Cutaneous T-Cell Lymphoma

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Overview of CTCL

Cutaneous T-cell lymphoma (CTCL) is a term that was created in 1979 at an international workshop sponsored by the National Cancer Institute (NCI) to describe a group of lymphoproliferative disorders characterized by localization of neoplastic T lymphocytes to the skin.[1, 2, 3, 4, 5]

When the term was first coined, it most often referred to mycosis fungoides/Sézary syndrome (see Mycosis Fungoides, discussed separately in this article), the most common cutaneous T-cell lymphoma (CTCL).[6, 7] 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 incidence of cutaneous T-cell lymphoma (CTCL) in the United States is reported to be increasing.[8] 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 (see the image below). The most common immunophenotype is CD4-positive. There is no common pathophysiology, as the term cutaneous T-cell lymphoma (CTCL) encompasses a wide variety of disorders.


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A 40-year-old woman complained of a recurrent skin rash, which she described as "bug bites." Skin biopsy results demonstrated an atypical lymphoid inf....

For patient education information, see the Blood and Lymphatic System Center, as well as Lymphoma and Skin Cancer.

Classification of CTCLs

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[9, 10] : the European Organization for Research and Treatment of Cancer (EORTC) classification for primary cutaneous lymphomas[9] and the World Health Organization (WHO) classification of hematologic malignancies.[10] A tumor, node, metastases (TNM) classification system for primary cutaneous lymphomas other than mycosis fungoides and Sézary syndrome has also been proposed.[11]

The EORTC classification focused on primary cutaneous lymphomas, which may vary from their nodal counterparts in clinical behavior, prognosis, and appropriate therapeutic approaches.[9] 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.[10] 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 (see Table 1, below).[12]

Table 1. WHO-EORTC Classification of Cutaneous T-Cell Lymphoma


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Table 2, below, summarizes various types of cluster designations and their representative cells.

Table 2. Cluster Designations


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CTCLs With Indolent Clinical Behavior

Primary cutaneous CD30-positive lymphoproliferative disorder and subcutaneous panniculiticlike T-cell lymphoma are reviewed in this section. Although mycosis fungoides/Sézary syndrome also belongs to the group of lymphomas with clinically indolent behavior, it is discussed separately in this article (see Mycosis Fungoides).

Primary cutaneous CD30-positive lymphoproliferative disorder

Anaplastic large cell lymphoma (ALCL), the 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 (see the following image).


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A 40-year-old woman complained of a recurrent skin rash, which she described as "bug bites." Skin biopsy results demonstrated an atypical lymphoid inf....

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.

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—although 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 as 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

In subcutaneous panniculiticlike T-cell lymphoma, erythematous subcutaneous nodules, which appear in crops, are localized to the extremities or trunk. These lesions may be confused with benign panniculitis and are often accompanied by fever, chills, weight loss, and malaise. They may also 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 World Health Organization– European Organization of Research and Treatment of Cancer (WHO-EORTC) term subcutaneous panniculitic type T-cell lymphoma refers only to the a/b type,[12] which appears to have a more indolent clinical course that is characterized by recurrent subcutaneous lesions. Although affected 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.[12] Clinically, this lymphoma is more aggressive, with dissemination to mucosal and other extranodal sites.

Aggressive CTCL Subtypes

In this section, the following are reviewed:

Provisional categories are also discussed, such as primary aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma and primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma. Although cutaneous g/d T-cell lymphoma also belongs in this category, it has been covered in Subcutaneous panniculiticlike T-cell lymphoma under Lymphomas With Indolent Clinical Behavior.

Adult T-cell lymphoma/leukemia

Most patients with adult T-cell lymphoma/leukemia are those with antibodies to HTLV-I1, a virus endemic to Southwest Japan, South America, Central Africa, and the Caribbean. 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 (WBC) 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, the malignant cells are positive for CD2, CD3, and CD5 but negative for CD7; CD4 and CD25 are positive. The 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 a 24-month median survival for the chronic form.

Nasal type extranodal NK T-cell lymphoma

In nasal type extranodal NK T-cell lymphoma, 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. This condition 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, the 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

PTCL-U 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 World Health Organization– European Organization of Research and Treatment of Cancer (WHO-EORTC) classification.[12]

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 (DLCL).

