Leukemic and Lymphomatous Infiltrates of the Skin

1

Define lymphoma

A lymphoma is a malignancy of the immune system that is characterized by an abnormal proliferation of lymphocytes. Lymphoma can arise in either B cells or T cells or natural killer lymphocytes. Lymphomas can be divided into two categories: Hodgkin's and non–Hodgkin's lymphomas (NHLs). NHLs are a heterogeneous group of malignancies. Within NHLs, there can be aggressive (fast-growing) or indolent (slow-growing) types. Indolent NHLs include follicular lymphoma and cutaneous T-cell lymphoma (CTCL), as well as other types.

2

Is there a T-cell lymphoma that begins in the skin?

Yes. CTCL is a primarily indolent, heterogeneous group of NHLs localized to the skin.

3

What is the most common subtype of CTCL?

Mycosis fungoides (MF) (60%) is the most common subtype of CTCL. Histologically, it has a polymorphous cellular infiltrate composed primarily of atypical mononuclear cells and a variable background infiltrate of polymorphonuclear leukocytes, eosinophils, and lymphocytes. The atypical mononuclear cells are moderately large and have a folded (cerebriform) nucleus. These cells are typically seen within the epidermis either singly or in small clusters (Pautrier's microabscesses) or may preferentially be seen in the basal cell layer. MF cells are primarily CD4-positive helper T cells.

4

How common is CTCL?

Although CTCL only comprises a fraction of all NHL diagnoses (~ 3%), the annual incidence of CTCL in the United States has increased dramatically across all age groups and races. CTCL occurs more frequently in men than women, and the incidence of MF rises with age. There are approximately 16,000 to 20,000 patients with MF in the United States, with about 1500 to 3000 new cases diagnosed each year. Higher incidence may be due to changes in classification schemes, improved detection, infectious agents, or environmental exposures.

Criscione VD, Weinstock MA. Incidence of cutaneous T-cell lymphoma in the United States, 1973–2002. Arch Dermatol . 2007;143:854–859.

5

How does mycosis fungoides begin?

Typically, MF begins with persistent scaly patches ( Fig. 45.1 ) that respond poorly to topical therapy with emollients and medium potency topical steroids. In the early stages, skin biopsy is frequently not diagnostic. The average time from onset of skin lesions to diagnosis is 7 years. In time, the patches thicken and become plaques ( Fig. 45.2 ). Eventually, skin tumors develop ( Fig. 45.3 ) and the lymph nodes can become involved. Peripheral blood involvement can be assessment by ratings defined by Sézary counts (SCs) and more sophisticated clonal and immunohistochemical analysis. Visceral disease is a late occurrence. Median survival for persons with patch- and plaque-stage disease is 12 years; for tumor-stage disease, it is 5 years; and for nodal or visceral disease, it is 3 years.

Epstein E, Levin D, Croft J, et al. Mycosis fungoides: survival, prognostic features, response to therapy, and autopsy findings. Medicine. 1972;51:61–72.

6

What is parapsoriasis?

The skin diseases included under this diagnosis are poorly understood and encompass a morass of confusing terms. Parapsoriasis is a term that means like psoriasis. Parapsoriasis and CTCL can appear identical in terms of the rash on the skin.

Small-plaque parapsoriasis is characterized by chronic, well-marginated, mildly scaly, slightly erythematous, and round to oval skin lesions measuring less than 4 to 5 cm in diameter. The long axes of the lesions are arranged in a parallel configuration, and the lesions occur on the trunk and proximal extremities in a pityriasis rosea–like pattern. The lesions have been likened to fingerprints and reported under the descriptive term of digitate dermatoses . This form of parapsoriasis does not progress to lymphoma.

Large-plaque parapsoriasis presents as palm-sized or larger lesions located most frequently on the thighs, buttocks, hips, lower abdomen, and shoulder girdle areas ( Fig. 45.4 ). The lesions may be pink, red-brown, or salmon-colored. They often have fine scale and show epidermal atrophy with cigarette-paper wrinkling. Some patients may have lesions with a netlike or reticular pattern with telangiectasia and fine scale. This clinical type of lesion is referred to as retiform parapsoriasis or poikiloderma atrophicans vasculare . Between 15% and 20% of patients with large-plaque parapsoriasis eventually develop MF. Many authorities consider it to be on a spectrum with MF.

Sehgal VN, Srivastava G, Aggarwal AK. Parapsoriasis: a complex issue. Skinmed. 2007;6:280–286.

7

What type of skin lesions are seen in patients with mycosis fungoides, the most common CTCL subtype?

