hyperuricemia. Abnormal liver function tests correlate with clinical hepatomegaly; either indicates visceral involvement. 7 Quantitative immunoglobulin analysis often shows markedly increased levels of IgA, with normal levels of IgG and IgM. 8 Increased IgE has been observed in SS. 6 RADIOGRAPHIC STUDIES

When MF involves the lung, the chest radiograph m a y show diffuse interstitial infiltrates, pleural effusions, nodular densities, or tumor masses. 7 ELECTROCARDIOGRAM

Cardiac metastases, although rare, can result in significant arrhythmias, prolonged PR intervals, interventricular conduction defects, and signs of cor pulmonale. 7 Refractory congestive heart failure may also be observed as a manifestation of cardiac metastases. IMMUNOLOGIC EVALUATION

Blaylock et al. observed that, unlike patients with Hodgkin's disease, MF patients have normal indices of cell-mediated immunity. 8 In their study 14 of 15 patients could be sensitized to dinitrochlorobenzene (DNCB), and all had reactive skin test responses to at least one of a battery of common antigens. When chaI~enged by novel antigens, MF patients produced circulating antibodies in titers similar to those produced in normal controls. Furthermore, MF and SS patients often become sensitized to topically applied chemotherapeutic agents. Patients with MF are capable of rejecting homografts until the terminal stages of their disease. 9 Tan et al. observed an unexpectedly high frequency of autoantibodies in MF patients. 1~ In studies of monocyte-macrophage function, defective chemotaxis was observed, although bacterial phagocytosis and intracellular killing were normal. H In in vitro studies of peripheral blood from MF patients, the numbers and function of T cells and B cells vary widely. 12 Details of the immunologic aspects of MF are discussed in the section on the abnormal cell.

HISTOLOGIC FINDINGS Early in the course of the disease the skin biopsy m a y reveal no evidence of MF. However, as the disease progresses, biopsy examinations of the lesions should be taken periodically so that the appearance of abnormal cells in the skin can be documented as early as possible. The characteristic abnormal T cell is found in both MF and SS, although it is often not found in biopsies until the disease is quite advanced. Its nature will be described further in the section on the abnormal cell. By the time the biopsy study reveals SC, up to 50% of patients already manifest tumors, ulcerations, and lymphadenopathy. Skin Early in the course of MF, the skin lesions are often indistinguishable from those of psoriasiform dermatitis, poikiloderma vasculare atrophicans, or chronic nonspecific dermatitis, and similar dermatoses. Biopsy studies may reveal only a few atypical cells. As the disease progresses the neoplastic infiltrate in the upper dermis becomes more dense. Biopsy results now show a larger number of atypical lymphocytes with hyperconvoluted nuclei, and in most instances epidermal infiltrates are seen. The skin biopsy study from a patient in the plaque stage shows a patch or band of abnormal cells that infiltrate the upper dermis. Usually, this infiltrate occupies less than 25% of the entire dermis. The cells are slightly larger than normal lymphocytes and contain irregular, hyperconvoluted, cerebriform nuclei. If the infiltrate is scanty, it m a y be concentrated around Fig 5 . - - A patchy infiltrate in the upper dermis with neoplastic mononuclear cells present in the epidermis. H and E; x 250.

Fig 6.--A higher magnification of Figure 5 shows a diffuse infiltrate in the epidermis. Dermal-epidermal junction is obscured by the infiltrate.

blood vessels or dermal appendages. Benign-appearing histiocytes, plasma cells, and eosinophils are seen in small numbers. As the skin lesions become more indurated, more of the abnormal cells infiltrate the dermis. In the tumor stage of the disease, these infiltrates often involve the subcutaneous tissue. This correlation is not always exact, and the pathologist cannot accurately predict the clinical stage of a particular patient. In most patients with MF, the neoplastic lymphoid cells infiltrate the epidermis. The infiltrate may consist of single cells scattered in the basal layers of the epidermis (Figs 5 and 6), or Fig 7.--A bandlike infiltrate is present in this patient with a few well-delineated Pautrier microabscesses. H and E; x 50.

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Fig 8.--The lymphoid cells in the dermis and epidermis are larger than normalappearing lymphocytes. The nuclei show irregularities. Note the neoplastic cells within the Pautrier microabscess. H and E; x 500.

it may form so-called Pautrier microabscesses (Fig 7). In Figure 8, a higher magnification illustrates the hyperchromatic hyperconvoluted cells of the Pautrier microabscesses. Similar collections of benign lymphocytes can occasionally be found in skin biopsy results from patients with eczema and chronic dermatitis. In the tumor phase biopsy study reveals cellular infiltrates in the skin that are more pleomorphic and may resemble the abnormal cells found in "histiocytic" (large cell) lymphoma. The lymphoid cells are larger, m a y have fewer convolutions, more vesicular nuclei, and the number of mitoses are more numerous. Fig 9.--A skin biopsy from the patient illustrated in Figure 3 shows an extensive and deeper dermal infiltrate without epidermal involvement. H and E; x 100.

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Fig 1 0 . I A higher power view of Figure 9 shows some larger abnormal-appearing neoplastic cells and a very large hyperchromatic and hyperconvoluted cell ("mycosis cell"). H and E; x 1000.

Hyperchromatic, bizarre nuclear irregularities are evident. At this point the ~'mycosis cell," which is defined as a hyperconvoluted, hyperchromatic cell reaching 20~ in diameter, is more frequently found. Its absence, however, does not exclude the diagnosis of mycosis fungoides (Figs 9 and 10). Another important disorder to be considered in the differential diagnosis based on biopsy results is lymphomatoid papulosis. In tissue section the infiltrate shows lymphoid cells of variable size Fig 11.--Skin biopsy from a patient with lymphomatoid papulosis. The infiltrate is dense and contains large lymphoid cells. Many of them have dark cytoplasm and exhibit large nucleoli. H and E; x500.

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with dark pyroninophilic cytoplasm. Some cells are quite large and represent stimulated lymphocytes (Fig 11). Since individual cells as well as groups of cells may be found in the epidermis, lymphomatoid papulosis may easily be confused with mycosis fungoides. Ultrastructurally, some of the cells in lymphomatoid papulosis also show cerebriform nuclei, although this may not be seen in every patient. Since lymphomatoid papulosis is a benign condition, with only occasional case reports stating that it developed into a malignancy, it is quite important to recognize this entity. Clinicopathologic correlation is very helpful, since lymphomatoid papulosis is readily recognized by dermatologists because of its typical appearance and distribution.

