Mycosis Fungoides
The term primary cutaneous lymphoma refers to a lymphoma initially diagnosed by skin biopsy in patients without evidence of extracutaneous disease. In the recent World Health Organization (WHO)/European Organization for Research and Treatment of Cancer (EORTC) classification for primary cutaneous lymphomas (1), a number of separate types of lymphoma are listed, most of which can be localized to the skin as shown in Table 72.1. The list also includes two systemic diseases that characteristically involve the skin: adult T-cell leukemia/lymphoma (Chapter 71) and CD4+/CD56+ hematodermic neoplasm (Chapter 59).
Cutaneous T-cell lymphoma is a term that was coined by Edelson (2) to include mycosis fungoides (MF), Sézary syndrome (SS), and other variants; this term is still used as a synonym for MF in the literature by some investigators. From the pathologic point of view, however, this term lacks precision because it is now known that many other types of T-cell lymphoma arise in skin (1). Despite this imprecision, MF is still overwhelmingly the most common type of cutaneous T-cell lymphoma, probably explaining the continued use of this term. In a database of 1,905 cutaneous lymphomas from the Netherlands and Austria collected between 1986 and 2002, MF and its variants represented 48%, and SS an additional 3%, of all cases (1). Mycosis fungoides also has been known for the longest period of time, initially described by Alibert in 1806.
In this chapter, we focus only on MF and its variants recognized in the WHO-EORTC classification. We also discuss SS, because this disease is thought to be closely related to MF, and SS was lumped together with MF in the WHO classification published in 2001 (3).
Definition
Mycosis fungoides is a distinctive type of cutaneous T-cell lymphoma composed of small- to medium-sized T cells with highly convoluted (cerebriform) nuclear contours. In most cases, the neoplastic cells display a tropism for infiltrating the epidermis (epidermotropism) (1). In the WHO-EORTC classification, it is recommended that the term MF be reserved for the classical type of disease characterized by cutaneous patches, plaques, and tumors (1).
Sézary syndrome was originally defined as a triad of erythroderma, generalized lymphadenopathy, and the presence of neoplastic Sézary cells in the blood, skin, or lymph nodes. Sézary cells were initially recognized based on morphologic criteria as large, highly convoluted lymphocytes. The definition of SS has evolved. The International Society for Cutaneous Lymphomas (ISCL) currently defines SS as a distinctive erythrodermic cutaneous T-cell lymphoma with hematologic evidence of leukemic involvement (4). Determination of leukemic involvement can be performed by either morphologic examination, flow cytometry immunophenotyping, cytogenetic analysis, or molecular studies. Of these approaches, flow cytometry immunophenotyping and the cytogenetic demonstration of a clone are the most reliable means of showing blood involvement by SS, whereas demonstration of a clone by molecular analysis, particularly if shown by polymerase chain reaction (PCR)-based methods, often requires additional support. Morphologic examination of peripheral blood smears is insensitive, particularly in patients with low numbers of SS cells. In our opinion, flow cytometry immunophenotyping is the most convenient method for demonstrating blood involvement and is an excellent means of quantifying the neoplastic T-cell population.
In some studies, a distinction between primary and secondary SS has been made (4,5). Primary SS arises in patients without a history of coexistent MF and affected patients usually have a short prodromal phase. Secondary SS occurs in patients who have MF, and usually in patients with a long history of cutaneous disease.
Variants
The WHO-EORTC classification specifically recognizes three variants of MF because they have different clinical features and/or prognosis: folliculotropic MF, pagetoid reticulosis, and granulomatous slack skin disease.
Cases of classical MF also occur that have unusual clinical or histologic manifestations. As these unusual features have no impact on prognosis, they are not recognized as variants in the WHO-EORTC classification (1). Nevertheless, these cases have been considered as MF variants in the literature by some investigators, and up to 15 or so of these variants are described in the literature (6,7). The more common clinical or distinctive of these clinical variants are (6,7,8,9,10,11,12) hypopigmented MF, papular MF, bullous MF, hyperkeratotic/verrucous MF, syringotropic MF, granulomatous MF, poikiloderma atrophicans vasculare, and acral or acral/oral MF.
