The diagnosis of cutaneous lymphoma mandates consideration of a large and diverse group of malignant B-cell or T-cell lymphocytes in various stages of differentiation. In this chapter we focus on skin, the primary site of cutaneous lymphoma. Historically, primary cutaneous lymphomas were thought to be of T-cell origin; cutaneous B-cell lymphomas (CBCLs) were assumed to be secondary, or a dissemination of a nodal B-cell lymphoma.With the advent of immunohistochemical and molecular genetic modalities, it has become clear that B-cell cutaneous lymphomas are, in fact, a distinct and important group of primary cutaneous lymphomas. The majority are low-grade malignancies that have a good prognosis and slow course. This chapter will focus on primary cutaneous T-cell lymphomas (CTCLs).
CTCLs are the largest group of cutaneous lymphomas, accounting for 65% to 80% of all cases. They are classified by the World Health Organization (WHO)/European Organization for Research and Treatment of Cancer (EORTC) classification (WHO-EORTC classification) as follows:
Mycosis fungoides (MF)
MF variants: Pagetoid reticulosis (localized), follicular, syringotropic, granulomatous, and granulomatous slack skin (GSS) syndrome
Sézary syndrome (SS)
CD30+ T-cell lymphoproliferative disorders of the skin
Subcutaneous panniculitis-like T-cell lymphoma (SPTL)
Primary cutaneous peripheral T-cell lymphoma (PTL), unspecified
Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma
Cutaneous gamma/delta-positive T-cell lymphoma (CGD-TCL)
Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma
Extranodal NK/T-cell lymphoma, nasal type
Adult T-cell leukemia/lymphoma (ATLL)
Angioimmunoblastic T-cell lymphoma
CTCL, most commonly evident as MF, is usually a clonal expansion of T-helper cells, less often of T suppressor/killer cells or NK cells, manifesting as a widespread and long-standing cutaneous eruption. MF is characterized by the relatively predictable and often gradual evolution of patches into plaques and tumors composed of skin-targeting malignant T cells. This progression may be gradual and the patient may outlive the disease.
Pagetoid reticulosis is a noteworthy variant of MF characterized by the presence of localized discrete cutaneous patches or plaques with an intraepidermal proliferation of neoplastic T cells. The term pagetoid reticulosis should be restricted to the localized type (Woringer-Kolopp type) and should not be used to describe the disseminated form (Ketron-Goodman type). Generalized cases should probably be classified as aggressive epidermotropic CD8+ CTCL, CGD-TCL, or tumor-stage MF.
GSS syndrome is a rare subtype of CTCL characterized by the development of folds of loose or “slack” skin in the major skin folds and, histologically, by an infiltrate of clonal T cells, with exceptionally large multinucleated giant cells sometimes showing inclusion of fragmented elastic fibers.
SS has been defined historically by the triad of erythroderma, generalized lymphadenopathy, and the presence of
neoplastic T cells (Sézary cells) in skin, lymph nodes, and peripheral blood, respectively. Others assert that the definition of SS should include one or more of the following:
An absolute Sézary cell count of least 1000/μL
Demonstration of immunophenotypical abnormalities (an expanded CD4+ T-cell population resulting in a CD4/CD8 ratio of more than 10:1; loss of any or all of the T-cell antigens CD2, CD3, CD4, CD5; or loss of both CD4 and CD5)
Demonstration of a T-cell clone in the peripheral blood by molecular or cytogenetic methods
ATLL is an aggressive T-cell neoplasm associated with human T-cell leukemia virus 1 (HTLV-1).While an indolent form involving the skin may occur, cutaneous findings are usually a manifestation of widely disseminated disease.
SPTL is a type of T-cell lymphoma characterized by the presence of primarily subcutaneous infiltrates of neoplastic T cells and macrophages, predominantly affecting the legs and often complicated by a hemophagocytic syndrome. There are at least two groups of SPTL with different histologies, phenotypes, and prognoses. Cases with an alpha/beta-positive T-cell phenotype are usually CD8+, are restricted to the subcutaneous tissue (with no dermal or epidermal involvement), and tend to run an indolent course. The SPTL designation is only used for patients with an alpha/beta-positive T-cell phenotype, whereas those with a gamma/delta T-cell phenotype are now categorized as having CGD-TCL.
Extranodal NK/T-cell lymphoma is an Epstein-Barr virus (EBV)-associated lymphoma usually with an NK cell, or, less commonly, a cytotoxic T-cell phenotype. The nasal cavity or nasopharynx is the most common site of involvement, and the skin is the second most common site. Cutaneous involvement may be primary or secondary; however, because both primary and secondary involvement are clinically aggressive and require the same type of treatment, distinction between the two cutaneous forms is largely academic.
Primary cutaneous PTL, type unspecified, encompasses those CTCLs that do not fit into any of the subtypes of CTCLs. These include the provisional entities described later, because primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma, CGD-TCL, and primary cutaneous small/medium CD4+ T-cell lymphoma are sufficiently characteristic that they can be separated as provisional entities:
Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma, a provisional entity, is characterized by a proliferation of epidermotropic CD8+ cytotoxic T cells and aggressive clinical behavior.
CGD-TCL is composed of a clonal proliferation of mature, activated gamma/delta T cells with a cytotoxic phenotype. It may be a primary or secondary cutaneous lymphoma.
Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma is the diagnosis used when a predominance of small- to medium-sized CD4+ pleomorphic T cells are present without a history of patches and plaques typical of MF.
The primary pathophysiologic mechanisms for the development of CTCL (i.e., MF) have not been elucidated. Genetic, genotraumatic, immunologic, and environmental etiologies have all been considered. Chronic exposure to various irritants has been considered in the pathogenesis of CTCL, but evidence thus far is not conclusive. A persistent antigen that over time leads to an accumulation of mutations in oncogenes, suppressor genes, and signal-transducing genes has been suggested. One of us has proposed the thymus-bypass hypothesis that aberrant differentiation, in which T cells differentiate in the skin (rather than thymus), may be a cause.
In the United States, the incidence of CTCL is approximately five cases per million people per year. It is assumed that there is a similar worldwide incidence with some possible increases among workers using machine cutting oils. Areas where HTLV-1 is endemic, such as certain Caribbean Islands, parts of South America, Central Africa, and southwest Japan have a higher incidence of ATLL. In Jamaica and selected other Caribbean Islands, childhood-infective dermatitis is viewed a marker of HTLV-1 infection. CTCL is more common in men than women with an approximate ratio of 2:1.Most patients with CTCL are middle aged or elderly. Peak incidence is during the 5th decade, although it may rarely occur in children. Children with CTCL usually have a mild course and excellent prognosis, though extension to tumor stage and death may occur.There also does not seem to be a male predominance in children with one series observing a female predominance.As CTCL in its incipient stage may present as a chronic, poorly defined dermatitis, the average duration from onset to diagnosis of CTCL is 4 to 6 years.Most cases are treated with myriad topical agents preceding biopsy that obscure histologic diagnosis.