Lymph Nodes Lymph node involvement in mycosis fungoides may be either focal or diffuse. In focal involvement, the thymus-dependent or paracortical areas are preferentially infiltrated, whereas the B cell areas, the lymphoid follicles, remain intact (Figs 12-14). With diffuse involvement, the lymph node architecture is totally effaced. This pattern of involvement clearly indicates a malignant lymphoma; however, the presence of convoluted and cerebriform nuclei aids in the diagnosis of mycosis fungoides (Fig 15). The neoplastic lymphocytes show irregularities similar to those seen in the skin (Fig 16). Accurate diagnosis of lymph node involvement in the early stages of MF is difficult because only a few single neoplastic cells occur throughout the lymph node, and detection of these

Fig 12.--Focally involved lymph node. The gray area in the cortex and paracortex represents tumor infiltrate. Typically, few follicles are left intact, H and E; •

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Fig 13.--Another lymph node shows a typical paracortical involvement with many yet-preserved follicles with germinal centers. H and E; x 50,

cells is, therefore, quite difficult. When the cells are found in clusters, however, they can be distinguished from mature lymphocytes by their nuclear irregularities. Such clusters may be seen in the paracortical regions as well as in the medullary cords. Dermatopathic lymphadenopathy may obscure the diagnostic features of MF in the lymph node. Dermatopathic lymphadenopathy is a nonspecific finding in patients with a variety of skin diseases and is characterized by expansion of the interfollicular areas by interdigitating histiocytes and macrophages containing Fig 14.--The interfollicular areas contain neoplastic lymphocytes with variation in the shape of their nuclei. H and E; x 500.

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Fig 15.--Lymph node biopsy with totally effaced architecture and diffuse involvement. The capsule on the top is also infiltrated by the neoplastic lymphocytes. H and E; x 250.

melanin pigment or iron (Fig 17). Many lymph node biopsy specimens from patients with MF show this abnormality, as illustrated in Figure 18. As mycosis fungoides spreads to the lymph nodes and other visceral organs, it remains the same T cell lymphoma and does not evolve into a different type of lymphoma, as was believed until quite recently. Fig 16.--A lymph node biopsy from a patient with advanced disease shows the larger and more hyperchromatic nuclei of the neoplastic cells. A cell in the center qualifies for a "mycosis cell." H and E; x 1000.

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Fig 1 7 . I A lymph node with dermatopathic lymphodermopathy. The gray, lighterstained area represents accumulation of many interdigitating histiocytes. A subcapsular sinus is open. H and E; •

Viscera At autopsy, extracutaneous involvement is detected in more t h a n 70% of patients. 13 The spleen and liver are the most frequent sites of involvement, and the lung is found to be infiltrated more often t h a n in other lymphomas. The spleen m a y be involved in either a diffuse or nodular pattern. In the spleen with nodular involvement, tumor cells invade Fig 1 8 . i T h i s lymph node biopsy shows both mycosis fungoides and dermatopathic lymphadenopathy. Note the hyperchromatic, irregular nuclei of the lymphoid cells and the larger, somewhat folded nuclei of the histiocytes. In the center a macrophage contains melanin pigment. H and E; x 50.

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Fig 19.--The spleen contains aggregates of neoplastic cells. They are replacing the white as well as the red pulp. H and E; •

the thymic dependent areas and the periarterial lymphoid sheath (Fig 19) and they can also be found scattered throughout the red pulp (Fig 20). The architecture of the spleen with diffuse involvement is completely obliterated, because both red pulp cords and sinuses are infiltrated by the neoplastic lymphocytes. The lung is more frequently involved by mycosis fungoides than in other non-Hodgkin's lymphomas (Fig 21). In the liver the cells tend to infiltrate the portal areas and, occasionally, the sinusoids (Fig 22). Diffuse bone marrow involvement is found in approximately one half of patients at autopsy; this is a larger Fig 20.--The periarteriolar sheath (the thymus-dependent area) is infiltrated by mycosis fungoides. H and E; • 250.

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Fig 21.--A lung nodule shows the neoplastic cells within the walls of a alveolar septae. H and E; x 250.

proportion than that observed ante mortem. The infiltrates in the lung, kidney, and brain are similar in pattern and distribution to other non-Hodgkin lymphomas (Figs 23 and 24). THE ABNORMAL CELL THE NORMAL IMMUNOLOGIC SYSTEM

Lymphocytes are categorized as thymus-derived (T cells) or bursa-derived (B cells), and these designations refer to their disFig 22,--In the liver the portal area contains a dense infiltrate. The sinusoids also contain neoplastic cells. H and E; x 250.

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Fig 23.--The infiltrates in the kidney are typical for a non-Hodgkin lymphoma. H and E; • 250.

tinct developmental pathways. The T cell undergoes differentiation under the control of the thymus. The B cell develops under the influence of the bursa of Fabricius in birds and of the bursal equivalent in man, postulated to be the bone marrow. In normal lymphoid tissue, T cells predominate in areas distinct from those of B cells and are seen in the paracortical areas of lymph nodes and the periarteriolar sheath of the white pulp of the spleen, while B cells are observed in the primary follicles and germinal centers. These cell types, however, are not strictly segregated and have ample opportunity for complex interaction Fig 24.--The rare involvement of the brain is periavascular and, again, characteristic of lymphoma involvement, • 250.

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with each other and with macrophages in tissue and monocytes in the circulation. H u m a n B and T cells are indistinguishable morphologically; therefore, we use cell surface markers to distinguish B cells from T cells. H u m a n T cells, when incubated with sheep erythrocytes, form E rosettes. H u m a n T cells also react to specific antisera. Normal B cells also have unique cell surface receptors by which they can be distinguished from other lymphocytes. Fluorescent antiserum to gammaglobulin absorbs to the surface immunoglobulin receptors on the B cell surface. Receptors for the third component of complement are demonstrated by the so-called EAC rosette technique. Most B cells have a receptor that combines with the Fc portion of immunoglobulin. Thus, when B cells are mixed with fluorescent IgG, the B cells will adsorb the IgG and fluoresce. A third population of lymphocytes, the null cells, seems to lack both B and T cell markers. This is probably a heterogeneous population of mononuclear cells for which no discrete function has been yet established. Clearly the percentage of null cells depends on the techniques used for identification of the B and T cell populations. T cells provide cellmediated immunity, whereas B cells are the progenitors of plasma cells that produce humoral immunity. To synthesize immunoglobulin, B cells require the presence of a subset of T cells, the helper T cell. Another subset, the suppressor T cell, inhibits B cell maturation and prevents immunoglobulin synthesis. H u m a n T cell populations can also be divided into subsets according to their cell surface receptors, which are capable of binding the Fc portion of either IgM or IgG. Approximately 75% of T cells are IgM receptor-positive (T~t cells), and somewhat less t h a n 20% are IgG receptor-positive (T~ cells). The remainder have no demonstrable receptors and are known as T null cells (T~). These subpopulations are also distinct in their sensitivity to radiation, corticosteroids, and thymopoietin. Functionally, helper T cell activity can be found in the T~t population and suppressor T cell activity, in the T~ fraction. 14 THE ABNORMAL CELL

A detailed description of the S~zary cell was not provided until 1961, when Taswell and Winkleman published their detailed description of SC as seen under the light microscope (Fig 25). ~ They described a cell with a large convoluted nucleus and a narrow rim of cytoplasm. Some cells contained periodic acid-Schiffpositive, diastase-resistant neutral mucopolysaccharide. Electron microscopic examination made the characteristic serpentine convolutions of the nucleus even more visible (Fig 26). The electron microscope also enabled researchers to confirm that the ab2O

