eMedicine Specialties > Hematology > Stem Cells and Disorders

Lymphoma, Cutaneous T-Cell

Author: Lauren C Pinter-Brown, MD, Director, Lymphoma Program, Clinical Professor of Medicine, Department of Internal Medicine, Division of Hematology and Oncology, UCLA Medical Center
Contributor Information and Disclosures

Updated: Nov 21, 2008

Introduction

Cutaneous T-cell lymphoma (CTCL) is a term that was created in 1979 to describe a group of lymphoproliferative disorders characterized by localization of neoplastic T lymphocytes to the skin. When the term was first coined, it most often referred to mycosis fungoides/Sézary syndrome, the most common cutaneous T-cell lymphoma (CTCL).^1,2 More recently, however, the many entities that comprise the cutaneous T-cell lymphomas (CTCLs) have been found to differ widely in biologic course, histologic appearance, and in some cases, immunologic and cytogenetic features and in their response to appropriate treatment.

The skin is the second most common extranodal site for lymphoma; gastrointestinal sites are first. Of all primary cutaneous lymphomas, 65% are of the T-cell type. The most common immunophenotype is CD4-positive.

The incidence of cutaneous T-cell lymphoma (CTCL) in the United States is reported to be increasing.³

For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education articles Lymphoma and Skin Cancer.  

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Pathophysiology

There is no common pathophysiology, as the term cutaneous T-cell lymphoma (CTCL) encompasses a wide variety of disorders.

Classification

Cutaneous T-cell lymphomas (CTCLs) have been defined in the past by an integration of histology, biology, immunology, and cytogenetic characteristics in 2 classification systems: the European Organization for Research and Treatment of Cancer (EORTC) classification for primary cutaneous lymphomas (1997)⁴ and the World Health Organization (WHO) classification of hematologic malignancies (2000).⁵

A tumor, node, metastases (TNM) classification system for primary cutaneous lymphomas other than mycosis fungoides and Sézary syndrome has also been proposed.⁶

The EORTC classification focused on primary cutaneous lymphomas, which may vary from their nodal counterparts in clinical behavior, prognosis, and appropriate therapeutic approaches. The classification also recognized that unlike the general group of lymphomas, a histologic diagnosis in a case of cutaneous lymphoma may not be the final diagnosis but, rather, a differential diagnosis that requires clinicopathologic correlation.

The WHO classification included cutaneous lymphomas in the general classification of lymphoma to facilitate the description of clinicopathologic entities in their entirety, reporting common features of disease entities that may present in multiple anatomic sites. The WHO classification allows oncologists, dermatologists, and pathologist to use a common language.

During consensus meetings, representatives of both systems reached an agreement on a new classification system in 2005, the WHO-EORTC Classification of Cutaneous Lymphomas.⁷

Table 1. WHO-EORTC Classification of Cutaneous T-Cell Lymphoma (adapted from Willemze et al. Blood. 2005;105(10):3768-85)⁷

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^* NR = not reported; NK = natural killer.⁷

Table 2. Cluster Designations

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Lymphomas With Indolent Clinical Behavior

Mycosis fungoides/Sézary syndrome

This is the most common cutaneous T-cell lymphoma (44%), leading some to use the term cutaneous T-cell lymphoma (CTCL) synonymously with mycosis fungoides).

Variants of mycosis fungoides that are recognized by WHO/EORTC include folliculotropic mycosis fungoides, granulomatous slack skin, and pagetoid reticulosis (Woringer-Kolopp disease).

Folliculotropic mycosis fungoides manifests with follicular papules, patchy alopecia, and comedolike lesions, particularly in the head and neck area. An infiltration of atypical lymphocytes is observed in the epithelium of hair follicles, and mucinous degeneration of the hair follicles (follicular mucinosis) may be seen. Topical treatments may not be effective because of the depth of infiltration.

Granulomatous slack skin is a condition characterized by the slow development of pendulous, lax skin, most commonly in the areas of the axillae and groin. Histologically, a granulomatous infiltration is seen accompanied by multinucleate giant cells with elastophagocytosis and near-complete loss of elastin in the dermis (demonstrated by elastin stain). Disease recurrence is common after surgical intervention. Radiation may be of use, but experience is limited in its use. One third of patients have been reported to have concomitant Hodgkin lymphoma or mycosis fungoides.

Pagetoid reticulosis (Woringer-Kolopp disease) manifests with a solitary, asymptomatic, well-defined, red, scaly patch or plaque on the extremities that may slowly enlarge. A heavy, strictly epidermal infiltrate of atypical lymphocytes is observed. The prognosis is excellent, and radiation therapy or surgical excision is the treatment of choice.

Although Sézary syndrome may be part of a continuum from erythrodermic mycosis fungoides, the WHO-EORTC classification for cutaneous lymphoma considers its behavior "aggressive."⁷

Primary cutaneous CD30-positive lymphoproliferative disorder

Anaplastic large cell lymphoma (ALCL), primary cutaneous type, manifests as a solitary nodule or ulcerating tumor (>2 cm) in patients without a history of or concurrent mycosis fungoides or lymphomatoid papulosis (LyP) and without evidence of extracutaneous disease. Extracutaneous dissemination, mainly to regional nodes, occurs 10% of the time.