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

Patients with PTCL-U generally have a poor prognosis and should be treated with systemic chemotherapy. The 4-year survival rate approaches 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

Although cutaneous g/d T-cell lymphoma belongs in this category, it is discussed in Subcutaneous panniculiticlike T-cell lymphoma under Lymphomas With Indolent Clinical Behavior. Primary aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma and primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma are reviewed below.

Primary aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma is a clinically aggressive, sometimes disseminated disease, which presents with eruptive papules, nodules, and tumors with central ulceration. This entity can also present with superficial patches and/or plaques. Affected patients have typically been treated with anthracycline-based systemic chemotherapy.

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

Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma presents with solitary or localized plaques or tumors in the face, neck, and/or upper trunk area. The disease typically has an indolent course, and solitary lesions may be treated with surgical excision or radiation. Histologically, dermal to subcutaneous infiltration with CD3, CD4+ malignant cells is seen, and focal epidermotropism may be seen.

Mycosis Fungoides

Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma (CTCL) (44%), which has led some authors to use this term synonymously with cutaneous T-cell lymphoma (CTCL). The term mycosis fungoides was first used in 1806 by Alibert, a French dermatologist, when he described a severe disorder in which large, necrotic tumors resembling mushrooms presented on a patient's skin (see the following image). Approximately 1000 new cases of mycosis fungoides occur per year (ie, 0.36 cases per 100,000 population).

This condition is more common in black than in white patients (incidence ratio = 1.6), and it occurs more frequently in men than in women (male-to-female ratio, 2:1). The most common age at presentation is 50 years; however, mycosis fungoides can also be diagnosed in children and adolescents with apparently similar outcomes.[13]


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Tumor phase mycosis fungoides (MF).

Etiology and Pathophysiology of MF

The etiology of mycosis fungoides remains unknown. However, various theories implicate occupational or environmental exposures (eg, Agent Orange), other forms of chronic antigenic stimulation, or viral exposures.

Mycosis fungoides is a malignant lymphoma characterized by the expansion of a clone of CD4+ (or helper) memory T cells (CD45RO+) that normally patrol and home in to the skin.[2] The malignant clone frequently lacks normal T-cell antigens such as CD2, CD5, or CD7. The normal and malignant cutaneous T cell homes in to skin by virtue of interactions with dermal capillary endothelial cells. Cutaneous T cells express cutaneous lymphocyte antigen (CLA), an adhesion molecule that mediates tethering of the T lymphocyte to endothelial cells in cutaneous postcapillary venules via its interaction with E selectin.[14]

Further promoting the proclivity of the cutaneous T cell to home in to the skin is the release by keratinocytes of cytokines, which infuse the dermis, coat the luminal surface of the dermal endothelial cells, and upregulate the adhesion molecules in the dermal capillary endothelial lumen, which react to CCR4 found on cutaneous T cells.

Extravasating into the dermis, the cells show an affinity for the epidermis, clustering around Langerhans cells as seen microscopically as Pautrier microabscesses. However, the malignant cells that adhere to the skin retain the ability to exit the skin via afferent lymphatics. They travel to lymph nodes and then through efferent lymphatics back to the blood to join the circulating population of CLA-positive T cells.

Thus, mycosis fungoides is fundamentally a systemic disease, even when the disease appears to be in an early stage and clinically limited to the skin.

Mycosis Fungoides Variants

Variants of mycosis fungoides that are recognized by WHO/EORTC include Sézary syndrome, folliculotropic mycosis fungoides, granulomatous slack skin, and pagetoid reticulosis (Woringer-Kolopp disease).[12]

Sézary syndrome

Sézary syndrome (SS) is a variant of mycosis fungoides, occurring in about 5% of all cases of mycosis fungoides. The patient with Sézary syndrome has generalized exfoliative erythroderma (see the image below), lymphadenopathy, and more than 1000 per mm3 of atypical T lymphocytes with cerebriform nuclei circulating in the peripheral blood or other evidence of a significant malignant T-cell clone in the blood such as clonal T-cell gene rearrangement (identical to that found in the skin).


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Erythroderma of Sézary syndrome (SS).