Fig 25.--Circulating S6zary cells from two different patients with typical nuclear irregularities. Wright-Giemsa; x 1200.

normal cells found in MF patients are S~zary cells. In 1973 Lutzner et al. described a variant of the SC that is smaller than the typical SC and has a characteristic irregular nucleus that is much less convoluted. 16 Prior to the early 1970s, many researchers thought that the SC was a monocyte or histiocyte. In 1974 Zucker-Franklin, Melton, and Quagliata discovered that the S~zary cell does not phagocytose latex particles. 17 Crossen et al. showed that SC are stimulated by phytohemagglutinin (PHA) to synthesize RNA and DNA and, subsequently, to d i v i d e - - a characteristic of lymphocytes, is In addition, these SC were also capable of stimulating the transformation of donor lymphocytes in mixed leukocyte cultures. Fig 26.--Transmission electron micrograph emphasizes the convoluted serpentine nucleus of S(~zarycell. • 13,000.

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Fig 27.--Two Sezary cells showing E rosette formation with sheep erythrocytes indicating their T cell nature. FicolI-Hypaque gradient-Wright-Giemsa; x 1200.

S6zary cells have been shown to have the following T cell characteristics: they spontaneously form E rosettes (Fig 27), and most SC are killed by T cell-specific heteroantisera. In patients with SS, the abnormal cells are found in the paracortical regions of involved lymph nodes. S6zary cells do not fluoresce when exposed to fluorescent antiserum to gammaglobulin, and the SC do not have cell surface complement receptors. Edelson et al. have suggested that the striking affinity of SC for epithelial structures is a property of the T lymphocyte. 19 In contrast to the remarkable affinity of S6zary cells for the epithelium, there is a striking absence of SC in the bone marrow until advanced stages of the disease are noted. Rappaport and Thomas reported bone marrow involvement in only 2 of 12 patients and microscopic involvement in 12 of 31 patients, all in patients who died with widespread extracutaneous disease. 13 In several patients reported by Zucker-Franklin, lymph node involvement could be demonstrated prior to hematologic involvement in SS patients. She concluded that the SC originates in lymphoid tissue rather than in bone marrow. 2~ Recent kinetic data have indicated that the skin might be the primary site for SC production. Broder and co-workers have established that the circulating malignant T cells of patients with SS are helper T cells. 2~ They observed that when added to purified populations of B cells, SC were able to perform a helper function, that is, stimulate B cells to synthesize immunoglobulin. A clue to the helper T cell nature of the abnormal cell in SS and MF patients is provided by the markedly elevated IgA levels in many MF patients and by increased levels of IgE in SS patients. 6' s These elevated immunoglobulin levels m a y be due to the increase in helper cell activity 22

caused by the increase in SC. Recently, Hopper and H a r e n described a patient with classic SS whose lymphocytes did not show helper cell function, but rather demonstrated suppressor T cell activity. 22 When the S~zary cells from this patient were cultured with normal peripheral blood lymphocytes, normal immunoglobulin synthesis was greatly suppressed. The degree of suppression of immunoglobulin synthesis noted was proportional to the number of SC in the coculture. In some cases of SS, the majority of T cells do not bear the T~ marker, b u t are T~ cells; in others, the population of T cells consists of equal numbers of T~ and T~t cells. These data indicate that the defect in SS is a lack of suppressor cells (T~), not a surplus of helper cells (T~). A lack of T~] cells would enable T cells to differentiate into T~ and T~ cells without any regulation. Experiments by Kurmani-Arab have shown that an MF patient lacked suppressor T cells that specifically regulate the development of helper T cells. 23 It was concluded that the lack of suppressor T cells causes an uncontrolled clonal proliferation of helper cells. However, this apparent lack of suppressor cell activity does not prove that the original defect in SS is lack of suppression. BENIGN OR MALIGNANT?

The S~zary cell has been found in other disorders (Table 1), as well as in normal individuals. 13' 24, 25 Is it a malignant cell or is it a normal cell responding to a particular stimulus? Cytogenetic studies have proved the malignant nature of TABLE 1.--DISORDERSIN WHICH MF/SS CELLS HAVE BEEN OBSERVED

Dermatoses Lichen planus Psoriasis Solar keratosis Pityriasis lichenoides et varioleformis acuta Allergic contact dermatitis Dermatophytosis

Collagen Vascular Discoid lupus erythematosus Nonspecific vasculitis Rheumatoid arthritis

Premalignant Lesions Parasporiasis en plaque Lymphomatoid papulosis

Malignant Basal cell carcinoma

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these cells. S6zary cells show heteroploidy, pseudodiploidy, and frequent marker, ring, and minute chromosomes. The predominant cell line of SC in vitro has a modal chromosome number of 76; small subpopulations have 98 to 100 chromosomes; and some have the normal 46. TM F u k u h a r a and associates have described hyperdiploid cells with clonal abnormalities from a lymph node involved with MF. 26 Van Vloten, Van Duijn, and Schaberg demonstrated abnormal DNA histograms in cells from lymph nodes of patients with MF diagnosed as dermatopathic lymphadenopathy. 27 Patients with these findings progressed to lymph node involvement with MF within one year. Erkman-Balis and Rappaport have confirmed that cytogenetic abnormalities can be used for diagnosis of lymph node involvement by MF. 28 The degree of cytogenetic atypia has been correlated with the rapidity of evolution of the disease. 29 Since S~zary cells are found in healthy individuals and in a variety of disorders, and because these cells respond to normal lymphocyte control mechanisms, a few investigators maintain that the S~zary cell is benign. The history of atopy in MF and SS patients has led some authors to theorize that the cell in question is an atypical b u t nonmalignant lymphocyte that responds to an as yet unidentified proliferative stimulus. 3~ This stimulus attracts large numbers of these atypical lymphocytes, which are not detectable by light or electron microscopy. In some cases, dedifferentiation or malignant transformation occurs, and a previously benign disease then becomes malignant. Even though the SC responds to mitogenic stimulation, the response is less than normal; a variable but significant number of samples from MF and SS patients in all series do not respond to these stimuli. 31 Thymidine incorporation studies also support the argument against the hypothesis that the SC is a benign lymphocyte responding to a stimulus. Low background counts in most cells indicate that these cells have not responded to mitogenic stimuliY Current data indicate a correlation between a poor prognosis and the signs of dedifferentiation, that is, absence of T cell surface receptors, increased cytogenetic and morphological atypia, and decreased functional capacity. 12' 33 Whether this implies an escape from immune surveillance of a prelymphomatous state to an overt expression of fundamentally malignant characteristics continues to be debated. Further study of these neoplastic T cells m a y contribute greatly to our understanding of SS, MF, and of normal T cells. At this point, the S~zary cell is considered to be a malignant lymphocyte that resembles the T cell in its distribution pattern in the tissues, its cell surface markers, and its function. 24

