eMedicine Specialties > Dermatology > Lymphoma and Related Processes

Cutaneous T-Cell Lymphoma

Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
W Clark Lambert, MD, PhD, Professor and Head, Dermatopathology, Departments of Pathology and Dermatology, UMDNJ-New Jersey Medical School

Updated: Nov 10, 2009

Introduction

Background

Cutaneous T-cell lymphomas (CTCLs) are the largest group of cutaneous lymphomas, representing 65% of all cutaneous lymphomas. The World Health Organization (WHO)/European Organization for Research and Treatment of Cancer (EORTC) classification (WHO-EORTC classification) is used to categorize CTCLs.^1,2,3 However, a substantial subset of T-cell primary cutaneous lymphomas remains that cannot be classified beyond the unspecified peripheral T-cell category, some of which may have an aggressive course.⁴

Mature T-cell and natural killer (NK) cell neoplasms according to the WHO-EORTC classification are as follows:

• Mycosis fungoides
  • Variants of mycosis fungoides (MF)
    • Pagetoid reticulosis (localized disease)
    • Follicular, syringotropic, granulomatous variant
  • Subtype of MF - Granulomatous slack skin (GSS) syndrome
• Sézary syndrome
• CD30⁺ T-cell lymphoproliferative disorders of the skin
  • Lymphomatoid papulosis
  • Primary cutaneous anaplastic large cell lymphoma
• Subcutaneous panniculitislike T-cell lymphoma
• Primary cutaneous peripheral T-cell lymphoma (PTL), unspecified
  • Subtypes of PTL
  • Primary cutaneous aggressive epidermotropic CD8⁺ T-cell lymphoma (provisional)
  • Cutaneous gamma/delta-positive T-cell lymphoma (CGD-TCL) (provisional)
  • Primary cutaneous CD4⁺ small/medium-sized pleomorphic T-cell lymphoma (provisional)
• Extranodal NK/T-cell lymphoma, nasal type
  • Variant - Hydroa vacciniformialike lymphoma
• Adult T-cell leukemia/lymphoma
• Angioimmunoblastic T-cell lymphoma

CTCL, most commonly seen as MF, is a relatively common clonal expansion of T helper cells and, more rarely, T suppressor/killer cells or NK cells, that usually appears as a widespread, chronic, cutaneous eruption. MF itself is often an epidermotropic disorder characterized by evolution of patches into plaques and tumors composed of small- to medium-sized skin-homing T cells, some (or, rarely, all) of which have convoluted, cerebriform nuclei.

Pagetoid reticulosis is a variant of MF and is characterized by the presence of localized 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 type (Ketron-Goodman type). Generalized cases should probably be classified as aggressive epidermotropic CD8⁺ CTCL, CGD-TCL, or tumor-stage MF.⁵

GSS syndrome is a rare subtype of CTCL characterized by the slow development of folds of lax 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. Granulomatous CTCLs are rare, so limited data on the clinicopathological and prognostic features are available.⁶ Patients with granulomatous MF and GSS display overlapping histologic features and differ clinically by the development of bulky skin folds in GSS.

Sézary syndrome (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. Some authorities believe the diagnosis of SS should include one or more of the following⁷ :

• 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

SS is an erythrodermic CTCL. Demonstration of a T-cell clone (preferably of the same T-cell clone in skin and peripheral blood) in combination with one of the aforementioned cytomorphological or immunophenotypical criteria has been suggested as minimal criteria for the diagnosis of SS, in order to exclude patients with benign inflammatory conditions simulating SS.

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive T-cell neoplasm etiologically linked with the human T-cell leukemia virus 1 (HTLV-1). Cutaneous lesions are usually a manifestation of widely disseminated disease, although a slowly progressive form that may only involve the skin may occur.⁸

Subcutaneous panniculitislike T-cell lymphoma (SPTL) is a cytotoxic T-cell lymphoma characterized by the presence of primarily subcutaneous infiltrates of small, medium, or large pleomorphic T cells and many macrophages, predominantly affecting the legs and often complicated by a hemophagocytic syndrome.⁹ At least 2 groups of SPTL with different histologies, phenotypes, and prognoses can be distinguished. 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 clinical course.^10,11 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.^1,2,3,11,12

Extranodal NK/T-cell lymphoma, nasal type, is an Epstein-Barr virus (EBV)–positive lymphoma of small, medium, or large cells, usually with an NK-cell, or, more rarely, a cytotoxic T-cell phenotype. The skin is the second most common site of involvement, with the nasal cavity/nasopharynx being the most common and the reason why it was once known as a lethal midline granuloma. Cutaneous involvement may be primary or secondary. Because both primary and secondary involvement are clinically aggressive and require the same type of treatment, distinction between the 2 cutaneous involvements seems unnecessary.^11,13,14

Primary cutaneous PTL, type unspecified, is the designation for CTCLs that do not fit into any of the better-defined subtypes of CTCL.^1,2,3 These include the 3 provisional entities described below, because primary cutaneous aggressive epidermotropic CD8⁺ cytotoxic T-cell lymphoma, CGD-TCL, and primary cutaneous small-medium CD4⁺ T-cell lymphoma can be separated out as provisional entities. The remaining diseases that do not fit into any of the better-defined subtypes of CTCL are characterized as follows:

• 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.⁵
• CGD-TCL is composed of a clonal proliferation of mature, activated gamma/delta T cells with a cytotoxic phenotype.^12,15,16 It may be 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.¹⁷

For additional information from other eMedicine articles, see T-Cell Disorders, Mycosis Fungoides, and Lymphoma, Cutaneous T-Cell.

Pathophysiology

The primary pathophysiologic mechanisms for the development of cutaneous T-cell lymphoma (CTCL) (ie, MF) have not been elucidated. MF may be preceded by a T-cell–mediated chronic inflammatory skin disease, which may occasionally progress to a fatal lymphoma. Karyotypic analysis of cutaneous and blood lymphocytes has shown several genetically aberrant T-cell clones in the same patient.

A genotraumatic T cell is one with a tendency to develop numerous clonal chromosomal aberrations. Normal T lymphocytes show apoptosis during in vitro culturing, whereas genotraumatic ones have the ability to develop clonal chromosomal aberrations to become immortalized. This concept implies genetic instability followed by T-cell proliferation. Successive cell divisions of a genotraumatic T-cell clone may produce multiple and complex chromosomal aberrations. Some may reprogram the genotraumatic cells to apoptosis, whereas one or more may produce the phenotypic alterations of malignancy if not eliminated in vivo.

Thus, one hypothesis is that the development of genotraumatic T lymphocytes is involved in the etiopathogenesis and the progression of MF. It would also predict that each patient would likely have a unique malignant clone, which, in fact, has been found to be the case.

CTCL is a group of T-cell proliferative disorders. Primary cutaneous lymphomas require distinction from histologically similar primary nodal ones because their clinical behavior, prognosis, and therapy are often different. In addition, a difference often exists between primary cutaneous and nodal lymphomas in the presence of specific translocations.

Frequency

United States

The incidence of CTCL is approximately 5 cases per million population per year.

International

Cutaneous T-cell lymphomas (CTCLs) account for 65% of cutaneous lymphomas. CTCLs have a worldwide distribution, with no well-identified increase in prevalence in any region. Some studies have identified an increase in prevalence in industrial populations (eg, among workers who use machine cutting oils). ATLL is endemic in areas with a high prevalence of HTLV-1 infection, such as southwest Japan, the Caribbean islands, South America, and parts of Central Africa. ATLL occurs in 1-5% of seropositive individuals after more than 2 decades of viral persistence.⁸ Nasal NK/T-cell lymphoma, which is associated with EBV infection, is more common in Asia, Central America, and South America.

Race

In the United States, CTCL is more common among Americans of sub-Saharan African lineage than those of European background, in a ratio of approximately 2:1.

Sex

CTCL is more common in men in a ratio of approximately 2:1.

Age

Most patients with CTCL are middle-aged or elderly. Many patients have had a poorly defined form of dermatitis for many years prior to the onset of CTCL. In a significant proportion of cases, the onset of the disease, or of a dermatitic precursor of the disease, occurred in childhood. CTCL starting in children younger than 10 years is exceedingly rare and does not show a male predominance; one series even reported a strong female predilection. Similar to adult patients, however, most children present in stage IA or IB and have a good-to-excellent prognosis with treatment, although cases progressing to plaque, tumor-stage disease, and death have been reported. Some patients with limited MF are described as having Woringer-Kolopp–type pagetoid reticulosis. These patients are usually middle-aged, with an age distribution in one series ranging from 13-68 years and a mean age of 55 years.

Clinical

History

Classic MF

Classic cutaneous T-cell lymphoma (CTCL) or mycosis fungoides (MF) is divided into 3 stages: patch (atrophic or nonatrophic), plaque, and tumor. Often, the first stage goes on for many years and is characterized by a nonspecific dermatitis usually consisting of patches, often on the lower trunk and buttocks. Sometimes, these patches have a thin, wrinkled quality, often with reticulated pigmentation. In this stage, pruritus is usually minimal or absent.

Stages IA and IB

Classic MF is usually preceded by a nonspecific indolent inflammatory process, manifesting as atopic dermatitis, nonspecific chronic dermatitis, or parapsoriasis, most commonly large-plaque parapsoriasis, which may progress over years to decades to early plaque-stage MF. Some authorities regard large-plaque parapsoriasis as patch-stage MF. In many cases, the disease never progresses beyond this stage, and the diagnosis of MF is never confirmed. In other cases, the disease appears from the beginning as rather well-defined superficial plaques that range from 2 cm to more than 20 cm in greatest diameter.

While well-developed plaques that are clinically diagnostic for MF are usually intensely pruritic, less characteristic ones typically are not, and the development of pruritus in such lesions is a sign of progression towards MF. Depending on whether the lesions involve up to 10% or involve 10% or more of the body surface, such cases are classified as stage IA or IB, respectively. Many cases remain at these stages for many years or decades without further progression.