The T-cell gene rearrangement is demonstrated by molecular or cytogenetic techniques and/or an expansion of cells with a malignant T-cell immunophenotype (an increase of CD4+ cells such that the CD4/CD8 ratio is >10, and/or an expansion of T cells with a loss of 1 or more of the normal T-cell antigens [eg, CD2, CD3, CD5]). The circulating malignant cells tend to be CD7- and CD26-negative.

Although Sézary syndrome may be part of a continuum from erythrodermic mycosis fungoides, the World Health Organization– European Organization of Research and Treatment of Cancer (WHO-EORTC) classification for cutaneous lymphoma considers its behavior "aggressive."[12]

Folliculotropic mycosis fungoides

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

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)

Pagetoid reticulosis 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.

Clinical Evaluation of MF

The skin rash of mycosis fungoides may consist of flat patches, plaques, or tumors, which may have a long natural history. The median duration from the onset of skin symptoms to diagnosis is 6 years. Early in the course of mycosis fungoides, as well as in erythrodermic cases, the skin lesions may be nonspecific, with a nondiagnostic biopsy result, so that confusion with benign conditions is common (eg, eczema, neurodermatitis, pseudolymphoma syndrome). Obtain repeated biopsies in those patients who have progressive chronic dermatosis or whose condition is refractory to topical treatments.

In patients who present with pruritus or erythroderma, often, the diagnosis of mycosis fungoides is made possible through the examination of a noncutaneous site (eg, blood, lymph nodes).

The physical examination is discussed by the following findings:

Flat skin patch, plaque, and tumors

The patch phase of mycosis fungoides is characterized by flat, usually erythematous, macules that may have a fine scale, may be single or multiple, and may be pruritic (see the image below). In dark-skinned individuals, the patches may appear as hypopigmented or hyperpigmented areas. As the patches become more infiltrative, they evolve into palpable plaques.


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Patch phase mycosis fungoides (MF).

The plaques tend to be raised, demonstrating fine-scale, well-demarcated, erythematous shapes with irregular borders (see the following image). Annular or serpiginous patterns with central clearing and pruritus are common.


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Plaque phase mycosis fungoides (MF).

Patches and plaques may affect any area of the skin, but they are often distributed asymmetrically in the areas that a bathing suit would cover (ie, hips, buttocks, groin, lower trunk, axillae, breasts). When mycosis fungoides affects the scalp, it is often accompanied by alopecia.

Skin tumors

Patients with evidence or a history of patchy or plaquelike skin lesions can also have tumors, which are red-violet nodules that may be dome-shaped, exophytic, or ulcerated (see the image below).


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Tumor phase mycosis fungoides (MF).

Skin erythroderma

Generalized erythroderma is often intensely symptomatic, with pruritus and scaling that can be profound (see the following images). The patients experience thickening of the facial skin folds (leonine facies), hyperkeratosis and fissuring of the palms and soles, onychodystrophy, ectropion of the eyelids, alopecia, and edema. Sun exposure may be painful as well as pruritic.


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Erythroderma of Sézary syndrome (SS).


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Nail changes of Sézary syndrome (SS).

Lymphadenopathy

Extracutaneous involvement is more clinically evident as the stage and extent of mycosis fungoides increases. Peripheral lymphadenopathy is the most frequent site of extracutaneous involvement in mycosis fungoides.

Evaluate palpable lymphadenopathy by obtaining a biopsy, because the result influences the patient's stage, prognosis, and treatment.

Staging of Mycosis Fungoides

Despite the fact that mycosis fungoides and Sézary syndrome are types of non-Hodgkin lymphoma, an entirely different staging system is used that is based on the particular skin findings and findings of extracutaneous disease that are observed in affected patients, as follows:

Diagnostic Tests for Mycosis Fungoides

Conduct a complete blood cell (CBC) count with differential, and review the buffy coat smear for Sézary cells.

Look for liver-associated enzyme abnormalities, and obtain uric acid and lactate dehydrogenase (LDH) levels. Abnormal transaminase values may indicate hepatic involvement. Uric acid and LDH are markers of bulky and/or biologically aggressive disease.

Conduct flow cytometric study of the blood (include available T cell–related antibodies) to detect a circulating malignant clone and to assess immunocompetence by quantifying the level of CD8-expressing lymphocytes.

Consider human immunodeficiency virus (HIV) and human T-cell lymphotrophic virus type I (HTLV-I) testing.