DIAGNOSIS

Accurate, early diagnosis of mycosis fungoides is essential if it is to be distinguished from the many benign dermatoses that it resembles. Treatment of MF as a benign disorder yields no benefit to the patient and allows the malignancy to progress. S K I N LESIONS

As mentioned before, the initial rash of MF is frequently confused with psoriasis en plaque, psoriasiform dermatitis, exfoliative dermatitis, and eczema. About 80% of all MF patients had been previously diagnosed as having parapsoriasis en plaque. When patients with these dermatoses do not respond to therapy, or when the lesions become more indurated than expected, the physician should suspect MF. Erythroderma is the major presenting sign in MF as well as many other benign and malignant diseases (Table 2). Biopsy examinations should be done periodically and the course of the lesions followed carefully. Histopathologic examination of biopsy specimens is required for accurate diagnosis of MF. Yet the characteristic S~zary cells have been demonstrated in skin cultures from normal volunteers as well as in a wide range of disorders, including collagen vascular disease, benign dermatoses, and other types of malignancies (see Table 1). In these diseases, the SC are usually found in tissue section rather than freely circulating in the peripheral blood. The numbers of S~zary-like cells found in patients with these disorders are small, and the cells may be difficult to demonstrate routinely, in contrast to the large numbers of readily identifiable SC found in patients with S~zary syndrome. When TABLE 2.--DIFFERENTIAL DIAGNOSIS OF ERYTHRODERMA34' 35

Primary Skin Disorders Psoriasis Pityriasis Eczema Neurodermatitis Seborrheic Dermatitis

Immunologic Skin Diseases Atopic Dermatitis Drug Reaction Graft versus Host Disease

Prelymphomatous States Parapsoriasis en plaque

Malignant Diseases Lymphoma Leukemia

Idiopathic Disease 25

the circulating SC are the small-cell variant, they may be confused with the normal small lymphocyte and the physician may conclude that the patient has chronic lymphocytic leukemia (CLL). The characteristic nuclear convolutions are often detectable only by electron microscopy. The 2% of CLL patients who also have erythroderma most likely have MF with the small SC variant. 19 The only other lymphoma in which SC have been found is the nodular, poorly differentiated lymphocytic malignant lymphoma (PDL-ML). 1S It is interesting to note, however, in both CLL and PDL-ML, most of the circulating malignant cells are B cells. As the disease progresses, the presence of lymphadenopathy suggests the differential diagnosis of Hodgkin's or a non-Hodgkin lymphoma. Lymph node biopsies and biopsies of other viscera may demonstrate a malignant lymphoma that is not readily identifiable as MF and that may be misclassified as other largecell or histiocytic lymphomas by nonexpert pathologists. Rappaport and Thomas have demonstrated that MF involvement of both lymph nodes and viscera is characterized by a specific cellular infiltrate that closely resembles that seen in the cutaneous lesion. 1SThey stated that the neoplastic cellular proliferation in cutaneous and extracutaneous tissue was distinct and different from other lymphoid and histiocytic neoplasms, and they rejected the earlier concept that MF evolves into other types of lymphomas. These researchers described several cases in which SC had infiltrated between the basement membrane and the epithelial lining of the renal tubules and other various organs, in TABLE 3.--CLINICAL TNM SCHEMEUSED TO DESCRIBEEXTENTOF DISEASEIN MF PATIENTS CLINICAL CATEGORY Wo

TI T2 Ts W4

NPo NP~ NVo NV, Mo MI

26

DEFINITION

No skin involvement Plaques, papules, or eczematous patches covering <10% of the body Same as above but covering >10% of the body Tumors with or without plaques or papules Generalized erythema alone No enlarged peripheral lymph nodes Enlarged peripheral lymph nodes No enlarged visceral lymph nodes Enlarged visceral lymph nodes No visceral organ involvement Visceral organs enlarged, tumorous, or functionally or radiographically abnormal

one instance completely replacing the lining and, thus, simulating adenocarcinoma. They also noted infiltration of the epithelial linings of the mucous membranes and, in the thymus, preservation of the epithelial component despite occasional massive involvement with MF. Epidermal infiltrates of neoplastic cells usually do not occur in other lymphomas, which have a characteristic "grenz zone" devoid of any infiltrates between the epidermis and the infiltrate in the dermis. In occasional cases of MF, there are no obvious epidermal infiltrates, and the presence of lymphoid cells with convoluted nuclei and the clinical history will indicate that the disease is MF. STAGING SCHEMES

None of the suggested classifications for mycosis fungoides has been useful or widely accepted. The classification scheme used by the Mycosis Fungoides Cooperative Group is a modified TNM system, as outlined by the American Joint Committee on Cancer Staging (Table 3). It is highly flexible but awkward, and a staging system has been derived from it (Table 4). This scheme incorporates SS with MF, treating them as two manifestations of the same disease. T H E STAGING LAPAROTOMY IN M F

A staging evaluation culminating in staging laparotomy was used for patients with MF undergoing evaluation at The University of Chicago. 36 It was hoped that the results of these procedures would help delineate appropriate therapy, especially TABLE 4.--STAGING CLASSIFICATIONOF MYCOSIS FUNGOIDES*

STAGE I II III IV V

CLINICAL CHARACTERISTICS OF SKIN LESIONS E r y t h e m a t o u s patches or minimally infiltrated plaques Moderately infiltrated papules or plaques, usually associated with erythematous patches Tumor or nodule formation, usually associated with papules, plaques, or erythematous lesions Any of above Any of~bove

LYMPH NODE INVOLVEMENT

VISCERAL INVOLVEMENT

0

0

0

0

0

0

+ +

0 +

*Patients with diffuse extensive erythroderma are classified separately according to the percentages of easily detectable S~zary cells on blood smears. 27

whether therapy should be systemic or limited to the skin. Staging laparotomies were performed on thirteen patients to determine the presence of visceral and abdominal lymph node involvement. The spleen was involved in four patients, the abdominal lymph nodes in three, and the liver in one. When neoplastic cells occurred in clusters or sheets, they were easily recognized. When the neoplastic infiltrate did not form cohesive masses, however, individual neoplastic cells were difficult to detect, especially in patients with limited stages of the disease. Since the use of staging laparotomy in the older MF population is more hazardous than in patients with Hodgkin's disease, staging laparotomy is not routinely recommended. TR EATM ENT INTRODUCTION

Historically, the treatment of mycosis fungoides has been designed for palliation in symptomatic patients. There are several reasons for this approach. First, the physician may not be able to prove the presence of MF definitely during its early stages. Second, early lesions may undergo apparently spontaneous remissions or may not progress for several decades. Finally, aggressive treatment seems to have no effect on survival. In 1972 Epstein et al. categorized 30 different types of treatment and the responses that were achieved over a 15-year period, 1954 to 196937 (Table 5). Treatment plans were adjusted according to patient status, immediate needs, response to previous therapy, and developing knowledge of drugs and techniques during the period under study. Most patients responded to initial therapy, be it radiation, steroids, or chemotherapy. The response rate was only slightly less for subsequent courses of TABLE 5.--MANAGEMENT RESULTSIN MYCOSIS FUNOOIDES, 1954-- 1969 RESPONSE RATE