Stages IIA and IIB

Clinical lymphadenopathy may develop (stage IIA), sometimes with progression of the plaques to form tumors (stage IIB), or tumors may form from plaques in the absence of lymphadenopathy (stage IIB). Either process usually takes years or even decades to develop. Once tumors form, they are prone to ulceration.

D'emblee MF

The sudden multifocal development tumors of apparent MF may rarely occur without preceding patches or plaques. Most, if not all, such cases probably represent primary cutaneous CD30⁺ pleomorphic, medium or large cell T-cell lymphomas.

Stage IVA and stage IVB

Development of lymph nodes histologically positive for tumor (stage IVA) and/or visceral lesions (stage IVB) may occur rather rapidly after tumor-stage disease develops and/or clinical lymphadenopathy is detected. Alternatively, either or both may arise from erythrodermic disease (stage III) at a very variable rate. Both are associated with a poor prognosis.

Transformation of MF

MF in any stage may suddenly become much more aggressive, progressing rapidly to more advanced stages. This is associated with the histologic appearance of large atypical cells; often, these are CD30⁺, and the process is termed large cell transformation.

Pagetoid reticulosis, localized (Woringer-Kolopp) type

Patients with this condition are usually first seen with a solitary psoriasiform or hyperkeratotic patch or plaque, which is usually localized on the extremities; it is slowly progressive. In contrast to classic MF, extracutaneous dissemination or disease-related deaths rarely occur.

Multilesional pagetoid reticulosis (Ketron-Goodman disease) has a clinical course similar to MF and is regarded as a variant of MF. Some cases may actually represent primary cutaneous epidermotropic CD8⁺ (cytotoxic) T-cell lymphoma.

Erythrodermic (stage III) MF

MF evident as an erythroderma but with too few circulating lymphocytes to warrant a diagnosis of SS is designated erythrodermic MF. Dermatopathic lymphadenopathy is present in these cases.

Variants of MF

• Folliculotropic MF (FMF) is commonly first evident clinically with alopecia, follicular cysts, or comedolike lesions and is usually associated with follicular mucinosis and strong epidermotropism.¹⁸ When mucin is present, the disease is also called alopecia mucinosa. However, the benign form of alopecia mucinosa, not associated with MF, must be distinguished from MF associated with mucinosis. The most relevant feature, with and without associated follicular mucinosis, is the deep follicular and perifollicular localization of the neoplastic infiltrates, which makes them less accessible to skin-targeted therapies.
• Hypopigmented MF tends to occur in young, slightly to moderately dark-skinned people of Indian, Latin American, or sub-Saharan African American heritage. It manifests as irregular but fairly well-demarcated hypopigmented or white patches. They are asymptomatic or are slightly pruritic and may appear with or without other lesions typical of MF.
• A granulomatous reaction pattern occasionally is seen in MF and its variants.
• Bullous MF manifests with flaccid, tense, or ruptured bullae arising on normal skin, an erythematous base, or within typical patch- or plaque-stage lesions of MF. It tends to arise on the trunk and extremities. Rarely, it may clinically resemble pemphigus vulgaris or even erythema multiforme.
• Pustular MF is often limited to the palms, but the lesions may occur elsewhere.
• Hyperpigmented MF is diffuse macular hyperpigmentation accompanied by typical MF, or, rarely, the hyperpigmentation may be the only manifestation. These lesions may resemble ashy dermatosis or may appear as more or less well-defined macules. Ultrastructural studies have revealed atypical lymphocytes and keratinocytes, macrophages, and Langerhans cells that contain giant melanosomes within lysosomes.
• Unilesional MF manifests as a single area of otherwise typical MF that, by definition, comprises a single lesion. Histological changes are identical to those that occur with multiple disseminated lesions of MF. The prognosis is excellent following treatment, although it may recur after surgical excision. In addition to hair follicles, atypical cells in MF may rarely be tropic to eccrine glands. In the even rarer syringotropic MF (syringolymphoid hyperplasia), these are the principal or only lesions observed. Both the eccrine duct and the eccrine gland are typically involved and eccrine epithelium may appear hyperchromatic and atypical, mimicking eccrine carcinoma. Lesions manifest as red to skin-colored papules, red-to-brown patches, or red scaly plaques. Hair loss without mucinous degeneration in the affected areas is common. All reported cases to date have been in men.
• Pagetoid reticulosis (Woringer-Kolopp disease) arises preferentially on acral skin as a single, slowly growing psoriasiform plaque. Dissemination or extracutaneous manifestation does not occur. The histologic hallmark of the disease is the pagetoid spread of haloed lymphoid cells in the epidermis.
• Poikilodermic MF is when poikiloderma (ie, poikiloderma vasculare atrophicans, which is a combination of atrophic, dry, dyspigmented skin and telangiectasia) develops in cases of otherwise typical MF; this is not an infrequent occurrence. Occasionally, it may predominate or even be the only presenting manifestation of the disease. It may rarely involve skin over the entire body.
• Other variants of MF include hyperkeratotic/verrucous and vegetating/papillomatous MF, typically arising in the axillae, perineum, cervical area (neck), and sometimes on the breasts near the areolae, resembling acanthosis nigricans or multiple seborrheic keratosis.
• Persistent pigmented purpuralike-to-lichenoid processes also may be a manifestation of MF.
• Mucosal involvement by MF is rare and may occur as part of generalized involvement in advanced cases, particularly those that have undergone large cell transformation; it is a poor prognostic sign.
• GSS syndrome is a distinct subtype of MF characterized by ponderous, more-or-less infiltrated folds of skin that arise slowly in intertriginous areas, especially the axillae and groin. GSS syndrome may give rise to Hodgkin disease.

The combination of erythroderma and leukemia is defined as SS. However, different clinicians use different criteria regarding the number of circulating atypical lymphocytes sufficient to warrant this diagnosis. According to some, the diagnosis is established in an erythrodermic patient if more than 5% of peripheral lymphocytes are atypical. Others use the absolute number of atypical lymphocytes in the peripheral blood (>1000/µL). In obvious cases, some use a quick and easy criterion of greater than 10 CD4⁺ T cells for every CD8⁺ T cell.

Lymphadenopathy is usually present, and the skin itself is usually edematous. Other frequently observed changes include palmar and/or plantar hyperkeratosis, alopecia, nail dystrophy, and ectropion. Hepatosplenomegaly may be present. As in other forms of MF, a nonspecific dermatitis and/or pruritus may precede the disease. Transformation of the disease to a more aggressive form is common. It may occur in lymph nodes even as skin lesions are showing improvement or a response to treatment.

Extranodal nasal-type NK/T-cell lymphoma is an EBV-positive lymphoma of small, medium, or large cells with an NK-cell or cytotoxic T-cell phenotype.¹⁹

Physical

Mycosis fungoides (MF) is a commonly epidermotropic cutaneous T-cell lymphoma (CTCL) characterized by small-to-medium T lymphocytes with cerebriform nuclei. The term MF is used only for the classic Alibert-Bazin type characterized by the evolution of patches, plaques, and tumors or for variants showing a similar clinical course. MF is the most common form of CTCL and accounts for almost 50% of all primary cutaneous lymphomas. MF has an indolent clinical course with slow progression over years or decades, from patches to more infiltrated plaques and, eventually, tumors.

• Initially, MF has a predilection for the buttocks and other sun-protected areas. In tumor-stage MF, the usual presentation is a combination of patches, plaques, and tumors; the tumors often show ulceration. However, if only tumors are present, without preceding or concurrent patches or plaques, a diagnosis of MF is highly unlikely and another type of CTCL should be considered.^1,2
• SS occurs almost exclusively in adults. It is characterized by erythroderma, often associated with marked pruritus and exfoliation, edema, and lichenification. Lymphadenopathy, alopecia, onychodystrophy, and palmoplantar hyperkeratosis are commonly associated.
• GSS syndrome shows circumscribed areas of pendulous lax skin with a predilection for the axillae and groin. An association with Hodgkin lymphoma or with classic MF may be apparent.²⁰ Most patients have an indolent clinical course.
• Acute ATLL is characterized by the presence of leukemia, lymphadenopathy, organomegaly, hypercalcemia, and, in approximately 50%, skin lesions. Skin lesions most commonly include nodules or tumors (33%), generalized papules (22%), or plaques (19%).⁸ Chronic and smoldering variants frequently manifest as skin lesions that closely resemble MF, whereas circulating neoplastic T cells are few or absent.
• SPTL is a rare form of CTCL; only alpha/beta-types are included. Patients are usually first seen with solitary or multiple nodules and plaques, mainly involving the legs, although they may be more generalized. Ulceration is uncommon, but systemic symptoms such as fever, fatigue, and weight loss may be present. A hemophagocytic syndrome may be present and is generally associated with a rapidly progressive course.²¹ Dissemination to extracutaneous sites is unusual. SPTL may be preceded for years or decades by a seemingly benign panniculitis suggestive of chronic erythema nodosum. Rarely, it may produce scalp alopecia.²²
• Primary cutaneous PTL, unspecified, is a heterogeneous group of diseases for which the common characteristic is a lack of typical features of MF.
• Cutaneous gamma/delta T-cell lymphoma¹² belongs to the PTL group.^2,3 It usually has an aggressive course and manifests with disseminated plaques and/or ulceronecrotic nodules or tumors, particularly on the extremities.²³
• Primary cutaneous aggressive epidermotropic CD8⁺ cytotoxic T-cell lymphoma, provisional entity, manifests localized or disseminated eruptive papules, nodules, and tumors that show central ulceration and necrosis or superficial, hyperkeratotic patches and plaques.^5,24
• Primary cutaneous CD4⁺ small/medium-sized pleomorphic T-cell lymphoma tends to be first apparent as a solitary plaque or tumor, generally on the face, neck, or upper trunk, although it may less commonly appear as one or several papules, nodules, or tumors.^17,25
• Extranodal NK/T-cell lymphoma, nasal type, usually appears as a midfacial destructive tumor or multiple plaques or tumors, often with ulceration, preferentially on the trunk and extremities. Systemic symptoms such as fever, malaise, and weight loss may be present, and some cases are accompanied by a hemophagocytic syndrome. Extranodal NK/T-cell lymphoma, nasal type, has a variant that clinically resembles hydroa vacciniforme in which children, mainly in Latin America and Asia, have a papulovesicular eruption that typically occurs on sun-exposed areas such as the face and upper extremities.^26,27

Causes

Chemical, physical, and microbial irritants have been discussed, but evidence related to an etiology is not convincing.¹ They may play the role of a persistent antigen, which, in a stepwise process, leads to an accumulation of mutations in oncogenes, suppressor genes, and signal-transducing genes.³

Differential Diagnoses

Other Problems to Be Considered

Erythroderma, nonlymphomatous
Erythema neurolyticum migrans

At times, disseminated infections such as leishmaniasis, leprosy, South American blastomycosis, coccidioidomycosis, and other deep fungal infections may mimic and require distinction from CTCL. Acne vulgaris, epidermal inclusion cysts, and insect bites may resemble FMF.

