Chapter 66: Cutaneous T-Cell Lymphoma (Mycosis Fungoides and Sézary Syndrome)

• Mycosis fungoides (and its variant Sézary syndrome)are malignant proliferations of mature memory T lymphocytes of the phenotype CD4+CD45RO+ (memory T cells). They invariably involve the skin and are the principal forms of cutaneous T-cell lymphoma.

• Other types of lymphoma may also have prominent skin involvement (see Table 66–1).

• Cutaneous T-cell lymphoma are two-fold more common in males than females.

• Median age at diagnosis is 55 years.

• In the United States, there are approximately 1000 cases per year representing about 1.5 percent of lymphomas.

• Patients usually present with nonspecific skin lesions (chronic dermatitis) occurring years before diagnosis.

• Early in disease, patients are often diagnosed with eczema (spongiotic dermatitis), psoriatic-like dermatitis, or other nonspecific dermatoses associated with pruritus.

• Histologic diagnosis may be difficult in early stages. Neoplastic infiltrates may be minimal, masked by normal inflammatory cells, and the neoplastic mature CD4+ phenotype may be misinterpreted as normal inflammatory cells.

• Mycosis fungoides may be divided into patch stage (patch-only disease), plaque stage (both patches and plaques) and tumor stage (more than one tumor along with patches and plaques).

• A patch is defined as a flat lesion with varying degrees of erythema with fine scaling; a plaque is defined as a demarcated, erythematous, brownish lesion, with variable scaling of at least 1 mm elevation above the skin surface; a tumor extends at least 5 mm above the surface (tumors are usually in a setting of patches and plaques) (see Fig. 66–1).

• Mycosis fungoides d'emblée is an aggressive form with a poor prognosis characterized by tumors arising de novo in the absence of patches or plaques.

• Lesions have a predisposition for skin folds and non–sun exposed areas (bathing-trunk distribution) but in later stages they can be generalized and involve the face, palms, soles, and other areas.

• Progression through stages usually occurs over years but some cases may present with late stage lesions.

• Pruritus may be mild or severe and is one of the principal quality of life issues for patients. It can lead to insomnia, depression, and suicidal ideation.

• Erythrodermic skin involvement occurs in about 5 percent of patients and can be slight to severe. It can be associated with scaling, keratoderma, painful fissures in the hands and feet, nail dystrophy and loss. Severely inflamed skin can lead to bacterial infection, fever, chills, and septicemia.

• Sézary syndrome describes patients with pruritus, generalized exfoliative erythroderma, lymphadenopathy, and CD4+ lymphocytes with hyperconvoluted nuclei in the blood (see Figs. 66–1 and 66–2). It has the worst prognosis of the various types of mycosis fungoides.

• Depending on stage of presentation, lymphadenopathy and other organ involvement may occur.

• Lymphadenopathy is usually evident in 50 percent of patients at diagnosis and increases as disease progresses.

Skin Biopsy

• Skin biopsy may be compatible with several benign dermatoses early in the disease.

• Classic mycosis fungoides lesions show a superficial lymphocytic infiltrate: lymphocytes may be large or small but have characteristic cerebriform nuclear convolutions. Epidermotropism with clusters of lymphocytes in the epidermis around Langerhans cells referred to as Pautrier abscesses. Later in the disease large lymphocytes may extend into the dermis.

Immunophenotype

• The neoplastic cells are mature helper-inducer T-cells expressing CD3,CD4, and CD45RO but not CD8. CD7, expressed on normal blood T cells, may be absent on mycosis fungoides lymphocytes in the skin and blood and on Sézary cells. Loss of CD26 expression is a hallmark of the neoplastic lymphocytes.

Cytochemistry

• Mycosis fungoides cells stain for acid phosphatase, α-naphthyl acetate esterase, and β-glucuronidase; but generally are negative for CD25, peroxidase, alkaline phosphatase, and esterase.

Blood and Marrow

• Mycosis fungoides cells may be found in the blood in advanced disease, and in this setting, the marrow also contains mycosis fungoides cells. In Sézary syndrome, blood and marrow involvement with neoplastic lymphocytes is the rule (see Figs. 66–2 and 66–3).