Synonyms
Cutaneous T-cell lymphoma (for MF and SS); Alibert-Bazin type of MF (classical MF); Tumor d’emblee (de novo tumor form of classical MF).
Synonyms for Folliculotropic Mycosis Fungoides
Follicular mucinosis (a general term that includes MF and other diseases); pilotropic MF; adnexotropic MF; folliculocentric MF.
Synonym for Pagetoid Reticulosis
Woringer-Kolopp disease.
Epidemiology And Pathogenesis
Mycosis fungoides is an uncommon lymphoid neoplasm. In the Surveillance, Epidemiology, and End Results (SEER) database from 1992–2001, the combination of MF and SS represented 1,773 of 114,548 (1.5%) lymphoid neoplasms (13). The
age-adjusted incidence rate was 0.52 per 100,000 person-years. In another study based on SEER data of 4,783 cases of cutaneous T-cell lymphoma collected from 1973–2002, Criscione and Weinstock (14) found that the age-adjusted incidence rate of cutaneous T-cell lymphoma was 6.4 per million person-years. Based on the time interval of this study, it seems likely that recently recognized types of T-cell lymphoma that arise in skin were incorrectly included under the rubric of cutaneous T-cell lymphoma. Nevertheless, since MF/SS represents most cases of cutaneous T-cell lymphoma, the data for the most part can be used for MF. In both studies, African-Americans had the highest incidence of MF, followed by Caucasians and then Asian-Americans (13,14). However, SS was more frequent in Caucasians than African-Americans (14). Men are affected more often than women, with the male-to-female ratio higher in Caucasian and Asian-Americans than in African-Americans (13,14). The male-to female ratio in Caucasians approached 2:1 (13). Criscione and Weinstock also reported that the incidence of MF increased for each 5-year interval, being 2.8 per million person-years in 1973–1977 up to 9.6 per million person-years in 1998–2002 (14). Increased MF incidence correlated with age and geographic variation. The incidence of MF increases with each decade of life, with the highest incidence—22.9 per million person-years—in patients over 80 years of age (14). Regarding geographic variation, areas with high physician density, high family income and home values, and a high frequency of residents with a college or postgraduate degree have a higher incidence of MF (14).
age-adjusted incidence rate was 0.52 per 100,000 person-years. In another study based on SEER data of 4,783 cases of cutaneous T-cell lymphoma collected from 1973–2002, Criscione and Weinstock (14) found that the age-adjusted incidence rate of cutaneous T-cell lymphoma was 6.4 per million person-years. Based on the time interval of this study, it seems likely that recently recognized types of T-cell lymphoma that arise in skin were incorrectly included under the rubric of cutaneous T-cell lymphoma. Nevertheless, since MF/SS represents most cases of cutaneous T-cell lymphoma, the data for the most part can be used for MF. In both studies, African-Americans had the highest incidence of MF, followed by Caucasians and then Asian-Americans (13,14). However, SS was more frequent in Caucasians than African-Americans (14). Men are affected more often than women, with the male-to-female ratio higher in Caucasian and Asian-Americans than in African-Americans (13,14). The male-to female ratio in Caucasians approached 2:1 (13). Criscione and Weinstock also reported that the incidence of MF increased for each 5-year interval, being 2.8 per million person-years in 1973–1977 up to 9.6 per million person-years in 1998–2002 (14). Increased MF incidence correlated with age and geographic variation. The incidence of MF increases with each decade of life, with the highest incidence—22.9 per million person-years—in patients over 80 years of age (14). Regarding geographic variation, areas with high physician density, high family income and home values, and a high frequency of residents with a college or postgraduate degree have a higher incidence of MF (14).