Consider obtaining polymerase chain reaction (PCR), Southern blot testing of the blood, or both if detecting a circulating clone of malignant cells in the blood will change medical management. Ideally, the abnormal clonal T-cell gene rearrangement detected in the blood should match that found in the skin. However, T-cell gene rearrangement by itself will not allow the physician to make a diagnosis of mycosis fungoides or Sézary syndrome. Disorders that are considered benign (eg, lymphomatoid papulosis) can have T-cell gene rearrangement.

Special considerations

The following scenarios may lead to medicolegal pitfalls:

Radiologic Studies for Mycosis Fungoides

Perform chest radiography to determine whether there is lung involvement.

Computed tomography (CT) scanning of the abdomen and pelvis may be performed in patients with advanced mycosis fungoides (stage IIB to stage IVB) or in patients with clinically suspected visceral disease.

Positron emission tomography (PET) scanning to determine visceral involvement can be considered in individual cases.

Biopsy in Mycosis Fungoides

Perform a skin punch biopsy, which is submitted on sodium chloride–soaked gauze to allow for both fixation and snap freezing.

Perform a bone marrow examination only if the patient has proven blood or nodal involvement.

Perform a lymph node biopsy if the nodes are palpable. In a study by Pai et al, the investigators determined that fine-needle aspiration (FNA) biopsy combined with immunophenotyping and T-cell receptor gamma chain PCR (TCR-gamma PCR) was “significantly useful” in evaluating lymphadenopathy in patients with cutaneous T-cell lymphoma (CTCL) (ie, mycosis fungoides and Sézary syndrome), “especially for triaging lymph nodes that would otherwise not be sampled or for evaluating multiple lymph nodes."[15]

The authors assessed a series of 11 FNA biopsy specimens from 10 mycosis fungoides and Sézary syndrome patients, and performed flow cytometric immunophenotyping and TCR-gamma PCR on the FNA biopsy material and correlated these with cytologic findings, with the following results[15] :

Mycosis Fungoides Histology

The criteria for the diagnosis of mycosis fungoides include the following[16] :

A Sézary cell is shown in the image below.


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Electron micrograph of Sézary cell.

Management of Mycosis Fungoides

The evaluation and treatment of individuals with mycosis fungoides is usually conducted on an outpatient basis. Symptomatic treatments, emollients, or antipruritics in combination with specific topical and systemic treatment are used.

Mycosis fungoides treatment selection should be based on the stage and previous treatment history.[3, 4, 17, 18, 19, 20, 21, 22, 23, 24, 25] In general, topical therapies are indicated for stage I patients, and systemic therapies or combinations of topical and systemic therapies are indicated for patients with stage IIB disease or greater or for patients with stage I mycosis fungoides whose condition has failed or is intolerant to topical treatments.

Sequential therapies that are stage appropriate are selected based on convenience and availability to the patient, as well as on short- and long-term toxicity profiles. Therapies may also be selected based on the probability that a given patient's condition will have a response and the time of onset of that response. Because infection is the major cause of death in patients with mycosis fungoides/Sézary syndrome, preservation of cellular immune function is desirable.

Encourage the use of supportive treatments in patients with mycosis fungoides to decrease pruritus and to lubricate the skin. Nonspecific antipruritic treatments used to control symptoms are useful and often necessary adjuncts to more specific therapies. Patients should avoid sun exposure and remain in a cool environment.

Consultations with a dermatologist, medical oncologist, and/or radiation oncologist may aid clinicians in the management of patients with mycosis fungoides.

Topical treatments

Topical mycosis fungoides treatments, such as topical steroids, topical retinoids, topical chemotherapy, and light treatment that may be enhanced by the ingestion of psoralen, are used to induce remissions, which may be lengthy in patients whose disease is largely confined to the skin.

Generally, in the patch or plaque phase of the disease, use topical steroids, topical retinoids, topical chemotherapy (eg, nitrogen mustard or bischloroethylnitrosourea [BCNU]), ultraviolet B (UV-B) light or UV-A light treatment enhanced with psoralen (PUVA), or total body electron beam radiation These modalities are also used in the tumor phase combined with systemic modalities (eg, PUVA plus interferon).