Lymph Node Biopsy

• Enlarged lymph nodes should have an excisional biopsy regardless of the T stage.

• Most early cases do not show effacement of node, but atypical lymphocytes in the paracortical T-cell zone are present.

• Later, lymph nodes may show partial or complete effacement and a monomorphic infiltrate of mycosis fungoides cells.

Chromosomal and Genic Findings

• The neoplastic lymphocytes have TCRVβ gene rearrangement.

• Cytogenetic findings are not seen consistently. Loss of 10q heterozygosity and microsatellite instability are present in advanced disease. Microsatellite instability is a condition in which damaged DNA results from defects in normal DNA repair. Microsatellites (sections of DNA), which consist of a sequence of repeating units of 1 to 6 base pairs in length, when unstable either shorten or lengthen.

• Homozygous deletions of tumor suppressor genes PTEN and CDKN2A on chromosomes 9p and 10p is associated with progressive disease.

• Mycosis fungoides is stratified according to the tumor, node, metastasis, blood (TNMB) classification (see Table 66–2).

• Staging is of importance because it determines the therapeutic approach.

• Cutaneous lesions are stratified using the T staging system (see Table 66–2).

• The presence of tumors (T3) may indicate a worse prognosis than erythroderma (T4).

• Lymph nodes are assigned the N category in the classification (Table 66–2).

• Superficial adenopathy, although present in many patients, is usually not prominent early in the disease but progresses with progressive skin involvement.

• Magnetic resonance imaging is used to identify intraabdominal adenopathy.

• The M stage (metastatic disease) is the most significant prognostic indicator (Table 66–2).

• Patients with liver, spleen, pleural, and lung involvement have a median survival less than 1 year.

• Blood involvement is categorized in the B category in the classification system (Table 66–2).

• The percentage of neoplastic T cells in blood increases with progressive disease but sensitive techniques can find small concentrations of neoplastic T cells in the blood at diagnosis in many patients.

• Several benign dermatoses can mimic mycosis fungoides and may even have TCR gene rearrangements. Examples are psoriasis and psoriasiform dermatoses (eczema, pityriasis rubra pilaris, drug eruptions, and others).

• Adult T-cell leukemia lymphoma may have skin lesions simulating mycosis fungoides. May have other distinctive clinical features and serum HTLV1 antibodies (see Chap. 67).

• Pagetoid reticulosis consists of cutaneous plaques. It affects young males and has a benign course.

• Primary cutaneous CD30-positive lymphomas may have tumors that mimic mycosis fungoides. This is an indolent disease and may regress spontaneously. It should be distinguished from CD30+ transformation of mycosis fungoides and secondary skin involvement of CD30+ nodal lymphoma.

• Lymphoid papulosis is a benign skin disorder. Crops of pruritic, painful erythematous papules or nodules that ulcerate and heal spontaneously.

• The clinical findings, results of skin and node biopsy, blood T cell analysis, immunophenotype of T cells, TCR studies, and observation often can distinguish these diseases from mycosis fungoides.

• Treatment is divided into skin-directed and systemic therapy.

• Skin-directed therapy is the mainstay in early phases of disease and as an adjunct for systemic disease.

• Therapeutic options for mycosis fungoides are listed in Table 66–3 and in Figure 66–4. Details of their use are described in Williams Hematology, 8th edition, Chap. 105, p.1601.

• Therapeutic modalities produce remission in most patients, but cure is uncommon.

• Topical glucocorticoids may be useful for pruritus, but they should not be used for long periods because they inhibit collagen synthesis and predispose to cutaneous infection. They should not be used on face, neck, or intertriginous areas. They can foster acne, glaucoma, and cataracts.

• Topical nitrogen mustard for early cutaneous disease has low toxicity but is not curative. It is also inconvenient to use as it must be applied daily to large areas of skin and frequent allergic responses occur. In responders, treatment should be continued for a year (or until lesions disappear) and then can be decreased in frequency for an additional year or two.