Radiation Orthovoltage radiation therapy Electron beam radiation therapy

Topical nitrogen mustard Systemic Chemotherapy Cyclophosphamide Nitrogen mustard Methotrexate Steroids

89% 88% 75% 62 % 59% 82% 59%

Adapted from Epstein, E.H., et al.: Medicine 15:61, 1972. 28

treatment. The type of initial therapy, however, had little influence on the patients' survival times. The only factor that correlated with increased survival was less extensive disease, as measured by the extent of tumors, ulcers, and lymphadenopathy. RADIATION THERAPY Radiation therapy has been the principal form of treatment of MF since 1902. Kilovoltage radiation was used initially and required that the patient be hospitalized..The radiosensitive skin infiltrates of MF responded rapidly to doses as low as 100 rad, although these responses were incomplete and brief. In 1953 Trump et al. reported the first use of high energy electrons for t r e a t m e n t of extensive superficial malignant lesions of the skin. ~s With this technique the physician is able to administer a uniform dose of radiation to a specific depth, allowing a much smaller dose delivery to sensitive areas. A larger port was available for treatment. Moreover, nearly all patients respond to their initial course of electron beam therapy with a marked decrease in symptoms, resolution of indurated skin and plaques, and healing of ulcers. Responses were rapid, although the duration of response was variable. Several courses of therapy could be given with minimal side effects. Treatment could be given daily over extended periods of time on an outpatient basis. The major complication of electron beam therapy is radiation dermatitis. Chronic skin changes, are directly related to the amount of radiation delivered. 39 Constitutional symptoms were rare. Hematologic values transiently were suppressed but seldom required that t r e a t m e n t be delayed. Fuks et al. have demonstrated that 85% of patients with limited disease treated with 2,000 to 3,500 rad of electrons achieved complete remissions. 4~ Mycosis fungoides, previously considered inevitably fatal, not only responded to aggressive therapy but also was potentially curable. Of the patients with limited plaque-stage disease, 96% achieved complete remissions. The overall survival rate was 46% at ten years. Even patients with widespread MF demonstrate improvement when treated with electrons. Most of these patients, however, relapse, often within months of their initial treatment. Electron beam therapy is a unique method of palliation with minimal toxicity in patients with widespread disfiguring lesions and visceral involvement. Palliation of deeper lymphomatous masses requires conventional radiation therapy. TOPICAL THERAPY Topical therapy is frequently sufficient for control of the cutaneous manifestation of MF. Although it does not prevent pro29

gression of MF to tumor stage or visceral involvement, rashes and plaques respond well to topical therapy, and in some cases palliation of the tumors is achieved. Furthermore, topical therapy is relatively nontoxic. Nitrogen mustard, steroids, and other chemotherapeutic agents have been used topically, and some investigators have begun to use ultraviolet light.

Nitrogen Mustard Solutions of nitrogen mustard applied to the cutaneous lesions of MF lead to improvement. Nitrogen mustard is relatively inexpensive, can be administered by the patient, and m a y be applied repeatedly over variable lengths of time without serious complications. Complete responses range from 30% to 90%. Patients with plaque-stage disease respond best, but the thickness of the lesions m a y determine the rapidity of response. Duration is variable, ranging from one to eighteen months. Periods of response are prolonged by use of maintenance applications. Van Scott and Kalmanson described the successful use of nitrogen m u s t a r d solutions applied to the patient's whole body. 41 When the topical applications were supplemented with intralesional injections of nitrogen mustard, 50% of patients achieved clinical remissions. Approximately one third remained diseasefree for several years, during which time topical therapy was continued. Patients with limited-stage skin disease fared best, but none of the patients with disease involving lymph nodes or viscera achieved complete remission. Patients manifested hypersensitivity reactions to the topically applied nitrogen mustard but could be desensitized by daily intravenous injections of small amounts of the drug. In fact, patients who had hypersensitivity reactions were more likely to achieve remission.

Steroids Steroids administered orally and in intralesion injections result in some improvement; however, the side effects are serious. While investigating whether the topical application of a fluorinated steroid preparation could reduce the skin reaction to radiation, Faber et al. discovered that the preparation itself caused involution of plaques and eczematous lesionsY Such t r e a t m e n t does not cause serious side effects, is noninvasive, and does not require hospitalization, although little effect is demonstrated on tumor-stage disease. Clinical improvement is associated with histologic improvement and appears to vary with the concentration of the steroid preparation used. The clinical effect is noted for as long as nine months when therapy is continuous. The topical application of steroids is a useful palliative procedure.

Other Chemotherapeutic Agents Other antineoplastic agents have been applied to MF lesions, but none as extensively or as successfully as nitrogen mustard. 3o

Topical nitrosourea compounds have produced useful responses in a high percentage of patients with limited skin disease, lasting from one month to three years. 43 Although complete remission rates with these drugs are substantially lower than those achieved with nitrogen mustard, patients highly allergic to nitrogen mustard may be treated successfully without evidence of cross-sensitivity. Side effects included temporary bone marrow suppression and hypersensitivity reactions. An ongoing doubleblind, multi-drug, multi-institutional study of chemotherapeutic agents applied topically has demonstrated improvement in patients treated with cytosine arabinoside, dianhydrogalactitol, DTIC, guanazole, VM-26, hydroxyurea, thioTEPA, and methotrexate.

Intralesional Therapy Indurated plaque- and tumor-stage disease does not respond well to topical chemotherapy or steroids, although intralesional injection of these agents has been of some benefit, especially as a means of palliation or as a supplement to topical treatment. 44 Injections are accompanied by increased patient discomfort and by the expected systemic side effects of the agent injected.