Workup

Laboratory Studies

• For cutaneous T-cell lymphomas (CTCLs) or mycosis fungoides (MF), clinical features, the history of the disease, and histomorphology and cytomorphology findings yield clues that lead to a diagnosis in most cases. However, demonstration of a dominant T-cell clone in skin biopsy specimens by a molecular assay (ie, Southern blot, polymerase chain reaction) constitutes an additional diagnostic criterion to distinguish CTCLs from inflammatory dermatoses.
• The diagnosis of SS should include one or more of the following⁷ :
  • An absolute Sézary cell count of least 1000 cells/µL
  • Demonstration of immunophenotypical abnormalities (an expanded CD4⁺ T-cell population resulting in a CD4/CD8 ratio of more than 10; 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: Flow cytometry may be useful for differential diagnosis of precursor and peripheral T-cell and NK-cell lymphomas.²⁸
• Following a diagnostic algorithm for the evaluation and diagnosis of erythroderma due to CTCL versus "reactive" causes of erythroderma may be helpful.²⁹
• See Histologic Findings.¹

Other Tests

• Neoplastic MF cells have a mature CD3⁺, CD4⁺, CD45RO⁺, CD8^- memory T-cell phenotype. Rarely, otherwise-classic MF may have a CD4^-, CD8⁺ mature T-cell phenotype.³⁰ An aberrant phenotype, such as loss of pan–T cell antigens (eg, CD2, CD3, CD5), is not unusual.
• An identical phenotype is seen in GSS syndrome and SS. Clonal T-cell receptor gene rearrangements are detected in most MF cases.³¹ Many structural and numerical chromosomal abnormalities have been described in the advanced stages of MF, but recurrent, MF-specific chromosomal translocations have not been identified. Chromosomal loss at 10q and abnormalities in P15, P16, and TP53 tumor suppressor genes are often evident with MF.
• The neoplastic T cells in pagetoid reticulosis may have either a CD3⁺, CD4⁺, CD8^- phenotype or a CD3⁺, CD4^-, CD8⁺ phenotype, with CD30 often being expressed.³²
• Genetic features show T-cell receptor genes to be clonally rearranged in persons with MF, GSS syndrome, or SS. Demonstration of clonal T cells in the peripheral blood is an important diagnostic criterion that allows differentiation between SS and benign forms of erythroderma.⁷ Recurrent chromosomal translocations are not detected in persons with SS, but complex karyotypes are common, as is a consistent pattern of identical chromosomal abnormalities in SS as seen in MF.³³
• The neoplastic T cells in ATLL express a CD3⁺, CD4⁺, CD8^- phenotype, with CD25 being highly expressed.⁸ T-cell receptor genes (TCR) are clonally rearranged; clonally integrated HTLV-1 genes are present and are useful in differentiating between chronic or smoldering variants of ATLL and classic MF or SS.
• Panniculitislike T-cell lymphoma shows an alpha/beta⁺, CD3⁺, CD4^-, CD8⁺ T-cell phenotype, with expression of cytotoxic proteins.¹¹ CD30 and CD56 are not expressed. Neoplastic T cells do show clonal TCR gene rearrangements, although neither specific genetic abnormalities nor EBV has been identified.
• Extranodal NK/T-cell lymphoma, nasal type, has neoplastic cells that express CD2, CD56, and cytoplasmic CD3.

Histologic Findings

In MF plaques, the histologic changes are diagnostic; epidermotropism is generally more pronounced than in MF patches. The presence of intraepidermal collections of atypical cells (Pautrier microabscesses) is a highly characteristic feature observed in only a minority of cases (10%). In the tumor stage, the dermal infiltrates become more diffuse and epidermotropism may be lost. The tumor cells increase in number and size, demonstrating variable proportions of small, medium, and large cerebriform blast cells with prominent nuclei and intermediate forms. Transformation to a diffuse large cell lymphoma of either CD30- or CD30⁺ phenotype may occur, portending a poor prognosis. Eosinophils, plasma cells, and histiocytes are frequent companions.

Folliculocentric MF shows a primarily perivascular and periadnexal localization of the dermal infiltrate with variable involvement of the follicular epithelium by small, medium, or sometimes large hyperchromatic cells with cerebriform nuclei and sparing of the epidermis (folliculotropism instead of epidermotropism).¹ Most have mucinous degeneration of the follicular epithelium (follicular mucinosis), best demonstrated with Alcian blue staining, and an admixture of eosinophils and sometimes plasma cells. Prominent infiltration of both follicular epithelium and eccrine sweat glands is often observed. Similar cases with prominent infiltration of eccrine sweat glands, often seen with alopecia, have been called syringotropic MF.³⁸ Basaloid folliculolymphoid hyperplasia is a distinctive finding in follicular MF.³⁹

Granulomatous MF shows sarcoidal, granuloma annulare–like, or giant cell–rich reactions.

GSS syndrome shows a dermal infiltrate composed of atypical T cells with a dissemination of many multinucleated giant cells containing fragments of elastic fibers.

Pagetoid reticulosis (Woringer-Kolopp disease) shows a hyperplastic epidermis with marked pagetoid infiltration by atypical haloed lymphoid cells, singly or arranged in nests. The upper dermis has a mixed infiltrate of lymphocytes or histiocytes.

The histology of SS may be nonspecific, but it is often similar to MF, although the cellular infiltrates in SS are more often monotonous,^40,41  and epidermotropism may sometimes be absent. Involved lymph nodes have a dense, monotonous infiltrate of Sézary cells with effacement of the normal lymph node architecture, whereas bone marrow infiltrates, when present, are often sparse and mainly interstitial.⁴²

In ATLL, the cutaneous nodules show a superficial or more diffuse infiltration of medium-to-large T cells with pleomorphic or multilobated nuclei, often with marked epidermotropism. The histologic picture may be the same as is seen with MF. In the smoldering type of ATLL, dermal infiltrates may be sparse, with only slightly atypical cells.

In SPTL, subcutaneous infiltrates simulate a panniculitis and show small, medium, or sometimes large pleomorphic T cells with hyperchromatic nuclei and often many macrophages.¹² The overlying epidermis and dermis are typically not involved.⁴³ Rimming of individual fat cells by neoplastic T cells is a helpful, although not completely specific, diagnostic feature.¹¹ Necrosis, karyorrhexis, and cytophagocytosis are common.

Primary cutaneous aggressive epidermotropic CD8⁺ cytotoxic T-cell lymphoma, characterized by a proliferation of epidermotropic CD8⁺ cytotoxic T cells, has an acanthotic or atrophic epidermis, necrotic keratinocytes, ulceration, and variable spongiosis, sometimes with blister formation.^5,24 Epidermotropism tends to be marked, ranging from a linear distribution to a pagetoid pattern throughout the epidermis.

CGD-TCL has 3 major histologic patterns of involvement that can be present in the skin: epidermotropic, dermal, and subcutaneous.¹² More than 1 is often present in the same patient in different biopsy specimens or within a single biopsy specimen.²³ The lymphoma cells are generally medium to large with coarsely clumped chromatin, with large blastic cells with vesicular nuclei and prominent nucleoli being infrequent and apoptosis and necrosis common, often with angioinvasion. The subcutaneous involvement may demonstrate rimming of fat cells.

Primary cutaneous CD4⁺ small/medium-sized pleomorphic T-cell lymphoma shows dense, diffuse, or nodular infiltrates within the dermis with a tendency to infiltrate the subcutis, and epidermotropism is often present focally. A predominance of small/medium-sized pleomorphic T cells may be seen, with a smaller proportion of large pleomorphic cells present.⁴⁴

Extranodal NK/T-cell lymphoma, nasal type, has dense dermal and often subcutaneous infiltrates with prominent angiocentricity and angiodestruction, often accompanied by extensive necrosis.^45,46

Primary cutaneous aggressive epidermotropic CD8⁺ cytotoxic T-cell lymphoma has a beta-F1⁺, CD3⁺, CD8⁺, granzymes-B⁺, perforin⁺, TIA-1⁺, CD45RA⁺, CD45RO, CD2^-, CD4^-, CD5^-, CD7^+/- phenotype.^17,24 It is usually associated with EBV seronegativity. The lymphoma cells show clonal TCR gene rearrangements, although specific genetic abnormalities have not been described.

