Introduction

A variety of non-Hodgkin lymphomas can involve the skin, either primarily or secondarily. Primary cutaneous lymphomas present in the skin with no evidence of extracutaneous disease at the time of diagnosis. They comprise a heterogeneous group of cutaneous T-cell lymphomas (CTCLs), cutaneous B-cell lymphomas (CBCLs), natural killer (NK) cell, and precursor hematopoietic neoplasms with distinct variability in clinical presentation, histopathology, immunophenotyping, gene rearrangement, and prognosis. The diversity of clinical and pathological manifestations among subsets of cutaneous lymphomas has led to much controversy over its diagnosis and classification and to the proposition of new variants and the establishment of consensus guidelines by a joint effort of the World Health Organization and European Organization for Research and Treatment of Cancer (WHO/EORTC) in 2005.¹ These guidelines were incorporated into the revised fourth WHO classification of tumors of hematopoietic and lymphoid tissues in 2008 using the existing framework for nodal lymphomas; however, differences remain, particularly to the subclassification of CBCLs.²

Based on the WHO/EORTC classification, cutaneous lymphomas are classified as indolent, intermediate, or aggressive.1,3 The two most commonly recognized types of CTCL are mycosis fungoides (MF), which is generally indolent, and Sézary syndrome (SS), which is an aggressive and leukemic form of disease (Table 107-1). MF and SS together comprise 53% of all cutaneous lymphomas and are often synonymously named as CTCL. Notably, cutaneous manifestations of human T-cell lymphotrophic virus type I (HTLV-I)–associated adult T-cell lymphoma/leukemia (ATLL) occur in about 50% of cases and can mimic a slowly progressing course of MF.^4,5 The second common CTCL type encompasses the spectrum of primary cutaneous CD30+ lymphoproliferative disorders, including lymphomatoid papulosis and cutaneous anaplastic large cell lymphoma; this CTCL type comprises 20% of all cutaneous lymphomas. Other, rarer types include the subcutaneous panniculitis–like T-cell lymphoma, which is generally indolent, and the group of primary cutaneous peripheral T-cell lymphomas (PTCLs) that includes the provisional entities cutaneous aggressive epidermotropic CD8+ T-cell lymphoma, cutaneous γ/δ T-cell lymphoma, and cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma, with the last generally recognized as more indolent than the others.

Extranodal natural killer (NK)/T-cell lymphoma, nasal type, is an aggressive Epstein-Barr virus–associated cytotoxic lymphoma. The skin is the second most commonly involved area after the upper aerodigestive tract, and the prognosis is poor. Blastic plasmacytoid dendritic cell neoplasm, derived from plasmacytoid dendritic cells, is another rare and aggressive immature hematopoietic neoplasm. It was previously also known as blastic NK cell lymphoma and CD4+/CD56+ hematodermic neoplasm.

Based on the WHO/EORTC classification, there are three main types of primary CBCL: cutaneous marginal zone lymphoma, follicle center cell lymphoma, and diffuse large B-cell lymphoma (DLBCL), leg type. These three types comprise 20% to 25% of all cutaneous lymphomas. Both cutaneous marginal zone lymphoma and follicle center cell lymphoma are recognized as indolent lymphomas, whereas cutaneous DLBCL, leg type, has a more intermediate behavior. Other morphologic variants of DLBCL and intravascular large B-cell lymphoma, defined by intravascular accumulation of malignant B-lymphocytes, are usually recognized as systemic lymphoma involving the skin.

Epidemiology

Cutaneous lymphomas represent about 3.9% of all non-Hodgkin lymphomas. Frequency and survival data used in the WHO/EORTC classification are based on Dutch and Austrian registries.¹ Cutaneous lymphoma incidence patterns were studied using data from 3884 patients from 16 Surveillance Epidemiology and End Results (SEER) program registries in the United States during 1980 through 2005.⁶ Data revealed that CTCLs account for 71% and CBCLs account for 29% of all lymphomas. MF accounted for 38% of all CTCLs, followed by cutaneous PTCL (20%) and CD30+ lymphoproliferative disorders (10%). The age-adjusted annual incidence of CTCLs in the United States with most cases classified as MF has increased from 2.8 per million (1973-1977) to 9.6 per million (1998-2002) according to data from Criscione and Weinstock, and from 5.0 per million to 12.7 per million, according to Bradford and associates.^6,7 MF is the most common type of CTCL, with a predominance of male patients of approximately 2 : 1 and a predominance of African-American patients of 1.6 : 1. The median age at presentation is between 50 and 70 years with only a small number of cases occurring in children and young adults. CBCL incidence rates are highest in non-Hispanic whites with a male predominance and an exponential increase with age. The most common primary CBCL subtypes are cutaneous DLBCL, follicle center cell lymphoma, and marginal zone lymphoma, comprising 40%, 30%, and 25% of all cases of CBCL, respectively.