• Topical retinoids (e.g., bexarotene) can induce complete responses in 20 percent and improvement in an additional 40 percent. Approved for use in patients refractory to another topical therapy. Must not be used in pregnant women.

• Phototherapy with ultraviolet (UV) radiation in the form of UVA or UVB spectrum can be useful in early disease, patches, and very thin plaques. Given at least three times per week for 4 to 8 weeks to achieve maximal response. May result in complete clearing of lesions. Acute cutaneous burning can occur and slight increase in long-term risk of other skin cancers.

• Psoralen with ultraviolet A light (PUVA): Psoralen dose of 0.6 mg/kg, orally, 2 hours before ultraviolet A light therapy, three times per week, followed by maintenance therapy given every 2 to 4 weeks indefinitely.

• PUVA results in 60 percent complete remission rate for patients with cutaneous plaques. Lower response rates for patients with generalized erythroderma or tumors. Adverse effects include mild nausea, pruritus, and sunburn-like changes.

• PUVA is not curative.

• Electron-beam therapy: 80 percent complete remission rate; 20 percent disease-free at 3 years; 4 Gy/week (total dose 36 Gy in 8 to 9 weeks). Can be given to specific lesions or to total skin surface.

• Oral retinoids (e.g., bexarotene) 300mg/m² per day induces overall response in about 50 percent of patients and a complete response in about 1 in 50 patients. Virtually all patients develop central hypothyroidism and hypertriglyceridemia. Requires treatment with thyroid replacement and lipid lowering agents. Headaches, leukopenia, pruritus may occur. Usually used in more advanced stages. Must not be given to pregnant women or those considering pregnancy.

• Histone deacetylase inhibitors (e.g., vorinostat and romidepsin), interferon-α, a variety of single agent chemotherapy (e.g., pralatrexate, cyclophosphamide, fludarabine, doxorubicin), and combined agent chemotherapy have been used. Single agent therapy is occasionally effective but duration of response has been short, usually. Combined agent therapy is more toxic, about 25 percent of patients have a good response but long-term disease-free survival is extremely uncommon (see Williams Hematology, 8th ed, Chap. 105, p. 1603).

• Several other therapies are under study.

• Median survival after diagnosis is about 12 years.

• Prognosis is dependent on the stage.

• Lymph node involvement signifies a poorer prognosis, and visceral involvement indicates poorest prognosis with median survival of less than 1 year.

• Fifty percent of deaths in patients with mycosis fungoides result from infection.

• Septicemia and bacterial pneumonia are common. Pseudomonas sp. and Staphylococcus sp. are particularly common and originate in skin.

• Herpes virus infection occurs in 10 percent of patients.

• Widespread organ involvement in late stages contributes to mortality.

• CD30+ cutaneous lymphoproliferative disease is the second most common cutaneous T-cell lymphoma after mycosis fungoides and represents about 25 percent of cutaneous T-cell disorders.

• Represents a spectrum from lymphomatoid papulosis, a benign self-limited form, to cutaneous anaplastic large cell lymphoma (ALCL), a more progressive form.

• CD30+ primary cutaneous ALCL presents with skin involvement without evidence of extracutaneous disease for at least 6 months after presentation (Fig. 66–5).

• CD30+ primary cutaneous ALCL can occur at any age; median incidence is about 65 years and males are affected slightly more than females.

• The lesions are brownish to violaceous nodules or tumors, solitary (often) but can be numerous and widely distributed, and may regress spontaneously.

• On biopsy, at least 75 percent of the cells should express CD30 and usually CD4 but are negative for CD15, do not express ALK-1, or have the t(2;5), unlike systemic ALCL.

• Lymphoid papulosis is a clonal, usually self-limited disease characterized by crops of erythematous, dome-shaped papules or nodules that may ulcerate. They regress over a few months with minor residuals of scarring or atrophy.

• Lymphoid papulosis, rarely, can evolve into a more aggressive cutaneous lymphoma. It is also associated with a higher incidence of lymphoid and non-lymphoid malignancies than unaffected persons.