CGD-TCL¹² lymphoma cells are generally of beta-F1^-, CD3⁺, CD2⁺, CD5^-, CD7^+/-, CD56⁺ phenotype with strong expression of cytotoxic proteins. Most lack both CD4 and CD8, although CD8 may be expressed in some cases.^23,47 In frozen-section specimens, the lymphoma cells are strongly positive for TCR-delta. If only paraffin sections are available, the absence of beta-F1 may be used to infer a gamma/delta origin.⁴⁸ The lymphoma cells show clonal rearrangement of the TCR -gamma gene, while TCR -beta may be rearranged or deleted, but it is not expressed. EBV test results are usually negative.²³

Primary cutaneous CD4⁺ small/medium-sized pleomorphic T-cell lymphoma, a CD3⁺, CD4⁺, CD8^-, CD30^- phenotypic lymphoma, sometimes has loss of pan–T-cell markers. Cytotoxic proteins are generally not expressed.¹⁷ The TCR genes are clonally rearranged.²⁵

Primary cutaneous PTL, type unspecified, shows an aberrant CD4⁺ T-cell phenotype with variable loss of pan–T-cell antigens. CD30 staining is negative or restricted to a few scattered tumor cells. Rare cases may show coexpression of CD56. Expression of cytotoxic proteins is uncommon.¹⁷

Staging

The staging systems for CTCL have been primarily designed to describe cases of MF and SS, but they also apply to the other entities within the CTCLs. In MF and SS and in many of these other diseases, the stage of the disease largely determines the prognosis.

Clinical staging of CTCL is straightforward; if patches and/or plaques, but no erythroderma or involvement of lymph nodes or viscera is present, the disease is in stage IA.

If the cutaneous involvement is less than 10% of the total body surface, the stage is IA. It is stage IB if 10% or more of the body surface is involved. If enlarged lymph nodes, histologically uninvolved with lymphoma, are also present, the disease is in stage IIA regardless of the extent of cutaneous involvement.

If skin tumors of lymphoma are present but no histologically proven internal involvement or erythroderma is present, the disease is in stage IIB, regardless of whether lymphadenopathy, patches, and/or plaques are also present. If erythroderma (ie, whole-body erythema) is present but histologically proven involvement of lymph nodes or viscera is not, the disease is in stage III, regardless of whether lymphadenopathy is noted.

If lymph nodes are involved with histologically proven lymphoma, the disease is in stage IVA. If viscera are involved with histologically proven lymphoma, it is in stage IVB.

These definitions are denoted in Table 1. Table 2 lists the TNMB (tumor, node, metastasis, blood) stage definitions. Table 3 is a comparison of the 2 systems.

Treatment

Medical Care

• When mycosis fungoides (MF) is confined to the skin (cutaneous T-cell lymphoma [CTCL]), skin-targeted therapies such as topical corticosteroids, heliotherapy, photochemotherapy (eg, psoralen plus UV-A [PUVA]), topical application of nitrogen mustard (mechlorethamine) or carmustine (BCNU), or radiotherapy, including total skin electron beam irradiation, are often effective a controlling manifestations.⁴⁹ Bexarotene is also sometimes used for disease confined to the skin. Psoriatic doses of methotrexate have been used, but some concern exists relating to large cell transformation occasionally observed in these patients.
• Treatment of stages T1 and T2 MF with total skin electron beam therapy is highly effective in early-stage MF without adjuvant therapy. Management of relapses with local radiotherapy or a second round of total skin electron beam irradiation is feasible, timesaving, and cost-effective.⁵⁰ In patients with limited patch-stage MF, topical steroids or bexarotene gel can be used.
• Tazarotene, long-term and low-dose oral etoposide, and imiquimod may be of value in the treatment of early CTCL.^51,52 One small pilot study showed tazarotene 0.1% gel to be a well-tolerated and effective adjuvant topical therapy for the treatment of refractory MF.⁵³
• Biological agents such as interferon alfa and other cytokines (eg, interleukin 2 [IL-2]), traditional and new retinoids such as bexarotene, and receptor-targeted cytotoxic fusion proteins (eg, DAB389I-2; denileukin diftitox) are increasingly being used. Combination therapy with bexarotene and PUVA should be considered for patients with treatment-resistant CTCL refractory to monotherapy.⁵⁴ However, the precise use of these new treatments, either as single-agent therapy or in combination with other therapies (eg, PUVA) in the treatment of MF, remains to be established.
• Multiagent chemotherapy is used with unequivocal lymph node or systemic involvement or in cases with widespread tumor-stage MF that is refractory to skin-targeted therapies and is not early patch/plaque-stage disease.
• Perifollicular localization of the dermal infiltrates in FMF is often less responsive to skin-targeted therapies (eg, PUVA, topical nitrogen mustard) than classic plaque-stage MF, and total skin electron beam irradiation is superior.⁵⁵ However, because sustained complete remissions are rarely achieved with electron beam therapy, PUVA combined with retinoids or interferon alfa should be considered, although persistent tumors can be effectively treated with local radiotherapy. Follicular CTCL may benefit from isotretinoin for persistent cysts and comedones.⁵⁶ Early syringotropic CTCL may be treated with local radiotherapy, with excellent local control.⁵⁷
• Extracorporeal photopheresis, either alone or in combination with other treatment modalities (eg, interferon alfa), is an effective treatment for SS and erythrodermic MF, with overall response rates of 30-80% and complete response rates of 14-25%.⁵⁸ The alleged superiority of extracorporeal photopheresis over the traditional low-dose chemotherapy regimens has not been proven. Beneficial results have also been described with interferon alfa, either alone or in combination with PUVA therapy, prolonged treatment with a combination of low-dose chlorambucil (2-4 mg/d) and prednisone (10-20 mg/d), or with methotrexate (MTX) (5-25 mg/wk), but complete responses are uncommon. Skin-directed therapies such as PUVA or potent topical steroids are good adjuvant therapies. Beneficial effects of bexarotene and alemtuzumab (anti-CD52) have been noted, but the long-term effects of these therapies remain to be established.⁵⁹
• Unrelated cord blood transplantation is a possible therapeutic option.⁶⁰ In one patient, it was given following myeloablative conditioning, which brought a complete remission. Although a relapse occurred 3 months later, discontinuation of immune suppressant therapy led to MF regression and a second complete remission that continued for more than 23 months.

Surgical Care

Localized MF may benefit from a number of therapeutic modalities, including radiotherapy, intralesional steroids, or surgical excision. One option is to excise a patch or plaque with a 0.5-cm margin and then control subsequent disease with either irradiation or photochemotherapy with PUVA, photodynamic therapy, or carbon dioxide laser surgery.⁶¹ Localized radiation or a surgical approach to localized MF can be used, with the latter having the advantage that a full dose of radiation can be delivered in the same location at a later time, thus preserving options for future therapy.

Medication

Cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of entities. One should distinguish indolent, low-risk mycosis fungoides (MF) and SS from aggressive HTLV-1–associated ATLL.⁶² Treatment for early-stage CTCL includes topical therapies with or without interferon alfa or oral agents, while advanced-stage patients often progress and are treated with chemotherapy and novel agents. Multiagent cytotoxic regimens may be palliative, but they seem to lack a demonstrated survival benefit.⁶³
 
Novel therapies for CTCL include bexarotene, which has demonstrated efficacy in advanced refractory CTCL. Other novel agents include the IL-2 fusion toxin (Ontak), IL-12, pentostatin (a potent adenosine deaminase inhibitor), histone deacetylase inhibitors (eg, depsipeptide), NF-kappa-B inhibitors, cytokine-receptor antagonists, immunomodulatory therapies, and allogeneic stem cell therapy. The value of new therapeutic approaches to CTCL needs to be critically assessed in regard to overall survival and disease-specific survival.

Chemotherapy agents

Inhibit neoplastic growth.

Chlorambucil (Leukeran)

Alkylates and cross-links strands of DNA, inhibiting DNA replication and RNA transcription.

Dosing

Adult

0.1-0.2 mg/kg/d PO or 3-6 mg/m²/d PO for 3-6 wk; adjust dose depending on blood cell counts or combine in low dose (2-4 mg/d) with prednisone (10-20 mg/d) or MTX (5-25 mg/wk) for SS

Pediatric

Not established for SS
0.1-0.2 mg/kg/d PO or 4.5 mg/m²/d for 3-6 wk; adjust dose depending on blood cell counts

Interactions

None reported

Contraindications

Documented hypersensitivity; previous resistance to medication

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in history of seizure disorders or patients diagnosed with bone marrow suppression

Vorinostat (Zolinza)

Histone deacetylase (HDAC) inhibitor. HDAC inhibition results in hypoacetylation of core nucleosomal histones, condenses chromatin structure, and represses gene transcription. Indicated for treatment of progressive, persistent, or recurrent CTCL.

Dosing

Adult

400 mg PO qd with food; if intolerant to therapy, may decrease dose to 300 mg PO qd; if necessary, further reduce to 300 mg PO qd for 5 consecutive days qwk

Pediatric

Not established

Interactions

Coadministration with other HDAC inhibitors (eg, valproic acid) has caused severe thrombocytopenia and GI bleeding; coadministration with warfarin prolongs PT and INR

Contraindications

None known

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Common adverse effects include diarrhea, nausea, anorexia, weight loss, vomiting, and constipation (antiemetics, antidiarrheals, or fluid and electrolyte replacement may be required to prevent dehydration); also commonly causes fatigue or chills; pulmonary embolism and deep vein thrombosis have been reported; dose-related thrombocytopenia and anemia have occurred (may require dose reduction or discontinuance); may cause hyperglycemia; data limited on effect on QTc (monitor potassium, magnesium, and calcium levels and perform periodic ECGs); data limited in patients with renal or hepatic insufficiency

Methotrexate (Trexall)

Folic acid antagonist inhibits dihydrofolate reductase, an enzyme needed to make DNA.