Etiology

Despite rising incidence rates of CTCL, its etiology remains elusive. It has been suggested that the condition results from persistent antigen stimulation; however, its antigen-driving process is not known. Microbiological, environmental, occupational, and lifestyle factors have been suggested in the etiology of CTCL, but none has yet been verified.10–10 Unlike ATLL, which is etiologically associated with HTLV-I, most patients with CTCL are serologically negative for HTLV-I.^11,12 Other investigators have found serologic evidence for Epstein-Barr virus and cytomegalovirus, but these findings have not been substantiated.^15–15 Immunosuppression and/or immunosuppressive therapy might be a risk factor for the development of CTCL, as documented in patients after treatment with tumor necrosis factor-α (TNF-α) antagonists, treatment of organ transplant or of Hodgkin disease, and in human immunodeficiency virus (HIV)-positive patients.^16–19

MF is the prototype of CTCL and the best-studied entity. MF classically presents as an indolent course, with slow progression over years or sometimes decades. The disease may evolve from erythematous patches to infiltrated plaques and eventually to tumors (Fig. 107-1). However, about 30% of patients have skin tumors (T3) or erythroderma (T4) only at initial presentation.²⁰ Patients usually have a prolonged history of a rash in sun-protected areas, such as the lower abdomen, upper thighs, buttocks, inner upper arms, and breasts in women. Pruritus may or may not have be associated. The majority of patients remain in clinical stages limited to the skin; however, 20% of patients progress into more aggressive and advanced disease with either cutaneous or extracutaneous tumor manifestations, with an estimated 5-year survival rate of 25% to 40%. MF has numerous clinical and histologic variants. Besides the conventional type of MF, three distinct variants have been recognized in the 2005 WHO/EORTC classification, including folliculotropic MF, pagetoid reticulosis, formerly known as Worringer-Kolopp disease, and granulomatous slack skin, characterized by the development of lax skin folds (Fig. 107-2).

Patients with folliculotropic MF have erythematous papules, plaques, and nodules with follicular involvement with or without alopecia; comedonal, acneiform, and cystic lesions; and associated intractable pruritus.²¹ Folliculotropic MF is frequently seen on the head and neck area in contrast to conventional MF. The clinical course of folliculotropic MF, particularly in early stages, is more aggressive; these patients respond poorly to topical therapy alone and require systemic therapy to achieve clinically meaningful responses. The 10-year progression-free survival is 45% compared with 91% in patients with conventional MF. Pagetoid reticulosis is a rare variant of MF with an indolent course and is predominantly seen in middle-aged men. Patients have a solitary psoriasiform plaque most often located on the lower extremity or foot. In contrast to classic MF, the epidermotropic atypical lymphocytes show a CD8+ phenotype by immunohistochemistry. Granulomatous slack skin is extremely rare and clinically characterized by indurated plaques resembling lax skin folds often in axillary and/or inguinal areas. On histology, there is a diffuse dermal infiltrate of giant cells and atypical lymphocytes with destruction of elastic fibers.^22,23

Sézary syndrome (SS) is part of the spectrum of erythrodermic CTCLs as proposed by the International Society for Cutaneous Lymphomas (ISCL) (Table 107-2).²⁴ Erythrodermic CTCLs can either develop de novo (as with SS) or as a progression of preexisting MF (as with erythrodermic MF). Patients who have erythrodermic MF may also have coexisting patches, plaques, or tumors. Three percent to 5 percent of all newly reported cases of CTCL are SS. SS is characterized by circulating, atypical, malignant T lymphocytes with cerebriform nuclei (Sézary cells), by the presence of erythroderma, and often by lymphadenopathy. Severe, disabling pruritus, ectropion, lymphoma-associated alopecia, palmoplantar keratoderma with fissures, and dystrophic nails are other common associated features (Fig. 107-3). Concomitant infections with dermatophytes or bacteria are common. Patients with SS are immunocompromised because of defective T-cell function and therefore predisposed for opportunistic skin infections such as colonization with Staphylococcus aureus.²⁵

A histopathological diagnosis of MF has proved to be difficult, because in initial and erythrodermic stages of disease inflammatory cells often predominate and may resemble benign dermatoses.²⁶ It is not uncommon that patients may undergo multiple biopsies before a diagnosis can be rendered. A diagnostic algorithm for early MF was proposed by the ISCL and the Cutaneous Lymphoma Task Force of the EORTC that takes the clinical and histopathological findings into account (Table 107-3).²⁷ Characteristic diagnostic features of classic MF/SS are a papillary dermal band–like infiltrate with atypical lymphocytes with hyperchromatic, hyperconvoluted nuclei, variable findings of inflammatory cells, and epidermotropism with infrequently seen Pautrier microabscesses (Fig. 107-4).²⁸ Most MF/SS patients have the phenotype of the CD4+ T-helper (Th)/memory lymphocyte. Only a small number of cases, such as pagetoid reticulosis or hypopigmented variant of MF, are of the cytotoxic/suppressor T-cell subset expressing a CD8+ phenotype. SS patients also show commonly nonspecific histopathological findings, and a definitive diagnosis may be made by flow cytometry.^29,30 It is important to differentiate tumor stage MF from non-MF subtypes of CTCL. In conventional MF, tumor lesions usually develop in the setting of patch/plaque disease and not de novo with the latter previously classified as tumor d’emblée type MF. It is now recognized that many of these cases represent non-MF cases and may fit best within the group of primary cutaneous PTCL, not otherwise specified.

Immunophenotyping by immunohistochemistry or by flow cytometry and molecular studies have an important role in the evaluation of CTCL and aid into the diagnosis. There is no unique marker for the malignant lymphocyte, but an increased CD4 to CD8 ratio with an aberrant loss of T-cell lineage markers such as CD5, CD7, and/or CD26 is a common finding.²⁹ A clonal gene rearrangement of the T-cell receptor can be detected in many cases and support the diagnosis using standard polymerase chain reaction (PCR) methods, but this has been complicated by the dilemma of clonality detected in benign skin disorders.* Furthermore, data on microsatellite DNA studies suggest that tumor cells may arise from multiple subclones and show a multiple-lineage progression.³¹