Chapter 65: Cutaneous T-Cell Lymphoma

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

• Other types of lymphoma may also have prominent skin involvement (see Table 65–1).

• In cases of CTCL in which erythrodermia is a prominent feature, the major considerations are shown in Table 65–2.

• CTCL is more common in males than females.

• Median age at diagnosis is 55 years.

• In the United States, there are approximately 3000 cases per year, representing about 3% of lymphomas.

• Americans of African descent have a higher incidence and more progressive disease than Americans of European descent.

• Asians and Hispanics are much less often affected.

• The etiology is unknown.

• 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; and a tumor extends at least 5 mm above the surface (tumors are usually in a setting of patches and plaques) (Figure 65–1).

• 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 advanced 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% of patients and can be slight to severe. It can be associated with scaling, keratoderma, painful fissures in the hands and feet, and 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 (Figures 65–2 and 65–3). It has the worst prognosis of the various types of CTCL.

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

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

Skin Biopsy

• Early in the disease, skin biopsy may be compatible with several benign dermatoses.

• Classic mycosis fungoides lesions show a superficial lymphocytic infiltrate: lymphocytes may be large or small but have characteristic cerebriform nuclear convolutions.

  — Epidermotropism is represented by 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.

Lymph Node Biopsy

• Enlarged lymph nodes should have an excisional biopsy regardless of the tumor 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 one to six base pairs in length, either shorten or lengthen when unstable.

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

• Mycosis fungoides is stratified according to the tumor, node, metastasis, blood (TNMB) classification (Table 65–3).

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

• Cutaneous lesions are stratified using the T staging system (Table 65–3).

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

• Lymph nodes are assigned the N category in the classification (Table 65–3).

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

• The M stage (metastatic disease) is the most significant prognostic indicator (Table 65–3).

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

• Blood involvement is categorized in the B category in the classification system (Table 65–3).

• 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.

• In most cases, lymph node architecture is not effaced, but dermatopathic changes are present with atypical lymphocytes in the T-cell paracortical areas. The latter finding carries prognostic significance (Table 65–4).

• 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.

  — Patients have other distinctive clinical features described in Chap. 66, including antibodies to the human T-cell lymphocytotropic virus (HTLV1).

• Pagetoid reticulosis (Woringer-Kolopp disease) 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 characterized by crops of pruritic, painful erythematous papules or nodules that ulcerate and heal spontaneously.

• 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 and Sézary syndrome are listed in Table 65–5.

• 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 (eg, bexarotene) can induce complete responses in 20% and improvement in an additional 40%. They are approved for use in patients refractory to another topical therapy.

  — Retinoids 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.

  — This therapy is given at least three times per week for 4 to 8 weeks to achieve maximal response.

  — It 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) involves a 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% complete remission rate for patients with cutaneous plaques but, 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 is associated with a 80% complete remission rate; patients are 20% disease-free at 3 years.

  — This therapy involves 4 Gy/wk (total dose 36 Gy in 9 weeks).

  — It can be given to specific lesions or to the total skin surface.

• Oral retinoids (eg, bexarotene) 300 mg/m² per day can induce response in about 50% of patients and a complete response in about 2% of patients.

  — Virtually all patients develop central hypothyroidism and hypertriglyceridemia, which requires treatment with thyroid replacement and lipid-lowering agents.

  — Headaches, leukopenia, and pruritus may occur.

  — Retinoids are usually used in more advanced stages.

  — These agents must not be given to pregnant women or those considering pregnancy.

• Histone deacetylase inhibitors (eg, vorinostat and romidepsin), interferon-α, and a variety of single-agent chemotherapy (eg, pralatrexate, cyclophosphamide, fludarabine, doxorubicin) have been used.

  — Single-agent chemotherapy is occasionally effective but duration of response has been short, usually.

• Combined agent chemotherapy, also, has been used.

  — Combined agent therapy is more toxic, about 25% of patients have a good response but long-term disease-free survival is extremely uncommon.

• Other therapies, including monoclonal antibodies and antibody conjugates, recombinant fusion proteins, and extracorporeal photopheresis have been used.

• Figure 65–4 illustrates the choice of treatment options related to the stage of disease.

• 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 the skin.

• Herpes virus infection occurs in 10% of patients.

• CD30+ cutaneous lymphoproliferative disease is the second most common CTCL after mycosis fungoides and represents approximately 25% of cutaneous T-cell disorders.

• This disorder 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 (Figure 65–5).

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

• The lesions are brownish to violaceous nodules or tumors. Often solitary, they can be numerous and widely distributed and may regress spontaneously.

• On biopsy, at least 75% 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.

• For localized disease, radiotherapy is usually utilized.

• 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 nonlymphoid malignancies than unaffected persons.

• Observation without specific therapy is often the best management. Other treatments can include low-dose methotrexate, brentuximab vedotin, and radiotherapy.