Phototherapy For many years, psoriasis patients have benefited from sunlight or a new form of therapy in which the affected areas are irradiated with ultraviolet light after the patient has been photosensitized by orally administered methoxsalen. This therapy is known as PUVA (psoralen with ultraviolet light in the A spectrum). Conventional ultraviolet light in the sunburn spectrum (UVB) does not affect MF because only a fraction of the light penetrates to the dermis. However, up to 60% of ultraviolet longrange light (UV-A) reaches the dermis, the site of the greatest population of tumor cells in MF or SS. Methoxsalen is a photosensitizing furocumarin with an action spectrum similar to that of UV-A light. Methoxsalen plus UV-A forms photoadducts with thymine that inhibit DNA synthesis in mammalian cells. Gilchrest et al. have successfully used PUVA to treat the cutaneous manifestations of MF in nine patients for 16 to 24 months. 45 One patient showed complete clearing of generalized plaques, except in a shielded control area that worsened during this period. Patients with less advanced plaque disease responded more favorably but in patients with both plaques and tumors, the tumors were not affected. The .long-term side effects of PUVA therapy are not known. Skin cancers have developed in man and laboratory animals. Further study is needed to determine the ultimate position of PUVA in the treatment plan for MF. 31

Systemic Chemotherapy Systemic chemotherapy has historically been reserved for patients with visceral dissemination or those for whom topical treatments have been exhausted. Rates of response to a variety of single-agent chemotherapeutic regimens have been catalogued by Epstein 3v and by Levi and Wiernick. 44 Mycosis fungoides responds favorably to a wide range of agents with differing mechanisms of action, given in a variety of drug schedules. Most studies regarding the effectiveness of chemotherapeutic agents in patients with MF and SS have been conducted under variable conditions involving uncontrolled, small, populations of patients. The drugs most frequently used have been alkylating agents, especially nitrogen mustard. Antimetabolites, vinca alkaloids, cytotoxic antibodies, and other miscellaneous agents have been used with variable success. Responses are typically of short duration, although occasional periods of extended disease-free remission have been achieved. Patients with less extensive disease achieve complete remission more often than those with advanced disease. Because of its topical efficacy, nitrogen mustard was one of the first agents to be used systemically in patients with advanced-stage disease. In one study low doses of nitrogen mustard given intravenously in TABLE 6.--RATES OF RESPONSE OF PATIENTS WITH MYCOSIS FUNGOIDES TO SINGLE CHEMOTHERAPEUTIC AGENTS

Alkylating Agents Nitrogen Mustard Cyclophosphamide Chlorambucil BCNU

Triethylenemelamine Antimetabolities Azaribine Methotrexate Cytotoxic Antibiotics Doxorubicin Bleomycin Actinomycin D Miscellaneous Vinblastine Vincristine Steroids VP16-213

NO. OF PATIENTS RESPONDING/ NO. OF PATIENTS TREATED

RESPONSE RATE

62/86 50/76 40/69 7/14 4/13

72% 66% 58% 50% 31%

12/13 35/57

92 % 61%

12/15 21/32 6/13

80% 66% 46%

7/14 3/13 24/46 7/11

50% 23% 52 % 64%

Adapted from Levi, J. A., and Wiernik, P. H.: Medicine 54:73, 1975. 32

late-stage disease were shown to produce objective responses in 78% of patients26 The information summarized in Table 6 demonstrates that single-agent therapy has been temporarily effective in small numbers of patients with advanced disease. Responses have been promising with doxorubicin and nitrogen mustard, but complete responses are infrequent, and neither of these agents can be recommended as being more effective than others. Without additional controlled studies, recommendations concerning chemotherapy of this disease will continue to be, at best, anecdotal.

Immunologic Treatment DELAYED-TYPE HYPERSENSITIVITY REACTIONS.--Ratner et al. have investigated the relationships between delayed-type hypersensitivity (DTH) reactions and the course of the skin disease in MF. 47 They observed a frequent history of allergic contact dermatitis, spontaneous periods of remission or arrest of early-stage disease, and occasional complete disappearance of lesions following an associated drug rash. Tests of delayed hypersensitivity in these patients were usually normal. To test whether the course of the skin disease could be altered by immunologic reactions directly affecting the skin, allergic contact reactions were imposed on skin involved with MF. The skin was sensitized with DNCB or other chemicals and rechallenged. The resultant skin reactions were associated with complete or partial clearing lasting several months in 22 of 31 plaques treated. Patients who develop contact sensitization to nitrogen mustard and are topically desensitized respond better to DTH treatment than patients who have not been sensitized. These findings, however, m a y only indicate that those who have DTH reactions have a better chance of survival because DTH reactivity is usually associated with early stage disease. Patients who do not demonstrate this reactivity have advanced disease and a poorer prognosis. ANTITHYMOCYTE GLOBULIN.--Discovery that the S~zary cell is a T-lymphocyte led to several administrations of antithymocyte globulin in the t r e a t m e n t of MF or SS. 4s-~1The total number of patients treated has been small (nine) and the disease usually far advanced and refractory to conventional modes of therapy; the responses were varied and brief. No conclusions regarding efficacy can be drawn as yet. T R A N S F E R FACTOR AND BACILLUS CALMETTE-GUERIN (BCG) IM-

MUNOTHERAPY.--Transfer factor used in association with radiation therapy in one patient brought about a remission. 52 Klein et al. suggested that BCG immunotherapy is useful to MF pa33

tients. ~3 Five patients who were sensitized to BCG were subsequently given topical intralesional purified protein derivative (PPD). In all five patients the skin lesions cleared. Responses lasted more than two years in three patients. One, who could not be sensitized, had no response to this form of therapy. To date, however, there exists little enthusiasm for either of these therapies. MULTIMODALITYTHERAPY.--The efficacy of combination electron beam radiotherapy and adjuvant topical nitrogen mustard has been investigated. 54 The patient population included those with limited-stage skin disease, who respond well to either of these modalities alone. Also included were patients with tumorstage disease and those with lymphadenopathy. Patients treated with electrons and adjuvant topical nitrogen mustard had a median disease-free survival of 25 months, compared with 17 months for the group treated with electrons alone. Multimodality therapy with electrons and combination chemotherapy is currently undergoing evaluation at The University of Chicago. 55 A small group of MF patients with advanced disease were treated with whole-body electron beam at tissue doses between 3,000 and 4,000 rad, followed by cyclic combination chemotherapy with MOPP (mustard, Oncovin, procarbazine, prednisone), or COPP (cyclophosphamide, Oncovin, procarbazine, prednisone). The actuarial survival at one year was 100% for the combination group vs. 83% for those treated with electrons alone. These encouraging initial results await further substantiation in larger trials.

Treatment of S~zary Syndrome SINGLE-AGENT CHEMOTHERAPY.--~GentIe" chemotherapy with chlorambucil and prednisone has been advocated by Winkleman for patients with SS. He and his colleagues maintained that SS usually retains its ~'benign" nature. In their study, only 4 of 28 S~zary syndrome patients progressed to frank lymphoma. Chlorambucil and prednisone have been used to induce complete remission in SS patients, whereas the mortality rate was extremely high with the use of standard aggressive combination chemotherapy programs. 5~Data from other centers have not confirmed these findings. Progression from classic S~zary syndrome to frank visceral involvement and death within five years has been commonplace. Specific recommendations concerning chemotherapy is difficult to make in the absence of controlled studies. COMBINATION CHEMOTHERAPY.--Trials of combination chemotherapy with MOPP and COMLA (Cytoxan, Oncovin, methotrexate, leucovorin rescue, and cytarabine), among others, have shown promising preliminary results in small, uncontrolled se34

T A B L E 7.--RESPONSE RATES IN PATIENTS WITH MYCOSIS FUNGOIDES TREATED WITH COMBINATION CHEMOTHERAPY*

DRUG COMBINATION

OBJECTIVE RESPONSES/ NO. OF PATIENTS TREATED

MOPP Chlorambucil + Prednisone COP COMLA M e t h o t r e x a t e a n d Bleomycin CHOP/HOP-COP/OAP COP + Bleomycin