TABLE 72.1. WHO-EORTC CLASSIFICATION OF PRIMARY CUTANEOUS LYMPHOMAS (1) | |||
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The pathogenesis of MF and SS are unknown. An inherited predisposition to MF seems likely. Certain histocompatibility locus antigens have been associated with MF, and MF can run in families. One study from Israel reported six Jewish families with familial MF and linked the disease with the human leukocyte antigen (HLA) class II alleles DRB1* 11 and DQB1* 03 (15). Other HLA alleles have been linked to MF as well, and MF has been reported in identical twins (16). In earlier studies, occupational exposure to chemicals was suggested as a risk factor. However, this has not been supported in case-controlled studies (17). Viruses have been implicated in MF, but the data for this are either controversial or unconfirmed. A defective (deleted) form of human T-cell lymphotropic virus (HTLV-1) provirus was detected in tissue biopsy or the peripheral blood specimens of patients with MF previously (18). However, other studies have presented persuasive data that the finding of defective HTLV-1, which is not consistently detected in MF lesions, is unlikely to be involved in pathogenesis (19). At the M. D. Anderson Cancer Center, seropositivity for cytomegalovirus infection was found to be associated with MF; the significance of this finding is yet to be determined, and it could be an epiphenomenon, perhaps related to compromised immune status (20).
Molecular studies have shown that a large percentage of MF lesions in patch stage, 80% to 90%, and almost all plaque- and tumor-stage MF lesions carry monoclonal T-cell receptor (TCR) gene rearrangements (21,22). The inconsistent presence of a monoclonal T-cell population in patch stage disease has led to two hypotheses: (a) MF is neoplastic at onset but techniques to detect the clonal T-cell population are insufficiently sensitive in early stage disease; or (b) persistent chronic antigenic stimulation induces a reactive T-cell infiltrate from which MF then evolves (23). In the second scenario, the nature of the antigen(s) involved is unknown. Drug therapy is known to induce MF-like skin lesions (also referred to as pseudo-MF) that usually resolve once the drug is discontinued. Antiepileptic agents (e.g., carbamazepine and phenytoin) are the most common offending drugs although other classes of drugs are also reported (24). This raises the possibility that these drugs may interact with cutaneous antigens to elicit a host immune response in the skin. Some evidence suggests that autoimmunity may be involved. Jones and colleagues (25) have reported in abstract form that patients with MF carry antibodies that can react with keratin 13. Other causes, such as an unknown infectious agent, cannot be excluded.
A number of studies have shown that helper T-cell type 2 (Th2)–specific genes and cytokines are upregulated in MF and
SS cells (26,27,28). A few of the better known Th2-associated cytokines include interleukin (IL)-4, IL-5, and IL-10 among others. Correspondingly, Th1–specific genes and cytokines are downregulated in MF (e.g., IL-2, interferon γ, and T-bet). The secretion of Th2 molecules by the neoplastic T-cells in MF most likely creates a milieu that plays a role in causing many of the clinical and histologic manifestations of MF, including hypereosinophilia, immunological abnormalities, and immunosuppression. Other cytokines found to play a role in MF pathogenesis include IL-15, IL-17 and IL-23 (29,30,31). Many kinds of chemokines are also expressed in MF and SS (32). Thus, the disease manifestations of MF depend both on the effects of neoplastic cell infiltration and the effects induced by neoplastic cell secretion. In early stage disease, effects induced by the secretion of various molecules typically outweigh direct effects as a result of the infiltration by neoplastic cells.