Dosing

Adult

5-25 mg/wk, with interferon alfa

Pediatric

Not established

Interactions

Oral aminoglycosides may decrease absorption and blood levels of concurrent oral MTX; charcoal lowers MTX levels; coadministration with etretinate may increase hepatotoxicity of MTX; folic acid or its derivatives contained in some vitamins may decrease response to MTX
Probenecid, NSAIDs, salicylates, procarbazine, and sulfonamides (including TMP-SMZ) can increase MTX plasma levels; may decrease phenytoin plasma levels; may increase plasma levels of thiopurines

Contraindications

Documented hypersensitivity; alcoholism; hepatic insufficiency; documented immunodeficiency syndromes; preexisting blood dyscrasias (eg, bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia); renal insufficiency

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Monitor CBC counts monthly and liver and renal function q1-3mo during therapy (monitor more frequently during initial dosing, dose adjustments, or when risk of elevated MTX levels (eg, dehydration); has toxic effects on hematologic, renal, GI, pulmonary, and neurologic systems; discontinue if significant drop in blood cell counts occurs; fatal reactions reported when administered concurrently with NSAIDs

Etoposide (VePesid, Toposar)

Inhibits topoisomerase II and causes DNA strand breakage, resulting in arrest of cell proliferation in late S or early G2 portion of cell cycle.

Dosing

Adult

100 mg/m² IV for days 1-5

Pediatric

Not established

Interactions

May prolong effects of warfarin and increase clearance of MTX; cyclosporine and etoposide have additive effects in cytotoxicity of tumor cells

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Bleeding and severe myelosuppression may occur

Romidepsin (Istodax)

Histone deacetylase (HDAC) inhibitor. Indicated for cutaneous T-cell lymphoma in patients who have received at least 1 prior systemic therapy.

Dosing

Adult

14 mg/m² IV infused over 4 h on days 1, 8, and 15 of 28-d cycle
Treatment discontinuation or interruption with or without dose reduction to 10 mg/m² may be required to manage adverse effects

Pediatric

Not established

Interactions

Binds to estrogen and may reduce effectiveness of estrogen-containing contraceptives; may increase effect of warfarin (prolonged PT, increased INR) when coadministered; coadministration with other drugs that prolong QT interval (eg, sotalol, dofetilide, erythromycin) may increase risk for serious arrhythmias
Strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase serum levels
Potent CYP3A4 inducers (eg, dexamethasone, carbamazepine, phenytoin, rifampin, rifabutin, rifapentine, phenobarbital, St. John's wort) may decrease serum levels

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Common adverse effects include nausea, vomiting, anorexia fatigue, infections, anemia, thrombocytopenia, and leukopenia; may prolong QT interval and induce arrhythmias (monitor electrolyte [potassium, magnesium]) levels; monitor ECG in patients at risk for arrhythmia (eg, congenital long QT syndrome, history of significant cardiovascular disease, coadministration of drugs that significantly prolong QT interval)

Fusion proteins

Denileukin diftitox (Ontak)

Fusion protein (amino acid sequence of diphtheria linked to IL-2 amino acid sequence) that selectively delivers cytotoxic activity of diphtheria toxin to targeted cells. Used only in T-cell lymphoma whose malignant cells express CD25 component of IL-2 receptor. Interacts with high-affinity IL-2 receptor on surface of malignant cells to inhibit intracellular protein synthesis, which, in turn, causes cell death.

Dosing

Adult

9-18 mcg/kg/d IV for 5 consecutive days administered q21d; duration of treatment not established; <2% response rate reported if no response by fourth cycle

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May impair immune function; associated with delayed-onset vascular leak syndrome (may occur within first 2 wk of infusion and persist or worsen after cessation); preexisting low serum albumin level may predispose or predict vascular leak syndrome; caution in preexisting cardiovascular disease and age >65 y; edema, hypotension, tachycardia, chest pain, headache, pain, nervousness, dizziness, hypocalcemia, and weight loss may occur

Bexarotene gel (Targretin Gel)

X-receptor–specific retinoid. May inhibit sebaceous gland differentiation and abnormal keratinization. Retinoid X-receptor–selective agonist.

Dosing

Adult

1% gel qd qod for first week, then qd for 1 wk, then increase to up to qid

Pediatric

Not established

Interactions

Contraindications

Pregnancy, documented hypersensitivity to medication or its class, vitamin A supplementation, diabetes mellitus if on insulin, or in patients taking gemfibrozil

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Bexarotene (Targretin)

An X-receptor–specific retinoid. May inhibit sebaceous gland differentiation and abnormal keratinization.

Dosing

Adult

300 mg/m²/d PO single dose w/meal; may be given with PUVA for treatment of resistant CTCL

Pediatric

Not established

Interactions

On basis of metabolism of bexarotene by cytochrome P-450 3A4, ketoconazole, itraconazole, erythromycin, gemfibrozil, grapefruit juice, and other inhibitors of cytochrome P-450 3A4 may increase serum levels; rifampin, phenytoin, phenobarbital, and other inducers of cytochrome P-450 3A4 may reduce plasma; caution when administering to patients using insulin, agents enhancing insulin secretion, or insulin sensitizers (may enhance their action)

Contraindications

Documented hypersensitivity; uncontrolled hyperlipidemia or hypothyroidism before drug initiation; do not administer to patients with risk factors for pancreatitis

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

When used in women of childbearing potential, obtain a negative pregnancy test 1 wk prior to therapy and monthly thereafter; instruct women of childbearing potential to use 2 reliable forms of contraception simultaneously, unless abstinence is the chosen method of contraception, for 1 mo prior, during, and 1 mo following discontinuation of drug; instruct male patients with sexual partners who are pregnant or have childbearing potential to use condoms during sexual intercourse while taking the drug and 1 mo afterward; perform fasting blood lipid determinations before therapy is initiated and qwk until lipid response to drug is established; obtain and serially monitor baseline CBC counts, liver function, and thyroid function tests; advise patients to limit vitamin A supplements and minimize exposure to sunlight and artificial UV

Biological response modulators

Immunomodulator/biologic agents.

Interferon alfa-2a (Intron-A)

Protein product manufactured by recombinant DNA technology. Mechanism of antitumor activity is not clearly understood; however, direct antiproliferative effects against malignant cells and modulation of host immune response may play important roles.

Dosing

Adult

Induction: 36 million U/d for 10-12 wk IM/SC
Maintenance: 36 million U 3 times/wk IM/SC (may escalate dose to 3-9-18 million U qd over 3 consecutive days followed by 36 million U/d for remaining 10-12 wk)

Pediatric

Not established

Interactions

Theophylline may increase toxicity by reducing clearance; cimetidine may increase antitumor effects; zidovudine and vinblastine may increase toxicity

Contraindications

Documented hypersensitivity; avoid in patients who have anaphylactic sensitivity to mouse immunoglobulin (IgG), egg protein, or neomycin; autoimmune hepatitis

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Depression and suicidal ideation may be adverse effects of treatment; infrequently, severe or fatal GI hemorrhage reported in association with therapy
Regarding bone marrow suppression, prior to initiation of therapy, perform tests to quantitate peripheral blood hemoglobin, platelets, granulocytes, hairy cells, and bone marrow hairy cells
Monitor patient periodically (eg, monthly) during treatment to determine response to treatment; if patient does not respond within 6 mo, discontinue treatment; if response occurs, continue treatment until no further improvement observed (not known whether continued treatment after that time is beneficial)

Antineoplastic agents

Monoclonal antibody against antigen on T cells.

Alemtuzumab (Campath)

Monoclonal antibody against CD52, an antigen found on B cells, T cells, and almost all CLL cells. Binds to CD52 receptor of lymphocytes, which slows proliferation of leukocytes

Dosing

Adult

3-10 mg IV over 2 h initially; titrate slowly to 30 mg and administer 3 times/wk for up to 12 wk if no adverse effects

Pediatric

Not established

Interactions

May increase virulence of live viral vaccines

Contraindications

Documented hypersensitivity; active systemic infections; underlying immunodeficiency (eg, AIDS)

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May cause pancytopenia, thrombocytopenia, autoimmune hemolytic anemia, and serious infusion reactions (premedicate with acetaminophen, diphenhydramine, and hydrocortisone, and gradually increase dose); fatal bacterial, viral, fungal, and protozoan infections reported; hypotension may occur with IV administration (can control by discontinuing or slowing rate of infusion); antibody is not selective for cancerous B cells and T cells and may eradicate all normal lymphocytes of B- and T-cell lineage (resulting lymphopenia; risk of infection can be profound and long-lasting); posttransplant lymphoproliferative disorders, nausea, and diarrhea may occur

Topical chemotherapy agents

Topical carmustine (BCNU)

Alkylates and cross-links DNA strands, inhibiting cell proliferation.

Dosing

Adult

Solution: 100 mg in 50 mL of 95% ethanol, then 5 mL solution mixed with 60 mL tap water and applied qd
Ointment: 100 mg in 50 mL 95% ethanol, then 20-40 mg mixed with 100 g of petrolatum and applied qd

Pediatric

Not established

Interactions

Coadministration with cimetidine may increase toxicity; coadministration with etoposide may cause severe hepatic dysfunction (hyperbilirubinemia, ascites, and thrombocytopenia)

Contraindications

Documented hypersensitivity; myelosuppression from previous chemotherapy; pregnancy

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in patients with depressed platelet, leukocyte, or erythrocyte count or with hepatic or renal impairment; perform baseline pulmonary function tests

Mechlorethamine solution or ointment (Mustargen)

Topical nitrogen mustard. Alkylating agent that inhibits DNA replication.

Dosing

Adult

Topical aqueous solution: 10 mg in 60 mL tap water applied qd
Topical ointment: 10 mg in 10 mL 95% absolute alcohol, then mixed with 100 g white petrolatum and applied qd

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity to medication or its class of drugs; pregnancy

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Delayed hypersensitivity (35-60%) can be overcome with use of topical steroids or desensitization; less common with use of ointment; associated with an increased risk of nonmelanoma skin cancers

Topical immune response modifiers

Imiquimod 5% cream (Aldara)

Binds to Toll-like receptors 7 and 8 and induces secretion of interferon alfa and other cytokines; mechanism of action unknown.