A majority of patients with the patch phase will have a response, usually to class I (highest potency) steroids; steroids lyse T lymphocytes and block cytokine secretion. Most cases of patch or plaque phase disease (76-90% complete responses) will respond to PUVA; psoralens inhibit DNA synthesis in tissues exposed to psoralen and UV-A. In addition, most cases of patch or plaque phase disease will respond (complete response rate, 60%) to topical chemotherapy agents, which inhibit cell growth and proliferation.

Retinoids are vitamin A analogues involved in the modulation of cell growth, division, reproduction, and differentiation.[26] Their biologic effects result from alterations in gene expressions that are mediated through 2 major types of nuclear receptors, the retinoic acid receptor (RAR) and the retinoic X receptor (RXR). Each receptor subtype likely controls the expression of both unique and common genes. Subclass-specific retinoids are available.

Systemic treatment

Systemic treatment, such as oral retinoids, recombinant alfa interferon, fusion toxins, monoclonal antibodies, and single-agent chemotherapy, can be used sequentially to palliate symptoms from more advanced mycosis fungoides. Many active agents, including antimetabolites, alkylating agents, topoisomerase II inhibitors, anthracyclines, and purine analogues exist. The most extensive data exist for the use of methotrexate.

Other examples of systemic treatment for mycosis fungoides include the following:

Biologic response modifiers may inhibit the proliferative capacity of malignant T cells by modulating cytokine production. These agents may also enhance the antitumor immune response by augmenting cell-mediated cytotoxicity.

Combination chemotherapy

Combination chemotherapy is generally not used, because the infectious complications and short response duration in mycosis fungoides outweigh the modest response rates (compared with other non-Hodgkin lymphomas). Increased survival is not demonstrated with the use of combination chemotherapy relative to sequential topical agents.

Bone marrow transplantation

Allogenic transplants are reported in the literature as case reports or small groups of patients.[3, 27] A German study suggested that "in young patients with a treatment-refractory course of mycosis fungoides, allogeneic stem cell transplantation" may be an important alternative option to manage mycosis fungoides, because "complete clinical remission can be obtained even in advanced stages."[3]

Prognosis of Mycosis Fungoides

Potential complications of mycosis fungoides include the following:

Mycosis fungoides and Sézary syndrome are incurable conditions in most patients, with the exception of those with stage IA disease.

Mortality and prognosis are related to the stage at diagnosis. Patients diagnosed with stage IA disease (patch or plaque skin disease limited to < 10% of the skin surface area) who undergo treatment, have an overall life expectancy similar to the age-, sex-, and race-matched controls. Patients who have stage IIB disease with cutaneous tumors have a median survival rate of 3.2 years, and those who have stage III disease (generalized erythroderma) have a median survival rate of 4-6 years. Patients with extracutaneous disease stage IVA (lymph nodes) or stage IVB (viscera) have a survival rate of less than 1.5 years.

An analysis of 20-year trends reporting on incidence and associated mortality of those with mycosis fungoides showed a decline in the mortality rate in the United States, perhaps related to an increased recognition and earlier diagnosis of the disease.[28] The overall mortality rate is 0.064 per 100,000 persons; however, the mortality rate widely varies depending on the stage of disease at diagnosis.

Late-stage mycosis fungoides or Sézary syndrome is associated with declining immunocompetence.[29] Death most often results from systemic infection, especially with Staphylococcus aureus, Pseudomonas aeruginosa, and other organisms.[30] Secondary malignancies, such as higher-grade non-Hodgkin lymphoma, Hodgkin disease, colon cancer, and cardiopulmonary complications (eg, high output failure, comorbid cardiopulmonary disease) also contribute to mortality.

Author

Lauren C Pinter-Brown, MD, Director of Lymphoma Program, Clinical Professor of Medicine, Department of Internal Medicine, Division of Hematology and Oncology, University of California, Los Angeles, Medical Center

Disclosure: Nothing to disclose.

Specialty Editors

Paul Schick, MD, Emeritus Professor, Department of Internal Medicine, Jefferson Medical College of Thomas Jefferson University; Research Professor, Department of Internal Medicine, Drexel University College of Medicine; Adjunct Professor of Medicine, Lankenau Hospital

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Marcel E Conrad, MD, Distinguished Professor of Medicine (Retired), University of South Alabama College of Medicine

Disclosure: No financial interests None None

Chief Editor

Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Disclosure: Nothing to disclose.