The disease is multifocal in skin approximately 30% of the time. CD30-positive (75% or more) membrane staining of the large lymphocytes or large clusters of CD30-positive atypical lymphocytes with pleomorphic or multiple nuclei and nucleoli are seen. Numerous mitotic figures can be observed. Unlike systemic anaplastic large cell lymphoma, anaplastic lymphoma kinase (ALK) staining is usually negative. In addition, A helpful tool for distinguishing cutaneous from systemic anaplastic large cell lymphoma is to test for the presence of the t(2;5) translocation; the t(2;5) translocation — while often, but not always present in cases of systemic anaplastic large cell lymphoma — is usually absent in primary cutaneous cases.

Differentiation from lymphomatoid papulosis is not always possible based on histologic criteria. Immunologically, atypical lymphocytes are CD4-positive, with variable loss of CD2, CD3, or CD5.

Staging is required per other non-Hodgkin lymphomas (eg, computed tomography [CT] scans, bone marrow examinations, blood work). Patients may experience spontaneous remissions with relapses. If no spontaneous remission occurs, radiation, surgical excision, or both are preferable. Chemotherapy is reserved for patients who have generalized lesions.

Lymphomatoid papulosis manifests as recurrent crops of self-healing, red-brown, centrally hemorrhagic or necrotic papules and nodules on the trunk or extremities, which can evolve to papulovesicular or pustular lesions. These lesions are much smaller than anaplastic large cell lymphoma (<2 cm). The lesions spontaneously resolve in 4-6 weeks, leaving hyperpigmentation or atrophic scars. Variable frequency and/or intensity of outbreaks can occur in different patients. Lymphomatoid papulosis is clinically benign, although clonal T-cell gene rearrangement can be demonstrated in 60-70% of cases. Hodgkin disease, mycosis fungoides, or cutaneous anaplastic large cell lymphoma is observed in 20% of cases.

Note: The term CD30-positive lymphoproliferative disorders includes entities such as anaplastic large cell lymphoma, primary cutaneous and systemic type, and lymphomatoid papulosis. Although at times pathologically indistinct, these entities are clinically distinct. Thus, clinicopathologic correlation in the management of these disorders is desirable.

 Subcutaneous panniculiticlike T-cell lymphoma

Erythematous subcutaneous nodules, which appear in crops, are localized to the extremities or trunk. These may be confused with benign panniculitis.

The lesions are often accompanied by fever, chills, weight loss, and malaise, and they may be accompanied by hemophagocytic syndrome, which may be associated with a rapidly progressive downhill course. Dissemination to extracutaneous sites is rare.

Histologically, early lesions show focally atypical lobular lymphocytic infiltration of the subcutaneous fat that may also be confused with benign panniculitis. Later, infiltration of pleomorphic lymphoid cells into fat, with rimming of individual fat cells by the neoplastic cells, is accompanied by frequent mitoses, karyorrhexis, and fat necrosis. Cytophagic histiocytic panniculitis (histiocytes phagocytizing red and white blood cells) can also complicate the histologic picture.

Immunologically, atypical lymphocytes stain positively for CD3 and CD8, with clonal rearrangement of the T-cell receptor gene documented.

Subcutaneous panniculiticlike T-cell lymphoma can be separated into 2 groups: those with a beta/delta (b/d; β/δ) phenotype and those with a gamma/delta (g/d; γ/δ) phenotype. The WHO-EORTC term subcutaneous panniculitic type T-cell lymphoma refers only to the a/b type,⁷ which appears to have a more indolent clinical course that is characterized by recurrent subcutaneous lesions. Although these patients were treated with chemotherapy or radiation in the past, it appears that patients treated with systemic steroids may remain in good clinical control.

A similar-appearing lymphoma with a g/d phenotype is CD8^– and CD56⁺. Histologically, the infiltration may not be limited to the subcutaneous tissue, and the course may be more aggressive. In the WHO-EORTC classification, this lymphoma is considered to be a different entity and is included in the group of cutaneous g/d lymphomas in a provisional category.⁷ Clinically, this lymphoma is more aggressive, with dissemination to mucosal and other extranodal sites.

Aggressive Subtypes

Adult T-cell lymphoma/leukemia (human T-cell lymphotropic virus–positive)

Most patients with this illness are adults with antibodies to human T-cell lymphotropic virus (HTLV-I1, a virus endemic to Southwest Japan, South America, Central Africa, and the Carribbean. Adult T-cell lymphoma/leukemia   develops in 1-5% of seropositive individuals, often 20 years after exposure.

In the acute form, cutaneous lesions, hepatosplenomegaly, lytic bone lesions, and infections are observed, along with an elevated white blood cell count and hypercalcemia.

In the chronic and smoldering forms, the skin rash is characterized by papules, nodules, plaques, or erythroderma with pruritus, which can resemble mycosis fungoides histologically and clinically.

Cells with hyperlobated nuclei (in a clover-leaf pattern) infiltrate the dermis and subcutis. Epidermotropism with Pautrier microabscesses can be seen in one third of cases.