Dosing

Adult

Apply qd

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Retinoids

Regulate genes that control cellular differentiation and proliferation.

Alitretinoin (Panretin)

Naturally occurring endogenous retinoid. Inhibits growth of Kaposi sarcoma by binding to retinoid receptors.

Dosing

Adult

0.1% gel: Apply topically bid/qid to affected cutaneous lesions

Pediatric

Not established

Interactions

Increases toxicity of DEET if used concurrently

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Preexisting CTCL; do not use occlusive dressing; avoid UV light exposure of treated areas

Tazarotene gel (Avage, Tazorac)

Retinoid prodrug whose active metabolite modulates differentiation and proliferation of epithelial tissue; may also have anti-inflammatory and immunomodulatory properties.

Dosing

Adult

Apply thin film qd to cover lesion (2 mg/cm²); not to exceed >20% of BSA

Pediatric

Children: Not established
Adolescents: Administer as in adults

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

May cause burning or stinging sensations; discontinue if excessive irritation; rinse thoroughly if contact with eyes, eyelids, or mouth; may cause severe irritation in eczematous skin; photosensitivity may occur

Steroids

Prednisone (Deltasone)

Immunosuppressant; should be used together with other agents such low-dose chlorambucil and interferon alfa.

Dosing

Adult

10-20 mg/d with low-dose chlorambucil and interferon alfa

Pediatric

Not established for this usage

Interactions

Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics

Contraindications

Documented hypersensitivity; viral infection, peptic ulcer disease, hepatic dysfunction, connective-tissue infections, and fungal or tubercular skin infections; GI bleeding or ulceration

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Abrupt discontinuation of may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use

Follow-up

Prognosis

• The prognosis for patients with cutaneous T-cell lymphomas (CTCLs) or mycosis fungoides (MF) is dependent on stage and, in particular, the type and extent of skin lesions and the presence of extracutaneous disease.²
  • Patients with limited patch/plaque-stage MF seem to have similar life expectancies to age-, sex-, and race-matched control populations. Ten-year disease-specific survival rates were 97-98% for patients with limited patch/plaque disease (covering <10% of the skin surface), 83% for patients with generalized patch/plaque disease (covering >10% of the skin surface), 42% for patients with tumor-stage disease, and approximately 20% for patients with histologically documented lymph node involvement.
  • Patients with effaced lymph nodes, visceral involvement, and transformation to large T-cell lymphoma have an aggressive clinical course and usually die of systemic involvement or infections.
  • Blood eosinophilia at baseline may also serve as a prognostic factor in patients with primary CTCL.⁶⁴
• The prognosis associated with FMF is worse than that for classic patch- and plaque-stage MF and corresponds more closely with tumor-stage disease (stage IIB). For this reason, some authors have proposed that FMF be staged with tumor-stage disease (stage IIB). FMF has shown a disease-specific 5-year survival rate of approximately 70-80%.⁶⁵
• With SS, the prognosis is often poor, with a median survival of 2-4 years.⁶⁶ The disease-specific 5-year survival rate has been reported to be 24%, with most patients dying of opportunistic infections due to immunosuppression.
• In patients with ATLL, the clinical subtype is the main prognostic factor. Survival in persons with acute or lymphomatous variants is poor, ranging from 2 weeks to more than 1 year. Chronic and smoldering forms have a more protracted clinical course and a longer survival, but transformation into an acute phase with an aggressive course may occur.^8,67
• SPTL (with a CD8⁺, alpha/beta⁺ T-cell phenotype) tends to have a protracted clinical course with recurrent subcutaneous nodules but without extracutaneous dissemination or the development of a hemophagocytic syndrome.¹¹ The 5-year survival rate of such patients may be greater than 80%.
• Unilesional pagetoid reticulosis (Woringer-Kolopp disease) progresses slowly. Patients usually have an excellent prognosis.
• Primary cutaneous PTL, type unspecified, is associated with a poor prognosis, with 5-year survival rates of less than 20%,⁶⁸  regardless of whether it manifested with solitary/localized lesions or generalized skin lesions.¹⁷
• Primary cutaneous CD4⁺ small/medium pleomorphic T-cell lymphoma (provisional entity) is associated with a relatively favorable prognosis, with an estimated 5-year survival rate of approximately 60-80%.¹⁷ Patients first seen with solitary or localized skin lesions tend to have an excellent prognosis.
• Primary cutaneous aggressive epidermotropic CD8⁺ cytotoxic T-cell lymphoma often has an aggressive clinical course, and patients have a median survival of 32 months.⁵
• CGD-TCL patients tend to have aggressive disease resistant to multiagent chemotherapy and/or radiation, with a median survival in 1 study of only 15 months.²³ A trend for decreased survival was noted for patients with subcutaneous fat involvement in comparison with patients who had epidermal or dermal disease only.
• Nasal type NK/T-cell lymphoma manifesting in the skin is highly aggressive, and patients have a median survival of less than 12 months.^45,69 The most important factor predicting a poor outcome is the initial presence of extracutaneous involvement. Patients first seen with only cutaneous involvement had a median survival of 27 months, compared with months for patients presenting with cutaneous and extracutaneous disease.⁶⁹ CD30⁺, CD56⁺ patients seem to have a better prognosis, possibly being examples of cutaneous anaplastic large cell lymphoma with coexpression of CD56.⁷⁰
• Granulomatous CTCLs tend to be therapy resistant, with a slowly progressive course apparently worse than that of classic nongranulomatous MF.⁶

Miscellaneous

Medicolegal Pitfalls

• The principal concern is following a patient with the patch stage of MF for years without recognizing its transition into a lymphoma.

Multimedia

Media file 1: Patch-stage cutaneous T-cell lymphoma. Courtesy of Jeffrey Meffert, MD.

Media file 2: Plaque-stage parapsoriasis.

Media file 3: Patch-stage mycosis fungoides progressing to plaque stage with cutaneous cigarette-paper appearance evident.

Media file 4: Erythematous partially confluent plaques in advancing mycosis fungoides.

Media file 5: Close-up view of advancing plaque-stage mycosis fungoides with partially confluent erythematous plaques.

Media file 6: Early patch-stage cutaneous T-cell lymphoma.

Media file 7: Hypopigmented cutaneous T-cell lymphoma. Courtesy of Jeffrey Meffert, MD.

Media file 8: Hypopigmented cutaneous T-cell lymphoma. Courtesy of Jeffrey Meffert, MD.

Media file 9: Nodular mycosis fungoides.

Media file 10: Tumor-stage cutaneous T-cell lymphoma.

Media file 11: Middle-aged woman with mycosis fungoides showing ulceration and marked depigmentation of advanced disease. Same patient as in Media Files 7, 9, and 10.

Media file 12: Middle-aged woman with mycosis fungoides showing ulceration and marked depigmentation of advanced disease. Same patient as in Media Files 8-10.

Media file 13: Middle-aged woman with mycosis fungoides showing ulceration and marked depigmentation of advanced disease. Same patient as in Media Files 7-9.

Media file 14: Middle-aged woman with mycosis fungoides showing ulceration and marked depigmentation of advanced disease. Same patient as in Media Files 7, 8, and 10.

Media file 15: Mycosis fungoides with large atypical T lymphocytes in both epidermis and dermis.

Media file 16: Mycosis fungoides with epidermal nest of large atypical T cells displaying bizarre, convoluted nuclei surrounded by a clear space (Pautrier microabscess).

References

1. Burg G, Kempf W. Etiology and pathogenesis of cutaneous lymphomas. In: Burg G, Kempf W. Cutaneous Lymphomas. London: Taylor & Francis; 2005.

2. Willemze R, Jaffe ES, Burg G, Cerroni L, Berti E, Swerdlow SH, et al. WHO-EORTC classification for cutaneous lymphomas. Blood. May 15 2005;105(10):3768-85. [Medline].

3. Burg G, Kempf W, Cozzio A, Dobbeling U, Feit J, Golling P, et al. Cutaneous malignant lymphomas: update 2006. J Dtsch Dermatol Ges. Nov 2006;4(11):914-33. [Medline].

4. Khamaysi Z, Ben-Arieh Y, Izhak OB, Epelbaum R, Dann EJ, Bergman R. The Applicability of the New WHO-EORTC Classification of Primary Cutaneous Lymphomas to a Single Referral Center. Am J Dermatopathol. Feb 2008;30(1):37-44. [Medline].

5. Berti E, Tomasini D, Vermeer MH, Meijer CJ, Alessi E, Willemze R. Primary cutaneous CD8-positive epidermotropic cytotoxic T cell lymphomas. A distinct clinicopathological entity with an aggressive clinical behavior. Am J Pathol. Aug 1999;155(2):483-92. [Medline].

6. Kempf W, Ostheeren-Michaelis S, Paulli M, Lucioni M, Wechsler J, Audring H, et al. Granulomatous mycosis fungoides and granulomatous slack skin: a multicenter study of the Cutaneous Lymphoma Histopathology Task Force Group of the European Organization For Research and Treatment of Cancer (EORTC). Arch Dermatol. Dec 2008;144(12):1609-17. [Medline].

7. Vonderheid EC, Bernengo MG, Burg G, Duvic M, Heald P, Laroche L, et al. Update on erythrodermic cutaneous T-cell lymphoma: report of the International Society for Cutaneous Lymphomas. J Am Acad Dermatol. Jan 2002;46(1):95-106. [Medline].

8. Setoyama M, Katahira Y, Kanzaki T. Clinicopathologic analysis of 124 cases of adult T-cell leukemia/lymphoma with cutaneous manifestations: the smouldering type with skin manifestations has a poorer prognosis than previously thought. J Dermatol. Dec 1999;26(12):785-90. [Medline].