References

  1. Diamandidou E, Cohen PR, Kurzrock R. Mycosis fungoides and Sezary syndrome. Blood. Oct 1 1996;88(7):2385-409. [View Abstract]
  2. Olsen E, Vonderheid E, Pimpinelli N, et al, and the ISCL/EORTC. Revisions to the staging and classification of mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC). Blood. Sep 15 2007;110(6):1713-22. [View Abstract]
  3. Hoff NP, Groffik A, Mota R, Pippirs U, Hengge UR, Kobbe G, et al. [Successful use of allogeneic stem cell transplantation for treatment-refractory mycosis fungoides] [German]. Hautarzt. Oct 2008;59(10):779-82. [View Abstract]
  4. Rook AH, Yoo EK, Grossman DJ, Kao DM, Fox FE, Niu Z. Use of biological response modifiers in the treatment of cutaneous T-cell lymphoma. Curr Opin Oncol. Mar 1998;10(2):170-4. [View Abstract]
  5. Koh HK, Charif M, Weinstock MA. Epidemiology and clinical manifestations of cutaneous T-cell lymphoma. Hematol Oncol Clin North Am. Oct 1995;9(5):943-60. [View Abstract]
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A 40-year-old woman complained of a recurrent skin rash, which she described as "bug bites." Skin biopsy results demonstrated an atypical lymphoid infiltrate, which was 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.

A 40-year-old woman complained of a recurrent skin rash, which she described as "bug bites." Skin biopsy results demonstrated an atypical lymphoid infiltrate, which was 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.

Tumor phase mycosis fungoides (MF).

Erythroderma of Sézary syndrome (SS).

Patch phase mycosis fungoides (MF).

Plaque phase mycosis fungoides (MF).

Tumor phase mycosis fungoides (MF).

Erythroderma of Sézary syndrome (SS).

Nail changes of Sézary syndrome (SS).

Electron micrograph of Sézary cell.

A 40-year-old woman complained of a recurrent skin rash, which she described as "bug bites." Skin biopsy results demonstrated an atypical lymphoid infiltrate, which was 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.

Patch phase mycosis fungoides (MF).

Plaque phase mycosis fungoides (MF).

Erythroderma of Sézary syndrome (SS).

Nail changes of Sézary syndrome (SS).

Electron micrograph of Sézary cell.

Tumor phase mycosis fungoides (MF).

WHO-EORTC ClassificationFrequency, %5-Year Survival Rate, %
Indolent Clinical Behavior
Mycosis fungoides4488
Mycosis fungoides variants and subtypes
—Folliculotropic mycosis fungoides480
—Pagetoid reticulosis< 1100
—Granulomatous slack skin< 1100
Primary cutaneous CD30+ lymphoproliferative disorder
—Primary cutaneous anaplastic large cell lymphoma895
—Lymphomatoid papulosis12100
Subcutaneous panniculiticlike T-cell lymphoma (provisional)182
Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma (provisional)275
Aggressive Clinical Behavior
Sézary syndrome3%24%
Adult T-cell leukemia/lymphomaNRNR
Extranodal NK/T-cell lymphoma, nasal typeNRNR
Primary cutaneous peripheral T-cell lymphoma, unspecified216
Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma (provisional)< 118
Cutaneous gamma/delta T-cell lymphoma (provisional)< 1NR
Precursor Hematologic Neoplasm (not a T-cell lymphoma)
CD4+/CD56+ hematodermic neoplasm (blastic NK-cell lymphoma)NRNR
Source: Adapted from Willemze et al. Blood. 2005;105(10):3768-85.[12]

EORTC = European Organization of Research and Treatment of Cancer; NR = not reported; NK = natural killer; WHO = World Health Organization.

CD TypeRepresentative CellsAlso Known As
CD2T, NKSheep RBC
CD3T
CD4T subsetHelper
CD5T
CD7T, NKProthymocyte
CD8T subset, NKSuppressor
CD25Active T, B, MIL-2R (Tac)
CD30Active T, BKi-1
CD45T subsetCLA
CD56NKNCAM
B = B cell; CLA = common leukocyte antigen; IL-2R = interleukin-2 receptor; M = M cell; NCAM = neural cell adhesion molecule; NK = natural killer; RBC = red blood cell; T = T cell; Tac = Tac antigen.