SS cells (26,27,28). A few of the better known Th2-associated cytokines include interleukin (IL)-4, IL-5, and IL-10 among others. Correspondingly, Th1–specific genes and cytokines are downregulated in MF (e.g., IL-2, interferon γ, and T-bet). The secretion of Th2 molecules by the neoplastic T-cells in MF most likely creates a milieu that plays a role in causing many of the clinical and histologic manifestations of MF, including hypereosinophilia, immunological abnormalities, and immunosuppression. Other cytokines found to play a role in MF pathogenesis include IL-15, IL-17 and IL-23 (29,30,31). Many kinds of chemokines are also expressed in MF and SS (32). Thus, the disease manifestations of MF depend both on the effects of neoplastic cell infiltration and the effects induced by neoplastic cell secretion. In early stage disease, effects induced by the secretion of various molecules typically outweigh direct effects as a result of the infiltration by neoplastic cells.
Our current molecular understanding of cellular pathways involved in MF and SS is very preliminary. A number of DNA transcription factors are activated in MF and SS. These include the nuclear factor (NF)-κB pathway, the STAT gene family (especially STAT5), myc, junD and others. Activation is most common in large plaques and tumors compared with patches and thin plaques. This topic has been reviewed by Dummer and colleagues (33). Due to its rarity, much less information regarding the pathogenesis of SS is currently available.
Clinical Findings
Classical Mycosis Fungoides
The incidence of MF increases with age (14). Most affected patients first develop skin lesions as adults, between the ages of 40 and 60 years. A long interval often passes between onset of skin symptoms and the first diagnosis of MF (34,35). For long periods, MF is restricted to the skin. However, the disease can progress, and late-stage disease is characterized by fever, weight loss, peripheral blood eosinophilia and atypical lymphocytosis, lymphadenopathy (often generalized), hepatosplenomegaly, and involvement of other viscera (34,35,36). Survival correlates with extent of involvement by MF, and this prognostic information is captured in the currently used staging system (discussed later).
Mycosis fungoides involving the skin can be divided into three stages: patches, plaques, and tumors (34,35,36). These lesions often involve sun-protected areas and are usually asymmetric, irregular, red to violaceous, and well demarcated. The most commonly involved skin sites include the axillae, breasts (in women), lower trunk, hips, buttocks, and groin (34,35,36). As was originally recognized by Bazin in the nineteenth century, lesions can begin as patches and then thicken into plaques and then tumors. However, all three types of lesions also can occur simultaneously, and plaques and tumors can arise de novo. It is important to remember, however, that de novo MF tumors (d’emblee) are uncommon; many cases reported in the older literature may be, in fact, examples of more recently recognized types of cutaneous T-cell lymphoma. Plaques and especially tumors can ulcerate, leading to local infection and septicemia (37).
Lymphadenopathy is often the first extracutaneous site of disease, and its presence in MF usually correlates with extensive skin disease (34,35,36). Most often, lymphadenopathy is regional and includes draining sites of extensive skin involvement. Generalized lymphadenopathy is often associated with visceral involvement. The most common sites of visceral involvement are the lungs, liver, spleen, and gastrointestinal tract. However, virtually any anatomic site can be involved by MF at time of autopsy (38,39). When detected at visceral sites, MF typically forms grossly recognizable tumors.
Stage is the most important prognostic information for patients with MF. The ISCL and EORTC groups have worked together to revise the classification and staging of MF and SS (40). As shown in Table 72.2, the tumor (T), lymph node (N), and metastasis (M) system has been modified for MF/SS patients. Skin disease is classified into: T1, limited disease involving less than 10% of the skin surface; T2, skin disease involving greater than 10% of the skin surface; T3, one or more tumors of at least 1.0 cm or greater in diameter; and T4, erythroderma covering at least 80% of the skin surface. Lymph node involvement ranges from N0 to N3, with N0 representing absence of clinically abnormal lymph nodes and N3 representing clinically abnormal lymph nodes that are histologically involved by MF. The N1 and N2 stages designate the presence of clinically abnormal lymph nodes that are histologically equivocal or suspicious, respectively. Visceral involvement is judged as absent (M0) or present (M1). The system also includes assessment of the peripheral blood as: B0, absence of significant blood involvement (≤5% atypical lymphocytes or Sézary cells); B1, low tumor burden in blood (>5% atypical lymphocytes); and B2, high tumor burden (defined most often as ≥1 × 109/L atypical lymphocytes with appropriate immunophenotypic or molecular support). Based on these various T, N, M, and B designations, disease burden can then be assigned a stage as shown in Table 72.3.