9. Weenig RH, Ng CS, Perniciaro C. Subcutaneous panniculitis-like T-cell lymphoma: an elusive case presenting as lipomembranous panniculitis and a review of 72 cases in the literature. Am J Dermatopathol. Jun 2001;23(3):206-15. [Medline].

10. Hoque SR, Child FJ, Whittaker SJ, Ferreira S, Orchard G, Jenner K, et al. Subcutaneous panniculitis-like T-cell lymphoma: a clinicopathological, immunophenotypic and molecular analysis of six patients. Br J Dermatol. Mar 2003;148(3):516-25. [Medline].

11. Massone C, Chott A, Metze D, Kerl K, Citarella L, Vale E, et al. Subcutaneous, blastic natural killer (NK), NK/T-cell, and other cytotoxic lymphomas of the skin: a morphologic, immunophenotypic, and molecular study of 50 patients. Am J Surg Pathol. Jun 2004;28(6):719-35. [Medline].

12. Burg G, Dummer R, Wilhelm M, Nestle F, Ott MM, Feller A, et al. A subcutaneous delta-positive T-cell lymphoma that produces interferon gamma. N Engl J Med. Oct 10 1991;325(15):1078-81. [Medline].

13. El Shabrawi-Caelen L, Cerroni L, Kerl H. The clinicopathologic spectrum of cytotoxic lymphomas of the skin. Semin Cutan Med Surg. Jun 2000;19(2):118-23. [Medline].

14. Miyamoto T, Yoshino T, Takehisa T, Hagari Y, Mihara M. Cutaneous presentation of nasal/nasal type T/NK cell lymphoma: clinicopathological findings of four cases. Br J Dermatol. Sep 1998;139(3):481-7. [Medline].

15. Arnulf B, Copie-Bergman C, Delfau-Larue MH, Lavergne-Slove A, Bosq J, Wechsler J, et al. Nonhepatosplenic gammadelta T-cell lymphoma: a subset of cytotoxic lymphomas with mucosal or skin localization. Blood. Mar 1 1998;91(5):1723-31. [Medline].

16. Jaffe ES, Krenacs L, Raffeld M. Classification of cytotoxic T-cell and natural killer cell lymphomas. Semin Hematol. Jul 2003;40(3):175-84. [Medline].

17. Bekkenk MW, Vermeer MH, Jansen PM, van Marion AM, Canninga-van Dijk MR, Kluin PM, et al. Peripheral T-cell lymphomas unspecified presenting in the skin: analysis of prognostic factors in a group of 82 patients. Blood. Sep 15 2003;102(6):2213-9. [Medline].

18. Roeschm A, Schleyer V, Landthaler M, Vogt T. Follicular mycosis fungoides: variability of a rare entity. Skinmed. Jan-Feb 2005;4(1):12-7. [Medline].

19. Kohler S. Extranodal NK/T-cell lymphoma, nasal type. In: LeBoit P, Burg G, Weedon D, Lyon SA. WHO Books: Tumors of the Skin. Geneva: World Health Organization IARC. X. 2006:191-2.

20. Clarijs M, Poot F, Laka A, Pirard C, Bourlond A. Granulomatous slack skin: treatment with extensive surgery and review of the literature. Dermatology. 2003;206(4):393-7. [Medline].

21. Marzano AV, Berti E, Paulli M, Caputo R. Cytophagic histiocytic panniculitis and subcutaneous panniculitis-like T-cell lymphoma: report of 7 cases. Arch Dermatol. Jul 2000;136(7):889-96. [Medline].

22. Torok L, Gurbity TP, Kirschner A, Krenacs L. Panniculitis-like T-cell lymphoma clinically manifested as alopecia. Br J Dermatol. Oct 2002;147(4):785-8. [Medline].

23. Toro JR, Liewehr DJ, Pabby N, Sorbara L, Raffeld M, Steinberg SM, et al. Gamma-delta T-cell phenotype is associated with significantly decreased survival in cutaneous T-cell lymphoma. Blood. May 1 2003;101(9):3407-12. [Medline].

24. Santucci M, Pimpinelli N, Massi D, Kadin ME, Meijer CJ, Muller-Hermelink HK, et al. Cytotoxic/natural killer cell cutaneous lymphomas. Report of EORTC Cutaneous Lymphoma Task Force Workshop. Cancer. Feb 1 2003;97(3):610-27. [Medline].

25. von den Driesch P, Coors EA. Localized cutaneous small to medium-sized pleomorphic T-cell lymphoma: a report of 3 cases stable for years. J Am Acad Dermatol. Apr 2002;46(4):531-5. [Medline].

26. Barrionuevo C, Anderson VM, Zevallos-Giampietri E, Zaharia M, Misad O, Bravo F, et al. Hydroa-like cutaneous T-cell lymphoma: a clinicopathologic and molecular genetic study of 16 pediatric cases from Peru. Appl Immunohistochem Mol Morphol. Mar 2002;10(1):7-14. [Medline].

27. Chen HH, Hsiao CH, Chiu HC. Hydroa vacciniforme-like primary cutaneous CD8-positive T-cell lymphoma. Br J Dermatol. Sep 2002;147(3):587-91. [Medline].

28. Karube K, Aoki R, Nomura Y, Yamamoto K, Shimizu K, Yoshida S, et al. Usefulness of flow cytometry for differential diagnosis of precursor and peripheral T-cell and NK-cell lymphomas: Analysis of 490 cases. Pathol Int. Feb 2008;58(2):89-97. [Medline].

29. Russell-Jones R. Diagnosing erythrodermic cutaneous T-cell lymphoma. Br J Dermatol. Jul 2005;153(1):1-5. [Medline].

30. Petrella T, Comeau MR, Maynadie M, Couillault G, De Muret A, Maliszewski CR, et al. 'Agranular CD4+ CD56+ hematodermic neoplasm' (blastic NK-cell lymphoma) originates from a population of CD56+ precursor cells related to plasmacytoid monocytes. Am J Surg Pathol. Jul 2002;26(7):852-62. [Medline].

31. Smoller BR, Santucci M, Wood GS, Whittaker SJ. Histopathology and genetics of cutaneous T-cell lymphoma. Hematol Oncol Clin North Am. Dec 2003;17(6):1277-311. [Medline].

32. Haghighi B, Smoller BR, LeBoit PE, Warnke RA, Sander CA, Kohler S. Pagetoid reticulosis (Woringer-Kolopp disease): an immunophenotypic, molecular, and clinicopathologic study. Mod Pathol. May 2000;13(5):502-10. [Medline].

33. Mao X, Lillington D, Scarisbrick JJ, Mitchell T, Czepulkowski B, Russell-Jones R, et al. Molecular cytogenetic analysis of cutaneous T-cell lymphomas: identification of common genetic alterations in Sézary syndrome and mycosis fungoides. Br J Dermatol. Sep 2002;147(3):464-75. [Medline].

34. Burg G, Zwingers T, Staegemeir E, Santucci M. Interrater and intrarater variabilities in the evaluation of cutaneous lymphoproliferative T-cell infiltrates. EORTC-Cutaneous Lymphoma Project Group. Dermatol Clin. Apr 1994;12(2):311-4. [Medline].

35. Santucci M, Biggeri A, Feller AC, Massi D, Burg G. Efficacy of histologic criteria for diagnosing early mycosis fungoides: an EORTC cutaneous lymphoma study group investigation. European Organization for Research and Treatment of Cancer. Am J Surg Pathol. Jan 2000;24(1):40-50. [Medline].

36. Santucci M, Smoller B. ISCL study on early diagnosis of mycosis fungoides. (in preparation).

37. Pimpinelli N, Olsen EA, Santucci M, Vonderheid E, Haeffner AC, Stevens S, et al. Defining early mycosis fungoides. J Am Acad Dermatol. Dec 2005;53(6):1053-63. [Medline].

38. Zelger B, Sepp N, Weyrer K, Grunewald K, Zelger B. Syringotropic cutaneous T-cell lymphoma: a variant of mycosis fungoides?. Br J Dermatol. Jun 1994;130(6):765-9. [Medline].

39. Gerami P, Guitart J. Basaloid folliculolymphoid hyperplasia: a distinctive finding in follicular mycosis fungoides. J Cutan Pathol. Dec 2007;34 Suppl 1:29-32. [Medline].

40. Imai S, Burg G, Braun-Falco O. Mycosis fungoides and Sezary's syndrome show distinct histomorphological features. Dermatologica. 1986;173(3):131-5. [Medline].

41. Kamarashev J, Burg G, Kempf W, Hess Schmid M, Dummer R. Comparative analysis of histological and immunohistological features in mycosis fungoides and Sézary syndrome. J Cutan Pathol. Sep 1998;25(8):407-12. [Medline].

42. Sibaud V, Beylot-Barry M, Thiebaut R, Parrens M, Vergier B, Delaunay M, et al. Bone marrow histopathologic and molecular staging in epidermotropic T-cell lymphomas. Am J Clin Pathol. Mar 2003;119(3):414-23. [Medline].

43. Takeshita M, Okamura S, Oshiro Y, Imayama S, Okamoto S, Matsuki Y, et al. Clinicopathologic differences between 22 cases of CD56-negative and CD56-positive subcutaneous panniculitis-like lymphoma in Japan. Hum Pathol. Feb 2004;35(2):231-9. [Medline].

44. Beljaards RC, Meijer CJ, Van der Putte SC, Hollema H, Geerts ML, Bezemer PD, et al. Primary cutaneous T-cell lymphoma: clinicopathological features and prognostic parameters of 35 cases other than mycosis fungoides and CD30-positive large cell lymphoma. J Pathol. Jan 1994;172(1):53-60. [Medline].

45. Chan JK, Sin VC, Wong KF, Ng CS, Tsang WY, Chan CH, et al. Nonnasal lymphoma expressing the natural killer cell marker CD56: a clinicopathologic study of 49 cases of an uncommon aggressive neoplasm. Blood. Jun 15 1997;89(12):4501-13. [Medline].