Immunologically, malignant cells are CD2-, CD3-, and CD5-positive and CD7-negative; CD4 and CD25 are positive. T-cell gene rearrangement is clonal, and the HTLV-1 genome is integrated into the neoplastic cells' genome.

Standard treatment with chemotherapy does not appear to affect survival. The use of zidovudine and interferon has been advocated.

The prognosis in those with adult T-cell lymphoma/leukemia is poor, with a 6-month median survival for the acute form and 24-month median survival for the chronic form.

Extranodal NK T-cell lymphoma, nasal type

The skin of the trunk and extremities and the aerodigestive tract are involved by multiple plaques and tumors, which are frequently accompanied by systemic symptoms such as fever and weight loss. An associated hemophagocytic syndrome may be observed. Nasal type extranodal NK T-cell lymphoma is more common in males, and it is more common in Asia, Central America, and South America.

Dermal and subcutaneous infiltration with invasion of the vascular walls and occlusion of the vessel lumen by lymphoid cells lead to tissue necrosis and ulceration.

The malignant cells are usually CD2- and CD56-positive (NK phenotype) with cytoplasmic but not surface CD3 positivity. The cells contain cytotoxic proteins (T-cell intracellular antigen 1) [TIA-1], granzyme B, and perforin). Epstein-Barr virus (EBV) tests are commonly positive. Rarely, cells may have a true cytotoxic T-cell phenotype.

Nasal type extranodal NK T-cell lymphoma is an aggressive disease that requires systemic therapy, although the experience with systemic chemotherapy has generally been poor.

Primary cutaneous peripheral T-cell lymphoma, unspecified

Peripheral T-cell lymphoma (PTCL) unspecified is a heterogeneous entity that manifests with localized or generalized plaques, nodules, and/or tumors. By definition, this group excludes all 3 provisional categories of PTCLs delineated in the WHO-EORTC classification.⁷

The absence of previous or concurrent patches or plaques consistent with mycosis fungoides differentiates these lesions from classic mycosis fungoides in transformation to diffuse large cell lymphoma.

Pleomorphic infiltration of small/large lymphocytes is observed diffusely infiltrating the dermis. Large, neoplastic T cells are present by greater than 30%. The immunophenotype is generally CD4⁺.

Patients with PTCL unspecified generally have a poor prognosis and should be treated with systemic chemotherapy.

Immunologically, most neoplastic lymphocytes show an aberrant CD4-positive phenotype with clonal rearrangement of T-cell receptor genes. Results from CD30 staining are negative.

The prognosis is poor, with the 4-year survival rate approaching 22%. Although a small percentage of patients may undergo spontaneous remission, a more aggressive behavior is more likely. Staging for systemic lymphoma and multiagent chemotherapy is recommended. If the patient has solitary or localized disease, radiation therapy could be considered as an initial treatment.

Provisional Categories

Primary aggressive epidermotropic CD8⁺ cytotoxic T-cell lymphoma

Clinically, this is an aggressive, sometimes disseminated disease, which presents with eruptive papules, nodules, and tumors with central ulceration. Primary aggressive epidermotropic CD8⁺ cytotoxic T-cell lymphoma can also present with superficial patches and/or plaques.

Histologically, epidermotropism with invasion and destruction of adnexal skin structures and angiocentricity with angioinvasion can be seen. The malignant cell is CD3- and CD8-positive and contains cytotoxic proteins. Clonal T-cell gene rearrangement is seen. EBV tests are typically negative.

These patients have typically been treated with anthracycline-based systemic chemotherapy.

Cutaneous g/ d T-cell lymphoma

This entity is discussed with subcutaneous panniculiticlike T-cell lymphoma (see Lymphomas With Indolent Clinical Behavior).

Primary cutaneous CD4⁺ small/medium-sized pleomorphic T-cell lymphoma

This lymphoma presents with solitary or localized plaques or tumors in the face, neck, and/or upper trunk area.

Histologically, dermal to subcutaneous infiltration with CD3, CD4⁺ malignant cells are seen. Focal epidermotropism may be seen.

Primary cutaneous CD4⁺ small/medium-sized pleomorphic T-cell lymphoma typically has an indolent course, and solitary lesions may be treated with surgical excision or radiation.

Multimedia

(Enlarge Image)

Media file 1: A 40-year-old woman complains of a recurrent skin rash, which she describes as "bug bites." Skin biopsy results demonstrate an atypical lymphoid infiltrate, which is CD30 positive. The clinical picture and pathologic findings are consistent with lymphomatoid papulosis. This condition has a benign natural history, despite clonal gene rearrangement in some cases, with skin eruptions occurring in self-limited crops, which do not require treatment.

Keywords

cutaneous T-cell lymphoma, T-cell lymphoma, CTCL, lymphoma, skin cancer, lymphoproliferative disorder, mycosis fungoides, MF, Sézary syndrome, follicular MF, pagetoid reticulosis, Woringer-Kolopp disease, anaplastic large cell lymphoma, ALCL, lymphomatoid papulosis, LyP, peripheral T-cell lymphoma, PTCL, granulomatous slack skin

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