Survival in patients with MF correlates with stage. In patients with stage IA disease, skin involvement limited to <10% of the skin surface, 10-year disease specific survival is almost 100% (essentially normal). The presence of more extensive skin disease (≥10%), often associated with clinically abnormal lymph nodes, reduces 10-year disease-specific survival to 83%. The presence of skin tumors further reduces 10-year disease-specific survival to 42%. In patients with histologically involved lymph nodes or visceral involvement, 10-year disease-specific survival is 20% or less, and MF clinically has an aggressive course (41,42). Addressing this issue in a different way, Kamarashev and colleagues (43) followed 42 patients with MF and assessed the length of time patients remained in various clinical stages. In their study, patients who initially presented in patch stage remained in that stage for a median of 7.2 years. By contrast, the median duration of the plaque and tumor stages was 2.3 and 1.8 years, respectively. Lymph node involvement and visceral disease persisted less than 1 year each. It is also important to remember that patients with MF also have an increased risk of second neoplasms, presumably due to acquired immunodeficiency; these neoplasms include non-Hodgkin lymphoma, classical Hodgkin lymphoma, melanoma, bladder cancer, and biliary cancer (44).
Choice of therapy in MF patients is greatly influenced by stage and prognosis. In patients with disease limited to skin, local therapies can be employed such as topical agents, photochemotherapy, or various forms of radiotherapy. In patients with lymph node or visceral involvement, multiagent chemotherapy is required (1).
Mycosis Fungoides Variants
Folliculotropic Mycosis Fungoides
This variant is characterized by preferential involvement of hair follicles with relative sparing of the overlying epidermis (45). Folliculotropic MF occurs mostly in adults and tends to involve the head and neck region. Skin lesions, which can be in the form of follicular papules, plaques, or tumors, are commonly associated with alopecia. Plaques involving the eyebrows and associated with alopecia are highly characteristic of folliculotropic MF. Pruritus is often severe, and secondary bacterial infections are common in patients with this variant. The 5-year disease-specific survival of patients with folliculotropic MF is
approximately 70% to 80%, worse than that of patients with classical MF (1,45). This variant, presumably because of its deeper location in the skin, is often less responsive to topical agents than classical MF.
approximately 70% to 80%, worse than that of patients with classical MF (1,45). This variant, presumably because of its deeper location in the skin, is often less responsive to topical agents than classical MF.
TABLE 72.2. ISCL/EORTC REVISION TO THE CLASSIFICATION OF MYCOSIS FUNGOIDES AND SÉZARY SYNDROME (40) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Pagetoid Reticulosis
This variant of MF is characterized by the presence of a single (or few) large or localized, erythematous, scaly or verrucous patch or plaque involving a distal extremity, most commonly the leg (46). This disease is very slowly progressive, and extracutaneous dissemination or disease-related deaths have not been reported (1,46). Local excision or radiation therapy directed to the lesion is usually curative.
TABLE 72.3. ISCL/EORTC REVISION TO THE STAGING OF MYCOSIS FUNGOIDES AND SÉZARY SYNDROME (40) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Granulomatous Slack Skin Disease
This extremely rare disease is characterized by pendulous, lax skin folds that arise in pre-existing plaques (47). These folds tend to occur in flexural areas, particularly the axillae and groin. Granulomatous slack skin disease is usually clinically indolent but an association with either classical Hodgkin lymphoma or classical MF is reported. Surgical excision is ineffective, and radiation therapy is often the initial therapeutic approach for these patients (1).
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