46. Natkunam Y, Smoller BR, Zehnder JL, Dorfman RF, Warnke RA. Aggressive cutaneous NK and NK-like T-cell lymphomas: clinicopathologic, immunohistochemical, and molecular analyses of 12 cases. Am J Surg Pathol. May 1999;23(5):571-81. [Medline].

47. de Wolf-Peeters C, Achten R. gammadelta T-cell lymphomas: a homogeneous entity?. Histopathology. Apr 2000;36(4):294-305. [Medline].

48. Jones D, Vega F, Sarris AH, Medeiros LJ. CD4-CD8-"Double-negative" cutaneous T-cell lymphomas share common histologic features and an aggressive clinical course. Am J Surg Pathol. Feb 2002;26(2):225-31. [Medline].

49. Knobler E. Current management strategies for cutaneous T-cell lymphoma. Clin Dermatol. May-Jun 2004;22(3):197-208. [Medline].

50. Ysebaert L, Truc G, Dalac S, Lambert D, Petrella T, Barillot I, et al. Ultimate results of radiation therapy for T1-T2 mycosis fungoides (including reirradiation). Int J Radiat Oncol Biol Phys. Mar 15 2004;58(4):1128-34. [Medline].

51. Onozuka T, Yokota K, Kawashima T, Shimada H, Kodama K, Kobayashi H, et al. An elderly patient with mycosis fungoides successfully treated with chronic low-dose oral etoposide therapy. Clin Exp Dermatol. Jan 2004;29(1):91-2. [Medline].

52. Dummer R, Urosevic M, Kempf W, Kazakov D, Burg G. Imiquimod induces complete clearance of a PUVA-resistant plaque in mycosis fungoides. Dermatology. 2003;207(1):116-8. [Medline].

53. Apisarnthanarax N, Talpur R, Ward S, Ni X, Kim HW, Duvic M. Tazarotene 0.1% gel for refractory mycosis fungoides lesions: an open-label pilot study. J Am Acad Dermatol. Apr 2004;50(4):600-7. [Medline].

54. Singh F, Lebwohl MG. Cutaneous T-cell lymphoma treatment using bexarotene and PUVA: a case series. J Am Acad Dermatol. Oct 2004;51(4):570-3. [Medline].

55. Jones GW, Hoppe RT, Glatstein E. Electron beam treatment for cutaneous T-cell lymphoma. Hematol Oncol Clin North Am. Oct 1995;9(5):1057-76. [Medline].

56. Leverkus M, Rose C, Brocker EB, Goebeler M. Follicular cutaneous T-cell lymphoma: beneficial effect of isotretinoin for persisting cysts and comedones. Br J Dermatol. Jan 2005;152(1):193-4. [Medline].

57. Jacob R, Scala M, Fung MA. A case of syringotropic cutaneous T-cell lymphoma treated with local radiotherapy. J Am Acad Dermatol. Jan 2009;60(1):152-4. [Medline].

58. Russell-Jones R. Extracorporeal photopheresis in cutaneous T-cell lymphoma. Inconsistent data underline the need for randomized studies. Br J Dermatol. Jan 2000;142(1):16-21. [Medline].

59. Lundin J, Hagberg H, Repp R, Cavallin-Stahl E, Freden S, Juliusson G, et al. Phase 2 study of alemtuzumab (anti-CD52 monoclonal antibody) in patients with advanced mycosis fungoides/Sezary syndrome. Blood. Jun 1 2003;101(11):4267-72. [Medline].

60. Fukushima T, Horio K, Matsuo E, Imanishi D, Yamasaki R, Tsushima H, et al. Successful cord blood transplantation for mycosis fungoides. Int J Hematol. Dec 2008;88(5):596-8. [Medline].

61. Lambert WC, Cohen PJ, Schwartz RA. Surgical management of mycosis fungoides. J Med. 1997;28(3-4):211-22. [Medline].

62. Foss F. Overview of cutaneous T-cell lymphoma: prognostic factors and novel therapeutic approaches. Leuk Lymphoma. 2003;44 Suppl 3:S55-61. [Medline].

63. Kaye FJ, Bunn PA Jr, Steinberg SM, Stocker JL, Ihde DC, Fischmann AB, et al. A randomized trial comparing combination electron-beam radiation and chemotherapy with topical therapy in the initial treatment of mycosis fungoides. N Engl J Med. Dec 28 1989;321(26):1784-90. [Medline].

64. Tancrede-Bohin E, Ionescu MA, de La Salmoniere P, Dupuy A, Rivet J, Rybojad M, et al. Prognostic value of blood eosinophilia in primary cutaneous T-cell lymphomas. Arch Dermatol. Sep 2004;140(9):1057-61. [Medline].

65. van Doorn R, Scheffer E, Willemze R. Follicular mycosis fungoides, a distinct disease entity with or without associated follicular mucinosis: a clinicopathologic and follow-up study of 51 patients. Arch Dermatol. Feb 2002;138(2):191-8. [Medline].

66. Scarisbrick JJ, Whittaker S, Evans AV, Fraser-Andrews EA, Child FJ, Dean A, et al. Prognostic significance of tumor burden in the blood of patients with erythrodermic primary cutaneous T-cell lymphoma. Blood. Feb 1 2001;97(3):624-30. [Medline].

67. Shimoyama M. Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma. A report from the Lymphoma Study Group (1984-87). Br J Haematol. Nov 1991;79(3):428-37. [Medline].

68. Fink-Puches R, Zenahlik P, Back B, Smolle J, Kerl H, Cerroni L. Primary cutaneous lymphomas: applicability of current classification schemes (European Organization for Research and Treatment of Cancer, World Health Organization) based on clinicopathologic features observed in a large group of patients. Blood. Feb 1 2002;99(3):800-5. [Medline].

69. Bekkenk MW, Jansen PM, Meijer CJ, Willemze R. CD56+ hematological neoplasms presenting in the skin: a retrospective analysis of 23 new cases and 130 cases from the literature. Ann Oncol. Jul 2004;15(7):1097-108. [Medline].

70. Mraz-Gernhard S, Natkunam Y, Hoppe RT, LeBoit P, Kohler S, Kim YH. Natural killer/natural killer-like T-cell lymphoma, CD56+, presenting in the skin: an increasingly recognized entity with an aggressive course. J Clin Oncol. Apr 15 2001;19(8):2179-88. [Medline].

71. Burg G, Kempf W. Therapy of cutaneous lymphomas. In: Burg G, Kempf W. Cutaneous Lymphomas. London: Taylor & Francis; 2005:475-528.

72. Burg G, Kempf W, Cozzio A, Feit J, Willemze R, S Jaffe E, et al. WHO/EORTC classification of cutaneous lymphomas 2005: histological and molecular aspects. J Cutan Pathol. Nov 2005;32(10):647-74. [Medline].

73. Santucci M, Biggeri A, Feller AC, et al. Efficacy of histologic criteria for diagnosing early mycosis fungoides: an EORTC cutaneous lymphoma study group investigation. European Organization for Research and Treatment of Cancer. Am J Surg Pathol. Jan 2000;24(1):40-50. [Medline].

Keywords

CTCL, mycosis fungoides, patch stage mycosis fungoides, large plaque parapsoriasis, plaque stage mycosis fungoides, tumor stage mycosis fungoides, d'emblee mycosis fungoides, primary cutaneous pleomorphic mycosis fungoides, medium-sized T-cell lymphoma, large cell CD30+ T-cell lymphoma, large cell CD30- T-cell lymphomas, solitary mycosis fungoides, unilesional mycosis fungoides, unilesional pagetoid reticulosis, Woringer-Kolopp disease, follicular mycosis fungoides, Sézary syndrome, Sezary syndrome, Sezary's syndrome, erythrodermic mycosis fungoides, granulomatous slack skin, granulomatous CTCL, granulomatous mycosis fungoides, angiocentric CTCL, subcutaneous CTCL, panniculitis-like CTCL, panniculitislike CTCL, lipotropic CTCL, panniculotropic CTCL, subcutaneous mycosis fungoides, suppressor T-cell CTCL, CD8+ CTCL, delta/gamma CTCL, NK cell CTCL, natural killer CTCL, KI-1+ large cell CTCL

Contributor Information and Disclosures

Author

Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi
Disclosure: Nothing to disclose.

Coauthor(s)

W Clark Lambert, MD, PhD, Professor and Head, Dermatopathology, Departments of Pathology and Dermatology, UMDNJ-New Jersey Medical School
W Clark Lambert, MD, PhD is a member of the following medical societies: American Academy of Dermatology, American College of Physicians, American Dermatological Association, American Society of Dermatopathology, International Academy of Pathology, Medical Society of New Jersey, Sigma Xi, and Society for Investigative Dermatology
Disclosure: Nothing to disclose.

Medical Editor

Günter Burg, MD, Professor and Chairman Emeritus, Department of Dermatology, University of Zürich School of Medicine; Delegate of The Foundation for Modern Teaching and Learning in Medicine Faculty of Medicine, University of Zürich, Switzerland
Günter Burg, MD is a member of the following medical societies: American Academy of Dermatology, American Dermatological Association, International Society for Dermatologic Surgery, North American Clinical Dermatologic Society, and Pacific Dermatologic Association
Disclosure: Nothing to disclose.

Pharmacy Editor

David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic, Northside Clinic
David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Managing Editor

Jeffrey Meffert, MD, Assistant Clinical Professor of Dermatology, University of Texas Health Science Center-San Antonio
Jeffrey Meffert, MD is a member of the following medical societies: American Academy of Dermatology, American Medical Association, Association of Military Dermatologists, and Texas Dermatological Society
Disclosure: Nothing to disclose.

CME Editor

Catherine M Quirk, MD, Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania
Catherine M Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology
Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

© 1994- by Medscape.
All Rights Reserved
(http://www.medscape.com/public/copyright)