Although the classic skin lesions are scaly patches, plaques, and tumors, a wide variety of skin lesions have been reported, such as follicular papules and pustules with or without alopecia (alopecia mucinosa). Bullous, erythrodermic, hypopigmented, hyperpigmented, vasculitic, and hyperkeratotic lesions also have been described.

A rare variant of MF is granulomatous slack skin disease ( Fig. 45.5 ). This disorder is characterized by the slow development of lax erythematous skin that eventually develops large pendulous folds of redundant integument. Histologic examination shows a dense atypical granulomatous infiltrate with destruction and phagocytosis of elastic tissue.

8

What are the other subtypes of CTCL?

In addition to MF (60%), there are other CTCL subtypes. Other CTCL subtypes include Sézary syndrome, primary cutaneous CD30-positive lymphoproliferative disorders (primary cutaneous anaplastic large cell lymphoma and lymphomatoid papulosis [LyP]), subcutaneous panniculitis-like T-cell lymphoma, primary cutaneous gamma/delta T-cell lymphoma, primary cutaneous aggressive epidermotropic CD8-positive cytotoxic T-cell lymphoma, and primary cutaneous small/medium CD4-positive T-cell lymphoma.

9

What is Sézary syndrome?

Sézary syndrome is named after the French dermatologist Albert Sézary, who first identified this leukemic variant of CTCL. Sézary syndrome (5%), the second most common subtype of CTCL ( Fig. 45.6 ), presents with the classic triad of erythroderma, lymphadenopathy, and atypical circulating mononuclear cells (Sézary cells). These cells are moderately large mononuclear cells with hyperconvoluted nuclei. The current assessment of peripheral blood involvement. B ₀ and B ₁ ratings are defined by SCs (B ₀ < 5% SCs; B ₁ > 5% SCs but either less than 1.0 K/μL absolute SCs or absence of a clonal TCR rearrangement, or both), while the current B ₂ rating is defined by clonal rearrangement of the TCR in conjunction with any one of the following: (1) > 1000 SCs/μL, (2) increased CD4 + or CD3 + population with CD4/CD8 > 10, or (3) an increase in CD4 + cells with an abnormal phenotype (i.e., > 40% CD4 +/CD7-; > 30% CD4 +/CD26-). However, the finding of circulating Sézary cells must be evaluated in context with the clinical picture and skin biopsy. Severe pruritus, ectropion, nail dystrophy, peripheral edema, alopecia, and keratoderma of the palms and soles are common associated features. The disease tends to wax and wane and generally progresses faster and is more resistant to treatment than the MF subtype.

10

What is the TNM (tumor, nodes, metastasis) classification of mycosis fungoides?

Staging of CTCL involves the evaluation of four disease compartments with clarifications on skin, lymph nodes, and viscera, and the incorporation of the blood rating. Stages IA and IB are determined by the extent of body surface area covered by patches and/or plaques and may have blood involvement. Patients with stage IIA disease have the same skin involvement as stage I plus lymphadenopathy, also with potential blood involvement. Stage IIB is associated with the development of skin tumors, and stage III, with a confluence of erythema covering 80% body surface area. Both stages IIB and III may also have blood or nodal involvement. Stage IIIB is identical to stage IIIA with the addition of low blood tumor burden. Both stages IVA and IVB may involve the lymph nodes or blood, but only patients with stage IVB have visceral involvement. Stage IVA is defined in terms of skin and either blood or nodal involvement and is subdivided into stage IVA ₁ and stage IVA ₂ . Stage IVA ₁ is defined by skin and blood involvement, where the blood rating equals 2, with a nodal rating of 0 to 2. Stage IVA ₂ is defined in terms of skin and nodal involvement, where the nodal rating equals 3, with a blood rating of 0 to 2.

Olsen E, Vonderheid E, Pimpinelli N, et al. Revisions to the staging and classification of mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC). Blood. 2007;110:1713–1722.

11

How is mycosis fungoides worked up?

See Table 45.1 for the CTCL essential diagnostic workup.

NCCN Clinical Practice Guidelines in Oncology. Non-Hodgkin's lymphomas . Version February 2015.

12

How is mycosis fungoides treated?

There are many treatments for MF. Treatments can be classified as skin-directed therapy or systemic therapy. See Table 45.2 .

National Cancer Institute. Mycosis fungoides and the Sézary syndrome treatment . http://www.cancer.gov/cancertopics/pdq/treatment/mycosisfungoides/healthprofessional/allpages . Accessed December 6, 2006.