3/4 7/13 3/4 1/1 9/10 12/12 11/12

RESPONSE RATE 75% 54% 75% 100% 90% 100% 92%

*See text for abbreviations.

ries (Table 7). Whether these treatment regimens have produced more durable responses or have significantly influenced survival awaits the results of larger ongoing prospective studies. As pointed out by Lutzner et al., MF and SS may not yield to aggressive chemotherapy, especially if the cell kinetics in these disorders proves to be similar to that in chronic lymphocytic leukemia, with a low growth fraction and slow cell removal. ~ LEUKOPHERESIS.--Leukopheresis for SS was introduced by Edelson et al., who attempted to decrease peripheral blood SC counts and to clear dermal infiltrates. ~7 Twelve leukophereses were performed in a patient who had the small-cell variant of SS that is often refractory to chemotherapy. After pheresis, the peripheral blood leukocyte count was progressively lowered from initial counts of 200,000/cu mm to 21,000/cu mm: a total of 36 x 1011 leukocytes were removed. The skin lesions cleared, and skin biopsy studies showed a marked reduction in S6zary cells. Further studies regarding the use of leukopheresis are needed. CONCLUSIONS AND RECOMMENDATIONS CONCERNING THERAPY

Mycosis fungoides responds to many types of treatment. The less extensive the disease, the more complete and more prolonged the response. Disease limited to plaque-stage skin involvement m a y be brought into clinical remission for years and may even be cured by whole body electron beam therapy or maintained topical chemotherapy. Recent developments in the treatment of limited-stage skin disease, such as the use of PUVA, m a y give similar results with less toxicity but have not yet been sufficiently tested. Effective regimens that prolong survival in patients with tumor-stage skin disease and in patients with visceral involvement are needed. We hope that through the efforts of the multi35

institutional Mycosis Fungoides Cooperative Study, the forms of t r e a t m e n t discussed above will be adequately evaluated. Referral of patients to centers participating in this study would facilitate this evaluation. SURVIVAL The length of survival of mycosis fungoides patients is variable and depends more on the time of diagnostic biopsy t h a n on the time of onset of the rash. From the date of which MF is confirmed by biopsy, the median survival is 4 to 5 years. 3~ Signs of visceral involvement appear within a median time of 2.6 years. The greater the extent of skin disease, as measured by the presence of tumors, ulcerated lesions, and lymphadenopathy, the more likely visceral involvement and the poorer the prognosis. The median survival is 18 months for patients with lymphadenopathy, and 3 to 6 months for those with visceromegaly. Patients who are more t h a n 50 years old or who have lymphocytopenia also have a poorer prognosis. The length of survival of patients with S~zary syndrome is less variable. The median survival was 5 years, with a range of 1 to 11 years. CAUSE OF DEATH The greatest t h r e a t to survival in MF/SS patients is infection. Undoubtedly, the breakdown of the skin defense barrier, especially during the ulcerated tumor phase, allows easy entry to bacteria, most commonly Staphylococcus aureus and Pseudomonas aeruginosa. Resultant septicemia and bronchopneumonia are common causes of death. At postmortem examination essentially all patients with MF are found to have skin infection. Patients with MF are increasingly susceptible to infection when the disease progresses, as normal circulating lymphocytes are replaced by neoplastic cells with decreased response mechanisms, monocyte chemotaxis is lost, and delayed hypersensitivity falters. At autopsy the viscera are involved by MF in more t h a n 70% of patients. Visceral involvement leads to death due to generalized debility and cachexia and specific organ failure. ACKNOWLEDGMENT The authors wish to t h a n k Pamela Jones for her secretarial aid. REFERENCES 1. Dick, H.M., MacKie, R.: Distribution of HLA antigens in patients with mycosis fungoides. Dermatologica 155:275, 1977. 2. Gisser, S.D., Young, I.: Mycosisfungoides-likecells. Their presence in a case 36

3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26.

of pityriasic dermitis with a comment on their significance as an indicator of primary T-cell dyscrasia. A m . J. Surg. Pathol. 2:97, 1978. Bluefarb, S.M.: Is mycosis fungoides an entity? Arch. Dermatol. 71:293, 1955. Symmers, D.: Mycosis fungoides as a clinical and pathologic nonexistent. Arch. Dermatol. Syph. 25:1, 1932. Clendenning, W.E., Brecher, G., Van Scott, E.J.: Mycosis fungoides. Natl. Cancer Inst. Monogr. 10:275, 1963. Lutzner, M.A., Edelson, R., Schein, P., et al.: Cutaneous T-cell lymphomas. The S~zary syndrome, mycosis fungoides, and related disorders. Ann. Intern. Med. 83:534, 1975. Block, J.B., et al.: Mycosis fungoides. Natural history and aspects of its relationship to other malignant lymphomas. A m . J. Med. 34:228, 1963. Blaylock, W.K., Clendenning, W.E., Carbone, P.P., et al.: Normal immunologic reactivity in patients with the lymphoma mycosis. Cancer 19:233, 1966. Clendenning, W.E., Van Scott, E.J.: Skin autografts and homografts in patients with the lymphoma mycosis fungoides. Cancer Res. 25:1844, 1965. Tan R.S.H., et al.: Mycosis fungoides-A disease of antigen persistence. Br. J. Dermatol. 91:607, 1974. Seitz, L.E., Golitz, L.E., Weston, W.L., et al.: Defective monocyte chemotaxis in mycosis fungoides. Arch. Dermatol. 113:1055, 1977. Cooperrider, P.A., Roenigk, H.H.: Selective immunological evaluation of mycosis fungoides. Arch. Dermatol. 114:63, 1978. Rappaport, H., Thomas, L.B.: Mycosis fungoides. The pathology of extracutaneous involvement. Cancer 34:1198, 1974. Waldron, J.A., et al.: Malignant lymphoma of peripheral T-lymphocyte origin. Cancer 40:1604, 1977. Taswell, H.F., Winkleman, R.K.: S~zary Syndrome--A malignant reticulemic erythroderma. J.A.M.A. 177:465, 1961. Lutzner, M.A., Emerit, I., Durepaire, R., et al.: Cytogenetic, cytophotometric, and ultrastructural study of large cerebriform cells of the S~zary syndrome and description of a small cell variant. J. Natl. Cancer. Instit. 50:1145, 1973. Zucker-Franklin, D.: Ultrastructural, immunologic, and functional studies on S~zary cells. A neoplastic variant of thymus-derived (T) lymphocytes. Proc. Natl. Acad. Sci. U.S.A. 71:1877, 1974. Crossen, P.E., et al.: The S~zary syndrome. Cytogenetic studies and identification of the S~zary cell as an abnormal lymphocyte. A m . J. Med. 50:24, 1971. Edelson, R.L., Kirkpatrick, C.H., Shevack, E.M., et al.: Preferential cutaneous infiltration by neoplastic thymus-derived lymphocytes. Morphologic and functional studies. Ann. Intern. Med. 80:685, 1974. Zucker-Franklin, D.: Thymus-dependent lymphocytes in lymphoproliferative disorders of the skin (S6zary syndrome and mycosis fungoides). J. Invest. Dermatol. 67:412, 1976. Broder, S., Edelson, R.L., Lutzner, M., et al.: The S~zary syndrome. A malignant proliferation of helper T-cells. J. Clin. Invest. 58:1297, 1976. Hopper, J.E., Haren, J.M.: Studies on a S~zary lymphocyte population with T-suppressor activity. Clin. Immunol. Immunopathol. 17:43, 1980. Kurmani-Arab. V.: Lack of functional immunoregulatory cells in a patient with mycosis fungoides and circulating S~zary cells. Brief communication. Natl. Cancer Inst. Monogr. 60:1295, 1978. Flaxman, R.A., Zelazny, G., Van Scott, E.J.: Nonspecificity of characteristic cells in mycosis fungoides. Arch. Dermatol. 104:141, 1971. Gisser, S.D., Young, I.: Mycosis fungoides-like cells. Their significance as an indicator or primary T-cell dyscrasia. A m . J. Surg. Pathol. 58:97, 1978. Fukuhara, S., et al.: Banding studies of chromosomes in patients with mycosis fungoides. Cancer 42:2262~ 1978. 37

27. Van Vloten, W.A., Van Duijn, A., Schaberg, A.: Cytodiagnostic use of feulgen-DNA measurements in cell imprints from the skin of patients with mycosis fungoides. Br. J. Dermatol. 91:365, 1974. 28. Erkman-Balis, B., Rappaport, H.: Cytogenetic studies in mycosis fungoides. Cancer 34:626, 1974. 29. Whang-Peng, J., Lutzner, M., Edelson, R., et al.: Cytogenetic studies and clinical implications in patients with S~zary Syndrome. Cancer 38:861, 1976. 30. Yeckley, J.A., Weston, W.L., Thorne, E.G., et al.: Production of S~zary-like cells from normal human lymphocytes. Arch. Dermatol. 111:29, 1975. 31. Braylan, R., Variakojis, D., Yachnin, S.: The S6zary syndrome lymphoid cell: Abnormal surface properties and mitogen responsiveness. Br. J. Haematol. 31:553, 1975. 32. Edelson, R.L., Lutzner, M., Kirkpatrick, C.H., et al.: Morphologic and functional properties of the atypical T-lymphocytes of the S~zary syndrome. Mayo Clin. Proc. 49:558, 1974. 33. Constantine, V.S.: Current concepts in mycosis fungoides. Its nosology, diagnosis and treatment. Int. J. Dermatol. 15:723, 1976. 34. Winkleman, R.K.: Clinical studies of T-cell erythroderma in the S~zary syndrome. Mayo Clin. Proc. 49:519, 1974. 35. Szur, L., Silvester, J.A.: Treatment of whole body surface with electrons. Lancet 1:1373, 1962. 36. Variakojis, D., Rosas-Uribe, A., Rappaport, H.: Mycosis fungoides. Pathologic findings in staging laparotomies. Cancer 33:1589, 1974. 37. Epstein, E.H., et al.: Mycosis fungoides. Survival, prognostic features, response to therapy, and autopsy findings. Medicine 15:61, 1972. 38. Trump, J.G., Wright, K.A., Evans, W.W., et al.: High energy electrons for the treatment of extensive superficial malignant lesions. A m . J. Roentgenol. Rad. Ther. Nucl. Med. 69:623, 1953. 39. Price, N.M.: Radiation dermatitis following electron beam therapy. An evaluation of patients ten years after total skin irradiation for mycosis fungoides. Arch. Dermatol. 114:63, 1978. 40. Fuks, Z.Y., Batshaw, M.A., Farber, E.M.: Prognostic signs and the management of the mycosis fungoides. Cancer 32:1385, 1973. 41. Van Scott, E.J., Kalmanson, J.D.: Complete remissions of mycosis fungoides induced by topical nitrogen mustard (HN~). Control of delayed hypersensitivity to HN 2 by desensitization and by induction of specific immunologic tolerance. Cancer 32:18, 1973. 42. Farber, E.M., Cox, A.J., Steinberg, J., et al.: Therapy of mycosis fungoides with topically applied flucinolone acetonide under occlusive dressing. Cancer 19:237, 1966. 43. Zackheim, H.S., Epstein, E.H.: Treatment of mycosis fungoides with topical nitrosourea compounds. Further studies. Arch. Dermatol. 111:1554, 1975. 44. Levi, J.A., Wiernik, P.H.: Management of mycosis fungoides--Current status and future prospects. Medicine 54:73, 1975. 45. Gilchrest, B.A., Parrish, J.A., Tannenbaum, L., et al.: Oral methoxsalen photochemotherapy of mycosis fungoides. Cancer 38:683, 1976. 46. Van Scott, E.J., Grekin, D.A., Kalmanson, J.D., et al.: Frequent low doses of intravenous mechlorethamine for late stage mycosis fungoides lymphoma. Cancer 36:1613, 1975. 47. Ratner, A.C., et al.: Alterations of lesions of mycosis fungoides lymphoma by direct imposition of delayed hypersensitivit:~ reactions. Cancer 21:83, 1968. 48. Barrett, A.J., et al.: Antilymphocyte gl Jbulin in the treatment of advanced S6zary syndrome. Lancet 1:940, 1976. 49. Fisher, R.I., et al.: Regression of a T-cell lymphoma after administration of antithymocyte globulin. Ann. Intern. Med. 88:799, 1978. 50. Gould, D.J., et al.: Failure of anti-thymocyte globulin treatment in T-cell lymphoma. Lancet December 24 1:1365, 1977. 38

51. Edelson, R.L., et al.: Anti-thymocyte globulin in treatment of T-cell lymphoma. Lancet July 30:249, 1977. 52. Zachariae, H., et al.: Transfer factor as therapeutic agent in MF. Arch. Dermatol. 112:1324, 1976. 53. Klein, E., Hollerman, O.A., Papermaster, B., et al.: Immunologic approaches to various types of cancer with the use of BCG and purified protein derivatives. Natl. Cancer Inst. Monogr. 39:229, 1973. 54. Price, N.M., et al.: The treatment of mycosis fungoides. Adjuvant topical mechlorethamine after electron beam therapy. Cancer 40:2851, 1977. 55. Griem, M.L.: Combined therapy in patients treated for mycosis fungoides. Unpublished data. 56. Winkleman, R.K., Linman, J.W.: Erythroderma with atypical lymphocytes (S~zary syndrome). Am. J. Med. 55:192, 1973. 57. Edelson, R., et al.: Successful management of the S~zary syndrome. Mobilization and removal of extravascular neoplastic T cells by leukapheresis. N. Engl. J. Med. 291:293, 1974.

39